Development Of Chronic Autoimmune Diseases Research Articles

COVID-19 and Autoimmunity: A Single Center Prospective Follow-up Study

Background Various factors, such as viral infections, can act as triggers for the development of autoimmune diseases. In our recent study we reported the presence of autoantibodies in patients diagnosed with COVID-19. To verify whether these autoantibodies persisted over time and led to the development of chronic autoimmune diseases, we conducted a follow-up study at 3 and 6 months after admission.

FRI0016 Critical role for the IL-23/TNF-alpha axis during TLR2/NOD2 mediated acute joint inflammation

BackgroundIL-23 is essential in the development of chronic autoimmune diseases and supports the maturation of pathogenic Th17 cells. Although the role of IL-23 during adaptive immunity in arthritis has been...

Recognition of Human Tumor Necrosis Factor α (TNF-α) by Therapeutic Antibody Fragment: ENERGETICS AND STRUCTURAL FEATURES

Human tumor necrosis factor α (TNF-α) exists in its functional state as a homotrimeric protein and is involved in inflammation processes and immune response of a human organism. Overproduction of TNF-α results in the development of chronic autoimmune diseases that can be successfully treated by inhibitors such as monoclonal antibodies. However, the nature of antibody-TNF-α recognition remains elusive due to insufficient understanding of its molecular driving forces. Therefore, we studied the energetics of binding of a therapeutic antibody fragment (Fab) to the native and non-native forms of TNF-α by employing calorimetric and spectroscopic methods. Global thermodynamic analysis of data obtained from the corresponding binding and urea-induced denaturation experiments has been supported by structural modeling. We demonstrate that the observed high affinity binding of Fab to TNF-α is an enthalpy-driven process due mainly to specific noncovalent interactions taking place at the TNF-α-Fab binding interface. It is coupled to entropically unfavorable conformational changes and accompanied by entropically favorable solvation contributions. Moreover, the three-state model analysis of TNF-α unfolding shows that at physiological concentrations, TNF-α may exist not only as a biologically active trimer but also as an inactive monomer. It further suggests that even small changes of TNF-α concentration could have a considerable effect on the TNF-α activity. We believe that this study sets the energetic basis for understanding of TNF-α inhibition by antibodies and its unfolding linked with the concentration-dependent activity regulation.

CD8+ T-Cell Deficiency, Epstein-Barr Virus Infection, Vitamin D Deficiency, and Steps to Autoimmunity: A Unifying Hypothesis

CD8+ T-cell deficiency is a feature of many chronic autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, dermatomyositis, primary biliary cirrhosis, primary sclerosing cholangitis, ulcerative colitis, Crohn's disease, psoriasis, vitiligo, bullous pemphigoid, alopecia areata, idiopathic dilated cardiomyopathy, type 1 diabetes mellitus, Graves' disease, Hashimoto's thyroiditis, myasthenia gravis, IgA nephropathy, membranous nephropathy, and pernicious anaemia. It also occurs in healthy blood relatives of patients with autoimmune diseases, suggesting it is genetically determined. Here it is proposed that this CD8+ T-cell deficiency underlies the development of chronic autoimmune diseases by impairing CD8+ T-cell control of Epstein-Barr virus (EBV) infection, with the result that EBV-infected autoreactive B cells accumulate in the target organ where they produce pathogenic autoantibodies and provide costimulatory survival signals to autoreactive T cells which would otherwise die in the target organ by activation-induced apoptosis. Autoimmunity is postulated to evolve in the following steps: (1) CD8+ T-cell deficiency, (2) primary EBV infection, (3) decreased CD8+ T-cell control of EBV, (4) increased EBV load and increased anti-EBV antibodies, (5) EBV infection in the target organ, (6) clonal expansion of EBV-infected autoreactive B cells in the target organ, (7) infiltration of autoreactive T cells into the target organ, and (8) development of ectopic lymphoid follicles in the target organ. It is also proposed that deprivation of sunlight and vitamin D at higher latitudes facilitates the development of autoimmune diseases by aggravating the CD8+ T-cell deficiency and thereby further impairing control of EBV. The hypothesis makes predictions which can be tested, including the prevention and successful treatment of chronic autoimmune diseases by controlling EBV infection.

