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Advances in the Diagnosis and Management of Pediatric Autoimmune Diseases

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A special issue of Diagnostics (ISSN 2075-4418). This special issue belongs to the section "Pathology and Molecular Diagnostics".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 10996

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Dr. Dimitri Poddighe

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1. Department of Medicine, Nazarbayev University School of Medicine, Nur-Sultan 010000, Kazakhstan
2. Clinical Academic Department of Pediatrics, National Research Center of Maternal and Child Health, University Medical Center, Nur-Sultan 010000, Kazakhstan
Interests: autoimmunity; pediatrics; rheumatology; gastroenterology; immunology
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Dr. Micol Romano

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1. Division of Paediatric Rheumatology, Department of Paediatrics, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON N6A 5C1, Canada
2. Canadian Behcet and Autoinflammatory Disease Center (CAN-BE-AID), University of Western Ontario, London, ON N6A 5C1, Canada
Interests: pediatric rheumatology; autoinflammatory diseases; systemic vasculitides; systemic lupus erythematosus
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Autoimmune diseases are medical conditions driven by the persistent activation of self-reactive B and/or T lymphocytes, due to the impairment of the physiological mechanisms of central and/or peripheral immunological tolerance. In general, these are multi-factorial disorders: they recognize a background of genetic predisposition (usually polygenic, but often not well-defined), where multiple and variable environmental factors superimpose in order to trigger the autoimmune pathological process. The role of the microbiome and, in general, epigenetic factors is also gradually emerging. Autoimmune diseases can manifest in children: several clinical and pathological aspects often differ from those shown by adult patients affected by the same autoimmune disease; moreover, the longer life expectancy and the ongoing growth process in children raise specific issues and questions in terms of medical management, therapeutic approach, and long-term complications. Finally, the current COVID-19 pandemic brought additional challenges in this specific field.

In this Special Issue, we aim to cover the current knowledge, ongoing progresses, and future perspectives in biomedical research on the diagnosis and medical management of pediatric autoimmune disorders. Moreover, articles investigating and discussing the immune-pathogenic and clinical peculiarities (including comorbidities) of autoimmune diseases and immune-mediated phenomena in children are also welcome.

Dr. Dimitri Poddighe
Dr. Micol Romano
Guest Editors

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Keywords

children
autoimmunity
autoinflammatory diseases
pediatric rheumatology
innovative and biological therapies
comorbidity
immune-mediated manifestations

Published Papers (9 papers)

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13 pages, 1688 KiB

Open AccessArticle

Celiac Disease in Uzbek Children: Insights into Disease Prevalence and Clinical Characteristics in Symptomatic Pediatric Patients

by Altinoy T. Kamilova, Gulnoza K. Azizova, Dimitri Poddighe, Zulkhumar E. Umarnazarova, Dilrabo A. Abdullaeva, Svetlana I. Geller and Noiba D. Azimova

Diagnostics 2023, 13(19), 3066; https://doi.org/10.3390/diagnostics13193066 - 27 Sep 2023

