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Tuberculosis and Autoimmunity

Department of Pathophysiology, St. Petersburg State Pediatric Medical University, Ministry of Healthcare of the Russian Federation, 194100 Saint Petersburg, Russia
Author to whom correspondence should be addressed.
Pathophysiology 2022, 29(2), 298-318;
Submission received: 22 March 2022 / Revised: 3 June 2022 / Accepted: 7 June 2022 / Published: 13 June 2022 / Corrected: 16 August 2022


Tuberculosis remains a common and dangerous chronic bacterial infection worldwide. It is long-established that pathogenesis of many autoimmune diseases is mainly promoted by inadequate immune responses to bacterial agents, among them Mycobacterium tuberculosis. Tuberculosis is a multifaceted process having many different outcomes and complications. Autoimmunity is one of the processes characteristic of tuberculosis; the presence of autoantibodies was documented by a large amount of evidence. The role of autoantibodies in pathogenesis of tuberculosis is not quite clear and widely disputed. They are regarded as: (1) a result of imbalanced immune response being reactive in nature, (2) a critical part of TB pathogenicity, (3) a beginning of autoimmune disease, (4) a protective mechanism helping to eliminate microbes and infected cells, and (5) playing dual role, pathogenic and protective. There is no single autoimmunity-mechanism development in tuberculosis; different pathways may be suggested. It may be excessive cell death and insufficient clearance of dead cells, impaired autophagy, enhanced activation of macrophages and dendritic cells, environmental influences such as vitamin D insufficiency, and genetic polymorphism, both of Mycobacterium tuberculosis and host.

1. Introduction

Tuberculosis (TB), a dangerous chronic infectious disease caused by Mycobacterium tuberculosis (Mtb), is still a threat to public health worldwide. A global total of around 10 million people became ill with TB in 2020 [1]. Drug resistance of Mtb [2], HIV infection, malnutrition, especially vitamin D deficiency, aging, autoimmune diseases, and abundant usage of immune suppressants contribute to increased incidence of TB [3].
Epidemiological studies associate microbial infections and autoimmunity (AI), hypothesizing infections to be able to trigger autoimmune diseases (AID) [4,5,6]. A number of studies have shown sera from patients with active TB to contain autoantibodies (AAB). TB has many different outcomes and complications. Autoimmunity (AI) is one of the processes characteristic of TB; at least, the presence of AABs was documented by a large amount of evidence. AABs, being typical for autoimmune disorders, are also present in different infectious diseases [5,6,7,8]. The role of AABs in the pathogenesis of TB development is widely disputed. They are considered (1) as a result of imbalanced immune response being reactive in nature [9,10,11]; (2) as a critical part of TB pathogenicity, leading to cavitation and transmission [12]; (3) as a beginning of AI disease [12,13]; (4) as a protective mechanism helping to dispose of microbes and infected cells [14]; and (5) as playing a dual role, pathogenic and protective [14]. Such diverse opinions lead to the conclusion that mechanisms involved may vary in each case. Mtb can trigger different pathways of the immune responses.
Several possible mechanisms of AI development in TB may be suggested. It may be excessive cell death and insufficient clearance of dead cells, impaired autophagy, enhanced activation of macrophages (Mphs) and dendritic cells (DCs), environmental influences such as vitamin D insufficiency, and genetic polymorphism, both of Mtb and host. Chronic presence of infection can be regarded as an endogenous adjuvant [15]. With the existence of different pathways of immune responses, the one receiving the support from additional factors dominates. Multiple surface Mtb molecules can differently orchestrate immune responses.
Little is known about mechanisms of autoimmunity development in TB; the knowledge is mainly “Lessons Learned from Autoimmune Diseases” [16].
The unique mechanism of AAB generation involving the autoreactive B-cells expressing T-bet transcription factor has been identified for classic AIDs and microbial infections [17,18,19]. The recognition of a nucleic acid by toll-like receptor 7 (TLR7) and synergistic stimulation by IFNγ of B cells lead to the induction of T-bet+ B-cells and production of IgG2a [20]. T-box transcription factor T-bet being protective against intracellular pathogens is prone to producing AABs [18].
Antiphospholipid antibodies (aPL) were detected in different AIDs and infections such as TB (reviewed in [21,22]). Lipid molecules stimulate innate-like B-1 B cells to antibody production [23]. They react with self-determinants, such as carbohydrates and glycolipids, and often cross-react with bacterial antigens. Phospholipids are major antigens stimulating B-1 B cells [23]. The IgM production by B-1 B cells requires long-term stimulation by lipid antigens of replicating mycobacteria [24].
Mycobacterial lipids have been shown to act as adjuvants. Complete Freund’s adjuvant (CFA), which includes components of Mtb and has a high adjuvant activity, is used in mice for the induction of AIDs such as experimental autoimmune encephalomyelitis (EAE) and uveitis [25]. Lipid components have been found to be essential for CFA’s adjuvant activity [26].
Mtb is recognized by multiple phagocytic receptors, among them pattern-recognition receptors, especially the TLR on Mphs and DCs. Polymorphisms in TLRs affect human susceptibility to TB [27,28] and may be associated with AI.
The genome of Mtb has been shown to encode a protein family PE/PPE/PGRS, present exclusively in the genus Mycobacterium [29]. The PE/PPE/PGRS proteins influence cell-envelope remodeling, host cell-death pathways and virulence [30], mycobacterial antigenic variation, immune evasion [31], innate immunity, and bacillary survival in Mphs [32,33]. Polymorphisms in the PE/PPE/PGRS protein family may influence different manifestations of TB, among them AI.
Cell death is an essential physiological and pathological process influencing the coordination of immune responses and AI [34]. Apoptosis of infected cells results in self-reactive T-cell promotion of AI in infections [35], and excessive Mph apoptosis in TB may potentially cause a most important mechanism. Mer tyrosine kinase (MerTK) has been reported to be a major Mph apoptotic-cell receptor, its functional defect causing inadequate AC clearance promoting AI and atherosclerosis [36].
Phagocytosis of infected apoptotic cells has recently been shown to result in simultaneous presence of both cellular and microbial antigens inside the same phagosome. This makes possible the presentation of self-antigens by MHC II molecules, causing generation of autoreactive Th17 cells, associated with AAB production [35].
Pyroptosis, manifesting by osmotic lysis and releasing distracted remnants and inflammatory cytokines [37], is characteristic of TB [38]. Pyroptotic cells release an important inflammatory protein high-mobility group box 1 (HMGB1) [39]. Complex HMGB1- DNA in vitro contributes to autoreactive B-cell formation [40]. Cytokines caspase 1-dependent IL-1b and IL-18 released by pyroptotic cells are thought to play a role in promoting AIDs [41].
Mycobacteria are known to modulate the host cell’s death. Apoptosis, pyroptosis, autophagy, and necrosis were documented in TB [42]. Many of the PE/PPE/PGRS family proteins of Mtb affect these types of cell death in TB [29,43,44,45].
Infections can be connected with the onset of SLE(systemic lupus erythematosus) [4,5,37]. Clearance deficiency may link infections with AIDs [4], SLE [46], and ANCA (Antineutrophil cytoplasmic antibody)-associated vasculitis [47].
High titers of various AABs are present in pulmonary TB patients with vitamin D deficiency [48,49,50,51]. Vitamin D deficiency was registered in multiple sclerosis (MS) [52,53], rheumatoid arthritis (RA) [54,55,56,57], and inflammatory bowel disease [53,57,58,59]. The role of vitamin D in autoimmune diseases was demonstrated in [57,60]. Vitamin D status and polymorphisms of vitamin D receptor were shown to influence the AID development trend [61].
Several cytokines are associated with AIDs. TGFβ and IL-6 promote the early stage of Th17 cell differentiation in mice [62], while IL-23 is necessary for the functional maturation and maintenance of highly pathogenic Th17 cells [63,64,65] essential for the development of AI [66,67,68]. Subset Th17.1, which is characterized by high pathogenicity in the pathogenesis of AIDs, was also detected in TB patients [3].
Genetic as well as nongenetic factors of both the bacterium and the host may have influence on the host response to Mycobacterium tuberculosis [69].

2. Occurrence of AABs in Active TB Patient Sera

Early reports have established links between Mtb and AI [7,8,70,71]. A number of studies connecting TB with AI investigated the AAB characteristics of AIDs. The list of AABs includes rheumatoid factor (RF), antinuclear antibodies (ANA), anti-dsDNA AAB, anticardiolipin antibody (ACA; IgM isotype predominant), antineutrophil cytoplasmic antibodies (ANCA), and anticyclic citrullinated peptide (anti-CCP) [8,9,11,48,50,72,73,74,75,76,77,78]. (Table 1)
Several reports demonstrated the presence in the active TB patients’ antinuclear antibodies [7,8,50,70,72,73], AAB to double-stranded DNA (dsDNA) [10,48,50,77], which are characteristic of SLE. ANCAs, also typical for autoimmune diseases, were revealed in TB patients by different methods and results did not depend on the stage of disease, category of tuberculosis, concomitant diseases, or drug therapy [74]. Another study established an increase in ANCAs and bactericidal/permeability increasing protein in sera of patients with pulmonary TB after treatment [75]. Anticyclic citrullinated proteins and rheumatoid factor were found in patients with active TB [76]. In our investigations [48] the increased level of AABs in TB patients most often occurred with respect to the dsDNA. The TB patients also demonstrated enhanced levels of AABs to different antigens, but AABs to TSH-receptor, to kidney antigens, and to insulin were prevailing. Sera of TB patients were examined [10] for autoantibodies to Ro antigen, La antigen, centromere protein, double-stranded DNA (dsDNA), topoisomerase I (Scl-70), Smith protein, ribonucleoprotein particle (RNP), histone protein, and histidyl-transfer RNA synthetase (Jo1). Anti-Scl-70, antihistone, and anticardiolipin IgG were the predominate autoantibodies in TB patients.
Some authors concluded that AABs present in TB do not lead to clinical manifestations of AIDs, even if AABs were characteristic of certain diseases [10,48,75]. However, the presence of anti-CCP and RF correlated with long fever [75]. Despite high prevalence of AABs to the thyroid gland and the TSH receptor in TB patients, no changes in concentrations of thyroid hormones and TSH were discovered, but a wider range of AABs was found in more severe fibrous cavernous TB than in infiltrative TB [48]. The authors, who demonstrated the presence of AABs to different antigens in the TB patients, suggested that AABs are reactive to TB instead of being pathognomonic, and do not need immunosuppressant therapy [10].
There is also a conflicting report. No valid relationship has been found between AAB prevalence and pulmonary tuberculosis in the case of active pulmonary tuberculosis from Uganda, South Africa, Peru, and Bangladesh [78]. However, AI in TB has been opined to be an essential process driving pathology in tuberculosis, causing cavitation and transmission [12].
TB patients may develop noninfectious reactive polyarthritis (Poncet’s disease) or TB rheumatism [9]. The rheumatologic manifestations of TB and the occurrence of TB associated with rheumatologic diseases are summarized in [9].
The opposite relationships were also observed, namely that AIDs enhanced risks of TB. TB has been demonstrated to have autoimmune manifestations such as nodular vasculitis [13], Sjögren’s syndrome, SLE, RA, dermatomyositis, and polymyositis [79]. TB risk in RA patients was found to be about four times higher compared with general populations [80].

3. The Unique Pathway of B-Cell Activation Causing IgG2a AAB Production

Recently, a similar mechanism of AAB generation for classic AIDs and microbial infections connected with the autoreactive B-cell population expressing the transcription factor T-bet has been identified [17,18,19,20]. T-bet+ B-cells were found to be major producers of AABs [18]. B cells expressing the transcription factor T-bet may take part in a number of protective and pathogenic immune responses [20]. Both in infectious and classical AI, the mechanism of activation of T-bet+ B-cells involves the recognition of a nucleic acid by toll-like receptor 7 (TLR7) and synergistic stimulation of IFNγ receptors on B cells [17,18]. These signals induce T-box transcription factor T-bet and IgG2a switching in B cells [19].
T-bet has been demonstrated to have an important role in the protective immunity against intracellular pathogens and is prone to producing AABs [20]. T-bet+ B cell induction and expansion were revealed in mouse AI models and in patients with autoimmune diseases such as SLE, MS, RA, Crohn’s disease, and Sjögren’s syndrome [18].

4. Antiphospholipid Antibodies

Antiphospholipid antibodies (aPL) were revealed in various clinical conditions (AID) and infections such as TB (reviewed in [21,22,24]). The increased levels of ACA in TB patients were found in several studies [8,10,11,50]. Many viral, bacterial, and parasitic infections can induce aPL, mainly ACA, which do not correlate with thrombosis risk and antiphospholipid syndrome [21].
The elevated concentration of antibodies against β2 glycoprotein IgG and ACA IgG normalized after TB treatment was shown in active TB patients [11]. A significant number of patients had high levels of AABs against proteinase 3 (PR3), myeloperoxidase (MPO), bactericidal/permeability-increasing protein (BPI), and lactoferrin. Most antilactoferrin and anti-MPO levels decreased after treatment, while anti-PR3 increased in most patients [75]. Antiphospholipid antibody levels were suggested to use as biomarker TB treatment in noncavitary TB patients due to their high TB-treatment sensitivity [24].
Phospholipids in the Mtb cell envelope are phosphatidylglycerol, phosphatidylinositol, cardiolipin, and its mannoside derivatives, as well as phosphatidylethanolamine [81]. Because some of them can only be found in mycobacteria, they can be potential biomarkers for diagnosis and treatment response [24,82].

5. B-1 B Cells Produce IgM Antiphospholipid Antibodies, Which Have Auto- and Polyreactive Properties

Lipid molecules cause antibody response by B-1 B cells, representing about 5% of B cell population. B-1 B cells express high levels of IgM and do not need T cells for proliferation [23]. B and T cells with self-reactive antigen receptors are usually deleted during their development in order to avoid AIDs. On the contrary, innate-like B-1 cells in mice are positively selected for self-reactivity as long-lived, self-renewing B cells that generate most of the circulating natural IgM [83]. They respond to self-determinants, such as carbohydrates and glycolipids, and often cross-react with bacterial antigens. Major stimulating B-1 B cells antigens are phospholipids [23]. IgM aPL antibodies have self- and polyreactive properties [83].
The IgM antibody production by B-1 B cells needs long-term stimulation by lipid antigens generated by replicating mycobacteria during TB. Dead host cells and Mtb cells release enough antigens to activate the B-1 B cells and induce IgM aPL antibody production [24].