Immune regulation: FcγRIIB—regulating the balance between protective and autoreactive immune responses

Immune regulation: FcγRIIB—regulating the balance between protective and autoreactive immune responses

Chronic Minocycline-Induced Autoimmunity in Children

To report our experience with minocycline-induced autoimmunity (MIA) in children, with an emphasis on the potential for chronicity. Retrospective cohort study of patients with development of rheumatologic symptoms while receiving minocycline between 1996 and 2006. Twenty-seven children were diagnosed with MIA at a single pediatric rheumatology practice. The mean age at onset was 16.5 +/- 1.39 years. The mean duration of minocycline use before diagnosis was 13.0 +/- 10.8 months. All patients presented with constitutional symptoms. Twenty-two had polyarthralgia, and 17 had polyarthritis, mostly affecting hands and feet. On the basis of disease duration after discontinuation of minocycline, we divided subjects into 3 categories: transient, intermediate, and chronic. Seven patients had development of chronic autoimmune disease that was still active at last follow-up, a mean of 31.6 +/- 13.0 (13-48) months after onset. Six patients followed an intermediate course, with resolution of symptoms within 12 months, and 14 patients had symptoms that resolved rapidly on discontinuation of minocycline. All patients with a chronic course had evidence of arthritis at presentation. A substantial proportion of children with MIA had development of chronic symptoms with the potential for significant morbidity. Physicians who prescribe minocycline should be aware of its propensity for inducing potentially serious autoimmune phenomena.

Autoantigen-Specific IL-10-Transduced T Cells Suppress Chronic Arthritis by Promoting the Endogenous Regulatory IL-10 Response

Deficient T cell regulation can be mechanistically associated with development of chronic autoimmune diseases. Therefore, combining the regulatory properties of IL-10 and the specificity of autoreactive CD4(+) T cells through adoptive cellular gene transfer of IL-10 via autoantigen-specific CD4(+) T cells seems an attractive approach to correct such deficient T cell regulation that avoids the risks of nonspecific immunosuppressive drugs. In this study, we studied how cartilage proteoglycan-specific CD4(+) T cells transduced with an active IL-10 gene (T(IL-10)) may contribute to the amelioration of chronic and progressive proteoglycan-induced arthritis in BALB/c mice. TCR-transgenic proteoglycan-specific T(IL-10) cells ameliorated arthritis, whereas T(IL-10) cells with specificity for OVA had no effect, showing the impact of Ag-specific targeting of inflammation. Furthermore, proteoglycan-specific T(IL-10) cells suppressed autoreactive proinflammatory T and B cells, as T(IL-10) cells caused a reduced expression of IL-2, TNF-alpha, and IL-17 and a diminished proteoglycan-specific IgG2a Ab response. Moreover, proteoglycan-specific T(IL-10) cells promoted IL-10 expression in recipients but did not ameliorate arthritis in IL-10-deficient mice, indicating that T(IL-10) cells suppress inflammation by propagating the endogenous regulatory IL-10 response in treated recipients. This is the first demonstration that such targeted suppression of proinflammatory lymphocyte responses in chronic autoimmunity by IL-10-transduced T cells specific for a natural Ag can occur via the endogenous regulatory IL-10 response.

Paralysis of CD4 +CD25 + regulatory T cell response in chronic autoimmune encephalomyelitis

Increasing evidence strongly suggest that CD4 +CD25 + regulatory T (Treg) cells play a pivotal role in suppressing the development of autoimmune diseases. However, it remains poorly understood how these cells are involved in the persistence of, or recovery from, the diseases. In the present study, we examined the role of CD4 +CD25 + Treg cells in chronic EAE and compared the results with those obtained in acute EAE. In EAE lesions, CD25 + cells decreased rapidly at the beginning of chronic EAE, whereas these cells were maintained at high levels during the recovery from acute EAE. The number of Foxp3 +CD4 +CD25 + Treg and levels of Foxp3 mRNA in the lymphoid organ were significantly lower in chronic EAE. Importantly, the regulatory function of individual CD4 +CD25 + Treg cells was maintained in animals with chronic EAE. Furthermore, adoptive transfer of activated CD4 +CD25 + Treg cells suppressed the development of chronic EAE. These findings suggest that impairment of the CD4 +CD25 + Treg response is critical for development of chronic autoimmune diseases, and can be adjustable by autologous Treg transplantation.