Cited by 1 | Viewed by 798

Abstract

Background: A few studies on pediatric Celiac Disease (CD) are available from Central Asia. Recent immunogenetic research has highlighted that the HLA-DQ2/8 genetic predisposition to CD as well as the dietary intake of gluten in this geographical area, are comparable to other regions of the world where CD prevalence is known to be 1% or higher. Methods: This is a prospective and cross-sectional study investigating the prevalence and clinical characteristics of CD in symptomatic children referred to the pediatric gastroenterology department of a tertiary hospital in Uzbekistan from 1 September 2021, until 31 July 2022. In addition to collecting the relevant information related to clinical manifestations and laboratory analyses from the clinical files, a specific survey was also administered to patients’ guardians. Serological, histopathological, and immunogenetic parameters specific to CD, fecal zonulin, and pancreatic elastases were assessed in CD patients. Results: The study population consisted of 206 children. Overall, almost all of them (n = 192; 93.2%) were referred because of gastrointestinal manifestations, which were associated with extra-gastrointestinal manifestations in most cases (n = 153; 74.3%); a minority (n = 14; 6.8%) was mainly referred due short stature and/or growth failure only. Among all of these study participants, CD was diagnosed in 11 children (5.3%). Notably, although diarrhea was similarly reported in CD and non-CD patients, watery diarrhea (type 7 according to the Bristol stool scale) was much more frequently and significantly observed in the former group. All of these CD patients showed anti-tTG IgA 10 times higher than the upper normal limit, except one child with lower serum levels of total IgA; however, all of them received a diagnostic confirmation by histopathological analysis due to the lack of EMA testing in the country. Notably, most CD children (82%) showed a Marsh III histological grading. Around half patients (54.5%) showed zonulin values above the reference range, whereas none showed insufficient levels of pancreatic elastase. However, no correlation or association between zonulin and clinical, laboratory, histopathological, and immunogenetic parameters was found. Conclusions: This study may further suggest a relevant prevalence of CD in Uzbek children, based on this partial picture emerging from symptomatic patients only. Additionally, we highlighted the prevalence of typical CD forms with watery diarrhea, which should strongly support a full diagnostic work-up for CD in the local clinical setting. The high levels of anti-tTG IgA and high Marsh grade might also lead us to speculate a significant diagnostic delay despite the classical clinical expression of CD. Full article

(This article belongs to the Special Issue Advances in the Diagnosis and Management of Pediatric Autoimmune Diseases)

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12 pages, 4294 KiB

Open AccessArticle

Identification of Autoantibodies to a Hybrid Insulin Peptide in Type 1 Diabetes

by Janet M. Wenzlau, Yong Gu, Aaron Michels, Marian Rewers, Kathryn Haskins and Liping Yu

Diagnostics 2023, 13(17), 2859; https://doi.org/10.3390/diagnostics13172859 - 04 Sep 2023

Cited by 1 | Viewed by 1203

Abstract

Type 1 diabetes (T1D) is a chronic autoimmune disease that attacks the insulin-producing b cells of the pancreatic islets. Autoantibodies to b cell proteins typically appear in the circulation years before disease onset, and serve as the most accurate biomarkers of T1D risk. Our laboratory has recently discovered novel b cell proteins comprising hybrid proinsulin:islet amyloid polypeptide peptides (IAPP). T cells from a diabetic mouse model and T1D patients are activated by these hybrid peptides. In this study, we asked whether these hybrid molecules could serve as antigens for autoantibodies in T1D and prediabetic patients. We analyzed sera from T1D patients, prediabetics and healthy age-matched donors. Using a highly sensitive electrochemiluminescence assay, sera were screened for binding to recombinant proinsulin:IAPP probes or truncated derivatives. Our results show that sera from T1D patients contain antibodies that bind larger hybrid proinsulin:IAPP probes, but not proinsulin or insulin, at significantly increased frequencies compared to normal donors. Examination of sera from prediabetic patients confirms titers of antibodies to these hybrid probes in more than 80% of individuals, often before seroconversion. These results suggest that hybrid insulin peptides are common autoantigens in T1D and prediabetic patients, and that antibodies to these peptides may serve as valuable early biomarkers of the disease. Full article

(This article belongs to the Special Issue Advances in the Diagnosis and Management of Pediatric Autoimmune Diseases)

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11 pages, 688 KiB

Open AccessArticle

Ultrasound and Clinical Alterations in the Foot of Children with Obesity and Diabetes

by Martina Pappalardo, Laura Gori, Emioli Randazzo, Riccardo Morganti, Michelangelo Scaglione, Margherita Valiani, Alessandra Beni, Maria Di Cicco, Diego G. Peroni, Ferdinando Franzoni and Pasquale Comberiati

Diagnostics 2023, 13(17), 2781; https://doi.org/10.3390/diagnostics13172781 - 28 Aug 2023