6. Mycobacterial Lipids Act as Adjuvants

Mycobacterial lipids have been shown to act as adjuvants. Adjuvants are a component in the vaccine stimulating innate immunity and memory-type immunity [25,84]; they are used to establish preferable types of immune responses [84].
Jules Freund created a powerful adjuvant composed of water-in-mineral oil emulsion and heat-killed mycobacteria. CFA, being highly effective, often causes granulomas, sterile abscesses, and ulcerative necrosis at the injection site and cannot be used for humans. CFA is used in experiments for modeling of AIDs such as uveitis and EAE [25]. The lipid components of CFA such as trehalose dimycolate (TDM, also known as cord factor) and mycolic-acid-containing glycolipids with strong adjuvant activity [85,86] have been shown to be a substantial factor of adjuvant activity [26]. TDM is a glycolipid in the mycobacterial cell envelope that was discovered in the 1950s as a most potent immune-stimulatory molecule [87].
Mycolic acids, important lipid components of the bacterial cell wall of Mycobacterium, have been demonstrated to be efficient adjuvant, and compared with CFA did not cause severe inflammatory responses induced by Th17. Instead of this, MA induced Th1-mediated moderate inflammation at the site of injection, activating dendritic cells by means of costimulatory molecules CD80/86 and CD40 and induction of promoting cytokines [88].

7. Mycobacterium Tuberculosis–Host Cell Interaction

Central to immune response is an interaction between host professional phagocytes and Mtb, which will determine development and outcome of TB. Alveolar Mphs are the host phagocytic cells that eliminate pathogens directly or indirectly, activating the host innate and adaptive immune responses without excessive inflammation and lung destruction [89].
Multiple receptors take part in endocytosis of Mtb: they are the complement receptor [90]; the monocyte-inducible C-type lectin (Mincle), identified as the receptor for TDM (trehalose-6,6′-dimycolate) [91]; surfactant protein A (Sp-A) and its receptors [92,93,94]; scavenger receptor [95]; mannose receptors [95,96]; and the DC-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN, CD209) [97,98]. DC-SIGN interactions with Mtb may be of benefit for either the pathogen or for the host due to restriction of tissue inflammation and immunopathology [99,100,101]. DC-SIGN is expressed on both wound-healing (IL-4-dependent) and regulatory (M-CSF-dependent) alternative (M2) macrophages [101]. Pattern-recognition receptors also respond to Mtb, among them the TLR-1, TLR-2, TLR-4, TLR-6, TLR7, and TLR-9 on Mphs and DCs, thereby driving phagocytosis, antigen presentation to T cells, and cytokine secretion [102,103,104].
Polymorphisms in TLRs affect human susceptibility to tuberculosis [27,28] and possibly to AI.
It was shown that the Mtb chaperone-like protein GroEL2 present on the Mtb cell envelope modulated Mph proinflammatory responses [105]. GroEL2 has been reported to be a major stimulator of immune response to Mtb-purified protein derivative (PPD) [106]. Cleavage of multimeric GroEL2 by the serine protease Hip1 resulted in the appearance of a cleaved form of GroEL2, which retarded innate immune responses to Mtb infection [107]. The full-length GroEL2 protein caused powerful proinflammatory responses activating DC maturation, antigen presentation to T cells, and inducing the Th1 subset development. The cleaved form of GroEL2 was unable to promote an efficient T-cell response [105]. The authors suggested that cleavage of GroEL2 averts optimal host response and that the prevalence of one of the two forms of GroEL2 during TB will determine the type of host immune response generated [105].
The microbial products can break self-tolerance and induce autoimmune manifestations, activating antigen-presenting cells. The development of EAE, even in genetically EAE-resistant mice, was observed after activation of APCs via TLR9 or TLR4 [108].

8. Unique Protein Family PE/PPE/PGRS Present on the Mtb Surface

Some molecules present on the Mtb surface are unique. The genome of Mtb encodes a protein family PE/PPE/PGRS, present exclusively in the genus Mycobacterium [109]. The complete genome sequence of the best-characterized strain of Mycobacterium tuberculosis, H37Rv, has been determined in 1998 by Cole et al. and a family of genes, the Proline–Glutamic acid/Proline–Proline–Glutamic acid (PE/PPE), has been identified [110]. These genes are principally characteristic of the pathogenic strains. The data on this important family of proteins are summarized in the review [29].
PE proteins are divided in three subfamilies: PE; PE/PPE; and PE_PGRS containing the polymorphic glycine-rich domain of variable sequence and size [29].
PE/PPE proteins have been reported to use the host inflammatory signaling and cell-death pathways to facilitate disease development [33]. It is widely recognized that PE_PGRS [polymorphic GC-rich-sequence (PGRS)] proteins are essential in TB pathogenesis [29,111,112].
The PE/PPE/PGRS are involved in cell-wall remodeling; they interfere with the host cell-death pathways and virulence [30], mycobacterial antigenic variation, immune evasion [31], and influence innate immunity and bacillary survival in macrophages [32,33]. Polymorphisms in the PE/PPE/PGRS protein family may influence different manifestations of TB, among them AI [112].

9. Mycobacterium tuberculosis Manipulates the Host Immune Response

The data showing that multiple molecules on the Mtb surface promote phagocytosis suggest that Mtb finds the intracellular environment of macrophages especially advantageous for surviving [113,114]. Mycobacteria manipulate host phagocytes to survive and replicate in these cells. PE_PGRS30 protein of Mtb blocks phagosome maturation [115]. Autophagy, a potent host defense mechanism, is impaired by several Mtb mechanisms [115,116,117,118,119]. PE_PGRS11 can induce maturation and activation of human DCs, which promotes the secretion of proinflammatory cytokines [120]. PE_PGRS17 binding to TLR2 activates the NF-κB signaling pathway, inducing TNF-α secretion [120].
Hyperactive immune response leads to robust inflammation, which induces dissemination and transmission of bacteria and possibly AI development.

10. PE_PGRS Proteins in TB Pathogenesis

Studies of pe_pgrs genes demonstrated that expression levels of different pe_pgrs genes could differ essentially [29], leading to a diverse picture and different outcome of TB. Each protein of the PE_PGRS family can fulfill its unique function without a specific protein partner. The identification of PE_PGRS proteins in Mtb and understanding their functions leads to the acknowledgement of their potent role in the TB pathogenesis [29]. It is possible to suggest the involvement of PE_PGRS proteins in AI promotion.

11. Excessive Cell Death as a Possible Mechanism of Autoimmunity

Cell death is a substantial physiological and pathological process involved in coordination of immune responses and AI [34]. Normally after cells die they are quickly and smoothly removed by phagocytes without inflammation [121,122]. However, during chronic infection, a large number of cells die, releasing massive amounts of cellular contents into the extracellular space. Released molecules are known as danger-associated molecular patterns (DAMPs) acting as damage signals, which attract additional immune cells to clear the threat and promote tissue repair [34]. The latest discoveries in the pathways of cell death and their effects were summarized in [34,42].
Apoptosis is immunologically silent cell elimination without inducing inflammation due to containing the distracted contents of dying cells within membrane-bound vesicles called apoptotic bodies [45,121]. Many cellular signals can lead to cell death in a controlled manner [123]. The morphological changes during apoptosis are cytoskeletal disruption, cell shrinkage, DNA fragmentation, and plasma membrane blebbing [124]. Many nuclear autoantigens have been shown to accumulate within apoptotic blebs [125,126]. It was shown that apoptotic vesicles from Mtb-infected macrophages had potent adjuvant effects, stimulating CD8 T cells in vivo [127].
Apoptotic bodies are engulfed later by another phagocyte in a process termed efferocytosis [128,129]. ACs release “find me” signals such as soluble lysophosphatidylcholine, CXC3CL1, sphingosine-1-phosphate, ATP, and UTP that attract phagocytes for the clearance of apoptotic bodies [130]. It was shown that in TB, such a role plays CX3CL1 and its receptor CX3CR1 [131]. The best-studied signal “eat me” is an oxidized phosphatidylserine and oxidized low-density lipoprotein on the surface of the phagocyte [130,132]. Phosphatidylserine, a membrane component of ACs, plays an important role in the clearance of apoptotic bodies by the efferocytosis process [128,133].
Apoptosis of infected cells has been shown to stimulate self-reactive T cells promoting AI in infections [35], and TB is an example of an infection characterized by massive macrophage apoptosis serving as a potential principal mechanism.
Phagocytosis of infected apoptotic cells results in the presence within the same phagosome of both cellular and microbial antigens. This makes possible the presentation of self-antigens by major histocompatibility complex class II (MHC II) molecules, leading to the generation of autoreactive Th17 cells, associated with autoantibody production [35].
Bacterial infections also cause pyroptosis [38], programmed cell death, accompanied by osmotic lysis, followed by release of inflammatory cytokines and cell contents [37]. Both nuclear and mitochondrial DNA are released by pyroptotic cells [134]. Pyroptotic cells release an important inflammatory protein high-mobility group box 1 (HMGB1), a nuclear DNA-binding protein [39]. Complex HMGB1-DNA in vitro can stimulate TLR9 and type I IFN production by dendritic cells and activate B cells through the receptor for advanced glycation end-products (RAGE), facilitating autoreactive B-cell formation [40]. Cytokines caspase 1-dependent IL-1b and IL-18 released by pyroptosis are thought to promote AIDs [41].

12. Defective Dead Cell Clearance in Etiopathogenesis of Autoimmune Diseases

Infections have been shown to be linked with the onset of SLE [4,5]. The potential connection between infections and AI could be clearance deficiency [4]. Apoptotic cells are frequently not cleared adequately in SLE [46,135,136,137,138]; as a result, autoantigens are presented to B cells by follicular DCs in secondary lymphoid tissues [135,136,139]. Nucleic acids and the proteins binding to nucleic acids are the main autoantigens in the AID SLE [37]. Nuclear and membrane autoantigens accumulate in lymphoid organs and is thought to activate the autoreactive B and T cells, causing the production of antinuclear and antiphospholipoprotein AABs [139]. The production of antinuclear AABs and binding them to apoptotic nuclear remnants leads to chronic tissue damage, and development of systemic AIDs [136]. It was hypothesized that impaired phagocytosis in ANCA-associated vasculitis leads to accumulation of apoptotic neutrophils, which further are exposed to secondary necrosis, leading to AAB formation [47].

13. Modulation of Cell-Death Pathways by Mycobacterium tuberculosis

Among the various cell-death types in TB were documented apoptosis, pyroptosis, autophagy, and necrosis [42]. Impairment of apoptosis and autophagy provides a survival niche to Mtb [114,140]. Mycobacteria can modulate the death of the host cells. The popular opinion is that virulent Mtb inhibits apoptosis, while avirulent mycobacteria stimulate it. Virulent strains H37Rv and GC1237 are the most effective inhibitors of experimentally induced cell death. However opposite data from different experimental systems evidence that cell death results from complex interrelations of pro- and anticytotoxic mechanisms [141]. RipA, a secretory peptidoglycan hydrolase, damages both autophagy and apoptosis in Mph for intracellular survival and virulence [119].
Some of the PE/PPE/PGRS family proteins were reported to promote apoptosis of infected Mphs [44,45,109]; PE25–PPE41 complex and PE_PGRS33 induce necrosis and inflammation [142], tissue damage, and persistence in the lung tissue [112], resulting in dissemination of the disease [43,44]. On the other hand, M. tuberculosis genes nuoG and secA2 have been discovered to inhibit apoptosis [42].
Apoptosis is usually considered to be a protecting mechanism of the host against Mtb at the early stage of TB. During later stages, it may promote the disease dissemination in lung granulomas [109]. The PE_PGRS5 protein of Mtb presented exclusively in the pathogenic Mycobacterium genus has been demonstrated to induce the apoptosis of Mphs [109].

14. MerTK Is a Major Macrophage Apoptotic-Cell Receptor

There is a strict correlation between SLE disease severity and the activation of an M2-like macrophage expressing CD163 and MerTK during the monocyte-to-macrophage differentiation [36]. Mer tyrosine kinase (MerTK) has been reported to be a number one Mph apoptotic cell (AC) receptor. Its functional defect causes defective AC clearance promoting AI and atherosclerosis [143]. Mer tyrosine kinase (MerTK), a member of the TAM (Tyro3, Axl, Mer) subfamily of receptors, is specifically involved in removal of early ACs, recognizing unmodified phosphatidylserine. Deficiencies in TAM receptors may contribute to human autoimmune diseases [144].
MerTK is expressed in primary and secondary lymphoid organs and is responsible for both central and peripheral tolerance through multiple mechanisms: clearance of AC-derived potential autoantigens [145]; reduction of proinflammatory cytokines production [146]; prevention of autoreactive B- and T-cell expansion [147,148]. In SLE patients, diminished AC removal is believed to promote the production of AABs against apoptotic material [129,138]. These patients had reduced plasma levels of the MerTK ligand Protein S [149], which may explain functionally defective AC clearance [36].
Populations of phagocytes M2c (CD163+) Mphs remove ACs, including apoptotic immune cells in healthy individuals, and release anti-inflammatory cytokines [150]. M-CSF was found to differentiate Mphs in the presence of IL-10, which express high levels of MerTK; such Mphs have M2c phenotypes. Gene polymorphisms of MerTK and its ligand growth arrest-specific 6 (Gas6) are connected with clinical manifestations in SLE patients [151,152].

15. Macrophage Polarization Programs

Mature Mphs can undergo functional polarization in response to environmental signals. Two well-appreciated Mph polarization programs are (M1) induced by LPS+IFNγ, secreting IL-12 and promoting Th1 differentiation; (M2) Mphs that are induced by IL-4: (M2a), secreting IL-4 and inducing Th2 polarization; (M2b) and (M2c), both secreting IL-10 and linked with regulatory T-cell (Treg) propagation [153]. These cells can switch from one phenotype to another. They can either facilitate a proinflammatory or an anti-inflammatory effect, which makes them a potential participant in the development of AIDs [154].
M1 macrophages are known to have proinflammatory effects, and their cytokines mediate autoimmune and chronic inflammatory diseases. M2-like macrophages mainly have anti-inflammatory properties. However, recent studies also demonstrated pro-inflammatory functions of these cells. Both macrophage types take part in the pathogenesis of SLE (reviewed by [155]).
Mtb can activate infected Mphs and thus change the cytokines and chemokine production. The ESAT-6 (early Secreted Antigenic Target 6 kDa) is thought to be one of the Mtb factors inducing the proinflammatory M1 phenotype at the start of the infection, which facilitates granuloma formation and then switches M polarization from M1 to M2 at a later stage of the infection [156].

