Redox state, cell death and autoimmune diseases: a gender perspective

Autoimmune disorders, redox balance and gender differences are closely connected. In fact, activation, proliferation and death of cells of different histotype, including blood and vascular cells, are under control of oxidative balance and are key players in autoimmune disease pathogenesis and progression. However, cells from male and female appear characterized by a huge series of differences in terms of reactive oxygen species production and oxidative stress susceptibility. In this review, we briefly summarize the possible implications of the redox state in the onset and progression of autoimmune diseases in a gender perspective.     

Macrophages in Lupus Nephritis: Exploring a potential new therapeutic avenue

Lupus nephritis (LN) is a serious complication of systemic lupus erythematosus (SLE) that occurs in about half of patients. LN is characterized by glomerular deposition of immune complexes, leading to subendothelial, mesangial and subepithelial electron dense deposits, triggering immune cell infiltration and glomerular as well as tubulointerstitial injury. Monocytes and macrophages are abundantly present in inflammatory lesions, both in glomeruli and the tubulointerstitium. Here we discuss how monocytes and macrophages are involved in this process and how monocytes and macrophages may represent specific therapeutic targets to control LN.     

Novel, non-antigen-specific therapeutic approaches to autoimmune/inflammatory diseases

Anti-TNF therapy has made a major impact on the treatment of inflammatory arthritides and Crohn's disease. It leads to prompt and prolonged clinical response, even in patients refractory to conventional therapy. Moreover, the progression of joint damage noted in patients with rheumatoid arthritis treated with methotrexate was prevented by an anti-TNF-alpha antibody, suggesting a genuine disease-modifying potential of TNF-alpha blockade.     

The role of regulatory T-cells in autoimmune rheumatic diseases

Regulatory T-cells CD4+CD25+Foxp3, possessing suppressory activity, play the key role in the development of autoimmune diseases, maintenance of peripheral tolerance in transplantation immunity, and the prevention of a pathological immune response to intestinal microflora or microbial infection. A decrease in the total number of circulating CD4+CD25+ regulatory T-cells and their suppressive activity have been found in patients suffering from various autoimmune diseases, such as type 1 diabetes, multiple sclerosis, autoimmune hepatitis, psoriatic arthritis, juvenile idiopathic arthritis, and systemic lupus erythematosus (SLE). The authors of this study investigated the phenotypic characteristics of peripheral blood lymphocytes in 31 SLE patients and the effect of treatment on the content of CD4+CD25+ T-cells before and after pulse therapy with methylprednisolone and cyclophosphan. The total number of regulatory T-cells in the group of untreated patients was almost twice lower vs. the group of healthy donors. As a result of the therapy, the proportion of regulatory T-cells increased significantly, although it did not reach the values in the control group. The data from this research confirm the development of a defect of CD4+CD25+ T-cells at the active phase of SLE, and a possibility to partially correct this defect with an effective therapy.     

Oral tolerance: therapeutic implications for autoimmune diseases

Oral tolerance is classically defined as the suppression of immune responses to antigens (Ag) that have been administered previously by the oral route. Multiple mechanisms of tolerance are induced by oral Ag. Low doses favor active suppression, whereas higher doses favor clonal anergy/deletion. Oral Ag induces Th2 (IL-4/IL-10) and Th3 (TGF-beta) regulatory T cells (Tregs) plus CD4+CD25+ regulatory cells and LAP+T cells. Induction of oral tolerance is enhanced by IL-4, IL-10, anti-IL-12, TGF-beta, cholera toxin B subunit (CTB), Flt-3 ligand, anti-CD40 ligand and continuous feeding of Ag. In addition to oral tolerance, nasal tolerance has also been shown to be effective in suppressing inflammatory conditions with the advantage of a lower dose requirement. Oral and nasal tolerance suppress several animal models of autoimmune diseases including experimental allergic encephalomyelitis (EAE), uveitis, thyroiditis, myasthenia, arthritis and diabetes in the nonobese diabetic (NOD) mouse, plus non-autoimmune diseases such as asthma, atherosclerosis, colitis and stroke. Oral tolerance has been tested in human autoimmune diseases including MS, arthritis, uveitis and diabetes and in allergy, contact sensitivity to DNCB, nickel allergy. Positive results have been observed in phase II trials and new trials for arthritis, MS and diabetes are underway. Mucosal tolerance is an attractive approach for treatment of autoimmune and inflammatory diseases because of lack of toxicity, ease of administration over time and Ag-specific mechanism of action. The successful application of oral tolerance for the treatment of human diseases will depend on dose, developing immune markers to assess immunologic effects, route (nasal versus oral), formulation, mucosal adjuvants, combination therapy and early therapy.     

