Neutrophil Extracellular Traps Caused by Gut Leakage Trigger the Autoimmune Response in Nonobese Diabetic Mice

Increased formation of neutrophil extracellular traps (NETs) is associated with gut leakage in type 1 diabetes (T1D). To explore the mechanism of how enteropathy exacerbated by NETs triggers pancreatic autoimmunity in T1D, we carried out a correlation analysis for NET formation with gut barrier functions and autoimmunity in nonobese diabetic (NOD) mice. Inducing chronic colitis or knocking out of peptidyl arginine deiminase type 4 (PAD4) in NOD mice were used to further study the effect of NET formation on the progression of T1D. Microbial alterations in Deferribacteres and Proteobacteria, along with the loss of gut barrier function, were found to be associated with increased endotoxin and abnormal formation of NETs in NOD mice. Both DSS-induced colitis and knockout of PAD4 in NOD mice indicated that PAD4-dependent NET formation was involved in the aggravation of gut barrier dysfunction, the production of autoantibodies, and the activation of enteric autoimmune T cells, which then migrated to pancreatic lymph nodes (PLNs) and caused self-damage. The current study thus provides evidence that PAD4-dependent NET formation is engaged in leaky gut triggering pancreatic autoimmunity and suggests that either degradation of NETs or inhibition of NET formation may be helpful for innovative therapeutic interventions in T1D.

Are polypropylene mesh implants associated with systemic autoimmune inflammatory syndromes? A systematic review

Purpose The surgical implantation of polypropylene (PP) meshes has been linked to the occurrence of systemic autoimmune disorders. We performed a systematic review to determine whether PP implants for inguinal, ventral hernia or pelvic floor surgery are associated with the development of systemic autoimmune syndromes. Methods We searched Embase, Medline, Web of Science, Scopus, Cochrane library, clinicaltrialsregister.eu, clinicaltrails.gov and WHO-ICTR platform. Last search was performed on November 24th 2021. All types of studies reporting systemic inflammatory/autoimmune response in patients having a PP implant for either pelvic floor surgery, ventral or inguinal hernia repair were included. Animal studies, case reports and articles without full text were excluded. We intended to perform a meta-analysis. The quality of evidence was assessed with the Newcastle–Ottawa Scale. This study was registered at Prospero (CRD42020220705). Results Of 2137 records identified, 4 were eligible. Two retrospective matched cohort studies focused on mesh surgery for vaginal prolapse or inguinal hernia compared to hysterectomy and colonoscopy, respectively. One cohort study compared the incidence of systemic conditions in women having urinary incontinence surgery with and without mesh. These reports had a low risk of bias. A meta-analysis showed no association when comparing systemic disease between mesh and control groups. Calculated risk ratio was 0.9 (95% CI 0.82–0.98). The fourth study was a case series with a high risk of bias, with a sample of 714 patients with systemic disease, 40 of whom had PP mesh implanted. Conclusion There is no evidence to suggest a causal relationship between being implanted with a PP mesh and the occurrence of autoimmune disorders.

The hidden danger in Syria: Silent Celiac Disease

Celiac disease (CD) is a disorder caused by an aberrant autoimmune response to gluten ingestion in genetically susceptible individuals. Its prevalence nears 1%, and it is not considered typical in the Middle East because of the lack of reports in the Arabic countries. Therefore, this study aimed to define the prevalence of celiac disease in the Syrian community. Healthy young adults and volunteers ranging between 5–65-year-old were tested from December 2018 till May 2019. Samples from the participant's sera were tested for anti-tissue transglutaminase antibody (tTG) IgA/IgG by ELISA using the human recombinant transglutaminase antigen. One hundred participants with a mean ± SD of 22 ± 14 years-old were recruited in the study. Only one participant was suspected of having celiac disease. The mean ± SD of anti-tTG IgA/IgG values were 9.81 ± 9.61 for IgA and 6.64 ± 6.60 for IgG. The study shows no significant difference in IgA or IgG titers between males and females at P = 0.7, P = 0.8, respectively. The estimation of seroprevalence of CD antibodies in a healthy Syrian population is close to 1%. We suggest that the underdiagnosed CD might pose a high risk in Syria, contrary to previous thoughts.