16. Immune Tolerance

Control of the T-cell tolerance to self-antigens carried out at several levels.
DCs present self-antigens to developing T cells in thymus and delete lymphocytes with autoreactivity [157]. Central tolerance control occurring in thymus through mechanism of selection leads to release into the circulation of high-affinity T cells specific for non-self-antigens, low-affinity T cells specific for self-antigens, and natural Treg (nTreg) with an intermediate affinity to both self- and non-self-antigens [158].
Two types of peripheral tolerance mechanism exist in a steady state after antigen capture by DCs [159]. One is the T-cell deletion involving activation of the programmed death 1 (PD-1) and the cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) on T cells [160]. Immune checkpoints CTLA-4 and PD-1 are negative regulators of T-cell immune function. A second is the induction of foxp3+ regulatory T cells (Tregs) [161,162,163]. Fms-like tyrosine kinase 3 ligand (flt-3L) is a hematopoietin necessary for expanding DC subsets and Tregs in vivo [164]. The use of flt-3L has been shown to be effective in treating AI in mice [164,165,166].
Dendritic cells—“specialized and regulated antigen processing machines” [167].
DCs in culture exist in two functionally and phenotypically distinct states: immature and mature. Immature DCs function as phagocytes and express relatively low levels of surface MHC class I and II and costimulatory molecules, and can not present antigen properly to T cells. Being activated by microbial products or proinflammatory cytokines, immature DCs transform into mature DCs, which are characterized by low phagocytic capacity but extreme capacity for T-cell stimulation [168].

17. Dendritic Cell Subsets

Several DC subsets have been identified by their ontogeny, phenotype, and transcriptional profile [169]. In humans, blood DCs are defined as CD303+, CD304+, CD123+, plasmacytoid DCs, and conventional DCs (cDCs), the latter divided into two subsets, the CD1c+ DCs and the CD141+ DCs [170]. More recently, a third subset of DCs, named monocyte-derived DCs (Mo-DCs), has been described in patients with RA and in other inflammatory states [171,172,173]. These cells differentiate from monocytes in inflamed tissues and induce Th1, Th17, or Th2 responses depending on the signal received [174].
All these subsets of DCs have been identified with altered phenotypes and functions in several chronic inflammatory/autoimmune disorders. Different changes of DC subsets were found in autoimmune disorders [175].
DCs are central regulators of the balance between immunity and tolerance, and alteration of the specialized DCs system is a common feature of both systemic and tissue-specific AIDs [170]. Plasmacytoid DCs in SLE patients produce high levels of INF-alpha, the specific cytokine of this disease, responsible for high activation of innate and adaptive immunity [176]. Pathogen signal molecules induce immunogenic DCs to promote effector functions of adaptive immune cells [177,178,179]. DC subsets and mechanisms involved in regulatory T-cell induction have been reviewed by [178].
The plasticity of DCs, dependent on different extents of maturity, may be used in cell-based therapy to restore immune tolerance in AIDs. The beneficial effect of tolerogenic DC (tolDC) has been demonstrated in autoimmune models in mice. They caused immune tolerance, resolution of immune responses and prevention of AI by inhibition of effector and autoreactive T cells and by promotion of Treg cells [179,180,181]. TolDCs have become promising cell-based therapies for treatment of AIDs [182,183,184,185,186].

18. Vitamin D, Autoimmunity, Tuberculosis

Vitamin D has been discovered to have an important immune-modulatory function, enhancing the innate and inhibiting the adaptive immune response and acting as an environmental factor facilitating AID development [52,53,54,55,56,57,60,187,188,189]. The optimal vitamin D concentration beneficial for health and preventing the risk of AIDs was declared to be 30–40 ng/mL 25(OH)D [190].
The vitamin D3 receptor (VDR) and the vitamin D3 activating enzyme 1-α-hydroxylase (CYP27B1) are expressed in many cell types, including immune cells, and thus they can produce active 1,25(OH)2D from circulating inactive 25(OH)D [191,192]. The 1,25(OH)2D then activates the VDR, which binds to nuclear receptors of the retinoic X receptor (RXR) family and induces antimicrobial peptides cathelicidin and defensins [193,194]. VDR gene polymorphisms influence susceptibility to pulmonary tuberculosis [195].
Vitamin D inhibits the maturation and antigen presentation of DCs [57,196] and changes the profile of T-helper cells (Th1, Th2, Th9, Th17) and Treg cells [197]. It was reported that vitamin D lowers Th1 cell function, leading to decreased production of TNF-alpha, IL-2, granulocyte macrophage colony-stimulating factor (GMCSF) and IFN-gamma [198,199]. However, vitamin D increases the differentiation and proliferation of Th2 and Treg cells, which in turn stimulates the production of their anti-inflammatory cytokines IL-4, IL-5, and IL-10, which further suppress the development of Th1, Th17, and Th9 cells, producing immune tolerance [200].

19. Influence of Vitamin D and Vitamin A on Dendritic Cells

It has long been known that metabolism of vitamin D and of vitamin A is an important regulator DC function [201]. VitD3 can cause DC tolerogenicity and suppress AIDs in murine models [202,203]. VitD3-induced CD141+ DCs had a stable CD83low immature phenotype even after exposure to an effective DC maturation cocktail consisting of TNF, IL-1β, IL-6, and PGE2 [204] and was characterized by poor T-cell stimulatory capacity [205]. The profitable effects of vitamin D3 treatment were received in EAE, an experimental model of MS [206].
The internal mechanism of the vitD3-induced immune-regulatory functions on DCs is the biological activity of IDO (Indoleamine 2,3-dioxygenase is a rate-limiting enzyme for the tryptophan catabolism). Both the injection of vitamin D3 and the adoptive transfer of vitamin D3-induced IDO + immature DCs result in a significant increase of amount of CD4+CD25+Foxp3+ regulatory T cells in the lymph nodes in a rat EAE [206]. Control of tryptophan metabolism by IDO in DCs is a regulator of innate and adaptive immune responses. In acute inflammatory reactions, cytokine IFN-γ induces IDO’s enzymatic function preventing harmful, exaggerated responses through the effects on tryptophan metabolism. IDO also can maintain the stable tolerance to self in a steady state, restraining AI [207,208].
Essential for the VitD3 reprogramming function is glucose oxidation and glycolysis activation [209,210], which is induced by recently identified as a critical checkpoint and direct transcriptional target of VitD3 glycolytic enzyme PFKFB4 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4) [209].
The use of vitamin D3 for the generation of tolDC was found as a most effective method among different others [209,210].
The important role played by retinoic acid has been evidenced in the in vitro generation and stabilization of Treg (Foxp3+RORγt+ T cell phenotype) as well as the immunosuppressive ability of such cells [211]. The cytokine transforming growth factor-beta (TGF-beta) converts naïve T cells into Treg cells that prevent AI, but in the presence of interleukin-6 (IL-6) TGF-beta stimulates the differentiation of naïve T lymphocytes into proinflammatory IL-17-producing Th17 cells, which induce AI and inflammation [212].
The vitamin A metabolite retinoic acid has been identified as a key regulator of TGF-beta-dependent immune responses, inhibiting the IL-6 induction of proinflammatory Th17 cells and stimulating anti-inflammatory Treg cell differentiation [211,212].
Immunosuppressive and anti-inflammatory agents are also known to promote tolerogenic DCs, which sometimes results in the expansion of regulatory T cells with suppressive activity. Low-molecular-weight drugs causing generation of tolDC could be used to better control different chronic inflammatory states such as AIDs or allograft rejection [213,214,215].

20. Effects of Vitamin D Analogs Supplementation in Autoimmune Diseases

The calcemic effect of calcitriol and VDR limits their clinical application; therefore, the invention of noncalcemic VDR ligands is needed to actualize the potential of VDR-targeting therapy [215]. Synthetic vitamin D analogs demonstrated protolerogenic potential, causing a significant reduction in IL-12p70 and IL23p19 as well as IL-6 and IL-17 production by the dendritic cells [216]. These data lead to the new approaches for treating inflammatory and AIDs.
Nonsteroidal small-molecule compounds were discovered that activate the VDR, but are devoid of hypercalcemia [217].

21. Low Concentration of Vitamin D and Autoimmune Diseases

Vitamin D insufficiency is associated with AID development such as MS [52,53,57,60,187,188], RA [54,55,56,57,60,187,188], insulin-dependent diabetes mellitus [60,187], and IBD [53,57,58,59,60,187,218] (Table 2). The role of vitamin D in autoimmune diseases was reviewed by [57,60,187,188].

22. Tuberculosis, Vitamin D Deficiency, and Autoimmunity

High titers of various AABs present in pulmonary TB patients with vitamin D deficiency [48,49,50,51]. We revealed calcitriol deficiency and lack of proper cathelicidin response to infection in various forms of TB [48]. At the same time, these TB patients were characteristic of increased production of Th1 and Th17-derived cytokines and had blood prolactin level increased, which is well-known stimulator of AI [219]. These features taken together could be responsible for a greater inclination of TB patients to AI, and patients actually demonstrated increased levels of AABs towards several antigens, especially in more severe fibrous-cavernous forms of TB [48].

23. IL-17 and Related Cytokines in Inflammatory Autoimmune Diseases

Dysregulation of protective immune responses may cause AIDs. Excessive generation of Th17 cells resulting in high production of IL-17 may lead to AIDs [62,66,67]. IL-17 was found in many human AIDs, including MS, RA, SLE, IBD, and psoriasis [62,66,68]. Today, six homologous molecules are known (IL-17A–IL-17F). Activation of IL-17A and/or IL-17F induces the expression of IL-1, IL-6, IL-8, and TNF, and promotes the production of granulocyte colony-stimulating factor (G-CSF) and chemokines, that maintain chronic inflammation [63]. The IL-17 realizes the proinflammatory functions through the activation of NF-κB, MAPK, and C/EBP cascades [62].

24. Cytokine Promotion of Th-Cell Differentiation

Human Th-cell differentiation is largely regulated by IL-12, IL-23, and TGF-β. The CD4(+) T-cell subsets, Th1, Th2, Th9,Th17, Th22, and Treg cells are differentiated from naïve CD4(+) T cells depending on the cytokines they receive, and are characterized by the production of distinct cytokines [62]. Th1 cells, which are induced by IL-12 and IFN-γ, mediate host defense against intracellular pathogens by expressing IFN-γ. IL-6 plus TGF-β induces Th17 cells which express IL-17 and contribute to the eradication of extracellular bacteria [62,64,65].
Many data evidence that TGFβ and IL-6 are essential factors for the early stage of Th17 cell differentiation in mice [62,64], while IL-23 plays a central role in the functional maturation and maintenance of autopathologic Th17 cells [64,220]. IL-23 stimulates the differentiation and expansion of activated CD4+ cells that produce IL-17, IL-6, and TNFα upon antigen-specific stimulation. IL-23 is necessary for the generation of autoantigen-specific, highly pathogenic Th17 cells associated with AI [66,67,68]. IL-23 is also required for B cell follicle formation in the infected lungs and for long-term control of Mtb [220].
Other proinflammatory cytokines such as TNF-α and IL-1β together with Th17 cells/IL17 play significant roles in the pathogenesis of several autoimmune and chronic inflammatory diseases [62].

25. Th Cells and Cytokines in Tuberculosis

Th1 and Th17 are the main effector cells mediating protection and pathology during TB. Th1 cells have been established to facilitate protective action by secreting IFN-γ and activating Mphs. IFNγ has long been known as a regulator of T-cell responses in mycobacterial disease contributing to the elimination of mycobacteria-infected cells [65].
The function of Th17 cells during TB infection is complex because the pathogenesis of TB largely depends on the gravity of inflammation. Multiple data on Th17 actions in TB received both on mouse models and clinical TB show different results. Th17 induces chemokine and cytokine production, leading to neutrophil recruitment, tissue damage, and inflammation [65]. It was suggested that IL-17 may be protective during acute infection and detrimental during chronic ones [221] and in multidrug-resistant TB [63].
Heterogeneous cell populations Th1 and Th17 include subpopulations with diverse cytokine profiles playing different roles in immune pathology and protection. Th17.1 produces IFN-γ/TNF-α and IL-17 differentiating from Th17 in the presence of IL-12 and inflammatory cytokines, primarily IL-1β [65]. Th17.1 cells were found to be extremely pathogenic in the course of AIDs, but the role for these cells in active TB remains unclear. Th17.1 cells were detected in the broncho-alveolar fluid and lungs TB patients [65].
More recently, additional immune pathways were revealed, especially important is the role of type I interferons both in TB and in AIDs [16].

26. Conclusions

Multifactorial immune response against Mycobacterium tuberculosis includes immunologic, genetic, and environmental factors. Pathogenesis of TB and AI has many common immunological pathways that increase the chance to develop AI. More studies are needed to investigate these common pathways, and many questions remain unanswered. Comprehension of these mechanisms is necessary for the improvement of both TB and AID prognosis and treatment.

Author Contributions

I.V.B.: conception and design, data collecting and analysis, manuscript writing; A.N.K.: data collecting; A.G.V.: manuscript editing. All authors have read and agreed to the published version of the manuscript.


This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.