IL-35: a new immunomodulator in autoimmune rheumatic diseases

IL-35 is a relatively new cytokine that emerges as an important immunomodulator. IL-35 belongs to IL-12 cytokine family that includes IL-12, IL-23, IL-27, and IL-35. These cytokines are heterodimers that share subunits and their receptors also share subunits. Whereas IL-12 and IL-23 are clearly proinflammatory cytokines, the role of IL-35 is less clear. In mice, IL-35 appears to be anti-inflammatory and to protect from autoimmune inflammatory diseases. IL-35 induces the expansion of a subset of regulatory T cells (Tregs) and Bregs and mediates their suppressive function and inhibits Th17 cells. It also upregulates osteoprotegerin and suppresses RANKL, thus inhibiting bone resorption. In autoimmune rheumatic diseases, findings are conflicting, although in systemic lupus erythematosus, there is reduced function of IL-35. In psoriatic arthritis, a disease characterized by bone erosion and bone formation in peripheral joints and bone formation in spinal joints, serum levels of IL-35 were found increased in one study. Further data are required to define the exact role of IL-35 in human autoimmune rheumatic diseases.     

调节性B淋巴细胞在自身免疫性疾病中的研究进展

自身免疫性疾病是指机体对自身成分产生免疫应答所致的一种疾病状态,这种自身免疫反应会影响相应器官的功能.在大多数自身免疫性疾病中,B淋巴细胞（简称B细胞）能产生自身抗体,因此一般被认为是自身免疫性疾病的”罪魁祸首”.最近大量研究发现,一类特殊的B细胞亚群即调节性B细胞（Bregs）能下调免疫反应,很好地维持免疫稳态,它们的丢失或缺乏会导致更加严重的自身免疫性疾病,且这种免疫调节功能主要通过自身分泌白细胞介素-10（IL-10）来实现.Bregs的起源、与其分化和功能相关的分子及其在自身免疫性疾病的作用将被进一步讨论.     

Carbohydrate mimicry: a new paradigm of autoimmune diseases

Molecular mimicry of microbial components by self components is thought to be the mechanism that accounts for the antigen and tissue specificity of immune responses in post-infectious autoimmune diseases. Little direct evidence exists, and research in this area has focused principally on T cell mediated anti-peptide responses, rather than on humoral responses to carbohydrate structures. Guillain-Barré syndrome, the most frequent cause of acute neuromuscular paralysis, sometimes occurs after Campylobacter jejuni enteritis. Recent studies have revealed that carbohydrate mimicry of the bacterial lipo-oligosaccharide by the human ganglioside is an important cause of the syndrome. This new concept that carbohydrate mimicry can cause an autoimmune disease provides a clue to inducing the resolution of pathogenesis of other immune-mediated diseases.     

Scanty congenital plasmodium parasites as a possible cause for several autoimmune diseases

Recently it was reported that 19.8% of the patients with rheumatoid factor, who had no previous history of malaria and had not visited endemic regions for at least the past five years, generated false-positive results in two rapid malaria tests that capture two different plasmodium antigens. This intriguing finding supports the hypothesis presented, suggesting systemic lupus erythematosus and possibly several other autoimmune diseases are caused by a scanty amount of persistent plasmodium parasites in the internal tissues, which provokes diverse autoantibodies production, and can be transmitted congenitally. This hypothesis suggests a comprehensive explanation for the predominance of autoimmune diseases in African populations in the West yet their infrequency in tropical Africa, and for the studies reporting that several of these diseases benefit from antimalarials. The implication of this hypothesis is that these autoimmune diseases are actually infectious, and may infect individuals who contracted malaria in the past or whose female ancestors had contracted it, and possibly blood transfusion recipients.     

