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Treating IgA Nephropathy: Quid Novi?

Abstract: IgA nephropathy is a common autoimmune renal disease resulting in kidney failure for patients with significant proteinuria. The therapeutic options are limited including non-specific treatment to reduce proteinuria accomplished by renin-angiotensin blockade. Strategies to control intrarenal inflammation include the administration of fish oil and for severe disease the use of immunosuppressive agents such as cyclophosphamide, glucocorticosteroids, and mycophenolate mofetil. In light of the limited option, there is an unmet need for novel therapeutic intervention in patients with progressive disease. Herein, we review the evidence for existing treatment choices and explore new immunopharmacologic agents being investigated for IgA nephropathy. ... Read more

The Role of Microbial Byproducts in Protection Against Immunological Disorders and the Hygiene Hypothesis

Abstract: Over the past three decades the incidence of allergic disorders and autoimmune diseases has risen and this trend is particularly prominent in developed nations. The hygiene hypothesis suggests that as a living environment becomes more sanitized, children are not exposed to microbial and parasitic stimulations that were once commonly acquired since early in life, leading to a lack of immune sensitization tending towards T helper 2 (Th2) dominance. This postulation is sufficient to explain allergic disorders, which mostly result from hyper Th2 responses, but inadequate to explain the increase in Th1 or Th17-based autoimmunity. Recent advances in experimental mouse models revealed that stimulation of Toll-like receptors (TLRs) by pathogen-associated molecular patterns could reduce symptoms of allergic airway disease and prevent the onset of autoimmunity. The underlying mechanism for the protective effects of TLR ligands is currently under intense investigation and there are indications that IL-10-producing B cells, regulatory T cells, and innate immune cells play an important role during this process. The finding that early exposure to microbial byproducts contributes to the modulation of immunological disorders may once again modify our interpretation of the hygiene hypothesis. ... Read more

Gut-mediated and HLA-B27-associated Arthritis: An Emphasis on Ankylosing Spondylitis and Crohn's Disease with a Proposal for the Use of New Treatment

Abstract: Ankylosing spondylitis (AS) and Crohn's disease (CD), especially when associated with spondylitis are interrelated conditions included within the categories of spondyloarthropathic disease entities. They share some common clinical, genetic, and microbiological findings. An extensive amount of studies which have been carried out by various independent groups throughout the world have shown that Klebsiella pneumoniae microorganisms could be suggested as the most likely etiopathogenetic triggers for AS and CD based on the molecular mimicry mechanism and the existence of the evidence for immunological, microbiological, and molecular link between Klebsiella and self antigens. It is proposed that the use of low starch diet in conjunction with the currently used treatment might help in the eradication of Klebsiella microbes from the bowel and could result in the stoppage and alleviation of the disease process in patients with AS and/or CD. ... Read more

Cytokine Regulation of B-cell Migratory Behavior Favors Formation of Germinal Centers in Autoimmune Disease

Abstract: Chemotaxis is essential for shaping immune responses and chemokine-receptor antagonists are now being evaluated as therapies for various inflammatory and autoimmune diseases. However, the dysregulation of chemotaxis in autoimmune disease may involve both promotion and inhibition of B-cell migration. This review focuses on the disparate mechanisms by which two inflammatory cytokines that have been associated with autoimmune disease, namely interferon-α (IFNα) and interleukin-17 (IL-17), may regulate B-cell migratory responses. Chemotactic responses play a key role in orchestrating the cell-cell interactions in the germinal centers (GCs). This process involves active shuttling of the antigen-carrying B cells between the marginal zone and the GCs. We have shown that in autoimmune BXD2 mice, the migration of marginal zone precursor B cells is promoted by high levels of IFNα produced by plasmacytoid dendritic cells in the marginal sinus that antagonize the activity of the S1P1 chemokine receptor. In contrast, within the GCs, interleukin-17A (IL-17A) upregulates the expression of regulators of G protein signaling (RGS) in B cells to desensitize the G protein-coupled receptor (GPCR) signaling pathway of CXCL12 and CXCL13 chemokines. This promotes a prolonged stable interaction of B and T cells in the GC that induces high levels of activation-induced cytidine deaminase (AICDA) thereby enabling development of pathogenic autoantibody-producing B cells. ... Read more