  1. WHO. Global Tuberculosis Report 2021; WHO: Geneva, Switzerland, 2021. [Google Scholar]
  2. Allué-Guardia, A.; García, J.I.; Torrelles, J.B. Evolution of Drug-Resistant Mycobacterium tuberculosis Strains and Their Adaptation to the Human Lung Environment. Front. Microbiol. 2021, 12, 612675. [Google Scholar] [CrossRef] [PubMed]
  3. Lyadova, I.; Nikitina, I. Cell Differentiation Degree as a Factor Determining the Role for Different T-Helper Populations in Tuberculosis Protection. Front. Immunol. 2019, 10, 972. [Google Scholar] [CrossRef]
  4. Schulze, C.; Munoz, L.; Franz, S.; Sarter, K.; Chaurio, R.; Gaipl, U.; Herrmann, M. Clearance deficiency—A potential link between infections and autoimmunity. Autoimmun. Rev. 2008, 8, 5–8. [Google Scholar] [CrossRef]
  5. Esposito, S.; Bosis, S.; Semino, M.; Rigante, D. Infections and systemic lupus erythematosus. Eur. J. Clin. Microbiol. 2014, 33, 1467–1475. [Google Scholar] [CrossRef] [PubMed]
  6. Rigante, D.; Esposito, S. Infections and Systemic Lupus Erythematosus: Binding or Sparring Partners? Int. J. Mol. Sci. 2015, 16, 17331–17343. [Google Scholar] [CrossRef] [PubMed]
  7. Isenberg, D.A.; Maddison, P.; Swana, G.; Skinner, R.P.; Swana, M.; Jones, M.; Addison, I.; Dudeney, C.; Shall, S.; Roiey, A.E.; et al. Profile of autoantibodies in the serum of patients with tuberculosis, klebsiella and other Gram-negative infections. Clin. Exp. Immunol. 1987, 67, 516–523. [Google Scholar]
  8. Adebajo, A.O.; Charles, P.; Maini, R.N.; Hazleman, B.L. Autoantibodies in malaria, tuberculosis and hepatitis B in a West African population. Clin. Exp. Immunol. 1993, 92, 73–76. [Google Scholar] [CrossRef]
  9. Franco-Paredes, C.; Díaz-Borjon, A.; Senger, M.A.; Barragan, L.; Leonard, M. The Ever-Expanding Association Between Rheumatologic Diseases and Tuberculosis. Am. J. Med. 2006, 119, 470–477. [Google Scholar] [CrossRef]
  10. Shen, C.-Y.; Hsieh, S.-C.; Yu, C.-L.; Wang, J.-Y.; Lee, L.-N.; Yu, C.-J. Autoantibody prevalence in active tuberculosis: Reactive or pathognomonic? BMJ Open 2013, 3, e002665. [Google Scholar] [CrossRef]
  11. Elkayam, O.; Bendayan, D.; Segal, R.; Shapira, Y.; Gilburd, B.; Reuter, S.; Agmon-Levin, N.; Shoenfeld, Y. The effect of anti-tuberculosis treatment on levels of anti-phospholipid and anti-neutrophil cytoplasmatic antibodies in patients with active tuberculosis. Rheumatol. Int. 2012, 33, 949–953. [Google Scholar] [CrossRef]
  12. Elkington, P.; Tebruegge, M.; Mansour, S. Tuberculosis: An Infection-Initiated Autoimmune Disease? Trends Immunol. 2016, 37, 815–818. [Google Scholar] [CrossRef] [PubMed]
  13. Chen, S.; Chen, J.; Chen, L.; Zhang, Q.; Luo, X.; Zhang, W. Mycobacterium tuberculosis Infection Is Associated with the Development of Erythema Nodosum and Nodular Vasculitis. PLoS ONE 2013, 8, e62653. [Google Scholar] [CrossRef]
  14. Rivera-Correa, J.; Rodriguez, A. Divergent Roles of Antiself Antibodies during Infection. Trends Immunol. 2018, 39, 515–522. [Google Scholar] [CrossRef]
  15. Shapira, Y.; Agmon-Levin, N.; Shoenfeld, Y. Mycobacterium tuberculosis, Autoimmunity, and Vitamin D. Clin. Rev. Allergy Immunol. 2009, 38, 169–177. [Google Scholar] [CrossRef]
  16. Mourik, B.C.; Lubberts, E.; De Steenwinkel, J.E.M.; Ottenhoff, T.H.M.; Leenen, P.J.M. Interactions between Type 1 Interferons and the Th17 Response in Tuberculosis: Lessons Learned from Autoimmune Diseases. Front. Immunol. 2017, 8, 294. [Google Scholar] [CrossRef] [PubMed]
  17. Rubtsova, K.; Rubtsov, A.V.; van Dyk, L.F.; Kappler, J.W.; Marrack, P. T-box transcription factor T-bet, a key player in a unique type of B-cell activation essential for effective viral clearance. Proc. Natl. Acad. Sci. USA 2013, 110, E3216–E3224. [Google Scholar] [CrossRef] [PubMed]
  18. Rubtsov, A.V.; Marrack, P.; Rubtsova, K. T-bet expressing B cells—Novel target for autoimmune therapies? Cell. Immunol. 2017, 321, 35–39. [Google Scholar] [CrossRef] [PubMed]
  19. Knox, J.J.; Myles, A.; Cancro, M.P. T-bet+ B cells: Generation, function, and fate. Immunol. Rev. 2019, 288, 149–160. [Google Scholar] [CrossRef]
  20. Rubtsov, A.V.; Rubtsova, K.; Fischer, A.; Meehan, R.T.; Gillis, J.Z.; Kappler, J.W.; Marrack, P. Toll-like receptor 7 (TLR7)–driven accumulation of a novel CD11c+ B-cell population is important for the development of autoimmunity. Blood 2011, 118, 1305–1315. [Google Scholar] [CrossRef]
  21. Sène, D.; Piette, J.-C.; Cacoub, P. Antiphospholipid antibodies, antiphospholipid syndrome and infections. Autoimmun. Rev. 2008, 7, 272–277. [Google Scholar] [CrossRef]
  22. Martirosyan, A.; Aminov, R.; Manukyan, G. Environmental Triggers of Autoreactive Responses: Induction of Antiphospholipid Antibody Formation. Front. Immunol. 2019, 10, 1609. [Google Scholar] [CrossRef] [PubMed]
  23. Hardy, R.R. B-1 B Cell Development. J. Immunol. 2006, 177, 2749–2754. [Google Scholar] [CrossRef] [PubMed]
  24. Goodridge, A.; Cueva, C.; Lahiff, M.; Muzanye, G.; Johnson, J.L.; Nahid, P.; Riley, L.W. Anti-phospholipid antibody levels as biomarker for monitoring tuberculosis treatment response. Tuberculosis 2012, 92, 243–247. [Google Scholar] [CrossRef]
  25. Apostolico, J.D.S.; Lunardelli, V.A.; Coirada, F.C.; Boscardin, S.B.; Rosa, D.S. Adjuvants: Classification, modus operandi, and licensing. J. Immunol. Res. 2016, 2016, 1459394. [Google Scholar] [CrossRef] [PubMed]
  26. Billiau, A.; Matthys, P. Modes of action of Freund’s adjuvants in experimental models of autoimmune diseases. J. Leukoc. Biol. 2001, 70, 849–860. [Google Scholar] [PubMed]
  27. Ma, X.; Liu, Y.; Gowen, B.B.; Graviss, E.A.; Clark, A.G.; Musser, J.M. Full-Exon Resequencing Reveals Toll-Like Receptor Variants Contribute to Human Susceptibility to Tuberculosis Disease. PLoS ONE 2007, 2, e1318. [Google Scholar] [CrossRef] [PubMed]
  28. Velez, D.R.; Wejse, C.; Stryjewski, M.E.; Abbate, E.; Hulme, W.F.; Myers, J.L.; Estevan, R.; Patillo, S.G.; Olesen, R.; Tacconelli, A.; et al. Variants in toll-like receptors 2 and 9 influence susceptibility to pulmonary tuberculosis in Caucasians, African-Americans, and West Africans. Qual. Life Res. 2010, 127, 65–73. [Google Scholar] [CrossRef]
  29. De Maio, F.; Berisio, R.; Manganelli, R.; Delogu, G. PE_PGRS proteins of Mycobacterium tuberculosis: A specialized molecular task force at the forefront of host–pathogen interaction. Virulence 2020, 11, 898–915. [Google Scholar] [CrossRef]
  30. Singh, P.; Rao, R.N.; Reddy, J.R.; Prasad, R.B.; Kotturu, S.K.; Ghosh, S.; Mukhopadhyay, S. PE11, a PE/PPE family protein of Mycobacterium tuberculosis is involved in cell wall remodeling and virulence. Sci. Rep. 2016, 6, 21624. [Google Scholar] [CrossRef]
  31. Akhter, Y.; Ehebauer, M.T.; Mukhopadhyay, S.; Hasnain, S. The PE/PPE multigene family codes for virulence factors and is a possible source of mycobacterial antigenic variation: Perhaps more? Biochimie 2012, 94, 110–116. [Google Scholar] [CrossRef]
  32. Tiwari, B.M.; Kannan, N.; Vemu, L.; Raghunand, T.R. The Mycobacterium tuberculosis PE Proteins Rv0285 and Rv1386 Modulate Innate Immunity and Mediate Bacillary Survival in Macrophages. PLoS ONE 2012, 7, e51686. [Google Scholar] [CrossRef] [PubMed]
  33. Sharma, N.; Shariq, M.; Quadir, N.; Singh, J.; Sheikh, J.A.; Hasnain, S.E.; Ehtesham, N.Z. Mycobacterium tuberculosis Protein PE6 (Rv0335c), a Novel TLR4 Agonist, Evokes an Inflammatory Response and Modulates the Cell Death Pathways in Macrophages to Enhance Intracellular Survival. Front. Immunol. 2021, 12, 696491. [Google Scholar] [CrossRef] [PubMed]
  34. Bertheloot, D.; Latz, E.; Franklin, B.S. Necroptosis, pyroptosis and apoptosis: An intricate game of cell death. Cell. Mol. Immunol. 2021, 18, 1106–1121. [Google Scholar] [CrossRef] [PubMed]
  35. Campisi, L.; Barbet, G.; Ding, Y.; Esplugues, E.; Flavell, R.A.; Blander, J.M. Apoptosis in response to microbial infection induces autoreactive TH17 cells. Nat. Immunol. 2016, 17, 1084–1092. [Google Scholar] [CrossRef]
  36. Zizzo, G.; Hilliard, B.A.; Monestier, M.; Cohen, P.L. Efficient Clearance of Early Apoptotic Cells by Human Macrophages Requires M2c Polarization and MerTK Induction. J. Immunol. 2012, 189, 3508–3520. [Google Scholar] [CrossRef]
  37. Qiu, C.; Caricchio, R.; Gallucci, S. Triggers of Autoimmunity: The Role of Bacterial Infections in the Extracellular Exposure of Lupus Nuclear Autoantigens. Front. Immunol. 2019, 10, 2608. [Google Scholar] [CrossRef]
  38. Liu, X.; Lieberman, J. A Mechanistic Understanding of Pyroptosis: The Fiery Death Triggered by Invasive Infection. Adv. Immunol. 2017, 135, 81–117. [Google Scholar] [CrossRef]
  39. Ardoin, S.P.; Pisetsky, D.S. The role of cell death in the pathogenesis of autoimmune disease: HMGB1 and microparticles as intercellular mediators of inflammation. Mod. Rheumatol. 2008, 18, 319–326. [Google Scholar] [CrossRef]
  40. Tian, J.; Avalos, A.M.; Mao, S.-Y.; Chen, B.; Senthil, K.; Wu, H.; Parroche, P.; Drabic, S.; Golenbock, D.T.; Sirois, C.M.; et al. Toll-like receptor 9–dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nat. Immunol. 2007, 8, 487–496. [Google Scholar] [CrossRef]
  41. Magna, M.; Pisetsky, D.S. The Role of Cell Death in the Pathogenesis of SLE: Is Pyroptosis the Missing Link? Scand. J. Immunol. 2015, 82, 218–224. [Google Scholar] [CrossRef]
  42. Parandhaman, D.K.; Enarayanan, S. Cell death paradigms in the pathogenesis of Mycobacterium tuberculosis infection. Front. Cell. Infect. Microbiol. 2014, 4, 31. [Google Scholar] [CrossRef] [PubMed]
  43. Tundup, S.; Mohareer, K.; Hasnain, S.E. Mycobacterium tuberculosis PE25/PPE41 protein complex induces necrosis in macrophages: Role in virulence and disease reactivation? FEBS Open Bio. 2014, 4, 822–828. [Google Scholar] [CrossRef] [PubMed]
  44. Meena, L.S. An overview to understand the role of PE_PGRS family proteins in Mycobacterium tuberculosis H37Rv and their potential as new drug targets. Biotechnol. Appl. Biochem. 2015, 62, 145–153. [Google Scholar] [CrossRef]
  45. Tiwari, B.; Ramakrishnan, U.M.; Raghunand, T.R. The Mycobacterium tuberculosis protein pair PE9 (Rv1088)-PE10 (Rv1089) forms heterodimers and induces macrophage apoptosis through Toll-like receptor 4. Cell. Microbiol. 2015, 17, 1653–1669. [Google Scholar] [CrossRef] [PubMed]
  46. Munoz, L.E.; Gaipl, U.S.; Franz, S.; Sheriff, A.; Voll, R.E.; Kalden, J.R.; Herrmann, M. SLE—A disease of clearance deficiency? Rheumatology 2005, 44, 1101–1107. [Google Scholar] [CrossRef] [PubMed]
  47. Ohlsson, S.M.; Pettersson, Å.; Ohlsson, S.; Selga, D.; Bengtsson, A.A.; Segelmark, M.; Hellmark, T. Phagocytosis of apoptotic cells by macrophages in anti-neutrophil cytoplasmic antibody-associated systemic vasculitis. Clin. Exp. Immunol. 2012, 170, 47–56. [Google Scholar] [CrossRef]
  48. Belyaeva, I.V.; Churilov, L.P.; Mikhailova, L.R.; Nikolaev, A.V.; Starshinova, A.A.; Yablonsky, P.K. Vitamin D, Cathelicidin, Prolactin, Autoantibodies, and Cytokines in Different Forms of Pulmonary Tuberculosis versus Sarcoidosis. IMAJ 2017, 19, 499–505. [Google Scholar]
