Review

15 pages, 1374 KiB

Open AccessReview

How Does cGAS Avoid Sensing Self-DNA under Normal Physiological Conditions?

by Wangli Zheng, Nanhua Chen, François Meurens, Wanglong Zheng and Jianzhong Zhu

Int. J. Mol. Sci. 2023, 24(19), 14738; https://doi.org/10.3390/ijms241914738 - 29 Sep 2023

Viewed by 1441

cGAS is a cytosolic DNA sensor that activates innate immune responses by producing the second messenger 2′3′-cGAMP, which activates the adaptor STING. cGAS senses dsDNA in a length-dependent but sequence-independent manner, meaning it cannot discriminate self-DNA from foreign DNA. In normal physiological conditions, [...] Read more.

cGAS is a cytosolic DNA sensor that activates innate immune responses by producing the second messenger 2′3′-cGAMP, which activates the adaptor STING. cGAS senses dsDNA in a length-dependent but sequence-independent manner, meaning it cannot discriminate self-DNA from foreign DNA. In normal physiological conditions, cellular DNA is sequestered in the nucleus by a nuclear envelope and in mitochondria by a mitochondrial membrane. When self-DNA leaks into the cytosol during cellular stress or mitosis, the cGAS can be exposed to self-DNA and activated. Recently, many studies have investigated how cGAS keeps inactive and avoids being aberrantly activated by self-DNA. Thus, this narrative review aims to summarize the mechanisms by which cGAS avoids sensing self-DNA under normal physiological conditions. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Immunology 2023)

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30 pages, 4180 KiB

Open AccessReview

NOD-like Receptors—Emerging Links to Obesity and Associated Morbidities

by Sarah Bauer, Lucy Hezinger, Fjolla Rexhepi, Sheela Ramanathan and Thomas A. Kufer

Int. J. Mol. Sci. 2023, 24(10), 8595; https://doi.org/10.3390/ijms24108595 - 11 May 2023

Cited by 5 | Viewed by 2923

Abstract

Obesity and its associated metabolic morbidities have been and still are on the rise, posing a major challenge to health care systems worldwide. It has become evident over the last decades that a low-grade inflammatory response, primarily proceeding from the adipose tissue (AT), [...] Read more.

Obesity and its associated metabolic morbidities have been and still are on the rise, posing a major challenge to health care systems worldwide. It has become evident over the last decades that a low-grade inflammatory response, primarily proceeding from the adipose tissue (AT), essentially contributes to adiposity-associated comorbidities, most prominently insulin resistance (IR), atherosclerosis and liver diseases. In mouse models, the release of pro-inflammatory cytokines such as TNF-alpha (TNF-α) and interleukin (IL)-1β and the imprinting of immune cells to a pro-inflammatory phenotype in AT play an important role. However, the underlying genetic and molecular determinants are not yet understood in detail. Recent evidence demonstrates that nucleotide-binding and oligomerization domain (NOD)-like receptor (NLR) family proteins, a group of cytosolic pattern recognition receptors (PRR), contribute to the development and control of obesity and obesity-associated inflammatory responses. In this article, we review the current state of research on the role of NLR proteins in obesity and discuss the possible mechanisms leading to and the outcomes of NLR activation in the obesity-associated morbidities IR, type 2 diabetes mellitus (T2DM), atherosclerosis and non-alcoholic fatty liver disease (NAFLD) and discuss emerging ideas about possibilities for NLR-based therapeutic interventions of metabolic diseases. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Immunology 2023)

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36 pages, 2616 KiB

Open AccessReview

A Concerted Vision to Advance the Knowledge of Diabetes Mellitus Related to Immune Checkpoint Inhibitors

by Maria V. Deligiorgi and Dimitrios T. Trafalis

Int. J. Mol. Sci. 2023, 24(8), 7630; https://doi.org/10.3390/ijms24087630 - 21 Apr 2023

Cited by 1 | Viewed by 1982

Abstract

The rubric of immune-related (ir) diabetes mellitus (DM) (irDM) encompasses various hyperglycemic disorders related to immune checkpoint inhibitors (ICPis). Beyond sharing similarities with conventional DM, irDM is a distinct, yet important, entity. The present narrative review provides a comprehensive overview of the literature [...] Read more.