CCR6-CCL20 axis as a therapeutic target for autoimmune diseases

Chemokine receptor CCR6 is expressed on various cells such as B cells, immature dendritic cells, innate lymphoid cells (ILCs), regulatory CD4 T cells, and Th17 cells. CCL20 is the only known high-affinity ligand that binds to CCR6 and drives CCR6⁺ cells' migration in tissues. CCL20 is mainly produced by epithelial cells, and its expression is increased by several folds under inflammatory conditions. Genome-wide association studies (GWAS) in patients with inflammatory bowel disease (IBD), psoriasis (PS), rheumatoid arthritis (RA), and multiple sclerosis (MS) showed a very strong correlation between the expression of CCR6 and disease severity. It has been shown that disruption of CCR6-CCL20 interaction by using antibodies or antagonists prevents the migration of CCR6 expressing immune cells at the site of inflammation and reduces the severity of the disease. This review discussed the importance of the CCR6-CCL20 axis in IBD, PS, RA, and MS, and recent advances in targeting the CCR6-CCL20 in controlling these autoimmune diseases.     

Human regulatory T cells: role in autoimmune disease and therapeutic opportunities

Summary The importance of regulatory T lymphocytes (Tregs) in the control of autoimmunity is now well established in a variety of experimental animal models. In addition, there are numerous studies suggesting that Treg deficits may be an underlying cause of human autoimmune diseases. The emergence of Tregs as an essential component of immune homeostasis provides a potential therapeutic opportunity for active immune regulation and long-term tolerance induction. In this article, we summarize the core basic science and animal model studies of Tregs, review the status of multiple biologic and small molecule chemical compounds to promote Treg development in vivo , and discuss recent advances for the identification and expansion of polyclonal and antigen-specific Tregs for adoptive immunotherapy. In summary, the review provides an in-depth analysis and highlights the challenges and opportunities for immune intervention with Treg-based therapeutics.     

B-cell targeted therapies in human autoimmune diseases: an updated perspective

Summary: The advent of therapies that specifically target the B-lymphocyte lineage in human disease has rejuvenated interest in the mechanistic biology by which B cells mediate autoimmunity. B cells have a multitude of effector functions including production of self-reactive antibodies, ability to present antigen to T lymphocytes in the context of costimulation, involvement in generation and maintenance of neo-organogenesis at sites of disease, and opposing function through production of both immunostimulatory and immunomodulatory cytokines. In this review, we first discuss the role of B cells in driving autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, and Sjögren’s syndrome, and discuss how studies in these diseases have revealed differentially important roles for the multiple B-cell effector functions. These data reveal the complex and interrelated roles of B cells working in concert with other components of the innate and adaptive immune system to drive pathogenesis. We then focus on data from mouse and human in which B cells in the setting of disease have been targeted with drugs directed against CD20, CD22, and the BAFF (B-cell activating factor belonging to the tumor necrosis factor family)/APRIL (a proliferation inducing ligand) pathways. Pre-clinical studies in animal models in addition to and clinical trials targeting B cells have added further to the understanding of the differential roles B cells play in disease both through demonstration of clinical efficacy in the context of B-cell depletion or modulation, and also by failure of B-cell targeting in some diseases and disease patient subgroups. Moving forward, it will be imperative to apply these lessons to new interventional trials to ensure better targeting of the B-cell lineage and concomitantly better selection of patients most likely to benefit from these therapies.     

SOCS signaling in autoimmune diseases: Molecular mechanisms and therapeutic implications

Suppressor of cytokine signaling (SOCS) proteins are mainly induced by various cytokines and have been described as classical inhibitors of cytokine signaling. SOCS signaling is involved in the regulation of immune cells, and recent findings suggest that SOCS proteins, especially SOCS1 and SOCS3, are often dysregulated in a wide variety of autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, psoriasis, and multiple sclerosis. Recent studies suggest that SOCS signaling could be therapeutically targeted in various autoimmune diseases. In this review, we discuss recent studies on the role of SOCS proteins in the development and pathogenesis of autoimmune diseases, as well as their clinical implications.