Abstract: There is a significant association between rheumatoid arthritis (RA) and periodontal disease (PD). Patients with longstanding active RA have been found to have a substantially increased frequency of PD compared with healthy subjects. Further, patients with PD have been shown to have a higher prevalence of RA than patients without periodontitis. Antibodies to Gram-negative, anaerobic periodontal pathogens such as Porphyromonas gingivalis, Prevotella intermedia, Prevotella melaninogenica, and Tannerella forsythia have been detected in the serum and synovial fluid of RA patients. These pathogens have also been identified in the synovial fluid of RA patients, with higher levels of bacterial DNA in RA patients than in controls. This review examines the association between periodontopathic bacteria and the etiology of RA. ... Read more

Abstract: Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease for which therapeutic advances in immunosuppressive and support therapy have significantly improved survival over the last 5 decades. Unfortunately, SLE still carries substantially increased rates of mortality and end stage renal disease which are even more elevated in younger patients. No new drugs have been approved for SLE in over 50 years. Hence, a lot of hope and excitement has been generated by the development of biological agents designed to eliminate B cells either through direct killing (anti-B cell antibodies such as rituximab) or attrition by inhibition of survival (anti-BLyS/BAFF agents such as belimumab). Indeed a strong rationale for targeting B cells in SLE is supported by the major pathogenic roles they play in SLE through both autoantibody production and multiple antibody-independent functions. These hopes, however, have been darted by the failure of two different phase III randomized placebo-controlled trials of rituximab. Yet, clinicians continue to use rituximab off-label with the belief that it provides significant benefit and can rescue patients with disease that is refractory to current modalities. Moreover, recent positive results of two large controlled trials of belimumab have restored confidence that B cell targeting may after all be of benefit in SLE. In this review we discuss the background and rationale for the use of anti-B cell agents in SLE, review the available results, and provide models that could help reconcile the opposing results observed in different studies. These models could also help frame the design and evaluation of current and future B cell therapies. ... Read more

Abstract: Crohn's disease is an immune-mediated disease that is characterized by chronic intestinal inflammation. Effector CD4+ T-lymphocytes are expanded in Crohn's disease-associated inflammatory lesions and play a critical role in the pathogenesis of this condition. Recently, a novel population of effector T-lymphocytes has been identified, which is clearly separated from the traditional Th1 and Th2 lineages and is characterized by the secretion of IL-17, hence its designation as Th17. The development of this population has been closely linked to IL-23, a member of the IL-12 family of cytokines. Converging lines of evidence support the hypothesis that the IL-23/Th17 axis is of pathogenic relevance for Crohn's disease. Protein and mRNA levels of IL-23, IL-17, and other Th17 effector cytokines, such as IL-21 and IL-22, are elevated in areas with active Crohn's disease-related inflammation, whereas lamina propria mononuclear cells from patients with Crohn's disease secrete increased amounts of IL-17 upon T-cell receptor-specific stimulation. Genome-wide association studies have identified several Crohn's disease-associated polymorphisms in genes that encode for proteins of the IL-23/Th17 pathway. Functional studies have shown that Th17-related effector cytokines induce pro-inflammatory responses that are components of the pathogenetic mechanisms of Crohn's disease, including recruitment of neutrophils via IL-8 induction, upregulation of inflammatory mediators such as TNF-α, IL-1β, and IL-6, and secretion of metalloproteinases by intestinal fibroblasts. Finally, in several animal models of intestinal inflammation, disease severity is ameliorated when the IL-23/Th17 pathway is rendered deficient. These findings point to a critically important role for IL-23/Th17-mediated immune responses in Crohn's disease pathogenesis and may offer unique therapeutic opportunities for patients. ... Read more

Abstract: Systemic lupus erythematosus (SLE) is a heterogeneous group of autoimmune disorders defined by a consensus of clinical and laboratory criteria. Much of the pathophysiology and therapy of SLE has focused on autoimmune B and T cells of the adaptive immune system. Recently, the role of macrophages, part of the innate immune system, in SLE pathogenesis has gained attention. The field of immunology in general has recently changed in the way that it approaches macrophages. Rather than viewing them as a single, concrete whole, it has become clear that different subpopulations of macrophages contribute to various immune and non-immune processes. Such a nomenclature may provide an ideal framework from which to study macrophage pathogenesis in SLE. Studies suggest that M1 subtype macrophages play an important inflammatory role in SLE pathogenesis. Further, apparently reduced populations of M2a and M2c subtype macrophages may contribute to the lack of anti-inflammatory activity apparent in the disease. M2b subtype macrophages may actually have a role in causing disease directly. Regulatory macrophages have yet to be explored thoroughly in SLE, though the presence of a few of their markers may mean that they are active in suppressing SLE-related inflammation. ... Read more