The rubric of immune-related (ir) diabetes mellitus (DM) (irDM) encompasses various hyperglycemic disorders related to immune checkpoint inhibitors (ICPis). Beyond sharing similarities with conventional DM, irDM is a distinct, yet important, entity. The present narrative review provides a comprehensive overview of the literature regarding irDM published in major databases from January 2018 until January 2023. Initially considered rare, irDM is increasingly being reported. To advance the knowledge of irDM, the present review suggests a concerted vision comprising two intertwined aspects: a scientific-centered and a patient-centered view. The scientific-centered aspect addresses the pathophysiology of irDM, integrating: (i) ICPi-induced pancreatic islet autoimmunity in genetically predisposed patients; (ii) altered gut microbiome; (iii) involvement of exocrine pancreas; (iv) immune-related acquired generalized lipodystrophy. The patient-centered aspect is both nurtured by and nurturing the four pillars of the scientific-centered aspect: awareness, diagnosis, treatment, and monitoring of irDM. The path forward is a multidisciplinary initiative towards: (i) improved characterization of the epidemiological, clinical, and immunological profile of irDM; (ii) standardization of reporting, management, and surveillance protocols for irDM leveraging global registries; (iii) patient stratification according to personalized risk for irDM; (iv) new treatments for irDM; and (v) uncoupling ICPi efficacy from immunotoxicity. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Immunology 2023)

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12 pages, 4402 KiB

Open AccessReview

Primary Cutaneous B-Cell Lymphomas with Large Cell Morphology: A Practical Review

by Andrea Ronchi, Paola Vitiello, Giuseppe D’Abbronzo, Stefano Caccavale, Giuseppe Argenziano, Antonello Sica, Roberto Alfano, Giovanni Savarese, Massimiliano Berretta, Immacolata Cozzolino and Renato Franco

Int. J. Mol. Sci. 2023, 24(7), 6204; https://doi.org/10.3390/ijms24076204 - 25 Mar 2023

Viewed by 3182

Abstract

Most primary cutaneous lymphomas consist of T-cell lymphomas or small cell lymphomas; however, the skin may also be affected by lymphomas with large cell morphology, as a primary or secondary localization. A minority of cases consist of primary cutaneous B-cell lymphomas (PCBCLs). PCBCLs [...] Read more.

Most primary cutaneous lymphomas consist of T-cell lymphomas or small cell lymphomas; however, the skin may also be affected by lymphomas with large cell morphology, as a primary or secondary localization. A minority of cases consist of primary cutaneous B-cell lymphomas (PCBCLs). PCBCLs are a heterogeneous group of rare neoplasms with an overlapping morphological and immunohistochemical picture of the different subtypes. Nevertheless, differential diagnosis in the setting of this group of neoplasms is mandatory to identify the correct therapy and prognosis, but it may be challenging since, due to the rarity of these neoplasms, they may not always be familiar to pathologists. Indeed, immunohistochemistry may not be enough to distinguish the different histotypes, which overlap in immunohistochemical features. Furthermore, the ever-increasing knowledge of the molecular features of systemic B-cell lymphomas, such as gene rearrangements with clinical significance, has led in recent years to further investigation into the molecular landscape of PCBCLs with large cell morphology. This work aimed to provide a practical diagnostic guide for pathologists dealing with primary cutaneous large B-cell lymphomas. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Immunology 2023)

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15 pages, 3067 KiB

Open AccessReview

IGFBP-6 Network in Chronic Inflammatory Airway Diseases and Lung Tumor Progression

by Santina Venuto, Anna Rita Daniela Coda, Ruperto González-Pérez, Onofrio Laselva, Doron Tolomeo, Clelia Tiziana Storlazzi, Arcangelo Liso and Massimo Conese

Int. J. Mol. Sci. 2023, 24(5), 4804; https://doi.org/10.3390/ijms24054804 - 02 Mar 2023

Cited by 1 | Viewed by 1963

Abstract

The lung is an accomplished organ for gas exchanges and directly faces the external environment, consequently exposing its large epithelial surface. It is also the putative determinant organ for inducing potent immune responses, holding both innate and adaptive immune cells. The maintenance of [...] Read more.

The lung is an accomplished organ for gas exchanges and directly faces the external environment, consequently exposing its large epithelial surface. It is also the putative determinant organ for inducing potent immune responses, holding both innate and adaptive immune cells. The maintenance of lung homeostasis requires a crucial balance between inflammation and anti-inflammation factors, and perturbations of this stability are frequently associated with progressive and fatal respiratory diseases. Several data demonstrate the involvement of the insulin-like growth factor (IGF) system and their binding proteins (IGFBPs) in pulmonary growth, as they are specifically expressed in different lung compartments. As we will discuss extensively in the text, IGFs and IGFBPs are implicated in normal pulmonary development but also in the pathogenesis of various airway diseases and lung tumors. Among the known IGFBPs, IGFBP-6 shows an emerging role as a mediator of airway inflammation and tumor-suppressing activity in different lung tumors. In this review, we assess the current state of IGFBP-6’s multiple roles in respiratory diseases, focusing on its function in the inflammation and fibrosis in respiratory tissues, together with its role in controlling different types of lung cancer. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Immunology 2023)

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17 pages, 2577 KiB

Open AccessReview

Tyk2 Targeting in Immune-Mediated Inflammatory Diseases

by Lluís Rusiñol and Luis Puig

Int. J. Mol. Sci. 2023, 24(4), 3391; https://doi.org/10.3390/ijms24043391 - 08 Feb 2023

Cited by 14 | Viewed by 7455

Abstract

The Janus kinase (Jak)/signal transducer and activating protein (STAT) pathways mediate the intracellular signaling of cytokines in a wide spectrum of cellular processes. They participate in physiologic and inflammatory cascades and have become a major focus of research, yielding novel therapies for immune-mediated [...] Read more.