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Abstract

Background. Alterations in plantar soft tissues are often reported in adults with diabetes, whereas data on children are conflicting. Also, the extent of foot damage caused by excess body fat in children has not been fully characterized yet. This study aimed to address the relationship between body mass and structural changes of the foot in children and adolescents with and without diabetes. Methods. In a case-control study, 43 participants (age 13 ± 2.6 years) were recruited, 29 (67%) with type 1 diabetes (T1D) and 14 (33%) controls. Anthropometric parameters [body mass index (BMI), waist circumference (WC), and waist-to-height ratio (WHtR)], foot posture index-6 (FPI-6) for static foot posture, and navicular drop test (NDT) for medial longitudinal arch height (MLA) were measured in all participants. The thickness of the midfoot plantar fascia (MPF) and medial midfoot fat pad (MMFP) were quantified using ultrasound. Results. No differences in clinical and ultrasonographical parameters were observed between the study groups. MMFP thickness was correlated with MPF thickness (p = 0.027). MMFP and MPF thicknesses were positively associated with BMI (p < 0.001 and p = 0.013, respectively), WC (p < 0.001 and p = 0.013), and WHtR (p < 0.001 and p = 0.026). The NDT measured on the right and left foot correlated with WHtR (p = 0.038 and p = 0.009, respectively), but not with WC and BMI. Conclusions. Children with T1D show structural alterations of plantar soft tissues which seem related to body mass increase rather than diabetes pathology. Ultrasound is a valuable tool to assess early structural changes of the foot in young people with an elevated BMI. Full article

(This article belongs to the Special Issue Advances in the Diagnosis and Management of Pediatric Autoimmune Diseases)

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11 pages, 657 KiB

Open AccessArticle

B Cell Lymphocytosis in Juvenile Dermatomyositis

by Christopher Costin, Amer Khojah, Elisa Ochfeld, Gabrielle Morgan, Saravanan Subramanian, Marisa Klein-Gitelman, Xiao-Di Tan and Lauren M. Pachman

Diagnostics 2023, 13(16), 2626; https://doi.org/10.3390/diagnostics13162626 - 08 Aug 2023

Cited by 1 | Viewed by 859

Abstract

In this study, we determined if B lymphocytosis may serve as a JDM biomarker for disease activity. Children with untreated JDM were divided into two groups based on age-adjusted B cell percentage (determined through flow cytometry): 90 JDM in the normal B cell group and 45 in the high B cell group. We compared through T-testing the age, sex, ethnicity, duration of untreated disease (DUD), disease activity scores for skin (sDAS), muscle (mDAS), total (tDAS), CMAS, and neopterin between these two groups. The patients in the high B cell group had a higher tDAS (p = 0.009), mDAS (p = 0.021), and neopterin (p = 0.0365). Secondary analyses included B cell values over time and BAFF levels in matched patients with JM (juvenile myositis) and concurrent interstitial lung disease (ILD); JM alone and healthy controls Patient B cell percentage and number was significantly higher after 3–6 months of therapy and then significantly lower on completion of therapy (p =< 0.0001). The JM groups had higher BAFF levels than controls 1304 vs. 692 ng/mL (p = 0.0124). This study supports B cell lymphocytosis as a JDM disease-activity biomarker and bolsters the basis for B cell-directed therapies in JDM. Full article

(This article belongs to the Special Issue Advances in the Diagnosis and Management of Pediatric Autoimmune Diseases)

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13 pages, 1457 KiB

Open AccessArticle

Plasma Proteomic Analysis Reveals the Potential Role of Lectin and Alternative Complement Pathways in IgA Vasculitis Pathogenesis

by Selcan Demir, Idil Yet, Melis Sardan Ekiz, Erdal Sag, Yelda Bilginer, Omur Celikbicak, Incilay Lay and Seza Ozen

Diagnostics 2023, 13(10), 1729; https://doi.org/10.3390/diagnostics13101729 - 12 May 2023