  49. Shoenfeld, Y.; Zandman-Goddard, G.; Stojanovich, L.; Cutolo, M.; Amital, H.; Levy, Y.; Abu-Shakra, M.; Barzilai, O.; Berkun, Y.; Blank, M.; et al. The mosaic of autoimmunity: Hormonal and environmental factors involved in autoimmune diseases—2008. Isr. Med Assoc. J. IMAJ 2008, 10, 8–12. [Google Scholar]
  50. Elkayam, O.; Caspi, D.; Lidgi, M.; Segal, R. Auto-antibody profiles in patients with active pulmonary tuberculosis. Int. J. Tuberc. Lung Dis. 2007, 11, 306–310. [Google Scholar]
  51. Zhao, X.; Yuan, Y.; Lin, Y.; Zhang, T.; Bai, Y.; Kang, D.; Li, X.; Kang, W.; Dlodlo, R.A.; Harries, A.D. Vitamin D status of tuberculosis patients with diabetes mellitus in different economic areas and associated factors in China. PLoS ONE 2018, 13, e0206372. [Google Scholar] [CrossRef]
  52. Adorini, L. Selective Immunointervention in Autoimmune Diseases: Lessons from Multiple Sclerosis. J. Chemother. 2001, 13, 219–234. [Google Scholar] [CrossRef]
  53. Cantorna, M.T. Vitamin D and its role in immunology: Multiple sclerosis, and inflammatory bowel disease. Prog. Biophys. Mol. Biol. 2006, 92, 60–64. [Google Scholar] [CrossRef] [PubMed]
  54. Cutolo, M.; Plebani, M.; Shoenfeld, Y.; Adorini, L.; Tincani, A. Vitamin D Endocrine System and the Immune Response in Rheumatic Diseases. Vitam. Horm. 2011, 86, 327–351. [Google Scholar] [CrossRef] [PubMed]
  55. Lin, J.; Liu, J.; Davies, M.L.; Chen, W. Serum Vitamin D Level and Rheumatoid Arthritis Disease Activity: Review and Meta-Analysis. PLoS ONE 2016, 11, e0146351. [Google Scholar] [CrossRef] [PubMed]
  56. Zou, J.; Thornton, C.; Chambers, E.S.; Rosser, E.C.; Ciurtin, C. Exploring the Evidence for an Immunomodulatory Role of Vitamin D in Juvenile and Adult Rheumatic Disease. Front. Immunol. 2021, 11, 616483. [Google Scholar] [CrossRef] [PubMed]
  57. Szodoray, P.; Nakken, B.; Gaal, J.; Jonsson, R.; Szegedi, A.; Zold, E.; Szegedi, G.; Brun, J.G.; Gesztelyi, R.; Zeher, M.; et al. The Complex Role of Vitamin D in Autoimmune Diseases. Scand. J. Immunol. 2008, 68, 261–269. [Google Scholar] [CrossRef]
  58. Peyrin-Biroulet, L.; Oussalah, A.; Bigard, M.-A. Crohn’s disease: The hot hypothesis. Med. Hypotheses 2009, 73, 94–96. [Google Scholar] [CrossRef]
  59. Rasouli, E.; Sadeghi, N.; Parsi, A.; Hashemi, S.J.; Nayebi, M.; Shayesteh, A. Relationship Between Vitamin D Deficiency and Disease Activity in Patients with Inflammatory Bowel Disease in Ahvaz, Iran. Clin. Exp. Gastroenterol. 2020, 13, 419–425. [Google Scholar] [CrossRef]
  60. Murdaca, G.; Tonacci, A.; Negrini, S.; Greco, M.; Borro, M.; Puppo, F.; Gangemi, S. Emerging role of vitamin D in autoimmune diseases: An update on evidence and therapeutic implications. Autoimmun. Rev. 2019, 18, 102350. [Google Scholar] [CrossRef]
  61. Marini, F.; Falcini, F.; Stagi, S.; Fabbri, S.; Ciuffi, S.; Rigante, D.; Cerinic, M.M.; Brandi, M.L. Study of vitamin D status and vitamin D receptor polymorphisms in a cohort of Italian patients with juvenile idiopathic arthritis. Sci. Rep. 2020, 10, 17550. [Google Scholar] [CrossRef]
  62. Zambrano-Zaragoza, J.F.; Romo-Martínez, E.J.; Durán-Avelar, M.D.J.; García-Magallanes, N.; Vibanco-Pérez, N. Th17 Cells in Autoimmune and Infectious Diseases. Int. J. Inflamm. 2014, 2014, 651503. [Google Scholar] [CrossRef] [PubMed]
  63. Basile, J.I.; Geffner, L.J.; Romero, M.M.; Balboa, L.; García, C.S.Y.; Ritacco, V.; García, A.; Cuffré, M.; Abbate, E.; López, B.; et al. Outbreaks of Mycobacterium tuberculosis MDR Strains Induce High IL-17 T-Cell Response in Patients with MDR Tuberculosis That Is Closely Associated with High Antigen Load. J. Infect. Dis. 2011, 204, 1054–1064. [Google Scholar] [CrossRef] [PubMed]
  64. Lee, Y.; Awasthi, A.; Yosef, N.; Quintana, F.J.; Xiao, S.; Peters, A.; Wu, C.; Kleinewietfeld, M.; Kunder, S.; Hafler, D.A.; et al. Induction and molecular signature of pathogenic TH17 cells. Nat. Immunol. 2012, 13, 991–999. [Google Scholar] [CrossRef] [PubMed]
  65. Lyadova, I.V.; Panteleev, A.V. Th1 and Th17 Cells in Tuberculosis: Protection, Pathology, and Biomarkers. Mediat. Inflamm. 2015, 2015, 854507. [Google Scholar] [CrossRef] [PubMed]
  66. van Hamburg, J.P.; Tas, S.W. Molecular mechanisms underpinning T helper 17 cell heterogeneity and functions in rheumatoid arthritis. J. Autoimmun. 2018, 87, 69–81. [Google Scholar] [CrossRef] [PubMed]
  67. Yasuda, K.; Takeuchi, Y.; Hirota, K. The pathogenicity of Th17 cells in autoimmune diseases. In Seminars in Immunopathology; Springer: Berlin/Heidelberg, Germany, 2019; Volume 41, pp. 283–299. [Google Scholar] [CrossRef]
  68. Yang, P.; Qian, F.; Zhang, M.; Xu, A.; Wang, X.; Jiang, B.; Zhou, L. Th17 cell pathogenicity and plasticity in rheumatoid arthritis. J. Leukoc. Biol. 2019, 106, 1233–1240. [Google Scholar] [CrossRef]
  69. Aravindan, P. Host genetics and tuberculosis: Theory of genetic polymorphism and tuberculosis. Lung India 2019, 36, 244–252. [Google Scholar] [CrossRef]
  70. Rapoport, B.L.; Morrison, R.C.; Sher, R.; Dos Santos, L. A study of autoantibodies in chronic mycobacterial infections. Int. J. Lepr. Other Mycobact. Dis. 1990, 58, 518–525. [Google Scholar]
  71. Lindqvist, K.J.; Coleman, R.E.; Osterland, C. Autoantibodies in chronic pulmonary tuberculosis. J. Chronic Dis. 1970, 22, 717–725. [Google Scholar] [CrossRef]
  72. Ganesh, R.; Ramalingam, V.; Raja, T.E.; Vasanthi, T. Antinuclear antibodies in Mycobacterium tuberculosis infection. Indian J. Pediatr. 2008, 75, 1188. [Google Scholar] [CrossRef]
  73. Kasikovic-Lecic, S.; Kerenji, A.; Pavlovic, S.; Kuruc, V.; Mitic, I.; Ilic, T. Autoantibodies in patients treated for active pulmonary tuberculosis. Med. Rev. 2008, 61, 333–342. [Google Scholar] [CrossRef] [PubMed]
  74. Flores-Suárez, L.F.; Cabiedes, J.; Villa, A.R.; Van Der Woude, F.J.; Alcocer-Varela, J. Prevalence of antineutrophil cytoplasmic autoantibodies in patients with tuberculosis. Rheumatology 2003, 42, 223–229. [Google Scholar] [CrossRef] [PubMed]
  75. Esquivel-Valerio, J.; Flores-Suárez, L.F.; Rodríguez-Amado, J.; Garza-Elizondo, M.A.; Rendon, A.; Salinas-Carmona, M.C. Antineutrophil cytoplasm autoantibodies in patients with tuberculosis are directed against bactericidal/permeability increasing protein and are detected after treatment initiation. Clin. Exp. Rheumatol. 2010, 28, S35. [Google Scholar]
  76. Elkayam, O.; Segal, R.; Lidgi, M.; Caspi, D. Positive anti-cyclic citrullinated proteins and rheumatoid factor during active lung tuberculosis. Ann. Rheum. Dis. 2006, 65, 1110–1112. [Google Scholar] [CrossRef]
  77. Shahzad, F.; Ali, A.; Mushtaq, A.; Javaid, K.; Nazir, A.; Pervez, A.; Kashif, M.; Bashir, N.; Abbas, A.; Tahir, R.; et al. Raised dsDNA autoantibodies in tuberculosis patients. Egypt. J. Chest Dis. Tuberc. 2019, 68, 28–31. [Google Scholar] [CrossRef]
  78. Cheng, M.P.; Butler-Laporte, G.; Parkes, L.O.; Bold, T.D.; Fritzler, M.J.; Behr, M.A. Prevalence of Auto-Antibodies in Pulmonary Tuberculosis. Open Forum Infect. Dis. 2019, 6, ofz114. [Google Scholar] [CrossRef] [PubMed]
  79. Ramagopalan, S.V.; Goldacre, R.; Skingsley, A.; Conlon, C.; Goldacre, M.J. Associations between selected immune-mediated diseases and tuberculosis: Record-linkage studies. BMC Med. 2013, 11, 97. [Google Scholar] [CrossRef]
  80. Tsuyuguchi, K.; Matsumoto, T. Biologics and mycobacterial diseases. Kekkaku [Tuberculosis] 2013, 88, 337–353. [Google Scholar]
  81. Brennan, P.J.; Nikaido, H. The envelope of mycobacteria. Annu. Rev. Biochem. 1995, 64, 29–63. [Google Scholar] [CrossRef]
  82. Takenami, I.; de Oliveira, C.C.; Petrilli, J.D.; Machado, A.; Riley, L.W.; Arruda, S. Serum antiphospholipid antibody levels as biomarkers for diagnosis of pulmonary tuberculosis patients. Int. J. Tuberc. Lung Dis. 2018, 22, 1063–1070. [Google Scholar] [CrossRef]
  83. Baumgarth, N. The double life of a B-1 cell: Self-reactivity selects for protective effector functions. Nat. Rev. Immunol. 2010, 11, 34–46. [Google Scholar] [CrossRef] [PubMed]
  84. Coffman, R.L.; Sher, A.; Seder, R.A. Vaccine Adjuvants: Putting Innate Immunity to Work. Immunity 2010, 33, 492–503. [Google Scholar] [CrossRef] [PubMed]
  85. Decout, A.; Silva-Gomes, S.; Drocourt, D.; Barbe, S.; André, I.; Cueto, F.J.; Lioux, T.; Sancho, D.; Pérouzel, E.; Vercellone, A.; et al. Rational design of adjuvants targeting the C-type lectin Mincle. Proc. Natl. Acad. Sci. USA 2017, 114, 2675–2680. [Google Scholar] [CrossRef] [PubMed]
  86. Ishikawa, E.; Mori, D.; Yamasaki, S. Recognition of Mycobacterial Lipids by Immune Receptors. Trends Immunol. 2017, 38, 66–76. [Google Scholar] [CrossRef]
  87. Noll, H.; Bloch, H.; Asselineau, J.; Lederer, E. The chemical structure of the cord factor of Mycobacterium tuberculosis. Biochim. Biophys. Acta 1956, 20, 299–309. [Google Scholar] [CrossRef]
  88. Kubota, M.; Iizasa, E.; Chuuma, Y.; Kiyohara, H.; Hara, H.; Yoshida, H. Adjuvant activity of Mycobacteria-derived mycolic acids. Heliyon 2020, 6, e04064. [Google Scholar] [CrossRef]
  89. Evren, E.; Ringqvist, E.; Willinger, T. Origin and ontogeny of lung macrophages: From mice to humans. Immunology 2020, 160, 126–138. [Google Scholar] [CrossRef]
  90. Schlesinger, L.S.; Bellinger-Kawahara, C.G.; Payne, N.R.; Horwitz, M.A. Phagocytosis of Mycobacterium tuberculosis is mediated by human monocyte complement receptors and complement component C3. J. Immunol. 1990, 144, 2771–2780. [Google Scholar]
  91. Ishikawa, E.; Mori, D.; Yamasaki, S. Direct recognition of the mycobacterial glycolipid, trehalose dimycolate, by C-type lectin Mincle. J. Exp. Med. 2009, 206, 2879–2888. [Google Scholar] [CrossRef]
  92. Schlesinger, L.S.; Torrelles, J.B.; Azad, A.K.; Henning, L.N.; Carlson, T.K. Role of C-type lectins in mycobacterial infections. Curr. Drug Targets 2008, 9, 102–112. [Google Scholar] [CrossRef]
  93. Torrelles, J.B.; Schlesinger, L.S. Integrating Lung Physiology, Immunology, and Tuberculosis. Trends Microbiol. 2017, 25, 688–697. [Google Scholar] [CrossRef] [PubMed]
  94. Garcia-Vilanova, A.; Chan, J.; Torrelles, J.B. Underestimated Manipulative Roles of Mycobacterium tuberculosis Cell Envelope Glycolipids During Infection. Front. Immunol. 2019, 10, 2909. [Google Scholar] [CrossRef] [PubMed]
  95. Ernst, J.D. Macrophage Receptors for Mycobacterium tuberculosis. Infect. Immun. 1998, 66, 1277–1281. [Google Scholar] [CrossRef] [PubMed]
  96. Rajaram, M.V.; Arnett, E.; Azad, A.K.; Guirado, E.; Ni, B.; Gerberick, A.D.; He, L.-Z.; Keler, T.; Thomas, L.J.; Lafuse, W.; et al. M. tuberculosis -Initiated Human Mannose Receptor Signaling Regulates Macrophage Recognition and Vesicle Trafficking by FcRγ-Chain, Grb2, and SHP-1. Cell Rep. 2017, 21, 126–140. [Google Scholar] [CrossRef]
  97. Lugo, G.; Troegeler, A.; Balboa, L.; Lastrucci, C.; Duval, C.; Mercier, I.; Bénard, A.; Capilla, F.; Al Saati, T.; Poincloux, R.; et al. The C-Type Lectin Receptor DC-SIGN Has an Anti-Inflammatory Role in Human M(IL-4) Macrophages in Response to Mycobacterium tuberculosis. Front. Immunol. 2018, 9, 1123. [Google Scholar] [CrossRef]