Genetics of Systemic Lupus Erythematosus: Contributions of Mouse Models in the Era of Human Genome-Wide Association Studies

Abstract: The past two years have brought great progress in the genetics of systemic lupus erythematosus (SLE) heralded by the publication of genome-wide association studies in humans and the identification of susceptibility genes in mouse models of spontaneous lupus. This influx of new information has revealed an ever-increasing interdependence between the mouse and human systems for unraveling the genetic basis of lupus susceptibility. SLE is a complex disease in which defects in several functional pathways have been identified. Genetic variants in a number of genes in these pathways have now been directly associated with lupus in both species. These discoveries have lead to a better understanding of the mechanisms of disease, and offer potential novel target for therapeutic intervention. As a large number of susceptibility genes are identified, lupus genetics will focus on mechanistic and molecular studies, in which mouse models will continue to serve a pre-eminent role. ... Read more

Cross-talk of Alloimmune Response and Autoimmunity: Role in Pathogenesis of Chronic Rejection

Abstract: Chronic rejection following organ transplantation continues to be a major problem in the long-term survival of the engraftment. Recent literature points to role of both the humoral and cellular alloimmune responses in the pathogenesis of chronic rejection. Our recent studies have provided evidence for alloimmune-response-induced de novo development of immune responses to self-antigens in the post-transplant period in the pathogenesis of chronic rejection following lung, heart, and kidney transplantation. This review details our current understanding of two distinct yet inter-dependent immune processes in the immunopathogenesis of chronic rejection. ... Read more

Vaccines and Autoimmune Diseases of the Adult

Abstract: Infectious agents contribute to the environmental factors involved in the development of autoimmune diseases possibly through molecular mimicry mechanisms. Hence, it is feasible that vaccinations may also contribute to the mosaic of autoimmunity. Evidence for the association of vaccinations and the development of these diseases is presented in this review. Infrequently reported post-vaccination autoimmune diseases include systemic lupus erythematosus, rheumatoid arthritis, inflammatory myopathies, multiple sclerosis, Guillain-Barré syndrome, and vasculitis. In addition, we will discuss macrophagic myofasciitis, aluminum containing vaccines, and the recent evidence for autoimmunity following human papilloma virus vaccine. ... Read more

Immune Modulation of Blood-derived Stem Cell as a Comprehensive Tool for Treating Type 1 Diabetes

Abstract: Type 1 diabetes (T1D) is an autoimmune disease in which the patient's immune system recognizes their pancreatic islet insulin-producing cells and destroys them. To cure T1D in a comprehensive manner, not only must the islet cells be replaced, the patient's immune system must also be properly regulated mostly in the form of suppression. Blood-derived new stem cells have shown promise in both aspects of this treatment. ... Read more

Natural Autoantibodies to Apoptotic Cell Membranes Regulate Fundamental Innate Immune Functions and Suppress Inflammation

Abstract: The evolution of the immune system has provided a multilevel system that interconnects the innate and adaptive immune systems to serve at least three central purposes: the defense from microbial pathogens, the capacity for discrimination of self- from non-self necessary for the prevention of autoimmune disease, and essential effector roles in wound repair and tissue remodeling. In recent studies, we have elucidated an unsuspected role for a class of naturally occurring autoreactive antibodies from the most primitive tier of B lymphocytes, which regulates fundamental functions of the innate immune system. Our findings also throw light onto long unresolved mysteries regarding the origins of the earliest waves of B lymphocyte development. ... Read more

New Hope for Rasmussen Encephalitis?

Abstract: Rasmussen encephalitis (RE) is characterized by chronic inflammation of one cerebral hemisphere which causes intractable epileptic seizures and progressive neurological deficits. Since antiepileptic pharmacotherapy is often ineffective the traditional therapy for Rasmussen encephalitis is hemispherectomy in one of its modern variants which renders the patient seizure free but leads to a severe deficit. To escape this dilemma, immunomodulatory therapeutic approaches such as rituximab, a monoclonal anti-CD20 antibody, offer an alternative and bear promising therapeutic potentials in Rasmussen encephalitis. ... Read more

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