Loss Of Immunological Self-tolerance Research Articles

Diet, DNA methylation and systemic lupus erythematosus: evidence and perspectives focused on personalized nutrition

Background: The pathoetiology of systemic lupus erythematosus (SLE) involves a multifactorial interaction consisting of various genetic, epigenetic and environmental factors. Considering epigenetic characteristics, notable alterations in DNA methylation, particularly hypomethylation in immune-related pathways, such as T cell receptor have been observed. In turn, these alterations are associated with the overexpression of genes related to autoimmunity and a loss of immunological self-tolerance. Furthermore, DNA hypomethylation levels in SLE may contribute to disease progression and also impact disease activity and clinical manifestations. Summary: It is well-established that nutritional epigenetics elucidates the role of nutrition and dietary factors on the interactions of metabolic systems with the molecules that bind to DNA, regulating gene expression. Specific nutritional interventions may reverse initial epigenetic patterns, thereby significantly impacting the chronic disease´s treatment and prognostic. In fact, dietary nutrients and bioactive food compounds may influence DNA methylation patterns by inhibiting enzymes related to DNA methylation reactions or by altering the availability of different substrates involved in DNA methylation process (e.g methyl-donor nutrients). Key Messages: The knowledge of how diet plays a role in changing DNA methylation patterns in SLE is in the early stages. While a few studies in the literature have assessed the effects of nutrient intake, supplementation, or treatment on DNA methylation levels and have demonstrated their relevance, further research is imperative to deepen our comprehension of the interactions between epigenetics and nutrients, which is vital for the development of novel precision nutrition approaches.

Neutrophils modulate the progression of B cell auto-reactivity in systemic lupus erythematosus

Abstract The central feature of systemic lupus erythematosus (SLE) pathogenesis is loss of immunologic self-tolerance. Here, we address a current controversy regarding whether neutrophils influence the development of B cell auto-reactivity SLE. While both human and murine lupus neutrophils produce factors known to fuel adaptive immune dysregulation, including type I interferon, B cell survival factors, and extracellular traps (a putative source of self-antigen), some studies have contended that neutrophils in peripheral lymphoid organs (PLO) suppress B cell activation and differentiation. In order to ask whether neutrophils exert regulatory or deleterious effects on loss of B cell self-tolerance and immune activation, we compare changes in SLE progression following neutrophil depletion in the NZB/W lupus model, either during or after establishment of disease. Following depletion early in disease, we observe pronounced acceleration of proteinuria, anti-dsDNA titers, and germinal center formation. However, neutrophil depletion after onset of overt disease pathology (including proteinuria) does not strongly alter SLE progression, implicating neutrophils as playing a protective role only apparent during disease onset. To elucidate the specific mechanisms underlying neutrophil effects on B cell auto-reactivity, we examine the cytokine profile of neutrophils in direct proximity to B cells in PLO during several stages of disease. With progression of disease, we observe an influx of interferon-alpha-producing neutrophils in direct proximity to B cells in PLO. These data delineate a shifting balance of both regulatory and activating roles for neutrophils in auto-reactive B cell activation/proliferation during SLE progression.

Diminished salivary epidermal growth factor secretion: a link between Sjögren’s syndrome and autoimmune gastritis?

Objectives: Healthy human labial salivary glands produce epidermal growth factor (EGF). In Sjögren’s syndrome (SS), EGF staining is diminished. SS is also associated with chronic autoimmune corpus gastritis. We therefore hypothesized that EGF secretion would be diminished in SS and that this could affect gastric target cells.Methods: Salivary EGF secretion in SS was compared to that in healthy controls using an enzyme-linked immunosorbent assay (ELISA). EGF receptor (EGFR) immunoreactive cells in the gastric corpus of healthy human subjects were analysed using immunostaining.Results: Salivary secretion of EGF was diminished in SS patients (232.4, range 52.6–618.4, vs. 756.6, range 105.3–1631.6 pg/min, p = 0.002). Proton-pump positive parietal cells were mostly EGFR immunoreactive whereas very few pepsinogen I (PGI)-positive cells were EGFR positive.Conclusions: As EGF is relatively acid resistant, salivary gland-derived EGF might participate in an exo/endocrine mode of parietal cell maintenance in the gastric corpus. Deficiency of salivary gland-derived EGF in SS patients may cause impairment of gastric parietal cells resulting in exposure of immunogenic cryptic antigens and loss of immunological self-tolerance.

The mechanisms and applications of T cell vaccination for autoimmune diseases: a comprehensive review.

Autoimmune diseases (ADs) are a spectrum of diseases originating from loss of immunologic self-tolerance and T cell abnormal autoreactivity, causing organ damage and death. However, the pathogenic mechanism of ADs remains unclear. The current treatments of ADs include nonsteroidal anti-inflammatory drugs (NSAIDS), antimalarials, corticosteroids, immunosuppressive drugs, and biological therapies. With the need to prevent side effects resulting from current treatments and acquire better clinical remission, developing a novel pharmaceutical treatment is extremely urgent. The concept of T cell vaccination (TCV) has been raised as the finding that immunization with attenuated autoreactive T cells is capable of inducing T cell-dependent inhibition of autoimmune responses. TCV may act as an approach to control unwanted adaptive immune response through eliminating the autoreactive T cells. Over the past decades, the effect of TCV has been justified in several animal models of autoimmune diseases including experimental autoimmune encephalomyelitis (EAE), murine autoimmune diabetes in nonobese diabetic (NOD) mice, collagen-induced arthritis (CIA), and so on. Meanwhile, clinical trials of TCV have confirmed the safety and efficacy in corresponding autoimmune diseases ranging from multiple sclerosis (MS) to systemic lupus erythematosus (SLE). This review aims to summarize the ongoing experimental and clinical trials and elucidate possible molecule mechanisms of TCV.