  98. Tailleux, L.; Schwartz, O.; Herrmann, J.-L.; Pivert, E.; Jackson, M.; Amara, A.; Legres, L.; Dreher, D.; Nicod, L.P.; Gluckman, J.C.; et al. DC-SIGN Is the Major Mycobacterium tuberculosis Receptor on Human Dendritic Cells. J. Exp. Med. 2002, 197, 121–127. [Google Scholar] [CrossRef]
  99. Tailleux, L.; Pham-Thi, N.; Bergeron-Lafaurie, A.; Herrmann, J.-L.; Charles, P.; Schwartz, O.; Scheinmann, P.; Lagrange, P.H.; De Blic, J.; Tazi, A.; et al. DC-SIGN Induction in Alveolar Macrophages Defines Privileged Target Host Cells for Mycobacteria in Patients with Tuberculosis. PLOS Med. 2005, 2, e381. [Google Scholar] [CrossRef]
  100. Tailleux, L.; Gicquel, B.; Neyrolles, O. Mycobacterium tuberculosis and Dendritic Cells: Whos Manipulating Whom? Curr. Immunol. Rev. 2005, 1, 101–105. [Google Scholar] [CrossRef]
  101. Domínguez-Soto, A.; Sierra-Filardi, E.; Puig-Kröger, A.; Pérez-Maceda, B.; Gómez-Aguado, F.; Corcuera, M.T.; Sánchez-Mateos, P.; Corbí, A.L. Dendritic Cell-Specific ICAM-3–Grabbing Nonintegrin Expression on M2-Polarized and Tumor-Associated Macrophages Is Macrophage-CSF Dependent and Enhanced by Tumor-Derived IL-6 and IL-10. J. Immunol. 2011, 186, 2192–2200. [Google Scholar] [CrossRef]
  102. Ryffel, B.; Fremond, C.; Jacobs, M.; Parida, S.K.; Botha, T.; Schnyder, B.; Quesniaux, V. Innate immunity to mycobacterial infection in mice: Critical role for toll-like receptors. Tuberculosis 2005, 85, 395–405. [Google Scholar] [CrossRef]
  103. Faridgohar, M.; Nikoueinejad, H. New findings of Toll-like receptors involved in Mycobacterium tuberculosis infection. Pathog. Glob. Health 2017, 111, 256–264. [Google Scholar] [CrossRef] [PubMed]
  104. Tsolaki, A.G.; Varghese, P.M.; Kishore, U. Innate Immune Pattern Recognition Receptors of Mycobacterium tuberculosis: Nature and Consequences for Pathogenesis of Tuberculosis. Adv. Exp. Med. Biol. 2021, 1313, 179–215. [Google Scholar] [CrossRef]
  105. Georgieva, M.; Sia, J.K.; Bizzell, E.; Madan-Lala, R.; Rengarajan, J. Mycobacterium tuberculosis GroEL2 Modulates Dendritic Cell Responses. Infect. Immun. 2018, 86, e00387-17. [Google Scholar] [CrossRef] [PubMed]
  106. Cho, Y.S.; Dobos, K.M.; Prenni, J.; Yang, H.; Hess, A.; Rosenkrands, I.; Andersen, P.; Ryoo, S.W.; Bai, G.-H.; Brennan, M.J.; et al. Deciphering the proteome of the in vivo diagnostic reagent “purified protein derivative” from Mycobacterium tuberculosis. Proteomics 2012, 12, 979–991. [Google Scholar] [CrossRef]
  107. Madan-Lala, R.; Sia, J.K.; King, R.; Adekambi, T.; Monin, L.; Khader, S.A.; Pulendran, B.; Rengarajan, J. Mycobacterium tuberculosis Impairs Dendritic Cell Functions through the Serine Hydrolase Hip1. J. Immunol. 2014, 192, 4263–4272. [Google Scholar] [CrossRef] [PubMed]
  108. Waldner, H.; Collins, M.; Kuchroo, V.K. Activation of antigen-presenting cells by microbial products breaks self tolerance and induces autoimmune disease. J. Clin. Investig. 2004, 113, 990–997. [Google Scholar] [CrossRef] [PubMed]
  109. Grover, S.; Sharma, T.; Singh, Y.; Kohli, S.; Singh, A.; Semmler, T.; Wieler, L.H.; Tedin, K.; Ehtesham, N.Z.; Hasnain, S.E. The PGRS Domain of Mycobacterium tuberculosis PE_PGRS Protein Rv0297 Is Involved in Endoplasmic Reticulum Stress-Mediated Apoptosis through Toll-Like Receptor 4. mBio 2018, 9, e01017-18. [Google Scholar] [CrossRef]
  110. Cole, S.T.; Brosch, R.; Parkhill, J.; Garnier, T.; Churcher, C.; Harris, D.; Gordon, S.V.; Eiglmeier, K.; Gas, S.; Barry, C.E., 3rd; et al. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 1998, 393, 537–544. [Google Scholar] [CrossRef]
  111. Delogu, G.; Pusceddu, C.; Bua, A.; Fadda, G.; Brennan, M.J.; Zanetti, S. Rv1818c-encoded PE_PGRS protein of Mycobacterium tuberculosis is surface exposed and influences bacterial cell structure. Mol. Microbiol. 2004, 52, 725–733. [Google Scholar] [CrossRef]
  112. Camassa, S.; Palucci, I.; Iantomasi, R.; Cubeddu, T.; Minerva, M.; De Maio, F.; Jouny, S.; Petruccioli, E.; Goletti, D.; Ria, F.; et al. Impact of pe_pgrs33 Gene Polymorphisms on Mycobacterium tuberculosis Infection and Pathogenesis. Front. Cell. Infect. Microbiol. 2017, 7, 137. [Google Scholar] [CrossRef]
  113. Price, J.V.; Vance, R.E. The Macrophage Paradox. Immunity 2014, 41, 685–693. [Google Scholar] [CrossRef] [PubMed]
  114. Mitchell, G.; Chen, C.; Portnoy, D.A. Strategies Used by Bacteria to Grow in Macrophages. Microbiol. Spectr. 2016, 4, 701–725. [Google Scholar] [CrossRef] [PubMed]
  115. Thi, E.P.; Hong, C.J.H.; Sanghera, G.; Reiner, N.E. Identification of the Mycobacterium tuberculosis protein PE-PGRS62 as a novel effector that functions to block phagosome maturation and inhibit iNOS expression. Cell. Microbiol. 2012, 15, 795–808. [Google Scholar] [CrossRef] [PubMed]
  116. Shin, D.-M.; Jeon, B.-Y.; Lee, H.-M.; Jin, H.S.; Yuk, J.-M.; Song, C.-H.; Lee, S.-H.; Lee, Z.-W.; Cho, S.-N.; Kim, J.M.; et al. Mycobacterium tuberculosis Eis Regulates Autophagy, Inflammation, and Cell Death through Redox-dependent Signaling. PLOS Pathog. 2010, 6, e1001230. [Google Scholar] [CrossRef] [PubMed]
  117. Saini, N.K.; Baena, A.; Ng, T.; Venkataswamy, M.M.; Kennedy, S.C.; Kunnath-Velayudhan, S.; Carreño, L.J.; Xu, J.; Chan, J.; Larsen, M.H.; et al. Suppression of autophagy and antigen presentation by Mycobacterium tuberculosis PE_PGRS47. Nat. Microbiol. 2016, 1, 16133. [Google Scholar] [CrossRef]
  118. Shariq, M.; Quadir, N.; Sheikh, J.A.; Singh, A.K.; Bishai, W.R.; Ehtesham, N.Z.; Hasnain, S.E. Post translational modifications in tuberculosis: Ubiquitination paradox. Autophagy 2021, 17, 814–817. [Google Scholar] [CrossRef]
  119. Shariq, M.; Quadir, N.; Sharma, N.; Singh, J.; Sheikh, J.A.; Khubaib, M.; Hasnain, S.E.; Ehtesham, N.Z. Mycobacterium tuberculosis RipA Dampens TLR4-Mediated Host Protective Response Using a Multi-Pronged Approach Involving Autophagy, Apoptosis, Metabolic Repurposing, and Immune Modulation. Front. Immunol. 2021, 12, 636644. [Google Scholar] [CrossRef]
  120. Bansal, K.; Elluru, S.R.; Narayana, Y.; Chaturvedi, R.; Patil, S.A.; Kaveri, S.V.; Bayry, J.; Balaji, K.N. PE_PGRS Antigens of Mycobacterium tuberculosis Induce Maturation and Activation of Human Dendritic Cells. J. Immunol. 2010, 184, 3495–3504. [Google Scholar] [CrossRef]
  121. Strasser, A.; O’Connor, L.; Dixit, V.M. Apoptosis Signaling. Annu. Rev. Biochem. 2000, 69, 217–245. [Google Scholar] [CrossRef]
  122. Fink, S.L.; Cookson, B.T. Apoptosis, Pyroptosis, and Necrosis: Mechanistic Description of Dead and Dying Eukaryotic Cells. Infect. Immun. 2005, 73, 1907–1916. [Google Scholar] [CrossRef]
  123. Epieterse, E.; Der Vlag, J.E. Breaking Immunological Tolerance in Systemic Lupus Erythematosus. Front. Immunol. 2014, 5, 164. [Google Scholar] [CrossRef]
  124. Saraste, A.; Pulkki, K. Morphologic and biochemical hallmarks of apoptosis. Cardiovasc. Res. 2000, 45, 528–537. [Google Scholar] [CrossRef]
  125. Rosen, A.; Casciola-Rosen, L.; Ahearn, J. Novel packages of viral and self-antigens are generated during apoptosis. J. Exp. Med. 1995, 181, 1557–1561. [Google Scholar] [CrossRef] [PubMed]
  126. Brinkmann, V.; Reichard, U.; Goosmann, C.; Fauler, B.; Uhlemann, Y.; Weiss, D.S.; Weinrauch, Y.; Zychlinsky, A. Neutrophil extracellular traps kill bacteria. Science 2004, 303, 1532–1535. [Google Scholar] [CrossRef] [PubMed]
  127. Winau, F.; Weber, S.; Sad, S.; de Diego, J.; Hoops, S.L.; Breiden, B.; Sandhoff, K.; Brinkmann, V.; Kaufmann, S.H.; Schaible, U.E. Apoptotic Vesicles Crossprime CD8 T Cells and Protect against Tuberculosis. Immunity 2006, 24, 105–117. [Google Scholar] [CrossRef]
  128. Henson, P.M. Cell Removal: Efferocytosis. Annu. Rev. Cell Dev. Biol. 2017, 33, 127–144. [Google Scholar] [CrossRef]
  129. Muñoz, L.E.; Janko, C.; Grossmayer, G.E.; Frey, B.; Voll, R.E.; Kern, P.; Kalden, J.R.; Schett, G.; Fietkau, R.; Herrmann, M.; et al. Remnants of secondarily necrotic cells fuel inflammation in systemic lupus erythematosus. Arthritis Care Res. 2009, 60, 1733–1742. [Google Scholar] [CrossRef]
  130. Hochreiter-Hufford, A.; Ravichandran, K. Clearing the Dead: Apoptotic Cell Sensing, Recognition, Engulfment, and Digestion. Cold Spring Harb. Perspect. Biol. 2013, 5, a008748. [Google Scholar] [CrossRef]
  131. Hingley-Wilson, S.M.; Connell, D.; Pollock, K.; Hsu, T.; Tchilian, E.; Sykes, A.; Grass, L.; Potiphar, L.; Bremang, S.; Kon, O.M.; et al. ESX1-dependent fractalkine mediates chemotaxis and Mycobacterium tuberculosis infection in humans. Tuberculosis 2014, 94, 262–270. [Google Scholar] [CrossRef]
  132. Gardai, S.J.; Bratton, N.L.; Ogden, C.A.; Henson, P.M. Recognition ligands on apoptotic cells: A perspective. J. Leukoc. Biol. 2006, 79, 896–903. [Google Scholar] [CrossRef]
  133. Birge, R.B.; Boeltz, S.; Kumar, S.; Carlson, J.; Wanderley, J.; Calianese, D.; Barcinski, M.; Brekken, R.A.; Huang, X.; Hutchins, J.T.; et al. Phosphatidylserine is a global immunosuppressive signal in efferocytosis, infectious disease, and cancer. Cell Death Differ. 2016, 23, 962–978. [Google Scholar] [CrossRef]
  134. Man, S.M.; Karki, R.; Kanneganti, T.-D. Molecular mechanisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious diseases. Immunol. Rev. 2017, 277, 61–75. [Google Scholar] [CrossRef] [PubMed]
  135. Muñoz, L.E.; Janko, C.; Schulze, C.; Schorn, C.; Sarter, K.; Schett, G.; Herrmann, M. Autoimmunity and chronic inflammation—Two clearance-related steps in the etiopathogenesis of SLE. Autoimmun. Rev. 2010, 10, 38–42. [Google Scholar] [CrossRef] [PubMed]
  136. Mahajan, A.; Herrmann, M.; Muñoz, L.E. Clearance Deficiency and Cell Death Pathways: A Model for the Pathogenesis of SLE. Front. Immunol. 2016, 7, 35. [Google Scholar] [CrossRef] [PubMed]
  137. Kuhn, A.; Herrmann, M.; Kleber, S.; Beckmann-Welle, M.; Fehsel, K.; Martin-Villalba, A.; Lehmann, P.; Ruzicka, T.; Krammer, P.H.; Kolb-Bachofen, V. Accumulation of apoptotic cells in the epidermis of patients with cutaneous lupus erythematosus after ultraviolet irradiation. Arthritis Care Res. 2006, 54, 939–950. [Google Scholar] [CrossRef] [PubMed]
  138. Munoz, L.; Lauber, K.; Schiller, M.; Manfredi, A.A.; Herrmann, M. The role of defective clearance of apoptotic cells in systemic autoimmunity. Nat. Rev. Rheumatol. 2010, 6, 280–289. [Google Scholar] [CrossRef] [PubMed]
  139. Baumann, I.; Kolowos, W.; Voll, R.E.; Manger, B.; Gaipl, U.; Neuhuber, W.L.; Kirchner, T.; Kalden, J.R.; Herrmann, M. Impaired uptake of apoptotic cells into tingible body macrophages in germinal centers of patients with systemic lupus erythematosus. Arthritis Care Res. 2002, 46, 191–201. [Google Scholar] [CrossRef]
  140. Cohen, S.B.; Gern, B.; Delahaye, J.L.; Adams, K.N.; Plumlee, C.R.; Winkler, J.K.; Sherman, D.R.; Gerner, M.Y.; Urdahl, K.B. Alveolar Macrophages Provide an Early Mycobacterium tuberculosis Niche and Initiate Dissemination. Cell Host Microbe 2018, 24, 439–446.e4. [Google Scholar] [CrossRef]