Cited by 2 | Viewed by 1242

Abstract

Background: IgA vasculitis (IgAV) is the most common form of childhood vasculitis. A better understanding of its pathophysiology is required to identify new potential biomarkers and treatment targets. Objective: to assess the underlying molecular mechanisms in the pathogenesis of IgAV using an untargeted proteomics approach. Methods: Thirty-seven IgAV patients and five healthy controls were enrolled. Plasma samples were collected on the day of diagnosis before any treatment was initiated. We used nano-liquid chromatography–tandem mass spectrometry (nLC–MS/MS) to investigate the alterations in plasma proteomic profiles. For the bioinformatics analyses, databases including Uniprot, PANTHER, KEGG, Reactome, Cytoscape, and IntAct were used. Results: Among the 418 proteins identified in the nLC–MS/MS analysis, 20 had significantly different expressions in IgAV patients. Among them, 15 were upregulated and 5 were downregulated. According to the KEGG pathway and function classification analysis, complement and coagulation cascades were the most enriched pathways. GO analyses showed that the differentially expressed proteins were mainly involved in defense/immunity proteins and the metabolite interconversion enzyme family. We also investigated molecular interactions in the identified 20 proteins of IgAV patients. We extracted 493 interactions from the IntAct database for the 20 proteins and used Cytoscape for the network analyses. Conclusion: Our results clearly suggest the role of the lectin and alternate complement pathways in IgAV. The proteins defined in the pathways of cell adhesion may serve as biomarkers. Further functional studies may lead the way to better understanding of the disease and new therapeutic options for IgAV treatment. Full article

(This article belongs to the Special Issue Advances in the Diagnosis and Management of Pediatric Autoimmune Diseases)

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11 pages, 2536 KiB

Open AccessArticle

Analysis of Peripheral Blood Basophils in Pediatric Systemic Lupus Erythematosus

by Kuanysh Dossybayeva, Yergali Bexeitov, Zaure Mukusheva, Zhaina Almukhamedova, Maykesh Assylbekova, Diyora Abdukhakimova, Marzhan Rakhimzhanova and Dimitri Poddighe

Diagnostics 2022, 12(7), 1701; https://doi.org/10.3390/diagnostics12071701 - 12 Jul 2022

Cited by 3 | Viewed by 1669

Abstract

Basophils are the least abundant circulating leukocytes, and their immunological role has not yet been completely elucidated. There is evidence supporting their immunomodulatory role in several pathological settings; recently, studies in both experimental models and humans suggested that basophil homeostasis may be altered in systemic lupus erythematosus (SLE). Here, we first assessed circulating basophils in children affected with pediatric SLE (pSLE). In this cross-sectional study, circulating basophils were enumerated by fluorescence-based flow cytometry analysis in children affected with pSLE, in addition to children suffering from juvenile idiopathic arthritis (JIA) or non-inflammatory/non-rheumatic conditions. This study included 52 pediatric patients distributed in these three groups. We observed a statistically significant reduction of peripherally circulating basophils in children with pSLE compared to the other two groups of patients. This preliminary study is consistent with the available studies in adult patients with SLE showing a reduced number of circulating basophils. However, further research is needed to draw final conclusions on basophils’ homeostasis in pSLE, in addition to their correlation with the disease activity and concomitant therapies. Full article

(This article belongs to the Special Issue Advances in the Diagnosis and Management of Pediatric Autoimmune Diseases)

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Review

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13 pages, 485 KiB

Open AccessReview

Selective IgM Deficiency: Evidence, Controversies, and Gaps

by Ivan Taietti, Martina Votto, Maria De Filippo, Matteo Naso, Lorenza Montagna, Daniela Montagna, Amelia Licari, Gian Luigi Marseglia and Riccardo Castagnoli

Diagnostics 2023, 13(17), 2861; https://doi.org/10.3390/diagnostics13172861 - 04 Sep 2023

Viewed by 1645

Abstract

Selective Immunoglobulin M deficiency (SIgMD) has been recently included in the inborn errors of immunity (IEI) classification by the International Union of Immunological Societies Expert Committee. The understanding of SIgMD is still extremely limited, especially so in cases of SIgMD in the pediatric population. The epidemiology of SIgMD in the pediatric population is still unknown. The pathogenesis of SIgMD remains elusive, and thus far no genetic nor molecular basis has been clearly established as a definitive cause of this primary immunodeficiency. Recurrent respiratory infections represent the main clinical manifestations in children, followed by allergic and autoimmune diseases. No conclusive data on the correct therapeutic management of SIgMD are available. Although, for most SIgMD patients, Ig replacement therapy is not required, it may be recommended for patients with significantly associated antibody deficiency and recurrent or severe infections. Prophylactic antibiotics and the prompt treatment of febrile illness are crucial. There is insufficient evidence on the prognosis of this condition. Therefore, further studies are required to define the disease trajectories and to increase our understanding of the molecular mechanisms underlying SIgMD in order to facilitate a better clinical, immunological, and prognostic characterization of the condition and develop tailored therapeutic management strategies. Full article