Eine unzureichende Erkennung und Beseitigung von sterbenden Zellen kann zur Entstehung von chronischer Autoimmunität führen

Not properly cleared dead cells are dangerous for the body. The dead cells accumulate, lose their membrane integrity, danger signals are released, and nuclear antigens get accessible in an inflammatory context. In times of increased apoptosis, tolerance can be broken, a chronic inflammation results which then can lead to an autoimmune reaction against nuclear constituents. An impaired clearance of dying cells represents a central pathogenic process in the development of chronic autoimmune diseases like in systemic lupus erythematosus (SLE). Many adaptor molecules and receptors are involved in the clearance of dying cells. Complement components, serum DNase I, phosphatidylserine, and modified glycoproteins participate crucially in the clearance of apoptotic and necrotic cells. We further observed intrinsic defects of macrophages of some SLE patients. Macrophages as well as granulocytes of some SLE patients showed heterogeneous clearance defects. Furthermore, we observed an accumulation of nuclear material in germinal centres of lymph nodes of some SLE patients. The non-ingested nuclear material may provide survival signals for autoreactive B cells and consecutively antinuclear autoantibodies (ANA) will be produced. We therefore conclude that drugs promoting the phagocytosis are important candidates of specific therapies in the future which expect a more gentle and purposive treatment of patients with SLE.

Virus-induced autoimmunity: Epitope spreading to myelin autoepitopes in theiler's virus infection of the central nervous system

Epidemiological studies indicate that host immunogenetics and history of infection, particularly by viruses, may be a necessary cofactor for the induction of a variety of autoimmune diseases. To date, however, there is no clear-cut evidence, either in experimental animal models or in human autoimmune disease, that supports either molecular mimicry (Wucherpfennig and Strominger, 1995; Fujinami and Oldstone, 1985) or a role for superantigens (Scherer et al., 1993) in the initiation of T cell-mediated autoimmunity. In contrast, the current data provide compelling evidence in support of a major role for epitope spreading in the induction of myelin-specific autoimmunity in mice persistently infected with TMEV. It is significant that two picornaviruses closely related to TMEV, coxsackievirus (Rose and Hill, 1996) and encephalomyocarditis virus (EMCV) (Kyu et al., 1992), have been similarly shown to persist (either the viral RNA or the infectious virus) in their target organs and have been associated with the development of chronic autoimmune diseases, including myocarditis and diabetes. Thus, inflammatory responses induced by viruses that trigger proinflammatory Th1 responses, and have the ability to persist in genetically susceptible hosts, may lead to chronic organ-specific autoimmune disease via epitope spreading. Epitope spreading has important implications for the design of antigen-specific therapies for the potential treatment of MS and other autoimmune diseases. This process indicates that autoimmune diseases are evolving entities and that the specificity of the effector autoantigen-specific T cells varies during the chronic disease process. Our experiments employing tolerance in R-EAE clearly indicate that antigen-specific treatment of ongoing disease is possible for preventing disease relapses, provided the proper relapse-associated epitope is targeted (Vanderlugt et al., 1999). However, the ability to identify relapse-associated epitopes in humans will be a difficult task because immunodominance will vary in every individual. The use of costimulatory antagonists that can induce anergy without requiring prior knowledge of the exact epitopes (Miller et al., 1995b), or the use of therapies that induce bystander suppression (Nicholson et al., 1997; Brocke et al., 1996), may thus be more practical current alternative therapies for the treatment of human autoimmune disease.

Down-Regulated Expression of TWEAK mRNA in Acute and Chronic Inflammatory Pathologies

TWEAK is a newly identified member of the Tumor Necrosis Factor (TNF) family of proteins which are involved in many immunoinflammatory mechanisms. The putative role of TWEAK in inflammation was analyzed in mice treated with lipopolysaccharide (LPS), a strong inducer of the immuno-inflammatory responses. TWEAK mRNA rapidly disappeared in all the tissues tested. Analysis of LPS-treated thioglycolate-elicited peritoneal macrophages revealed that the rapid loss of TWEAK mRNA was due to its active destabilization. In chronic pathologies like autoimmune hemolytic anemia in the NZB mouse strain or systemic lupus erythematosus (SLE) in the BXSB mouse strain, TWEAK mRNA was shown to be reduced concomitantly to the development of chronic autoimmune diseases. These results demonstrated that TWEAK mRNA, contrary to TNF mRNA, is stable, ubiquitously distributed in tissues, and is down-regulated after LPS treatment or in chronic inflammation, suggesting that TWEAK could be an important factor, along with TNF, in acute and chronic inflammations.