  141. Butler, R.E.; Brodin, P.; Jang, J.; Jang, M.-S.; Robertson, B.D.; Gicquel, B.; Stewart, G.R. The Balance of Apoptotic and Necrotic Cell Death in Mycobacterium tuberculosis Infected Macrophages Is Not Dependent on Bacterial Virulence. PLoS ONE 2012, 7, e47573. [Google Scholar] [CrossRef]
  142. Basu, S.; Pathak, S.K.; Banerjee, A.; Pathak, S.; Bhattacharyya, A.; Yang, Z.; Talarico, S.; Kundu, M.; Basu, J. Execution of Macrophage Apoptosis by PE_PGRS33 of Mycobacterium tuberculosis Is Mediated by Toll-like Receptor 2-dependent Release of Tumor Necrosis Factor-α. J. Biol. Chem. 2007, 282, 1039–1050. [Google Scholar] [CrossRef]
  143. Zizzo, G.; Guerrieri, J.; Dittman, L.M.; Merrill, J.T.; Cohen, P.L. Circulating levels of soluble MER in lupus reflect M2c activation of monocytes/macrophages, autoantibody specificities and disease activity. Arthritis Res. Ther. 2013, 15, R212. [Google Scholar] [CrossRef] [PubMed]
  144. Lemke, G.; Burstyn-Cohen, T. TAM receptors and the clearance of apoptotic cells. Ann. N. Y. Acad. Sci. 2010, 1209, 23–29. [Google Scholar] [CrossRef] [PubMed]
  145. Cohen, P.L.; Caricchio, R.; Abraham, V.; Camenisch, T.D.; Jennette, J.C.; Roubey, R.A.; Earp, H.S.; Matsushima, G.; Reap, E.A. Delayed Apoptotic Cell Clearance and Lupus-like Autoimmunity in Mice Lacking the c-mer Membrane Tyrosine Kinase. J. Exp. Med. 2002, 196, 135–140. [Google Scholar] [CrossRef]
  146. Alciato, F.; Sainaghi, P.P.; Sola, D.; Castello, L.M.; Avanzi, G.C. TNF-α, IL-6, and IL-1 expression is inhibited by GAS6 in monocytes/macrophages. J. Leukoc. Biol. 2010, 87, 869–875. [Google Scholar] [CrossRef] [PubMed]
  147. Shao, W.-H.; Kuan, A.P.; Wang, C.; Abraham, V.; Waldman, M.A.; Vogelgesang, A.; Wittenburg, G.; Choudhury, A.; Tsao, P.Y.; Miwa, T.; et al. Disrupted Mer receptor tyrosine kinase expression leads to enhanced MZ B-cell responses. J. Autoimmun. 2010, 35, 368–374. [Google Scholar] [CrossRef] [PubMed]
  148. Wallet, M.A.; Flores, R.R.; Wang, Y.; Yi, Z.; Kroger, C.J.; Mathews, C.E.; Earp, H.S.; Matsushima, G.; Wang, B.; Tisch, R. MerTK regulates thymic selection of autoreactive T cells. Proc. Natl. Acad. Sci. USA 2009, 106, 4810–4815. [Google Scholar] [CrossRef] [PubMed]
  149. Suh, C.-H.; Hilliard, B.; Li, S.; Merrill, J.T.; Cohen, P.L. TAM receptor ligands in lupus: Protein S but not Gas6 levels reflect disease activity in systemic lupus erythematosus. Arthritis Res. Ther. 2010, 12, R146. [Google Scholar] [CrossRef]
  150. Voll, R.E.; Herrmann, M.; Roth, E.A.; Stach, C.; Kalden, J.R.; Girkontaite, I. Immunosuppressive effects of apoptotic cells. Nature 1997, 390, 350–351. [Google Scholar] [CrossRef]
  151. Rothlin, C.V.; Ghosh, S.; Zuniga, E.I.; Oldstone, M.B.; Lemke, G. TAM Receptors Are Pleiotropic Inhibitors of the Innate Immune Response. Cell 2007, 131, 1124–1136. [Google Scholar] [CrossRef]
  152. Cheong, H.S.; Lee, S.O.; Choi, C.-B.; Sung, Y.-K.; Shin, H.D.; Bae, S.-C. MERTK polymorphisms associated with risk of haematological disorders among Korean SLE patients. Rheumatology 2007, 46, 209–214. [Google Scholar] [CrossRef]
  153. Martinez, F.O.; Sica, A.; Mantovani, A.; Locati, M. Macrophage activation and polarization. Front. Biosci. 2008, 13, 453–461. [Google Scholar] [CrossRef] [PubMed]
  154. Funes, S.C.; Rios, M.; Escobar-Vera, J.; Kalergis, A.M. Implications of macrophage polarization in autoimmunity. Immunology 2018, 154, 186–195. [Google Scholar] [CrossRef] [PubMed]
  155. Ahamada, M.M.; Jia, Y.; Wu, X. Macrophage Polarization and Plasticity in Systemic Lupus Erythematosus. Front. Immunol. 2021, 12, 734008. [Google Scholar] [CrossRef] [PubMed]
  156. Refai, A.; Gritli, S.; Barbouche, M.-R.; Essafi, M. Mycobacterium tuberculosis Virulent Factor ESAT-6 Drives Macrophage Differentiation Toward the Pro-inflammatory M1 Phenotype and Subsequently Switches It to the Anti-inflammatory M2 Phenotype. Front. Cell. Infect. Microbiol. 2018, 8, 327. [Google Scholar] [CrossRef] [PubMed]
  157. Matzinger, P.; Guerder, S. Does T-cell tolerance require a dedicated antigen-presenting cell? Nature 1989, 338, 74–76. [Google Scholar] [CrossRef]
  158. Volkmann, A.; Zal, T.; Stockinger, B. Antigen-presenting cells in the thymus that can negatively select MHC class II-restricted T cells recognizing a circulating self antigen. J. Immunol. 1997, 158, 693–706. [Google Scholar]
  159. Steinman, R.M.; Idoyaga, J. Features of the dendritic cell lineage. Immunol. Rev. 2010, 234, 5–17. [Google Scholar] [CrossRef]
  160. Probst, H.C.; McCoy, K.; Okazaki, T.; Honjo, T.; van den Broek, M. Resting dendritic cells induce peripheral CD8+ T cell tolerance through PD-1 and CTLA-4. Nat. Immunol. 2005, 6, 280–286. [Google Scholar] [CrossRef]
  161. Tarbell, K.V.; Petit, L.; Zuo, X.; Toy, P.; Luo, X.; Mqadmi, A.; Yang, H.; Suthanthiran, M.; Mojsov, S.; Steinman, R.M. Dendritic cell–expanded, islet-specific CD4+ CD25+ CD62L+ regulatory T cells restore normoglycemia in diabetic NOD mice. J. Exp. Med. 2007, 204, 191–201. [Google Scholar] [CrossRef]
  162. Luo, X.; Tarbell, K.V.; Yang, H.; Pothoven, K.; Bailey, S.L.; Ding, R.; Steinman, R.M.; Suthanthiran, M. Dendritic cells with TGF-β1 differentiate naïve CD4+ CD25 T cells into islet-protective Foxp3+ regulatory T cells. Proc. Natl. Acad. Sci. USA 2007, 104, 2821–2826. [Google Scholar] [CrossRef]
  163. Belkaid, Y.; Oldenhove, G. Tuning Microenvironments: Induction of Regulatory T Cells by Dendritic Cells. Immunity 2008, 29, 362–371. [Google Scholar] [CrossRef] [PubMed]
  164. Darrasse-Jèze, G.; Deroubaix, S.; Mouquet, H.; Victora, G.D.; Eisenreich, T.; Yao, K.-H.; Masilamani, R.F.; Dustin, M.L.; Rudensky, A.; Liu, K.; et al. Feedback control of regulatory T cell homeostasis by dendritic cells in vivo. J. Exp. Med. 2009, 206, 1853–1862. [Google Scholar] [CrossRef] [PubMed]
  165. O’Keeffe, M.; Brodnicki, T.C.; Fancke, B.; Vremec, D.; Morahan, G.; Maraskovsky, E.; Steptoe, R.; Harrison, L.C.; Shortman, K. Fms-like tyrosine kinase 3 ligand administration overcomes a genetically determined dendritic cell deficiency in NOD mice and protects against diabetes development. Int. Immunol. 2005, 17, 307–314. [Google Scholar] [CrossRef] [PubMed]
  166. Whartenby, K.A.; Calabresi, P.A.; McCadden, E.; Nguyen, B.; Kardian, D.; Wang, T.; Mosse, C.; Pardoll, D.M.; Small, D. Inhibition of FLT3 signaling targets DCs to ameliorate autoimmune disease. Proc. Natl. Acad. Sci. USA 2005, 102, 16741–16746. [Google Scholar] [CrossRef]
  167. Mellman, I.; Steinman, R.M. Dendritic Cells: Specialized and regulated antigen processing machines. Cell 2001, 106, 255–258. [Google Scholar] [CrossRef]
  168. Banchereau, J.; Steinman, R.M. Dendritic cells and the control of immunity. Nature 1998, 392, 245–252. [Google Scholar] [CrossRef]
  169. Coutant, F.; Pin, J.-J.; Miossec, P. Extensive Phenotype of Human Inflammatory Monocyte-Derived Dendritic Cells. Cells 2021, 10, 1663. [Google Scholar] [CrossRef]
  170. Macri, C.; Pang, E.S.; Patton, T.; O’Keeffe, M. Dendritic cell subsets. In Seminars in Cell & Developmental Biology; Academic Press: Cambridge, MA, USA, 2018; Volume 84, pp. 11–21. [Google Scholar] [CrossRef]
  171. Segura, E.; Touzot, M.; Bohineust, A.; Cappuccio, A.; Chiocchia, G.; Hosmalin, A.; Dalod, M.; Soumelis, V.; Amigorena, S. Human Inflammatory Dendritic Cells Induce Th17 Cell Differentiation. Immunity 2013, 38, 336–348. [Google Scholar] [CrossRef]
  172. Eguíluz-Gracia, I.; Bosco, A.; Dollner, R.; Melum, G.R.; Lexberg, M.H.; Jones, A.C.; Dheyauldeen, S.A.; Holt, P.G.; Bækkevold, E.S.; Jahnsen, F.L. Rapid recruitment of CD14+ monocytes in experimentally induced allergic rhinitis in human subjects. J. Allergy Clin. Immunol. 2016, 137, 1872–1881.e12. [Google Scholar] [CrossRef]
  173. Richter, L.; Landsverk, O.J.B.; Atlasy, N.; Bujko, A.; Yaqub, S.; Horneland, R.; Øyen, O.; Aandahl, E.M.; Lundin, K.E.A.; Stunnenberg, H.G.; et al. Transcriptional profiling reveals monocyte-related macrophages phenotypically resembling DC in human intestine. Mucosal Immunol. 2018, 11, 1512–1523. [Google Scholar] [CrossRef]
  174. Gu, F.-F.; Wu, J.-J.; Liu, Y.-Y.; Hu, Y.; Liang, J.-Y.; Zhang, K.; Li, M.; Wang, Y.; Zhang, Y.-A.; Liu, L. Human Inflammatory Dendritic Cells in Malignant Pleural Effusions Induce Th1 Cell Differentiation. Cancer Immunol. Immunother. 2020, 69, 779–788. [Google Scholar] [CrossRef] [PubMed]
  175. Coutant, F.; Miossec, P. Altered dendritic cell functions in autoimmune diseases: Distinct and overlapping profiles. Nat. Rev. Rheumatol. 2016, 12, 703–715. [Google Scholar] [CrossRef] [PubMed]
  176. Mok, M.Y. Tolerogenic dendritic cells: Role and therapeutic implications in systemic lupus erythematosus. Int. J. Rheum. Dis. 2014, 18, 250–259. [Google Scholar] [CrossRef] [PubMed]
  177. Steinman, R.M. Lasker Basic Medical Research Award. Dendritic cells: Versatile controllers of the immune system. Nat. Med. 2007, 13, 1155–1159. [Google Scholar] [CrossRef] [PubMed]
  178. Merad, M.; Sathe, P.; Helft, J.; Miller, J.; Mortha, A. The Dendritic Cell Lineage: Ontogeny and Function of Dendritic Cells and Their Subsets in the Steady State and the Inflamed Setting. Annu. Rev. Immunol. 2013, 31, 563–604. [Google Scholar] [CrossRef] [PubMed]
  179. Lugt, B.V.; Riddell, J.; Khan, A.A.; Hackney, J.A.; Lesch, J.; Devoss, J.; Weirauch, M.T.; Singh, H.; Mellman, I. Transcriptional determinants of tolerogenic and immunogenic states during dendritic cell maturation. J. Cell Biol. 2017, 216, 779–792. [Google Scholar] [CrossRef]
  180. Rutella, S.; Danese, S.; Leone, G. Tolerogenic dendritic cells: Cytokine modulation comes of age. Blood 2006, 108, 1435–1440. [Google Scholar] [CrossRef]
  181. Vendelova, E.; Ashour, D.; Blank, P.; Erhard, F.; Saliba, A.-E.; Kalinke, U.; Lutz, M.B. Tolerogenic Transcriptional Signatures of Steady-State and Pathogen-Induced Dendritic Cells. Front. Immunol. 2018, 9, 333. [Google Scholar] [CrossRef]
  182. Obreque, J.; Vega, F.; Torres, A.; Cuitino, L.; Mackern-Oberti, J.P.; Viviani, P.; Kalergis, A.; Llanos, C. Autologous tolerogenic dendritic cells derived from monocytes of systemic lupus erythematosus patients and healthy donors show a stable and immunosuppressive phenotype. Immunology 2017, 152, 648–659. [Google Scholar] [CrossRef]
  183. Wu, H.J.; Lo, Y.; Luk, D.; Lau, C.S.; Lu, L.; Mok, M.Y. Alternatively activated dendritic cells derived from systemic lupus erythematosus patients have tolerogenic phenotype and function. Clin. Immunol. 2015, 156, 43–57. [Google Scholar] [CrossRef]
  184. Esmaeili, S.; Mahmoudi, M.; Rezaieyazdi, Z.; Sahebari, M.; Tabasi, N.; Sahebkar, A.; Rastin, M. Generation of tolerogenic dendritic cells using Lactobacillus rhamnosus and Lactobacillus delbrueckii as tolerogenic probiotics. J. Cell. Biochem. 2018, 119, 7865–7872. [Google Scholar] [CrossRef] [PubMed]