Antituberculosis Drug-induced Linear IgA Dermatosis

Introduction: Linear IgA dermatosis is a rare autoimmune vesiculobullous disease characterized by homogeneous linear IgA deposits in basement membrane of epidermis, and it can be idiopathic or drug-induced. The pathogenesis of drug-induced linear IgA dermatosis is not fully known yet, but it is associated with specific T cells. The clinical manifestations of the disease include vesiculobullous eruption, erythematous plaques, or string of pearls. Most cases still need additional therapy to avoid the expansion of the disease. Case Presentation: In this study, we present a 17-year-old male patient with erythema plaques, vesicles, and bullae with erosion in facial, oral, neck, trunk, genital, and extremities, pruritus, and burning sensation. The patient was undergoing pulmonary tuberculosis (TB) treatment for one week. Physical examination was done, and total BSA 10% and negative Asboe-Hansen sign were seen. The treatment consisted of delaying administration of TB drugs, desoximetasone cream 0.25%, cetirizine 10 mg, and aspiration of bullae. Conclusions: Drug-induced linear IgA dermatosis can occur at any age due to the administration of rifampicin and other antibiotics, angiotensin-I converting enzyme (ACE) inhibitors, or nonsteroidal anti-inflammatory drugs (NSAIDs). The drug can stimulate specific T cells that release Th2 cytokines to produce IgA antibodies against the basement membrane of epidermis. Drugs may cause an autoimmune response by cross-reaction with the target epitope, altering the conformation of epitopes, or exposing previously sequestered antigens to the immune system. The causative drug was stopped, and methyl prednisolone 0.5 - 1 mg/kg/day was given as initial therapy. In this study, we reported a rare case of a 17-year-old male with anti-TB drug-induced linear IgA dermatosis. Diagnosis was done based on clinical manifestation, histopathology, and immunofluorescence. The causative drug was stopped, the patient was given topical and systemic steroid therapy and drug desensitization. Remission was noted after six weeks of therapy, and oral steroid was slowly tapered and stopped on day 42. After stopping oral steroids, no lesions were reported. A 6-month follow-up revealed no signs of recurrence.

The Neoepitopes on Methylglyoxal- (MG-) Glycated Fibrinogen Generate Autoimmune Response: Its Role in Diabetes, Atherosclerosis, and Diabetic Atherosclerosis Subjects

Objectives. In diabetes mellitus, hyperglycemia-mediated nonenzymatic glycosylation of fibrinogen protein plays a crucial role in the pathogenesis of micro- and macrovascular complications especially atherosclerosis via the generation of advanced glycation end products (AGEs). Methylglyoxal (MG) induces glycation of fibrinogen, resulting in structural alterations that lead to autoimmune response via the generation of neoepitopes on protein molecules. The present study was designed to probe the prevalence of autoantibodies against MG-glycated fibrinogen (MG-Fib) in type 2 diabetes mellitus (T2DM), atherosclerosis (ATH), and diabetic atherosclerosis (T2DM-ATH) patients. Design and Methods. The binding affinity of autoantibodies in patients’ sera (T2DM, n = 100 ; ATH, n = 100 ; and T2DM-ATH, n = 100 ) and isolated immunoglobulin G (IgG) against native fibrinogen (N-Fib) and MG-Fib to healthy subjects (HS, n = 50 ) was accessed by direct binding ELISA. The results of direct binding were further validated by competitive/inhibition ELISA. Moreover, AGE detection, ketoamines, protein carbonyls, hydroxymethylfurfural (HMF), thiobarbituric acid reactive substances (TBARS), and carboxymethyllysine (CML) concentrations in patients’ sera were also determined. Furthermore, free lysine and free arginine residues were also estimated. Results. The high binding affinity was observed in 54% of T2DM, 33% of ATH, and 65% of T2DM-ATH patients’ samples with respect to healthy subjects against MG-Fib antigen in comparison to N-Fib ( p < 0.05 to p < 0.0001 ). HS sera showed nonsignificant binding ( p > 0.05 ) with N-Fib and MG-Fib. Other biochemical parameters were also found to be significant ( p < 0.05 ) in the patient groups with respect to the HS group. Conclusions. These findings in the future might pave a way to authenticate fibrinogen as a biomarker for the early detection of diabetes-associated micro- and macrovascular complications.

Cepharanthine Blocks Presentation of Thyroid and Islet Peptides in a Novel Humanized Autoimmune Diabetes and Thyroiditis Mouse Model