Therapeutic Effect of Human Amniotic Membrane–Derived Cells on Experimental Arthritis and Other Inflammatory Disorders

Rheumatoid arthritis (RA) is an autoimmune disease caused by loss of immunologic self tolerance and characterized by chronic joint inflammation. Cells isolated from human amniotic membrane (HAMCs) were recently found to display immunosuppressive properties. The aim of this study was to characterize the effect of HAMCs on antigen-specific T cell responses in RA patients and to evaluate their therapeutic potential in a preclinical experimental model of RA. We investigated the effects of HAMCs on collagen-reactive T cell proliferation and cytokine production, on the production of mediators of inflammation by synoviocytes, and on the generation of Treg cells in peripheral blood mononuclear cells and synovial membrane cells isolated from RA patients. Mice with collagen-induced arthritis (CIA) were treated with HAMCs after disease onset, and clinical scores and joint levels of mediators of inflammation were evaluated. We determined Th1/Th17-mediated autoreactive responses in the mice by measuring the proliferation and the cytokine profile of lymph node cells restimulated with collagen. Treatment with HAMCs suppressed synovial inflammatory responses and antigen-specific Th1/Th17 activation in cells isolated from RA patients. Moreover, HAMCs stimulated the generation of human CD4+CD25+FoxP3+ Treg cells with a capacity to suppress collagen-specific T cell responses. Systemic infusion of HAMCs significantly reduced the incidence and severity of CIA by down-regulating the 2 deleterious components of disease: Th1-driven autoimmunity and inflammation. In mice with CIA, HAMC treatment decreased the production of various inflammatory cytokines and chemokines in the joints, impaired antigen-specific Th1/Th17 cell expansion in the lymph nodes, and generated peripheral antigen-specific Treg cells. HAMCs also protected the mice from experimental sepsis, inflammatory bowel disease, and autoimmune encephalomyelitis. HAMCs have emerged as attractive candidates for a cell-based therapy for RA.

Treatment of experimental arthritis by inducing immune tolerance with human adipose‐derived mesenchymal stem cells

Rheumatoid arthritis (RA) is a chronic autoimmune disease caused by loss of immunologic self tolerance and characterized by chronic joint inflammation. Adult mesenchymal stem cells (MSCs) were recently found to suppress effector T cell responses and to have beneficial effects in various immune disorders. The purpose of this study was to examine a new therapeutic strategy for RA based on the administration of human adipose-derived MSCs (AD-MSCs). DBA/1 mice with collagen-induced arthritis were treated with human AD-MSCs after disease onset, and clinical scores were determined. Inflammatory response was determined by measuring the levels of different mediators of inflammation in the joints and serum. The Th1-mediated autoreactive response was evaluated by determining the proliferative response and cytokine profile of draining lymph node cells stimulated with the autoantigen. The number of Treg cells and the suppressive capacity on self-reactive Th1 cells were also determined. Systemic infusion of human AD-MSCs significantly reduced the incidence and severity of experimental arthritis. This therapeutic effect was mediated by down-regulating the 2 deleterious disease components: the Th1-driven autoimmune and inflammatory responses. Human AD-MSCs decreased the production of various inflammatory cytokines and chemokines, decreased antigen-specific Th1/Th17 cell expansion, and induced the production of antiinflammatory interleukin-10 in lymph nodes and joints. Human AD-MSCs also induced de novo generation of antigen-specific CD4+CD25+FoxP3+ Treg cells with the capacity to suppress self-reactive T effector responses. Human AD-MSCs emerge as key regulators of immune tolerance by inducing the generation/activation of Treg cells and are thus attractive candidates for a cell-based therapy for RA.

High Frequency of Skewed X-Chromosome Inactivation in Females with Autoimmune Thyroid Disease: A Possible Explanation for the Female Predisposition to Thyroid Autoimmunity

Autoimmune thyroid diseases (AITD) comprise Graves' disease (GD) and Hashimoto's thyroiditis (HT). They are characterized by loss of immunological self-tolerance and female preponderance. Theoretically, X chromosome inactivation (XCI) and resultant tissue chimerism could offer an explanation for the female predisposition to AITD. Our aim was to examine whether skewed XCI is associated with AITD. We first conducted a classical case-control study of twin individuals with and without AITD, and then a case-control study of twin pairs discordant for AITD. Participants included 32 female twins with AITD and a control group of 96 healthy female twin individuals. XCI analysis was performed by enzymatic predigestion of DNA with a methylation-sensitive enzyme followed by PCR of the polymorphic CAG repeat of the androgen receptor gene. The XCI pattern was classified as skewed when 80% or more of the cells preferentially inactivated the same X chromosome. We assessed the prevalence of skewed XCI. The frequency of skewed XCI in female twins with AITD, GD, and HT was 34, 37, and 31%, respectively, which was higher than the prevalence in the corresponding control populations, 11% (P = 0.003), 14% (P = 0.045), and 8% (P = 0.057), respectively. Similar results were found in twin pairs discordant for AITD. Overall, skewed XCI was associated with an increased risk of developing AITD, with an odds ratio of 9.0 (95% confidence interval, 1.64-49.4) (P = 0.022). These observations suggest a possible role of XCI in the etiology of AITD and may in part explain the female preponderance of AITD.