Abstract: Patients with autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and Sjögren's syndrome have an increased risk of developing B-cell non-Hodgkin's lymphomas but the mechanisms behind this phenomenon remain unknown. By focusing on recent research reports we explore and discuss some of the proposed mechanisms that contribute to this link. The complexity is enormous and can involve genetic and environmental factors, chronic immune stimulation by antigens, and even the treatment for these autoimmune diseases. These mechanisms can be combined in different ways causing great variability in one's predisposition to lymphomagenesis. Knowing more about these pathways is urgent. The more we know about autoimmune diseases the better we can treat our patients effectively and the more we can prevent lymphomas from developing. ... Read more

Abstract: A large body of evidence implicates the immune system in the pathogenesis and modulation of atherosclerosis. Dendritic cells and lymphocytes are among the many components of the immune system that are involved in modulating atherogenesis. This review focuses on the current knowledge of the complex role of the dendritic cells and lymphocytes in atherogenesis and the potential for immune-modulation therapies for atherosclerosis. ... Read more

Abstract: Systemic sclerosis (SSc) is a complex fibrosing autoimmune disease that has variable clinical manifestations and morbidity/mortality secondary to organ damage due to vasculopathy and/or fibrosis. Initial events in the pathogenesis are manifested by fibroproliferative vasculopathy that compromises delivery of blood to critical organs. There is evidence of autoimmunity early in the disease which persists and is accompanied by fibrotic processes that leave large accumulations of collagen and other matrix components in the intima of blood vessels and extracellularly in the connective tissue of organs affected by the disease. It has recently been realized that the lysophospholipids -- lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), which are elevated in sera of SSc patients, are capable of producing many of the abnormalities observed in the vasculature, immune system, and connective tissue of patients with this disease. This article reviews key abnormalities of the vasculature, immune system, and connective tissue in SSc that could be mediated by LPA/S1P. ... Read more

Abstract: Rheumatoid arthritis (RA) is the most common chronic inflammatory disorder of the musculoskeletal system that may cause permanent joint damage. The disease has a major impact on the quality of life of affected individuals, costs for the health care system, and society. Currently, no curative treatment is available, and patients are subjected to a prolonged course of treatment. Due to their role in the pathogenesis of RA, B cells have become an attractive target for therapy. Rituximab (Mabthera^®/Rituxan^®) is a therapeutic monoclonal antibody against CD20 expressed on B cells, which is effective in depleting B cells and approved worldwide for the treatment of RA. Rituximab was shown to be highly beneficial in decreasing clinical symptoms, safe, and well tolerated. However, clinical experience revealed that approximately 30-40% of RA patients do not respond to it. Given the destructive nature of RA, the risk of adverse effects, and considerable costs for therapy, there is a strong need to make predictions on the clinical outcome before the start of therapy. Since nearly all treated patients experience an effective depletion of circulating B cells, questions have been raised concerning the mechanism of action. In this review, novel developments, in particular the findings on the role of the interferon system, will be highlighted. This may add new and important information to our understanding of the mechanism that underlies the clinical outcome of rituximab treatment and may lead to the identification of biomarkers to predict the response. ... Read more

Abstract: Type 1 diabetes is an organ-specific autoimmune disease caused by chronic inflammation (insulitis), which damages the insulin producing β-cells of the pancreatic Islets of Langerhans. Dendritic cells (DCs) are generally the first cells of the immune system to process β-cell autoantigens and, by promoting autoreactivity, play a major role in the onset of insulitis. Although no cure for diabetes presently exists, the onset of insulitis can be diminished in the non-obese diabetic (NOD) mouse type 1 diabetes model by inoculation with endogenous β-cell autoantigens. These include the single peptide vaccines insulin, GAD₆₅ (glutamic acid decarboxylase), and DiaPep277 (an immunogenic peptide from the 60-kDa heat shock protein). DiaPep277 is the only autoantigen so far to demonstrate positive results in human clinical trials. Diamyd (an alum adjuvant + recombinant GAD₆₅ protein formulation) has shown great promise for suppressing β-cell autoreactivity in phase I and II clinical trials. While Diamyd preserved residual insulin secretion in early-onset type 1 diabetes patients, it did not reduce the amounts of insulin required to maintain euglycemia. Recently, multi-component vaccines composed of the anti-inflammatory cytokine (IL-10) and insulin or GAD₅₅ linked to an immunostimulatory molecule, the cholera toxin B subunit, were shown to safely and completely inhibit diabetes onset in NOD mice. This result suggests that multi-component vaccine strategies are promising for prevention and reversal of diabetes autoimmunity in humans. Here we focus on the development of autoantigen vaccines for type 1 diabetes and demonstrate that multi-component vaccines are promising candidates for type 1 diabetes clinical studies. ... Read more

Abstract: Interleukin-21 (IL-21), a cytokine produced by activated CD4+ T cells, activated natural killer T cells, and T follicular cells, has been reported to play a crucial role in the tissue-damaging T cell response in various organs, such as gut, skin, pancreas, and joints. This pathogenic effect is strictly linked to the ability of IL-21 to enhance the functional activities of multiple immune and non-immune cells. Consistently, studies from various laboratories have shown that blockade of IL-21 limits the progression of T cell-mediated inflammatory diseases in mice. Here we review the present knowledge on the expression and role of IL-21 in T cell-mediated pathologies. ... Read more