  185. Hossein-Khannazer, N.; Torabi, S.; Hosseinzadeh, R.; Shahrokh, S.; Aghdaei, H.A.; Memarnejadian, A.; Kadri, N.; Vosough, M. Novel cell-based therapies in inflammatory bowel diseases: The established concept, promising results. Hum. Cell 2021, 34, 1289–1300. [Google Scholar] [CrossRef] [PubMed]
  186. Passeri, L.; Marta, F.; Bassi, V.; Gregori, S. Tolerogenic Dendritic Cell-Based Approaches in Autoimmunity. Int. J. Mol. Sci. 2021, 22, 8415. [Google Scholar] [CrossRef] [PubMed]
  187. Cantorna, M.T.; Mahon, B.D. Mounting Evidence for Vitamin D as an Environmental Factor Affecting Autoimmune Disease Prevalence. Exp. Biol. Med. 2004, 229, 1136–1142. [Google Scholar] [CrossRef]
  188. Antico, A.; Tampoia, M.; Tozzoli, R.; Bizzaro, N. Can supplementation with vitamin D reduce the risk or modify the course of autoimmune diseases? A systematic review of the literature. Autoimmun. Rev. 2012, 12, 127–136. [Google Scholar] [CrossRef] [PubMed]
  189. Taha, R.; Abureesh, S.; Alghamdi, S.; Hassan, R.Y.; Cheikh, M.M.; Bagabir, R.A.; Almoallim, H.; Abdulkhaliq, A. The Relationship Between Vitamin D and Infections Including COVID-19: Any Hopes? Int. J. Gen. Med. 2021, 14, 3849–3870. [Google Scholar] [CrossRef]
  190. Souberbielle, J.-C.; Body, J.-J.; Lappe, J.M.; Plebani, M.; Shoenfeld, Y.; Wang, T.; Bischoff-Ferrari, H.; Cavalier, E.; Ebeling, P.R.; Fardellone, P.; et al. Vitamin D and musculoskeletal health, cardiovascular disease, autoimmunity and cancer: Recommendations for clinical practice. Autoimmun. Rev. 2010, 9, 709–715. [Google Scholar] [CrossRef]
  191. Fritsche, J.; Mondal, K.; Ehrnsperger, A.; Andreesen, R.; Kreutz, M. Regulation of 25-hydroxyvitamin D3-1α-hydroxylase and production of 1α,25-dihydroxyvitamin D3 by human dendritic cells. Blood 2003, 102, 3314–3316. [Google Scholar] [CrossRef]
  192. Hewison, M. An update on vitamin D and human immunity. Clin. Endocrinol. 2012, 76, 315–325. [Google Scholar] [CrossRef]
  193. Pike, J.W.; Meyer, M.B.; Bishop, K.A. Regulation of target gene expression by the vitamin D receptor—An update on mechanisms. Rev. Endocr. Metab. Disord. 2011, 13, 45–55. [Google Scholar] [CrossRef]
  194. Haussler, M.R.; Whitfield, G.K.; Kaneko, I.; Haussler, C.A.; Hsieh, D.; Hsieh, J.-C.; Jurutka, P.W. Molecular Mechanisms of Vitamin D Action. Calcif. Tissue Int. 2013, 92, 77–98. [Google Scholar] [CrossRef] [PubMed]
  195. Medapati, R.V.; Suvvari, S.; Godi, S.; Gangisetti, P. NRAMP1 and VDR gene polymorphisms in susceptibility to pulmonary tuberculosis among Andhra Pradesh population in India: A case–control study. BMC Pulm. Med. 2017, 17, 89. [Google Scholar] [CrossRef] [PubMed]
  196. Penna, G.; Adorini, L. 1α,25-Dihydroxyvitamin D3Inhibits Differentiation, Maturation, Activation, and Survival of Dendritic Cells Leading to Impaired Alloreactive T Cell Activation. J. Immunol. 2000, 164, 2405–2411. [Google Scholar] [CrossRef]
  197. Cantorna, M.T.; Snyder, L.; Lin, Y.-D.; Yang, L. Vitamin D and 1,25(OH)2D Regulation of T cells. Nutrients 2015, 7, 3011–3021. [Google Scholar] [CrossRef] [PubMed]
  198. Mora, J.R.; Iwata, M.; von Andrian, U.H. Vitamin effects on the immune system: Vitamins A and D take centre stage. Nat. Rev. Immunol. 2008, 8, 685–698. [Google Scholar] [CrossRef] [PubMed]
  199. Daniel, C.; Sartory, N.A.; Zahn, N.; Radeke, H.H.; Stein, J.M. Immune Modulatory Treatment of Trinitrobenzene Sulfonic Acid Colitis with Calcitriol Is Associated with a Change of a T Helper (Th) 1/Th17 to a Th2 and Regulatory T Cell Profile. J. Pharmacol. Exp. Ther. 2008, 324, 23–33. [Google Scholar] [CrossRef]
  200. Adorini, L.; Penna, G. Dendritic cell tolerogenicity: A key mechanism in immunomodulation by vitamin D receptor agonists. Hum. Immunol. 2009, 70, 345–352. [Google Scholar] [CrossRef]
  201. Ritprajak, P.; Kaewraemruaen, C.; Hirankarn, N. Current Paradigms of Tolerogenic Dendritic Cells and Clinical Implications for Systemic Lupus Erythematosus. Cells 2019, 8, 1291. [Google Scholar] [CrossRef]
  202. Adorini, L. Tolerogenic dendritic cells induced by vitamin D receptor ligands enhance regulatory T cells inhibiting autoimmune diabetes. Ann. N. Y. Acad. Sci. 2003, 987, 258–261. [Google Scholar] [CrossRef]
  203. Borghi, M.; Puccetti, M.; Pariano, M.; Renga, G.; Stincardini, C.; Ricci, M.; Giovagnoli, S.; Costantini, C.; Romani, L. Tryptophan as a Central Hub for Host/Microbial Symbiosis. Int. J. Tryptophan Res. 2020, 13, 1178646920919755. [Google Scholar] [CrossRef]
  204. Jonuleit, H.; Kühn, U.; Müller, G.; Steinbrink, K.; Paragnik, L.; Schmitt, E.; Knop, J.; Enk, A.H. Pro-inflammatory cytokines and prostaglandins induce maturation of potent immunostimulatory dendritic cells under fetal calf serum-free conditions. Eur. J. Immunol. 1997, 27, 3135–3142. [Google Scholar] [CrossRef] [PubMed]
  205. Chu, C.-C.; Ali, N.; Karagiannis, P.; Di Meglio, P.; Skowera, A.; Napolitano, L.; Barinaga, G.; Grys, K.; Sharif-Paghaleh, E.; Karagiannis, S.; et al. Resident CD141 (BDCA3)+ dendritic cells in human skin produce IL-10 and induce regulatory T cells that suppress skin inflammation. J. Exp. Med. 2012, 209, 935–945. [Google Scholar] [CrossRef] [PubMed]
  206. Farias, A.S.; Spagnol, G.S.; Bordeaux-Rego, P.; Oliveira, C.O.; Fontana, A.G.M.; de Paula, R.F.; Santos, M.P.; Pradella, F.; Moraes, A.S.; Oliveira, E.C.; et al. Vitamin D3Induces IDO+ Tolerogenic DCs and Enhances Treg, Reducing the Severity of EAE. CNS Neurosci. Ther. 2013, 19, 269–277. [Google Scholar] [CrossRef] [PubMed]
  207. Fallarino, F.; Grohmann, U.; Puccetti, P. Indoleamine 2,3-dioxygenase: From catalyst to signaling function. Eur. J. Immunol. 2012, 42, 1932–1937. [Google Scholar] [CrossRef] [PubMed]
  208. Chen, W. IDO: More than an enzyme. Nat. Immunol. 2011, 12, 809–811. [Google Scholar] [CrossRef]
  209. Vanherwegen, A.-S.; Eelen, G.; Ferreira, G.B.; Ghesquière, B.; Cook, D.P.; Nikolic, T.; Roep, B.; Carmeliet, P.; Telang, S.; Mathieu, C.; et al. Vitamin D controls the capacity of human dendritic cells to induce functional regulatory T cells by regulation of glucose metabolism. J. Steroid Biochem. Mol. Biol. 2018, 187, 134–145. [Google Scholar] [CrossRef]
  210. Ferreira, G.B.; Vanherwegen, A.-S.; Eelen, G.; Gutiérrez, A.C.F.; Van Lommel, L.; Marchal, K.; Verlinden, L.; Verstuyf, A.; Nogueira, T.; Georgiadou, M.; et al. Vitamin D3 Induces Tolerance in Human Dendritic Cells by Activation of Intracellular Metabolic Pathways. Cell Rep. 2015, 10, 711–725. [Google Scholar] [CrossRef]
  211. Martínez-Blanco, M.; Lozano-Ojalvo, D.; Pérez-Rodríguez, L.; Benedé, S.; Molina, E.; López-Fandiño, R. Retinoic Acid Induces Functionally Suppressive Foxp3+RORγt+ T Cells In Vitro. Front. Immunol. 2021, 12, 675733. [Google Scholar] [CrossRef]
  212. Mucida, D.; Park, Y.; Kim, G.; Turovskaya, O.; Scott, I.; Kronenberg, M.; Cheroutre, H. Reciprocal TH 17 and Regulatory T Cell Differentiation Mediated by Retinoic Acid. Science 2007, 317, 256–260. [Google Scholar] [CrossRef]
  213. Adorini, L.; Giarratana, N.; Penna, G. Pharmacological induction of tolerogenic dendritic cells and regulatory T cells. Semin. Immunol. 2004, 16, 127–134. [Google Scholar] [CrossRef]
  214. Adorini, L.; Penna, G. Induction of tolerogenic dendritic cells by vitamin D receptor agonists. Handb. Exp. Pharmacol. 2009, 188, 251–273. [Google Scholar] [CrossRef]
  215. Choi, M.; Makishima, M. Therapeutic applications for novel non-hypercalcemic vitamin D receptor ligands. Expert Opin. Ther. Patents 2009, 19, 593–606. [Google Scholar] [CrossRef] [PubMed]
  216. Maestro, M.A.; Molnár, F.; Carlberg, C. Vitamin D and Its Synthetic Analogs. J. Med. Chem. 2019, 62, 6854–6875. [Google Scholar] [CrossRef] [PubMed]
  217. Khedkar, S.A.; Samad, M.A.; Choudhury, S.; Lee, J.Y.; Zhang, D.; Thadhani, R.I.; Karumanchi, S.A.; Rigby, A.C.; Kang, P.M. Identification of Novel Non-secosteroidal Vitamin D Receptor Agonists with Potent Cardioprotective Effects and devoid of Hypercalcemia. Sci Rep. 2017, 16, 8427. [Google Scholar] [CrossRef]
  218. Battistini, C.; Ballan, R.; Herkenhoff, M.; Saad, S.; Sun, J. Vitamin D Modulates Intestinal Microbiota in Inflammatory Bowel Diseases. Int. J. Mol. Sci. 2020, 22, 362. [Google Scholar] [CrossRef] [PubMed]
  219. Borba, V.V.; Zandman-Goddard, G.; Shoenfeld, Y. Prolactin and autoimmunity: The hormone as an inflammatory cytokine. Best Pract. Res. Clin. Endocrinol. Metab. 2019, 33, 101324. [Google Scholar] [CrossRef]
  220. Khader, S.A.; Guglani, L.; Rangel-Moreno, J.; Gopal, R.; Junecko, B.A.F.; Fountain, J.J.; Martino, C.; Pearl, J.E.; Tighe, M.; Lin, Y.-Y.; et al. IL-23 Is Required for Long-Term Control of Mycobacterium tuberculosis and B Cell Follicle Formation in the Infected Lung. J. Immunol. 2011, 187, 5402–5407. [Google Scholar] [CrossRef]
  221. Maione, F.; Paschalidis, N.; Mascolo, N.; Dufton, N.; Perretti, M.; D’Acquisto, F. Interleukin 17 sustains rather than induces inflammation. Biochem. Pharmacol. 2009, 77, 878–887. [Google Scholar] [CrossRef]
Table 1. The autoantibodies in tuberculosis.
Table 1. The autoantibodies in tuberculosis.
rheumatoid factor (RF)rheumatoid arthritis, Sjögren’s syndrome[7,73,76]
antinuclear antibodies (ANA)SLE, Sjögren’s syndrome, scleroderma, dermatomyositis[7,8,50,70,72,73]
anti-dsDNA antibodiesSLE[10,48,50,77]
antineutrophilic cytoplasmatic antibodies (ANCA)ANCA-associated systemic vasculitis[11,74,75]
anticyclic citrullinated peptide (anti-CCP)rheumatoid arthritis[76]
anti-Scl-70, antihistone antibodiessystemic sclerosis, SLE[10]
antiphospholipid antibodies (aPL): the lupus anticoagulant (LA), anticardiolipin antibody (ACA), anti-beta 2 glycoprotein 1 (anti-ß2 GPI), anti-prothrombinantiphospholipid syndrome, SLE[21,22,24]
anticardiolipin antibody (ACA; IgM)SLE, antiphospholipid syndrome[8,10,11,50]
antibodies against β2 glycoprotein IgGantiphospholipid syndrome, SLE[11]
antibodies against proteinase 3, myeloperoxidase, bactericidal/permeability-increasing protein, lactoferrinsystemic vasculitis[75]
AAB—autoantibodies, AID—autoimmune disease, TB—tuberculosis, SLE—systemic lupus erythematosus.
Table 2. Vitamin D deficiency and autoimmunity.
Table 2. Vitamin D deficiency and autoimmunity.
Association of Vitamin D deficiency with AIDsReferences
Type 1 DM[60,187]
Tuberculosis, vitamin D deficiency,
and autoimmunity
MS—multiple sclerosis, RA—rheumatoid arthritis, DM—diabetes mellitus, IBD—inflammatory bowel disease, SLE—systemic lupus erythematosus.
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Belyaeva, I.V.; Kosova, A.N.; Vasiliev, A.G. Tuberculosis and Autoimmunity. Pathophysiology 2022, 29, 298-318.

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Belyaeva IV, Kosova AN, Vasiliev AG. Tuberculosis and Autoimmunity. Pathophysiology. 2022; 29(2):298-318.

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Belyaeva, Irina V., Anna N. Kosova, and Andrei G. Vasiliev. 2022. "Tuberculosis and Autoimmunity" Pathophysiology 29, no. 2: 298-318.

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