The Janus kinase (Jak)/signal transducer and activating protein (STAT) pathways mediate the intracellular signaling of cytokines in a wide spectrum of cellular processes. They participate in physiologic and inflammatory cascades and have become a major focus of research, yielding novel therapies for immune-mediated inflammatory diseases (IMID). Genetic linkage has related dysfunction of Tyrosine kinase 2 (Tyk2)—the first member of the Jak family that was described—to protection from psoriasis. Furthermore, Tyk2 dysfunction has been related to IMID prevention, without increasing the risk of serious infections; thus, Tyk2 inhibition has been established as a promising therapeutic target, with multiple Tyk2 inhibitors under development. Most of them are orthosteric inhibitors, impeding adenosine triphosphate (ATP) binding to the JH1 catalytic domain—which is highly conserved across tyrosine kinases—and are not completely selective. Deucravacitinib is an allosteric inhibitor that binds to the pseudokinase JH2 (regulatory) domain of Tyk2; this unique mechanism determines greater selectivity and a reduced risk of adverse events. In September 2022, deucravacitinib became the first Tyk2 inhibitor approved for the treatment of moderate-to-severe psoriasis. A bright future can be expected for Tyk2 inhibitors, with newer drugs and more indications to come. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Immunology 2023)

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13 pages, 1295 KiB

Open AccessReview

Occupational Skin Dermatitis among Healthcare Workers Associated with the COVID-19 Pandemic: A Review of the Literature

by Yu Sawada

Int. J. Mol. Sci. 2023, 24(3), 2989; https://doi.org/10.3390/ijms24032989 - 03 Feb 2023

Cited by 2 | Viewed by 2804

Abstract

The skin is the outermost layer of the human body and is continually exposed to numerous external stimuli, which can cause unwanted skin irritation. Occupational skin diseases are the most prevalent form of work-related illness and are found in a variety of sectors, [...] Read more.

The skin is the outermost layer of the human body and is continually exposed to numerous external stimuli, which can cause unwanted skin irritation. Occupational skin diseases are the most prevalent form of work-related illness and are found in a variety of sectors, particularly healthcare. During the recent COVID-19 pandemic, healthcare professionals experienced a variety of unexpected, unusual occupational skin diseases associated with COVID-19-engaged employment. Because the clinical characteristics of these types of skin inflammation are unique, this review focuses on the characteristics of a large category of occupational workers, namely COVID-19-engaged healthcare professionals. Furthermore, we examined the potential pathogeneses of occupational skin disorders associated with COVID-19-engaged labor, as well as different preventative methods. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Immunology 2023)

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23 pages, 4371 KiB

Open AccessReview

Natural Killer Cell-Based Immunotherapy against Glioblastoma

by Takayuki Morimoto, Tsutomu Nakazawa, Ryosuke Maeoka, Ichiro Nakagawa, Takahiro Tsujimura and Ryosuke Matsuda

Int. J. Mol. Sci. 2023, 24(3), 2111; https://doi.org/10.3390/ijms24032111 - 20 Jan 2023

Cited by 5 | Viewed by 4208

Abstract

Glioblastoma (GBM) is the most aggressive and malignant primary brain tumor in adults. Despite multimodality treatment involving surgical resection, radiation therapy, chemotherapy, and tumor-treating fields, the median overall survival (OS) after diagnosis is approximately 2 years and the 5-year OS is poor. Considering [...] Read more.

Glioblastoma (GBM) is the most aggressive and malignant primary brain tumor in adults. Despite multimodality treatment involving surgical resection, radiation therapy, chemotherapy, and tumor-treating fields, the median overall survival (OS) after diagnosis is approximately 2 years and the 5-year OS is poor. Considering the poor prognosis, novel treatment strategies are needed, such as immunotherapies, which include chimeric antigen receptor T-cell therapy, immune checkpoint inhibitors, vaccine therapy, and oncolytic virus therapy. However, these therapies have not achieved satisfactory outcomes. One reason for this is that these therapies are mainly based on activating T cells and controlling GBM progression. Natural killer (NK) cell-based immunotherapy involves the new feature of recognizing GBM via differing mechanisms from that of T cell-based immunotherapy. In this review, we focused on NK cell-based immunotherapy as a novel GBM treatment strategy. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Immunology 2023)

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