Autoimmune polyglandular syndrome type 3 variant (APS3v) refers to an autoimmune condition in which both type 1 diabetes (T1D) and autoimmune thyroiditis (AITD) develop in the same individual. HLA-DR3 confers the strongest susceptibility to APS3v. Previously we reported a unique amino acid signature pocket that predisposes to APS3v. We found that this pocket is flexible and can trigger APS3v by presenting both thyroid (Tg.1571, TPO.758) and islet (GAD.492) peptides to induce autoimmune response. We hypothesized that blocking the specific APS3v-HLA-DR3 pocket from presenting thyroid/islet antigens can block the autoimmune response in APS3v. To test this hypothesis we performed a virtual screen of small molecules blocking APS3v-HLA-DR3, and identified 11 small molecules hits that were predicted to block APS3v-HLA-DR3. Using the baculovirus-produced recombinant APS3v-HLA-DR3 protein we tested the 11 small molecules in an in vitro binding assay. We validated 4 small molecule hits, S9, S5, S53 and S15, that could block the APS3v-HLA-DR3 pocket in vitro. We then developed a novel humanized APS3v mouse model induced by co-immunizing a peptide mix of Tg.1571, TPO.758 and GAD.492. The immunized mice developed strong T-cell and antibody responses to the thyroid/islet peptides, as well as mouse thyroglobulin. In addition, the mice showed significantly lower free T4 levels compared to controls. Using the APS3v mouse model, we showed that one of the 4 small molecules, Cepharanthine (S53), blocked T-cell activation by thyroid/islet peptides ex vivo and in vivo. These findings suggested Cepharanthine may have a therapeutic potential in APS3v patients carrying the specific APS3v-HLA-DR3 pocket.

Pathogenetic value of cell infiltrate in immunoinflammatory rheumatic diseases

Cell infiltrate is a morphological substrate of immunoinflammatory rheumatic diseases. The systemic wide progressive disorganization of loose fibrous connective tissue is accompanied by the loss of tolerance with its own autoantigenes, activation of macrophagal-monocyte cells and autoreactive clones of T and B lymphocytes. Hyperproduction of pro-inflammatory chemokines and cytokines, local adhesive ligandreceptor interactions, endothelial reaction and angiogenesis contribute to the formation of cell infiltrate, ectopic lymphoid structures and GZT-granulomas in situ. The autoimmune response is the result of successive systemic and local molecular cellular events in which the mechanisms of congenital and adaptive immunity are involved. When interpreting immunopathogenesis of rheumatic diseases, all models and schemes adopted in the field of fundamental immunology are used. This is a model of MHC-restrictions, a model of molecular mimicry, or cross of the antigen presentation, a model of disrupting central or peripheral tolerance to auto-antigens, a model of candidate “triggers” of autoimmune and autoinflammatory processes, a model of associations of alleles MHC I and II classes with specific, nosologically unique, rheumatic diseases.

The Role of Exposomes in the Pathophysiology of Autoimmune Diseases I: Toxic Chemicals and Food

Autoimmune diseases affect 5–9% of the world’s population. It is now known that genetics play a relatively small part in the pathophysiology of autoimmune disorders in general, and that environmental factors have a greater role. In this review, we examine the role of the exposome, an individual’s lifetime exposure to external and internal factors, in the pathophysiology of autoimmune diseases. The most common of these environmental factors are toxic chemicals, food/diet, and infections. Toxic chemicals are in our food, drink, common products, the air, and even the land we walk on. Toxic chemicals can directly damage self-tissue and cause the release of autoantigens, or can bind to human tissue antigens and form neoantigens, which can provoke autoimmune response leading to autoimmunity. Other types of autoimmune responses can also be induced by toxic chemicals through various effects at the cellular and biochemical levels. The food we eat every day commonly has colorants, preservatives, or packaging-related chemical contamination. The food itself may be antigenic for susceptible individuals. The most common mechanism for food-related autoimmunity is molecular mimicry, in which the food’s molecular structure bears a similarity with the structure of one or more self-tissues. The solution is to detect the trigger, remove it from the environment or diet, then repair the damage to the individual’s body and health.

Microglia and Macrophages in Neuroprotection, Neurogenesis, and Emerging Therapies for Stroke

Stroke remains the number one cause of morbidity in the United States. Within weeks to months after an ischemic event, there is a resolution of inflammation and evidence of neurogenesis; however, years following a stroke, there is evidence of chronic inflammation in the central nervous system, possibly by the persistence of an autoimmune response to brain antigens as a result of ischemia. The mechanisms underlying the involvement of macrophage and microglial activation after stroke are widely acknowledged as having a role in ischemic stroke pathology; thus, modulating inflammation and neurological recovery is a hopeful strategy for treating the long-term outcomes after ischemic injury. Current treatments fail to provide neuroprotective or neurorestorative benefits after stroke; therefore, to ameliorate brain injury-induced deficits, therapies must alter both the initial response to injury and the subsequent inflammatory process. This review will address differences in macrophage and microglia nomenclature and summarize recent work in elucidating the mechanisms of macrophage and microglial participation in antigen presentation, neuroprotection, angiogenesis, neurogenesis, synaptic remodeling, and immune modulating strategies for treating the long-term outcomes after ischemic injury.