Isolation and Characterization of NUC70, a Cytoplasmic, Hematopoietic Apoptotic Endonuclease

Endonucleolytic DNA fragmentation is the common end point and the prevailing indicator of apoptosis. We have identified a 70-kDa endonuclease (NUC70) that is activated in drug-induced apoptosis of human hematopoietic cells. We purified NUC70 to homogeneity and generated a rabbit polyclonal antibody to distinguish it from previously identified nucleases. Biochemical characterization of isolated NUC70 demonstrates that it is Ca2+/Mg2+-dependent and active over a pH range of 6-8. When incubated with isolated HeLa nuclei, NUC70 was capable of generating internucleosomal DNA fragmentation. This endonucleolytic activity was inhibited by Zn2+, aurintricarboxylic acid, N-ethylmaleimide, spermine, and iodoacetamide. Western immunoblots using the anti-NUC70 antibody and DNA-SDS-polyacrylamide gel electrophoresis assays indicate that NUC70 expression and activity is restricted to human hematopoietic cells. No such activity was detected in human epithelial cell lines or murine hematopoietic cells. We also observed no difference in levels of NUC70 expression between apoptotic and nonapoptotic cells, suggesting that activation of NUC70 may be by posttranslational modification. We demonstrate that NUC70 activity is diminished in cells pretreated with the caspase inhibitors z-DEVD-fmk, z-VAD-fmk, and Z-CH2-Asp-DCB. Time course studies of cytoplasmic and nuclear endonuclease activities during apoptosis show that NUC70 is a cytoplasmic endonuclease that is translocated to the nucleus after the initiation of apoptosis. We confirmed this with immunostaining studies using anti-NUC70 antibody. These results demonstrate that NUC70 is an endogenous cytoplasmic endonuclease that is activated during apoptosis in a caspase-dependent mechanism.

Reduced Aggressiveness and Low Testosterone Levels in Autoimmune MRL-lpr Males

Šakić, B., L. Gurunlian, S. D. Denberg.Reduced aggressiveness and low testosterone levels in autoimmune MRL-lpr males.PHYSIOL BEHAV 63(2) 305–309, 1998.—Autoimmune, lupus-prone MRL-lpr mice float excessively in the forced swim test, explore novel objects and places less, and show blunted responsiveness to palatable stimuli, which is consistent with the hypothesis that the development of chronic autoimmune disease alters emotional reactivity and/or motivation. The present study measures isolation-induced fighting, a model of “affective” aggression, in lupus-prone MRL-lpr and control MRL +/+ males. When compared with controls, autoimmune MRL-lpr mice show reduced aggressiveness, as evidenced by fewer fighting contacts, longer attack latency, shorter fighting episodes and shorter duration of fighting. In addition, reduced testosterone levels accompany serological signs of autoimmunity in the MRL-lpr males. The present results support the hypothesis that affective responsiveness is altered in lupus-prone mice and may suggest limbic system dysfunction during chronic autoimmune/inflammatory disease. The question of whether immune activation alters behavior by a direct effect on the nervous system, or also via the endocrine system, requires further study.

Breakdown of self-tolerance in anergic B lymphocytes

Production of autoantibodies, which characterizes most autoimmune diseases, is normally avoided by active elimination or functional inactivation (anergy) of B and T lymphocytes bearing receptors for self antigens. The mechanisms leading to the escape of self-reactive clones from these normal tolerance mechanisms in autoimmune diseases nevertheless remain obscure. Here, we demonstrate that clonal anergy in B lymphocytes is a reversible process, and that silenced self-reactive B cells can be reactivated under particular conditions to give rise to vigorous antibody responses. Reactivation of anergic lymphocytes may explain many examples of transient autoimmune reactions in normal individuals, and may under pathological conditions be important in the development of chronic autoimmune disease.

Susceptibility and resistance of human autoimmune T cell activation to the immunoregulatory effects of transforming growth factor (TGF) β 1, β 2 and β 1.2

The transforming growth factors type β (TGF-β) regulate immune responses by suppresing a variety of leukocyte functions. Using a panel of human autoimmune T cell specific for the acetylcholine 3eceptor (AchR) we investigated the immunoregulatory effects of TGF-β 1, TGF-β 2, and TGF-β 1.2. The cytokines have identical effects inhibiting activation of most T line cells and the activation-dependent changes in interleukin-2 (IL-2) receptor and T cell receptor expression. IL-2-dependent growth was not modulated by TGF-β. However, autoimmune T cell lines specific for AchR differ in their susceptibility to TGF-β and some are completely refractory. Resistance of autoimmune T cell activation to immunosuppressive cytokines might be an element in the development of chronic autoimmune disease.