(This article belongs to the Special Issue Advances in the Diagnosis and Management of Pediatric Autoimmune Diseases)

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17 pages, 621 KiB

Open AccessReview

Juvenile Autoimmune Hepatitis: Recent Advances in Diagnosis, Management and Long-Term Outcome

by Silvia Nastasio, Antonella Mosca, Tommaso Alterio, Marco Sciveres and Giuseppe Maggiore

Diagnostics 2023, 13(17), 2753; https://doi.org/10.3390/diagnostics13172753 - 24 Aug 2023

Cited by 1 | Viewed by 1147

Abstract

Juvenile autoimmune hepatitis (JAIH) is severe immune-mediated necro-inflammatory disease of the liver with spontaneous progression to cirrhosis and liver failure if left untreated. The diagnosis is based on the combination of clinical, laboratory and histological findings. Prothrombin ratio is a useful prognostic factor to identify patients who will most likely require a liver transplant by adolescence or early adulthood. JAIH treatment consists of immune suppression and should be started promptly at diagnosis to halt inflammatory liver damage and ultimately prevent fibrosis and progression to end-stage liver disease. The risk of relapse is high especially in the setting of poor treatment compliance. Recent evidence however suggests that treatment discontinuation is possible after a prolonged period of normal aminotransferase activity without the need for liver biopsy prior to withdrawal. Full article

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12 pages, 4463 KiB

Open AccessBrief Report

Laser Flare Photometry to Monitor Childhood Chronic Uveitis: A Preliminary Report of a Monocentric Italian Experience

by Ilaria Maccora, Cinzia De Libero, Matilde Peri, Gioia Danti, Alessio Rossi, Edoardo Marrani, Roberta Pasqualetti, Ilaria Pagnini, Maria Vincenza Mastrolia and Gabriele Simonini

Diagnostics 2023, 13(20), 3179; https://doi.org/10.3390/diagnostics13203179 - 11 Oct 2023

Cited by 1 | Viewed by 758

Abstract

Background: Childhood chronic non-infectious uveitis (cNIU) is a challenging disease that needs close monitoring. Slit lamp evaluation (SLE) is the cornerstone of ophthalmological evaluation for uveitis, but it is affected by interobserver variability and may be problematic in children. Laser flare photometry (LFP), a novel and objective technique, might be used in children with uveitis. Aim: The aim of this study was to attempt the use of LFP in cNIU clinical practice. Methods: Children, attending the Rheumatology Unit and who were scheduled to receive ophthalmological evaluation, were prospectively enrolled to concomitantly receive SLE and LFP. SLE was performed blind to LFP measure. Demographic, laboratory, clinical, and ophthalmology data were collected. Results: A total of 29 children (58 eyes) were enrolled, including 3 with juvenile idiopathic arthritis without uveitis (JIA-no-U), 15 with JIA-associated uveitis (JIA-U), and 11 with idiopathic chronic uveitis (ICU). We observed significantly higher LFP values in the eyes of children with uveitis compared to the others (10.1 IQR 7.1–13.6 versus 6.2 IQR 5.8–6.9, p = 0.007). Accordance between the SLE and LFP measures, at baseline (ρ.498, p < 0.001) and during the follow-up (LFP II ρ 0.460, p < 0.001, LFP III ρ 0.631, p < 0.001, LFP IV ρ 0.547, p = 0.006, LFP V ρ 0.767, p = 0.001), was detected. We evaluated significant correlation between LFP values and the presence of complications (ρ 0.538, p < 0.001), especially with cataract formation (ρ 0.542, p < 0.001). Conclusions: In this cohort, LFP measurements showed a good correlation with SLE. LFP values showed a positive correlation with the presence of complications. LFP might be considered as a reliable objective modality to monitor intraocular inflammation in cNIU. Full article

(This article belongs to the Special Issue Advances in the Diagnosis and Management of Pediatric Autoimmune Diseases)

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