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T Cells, B Cells, and Polarized Immune Response in the Pathogenesis of Fibrosis and Systemic Sclerosis

Posted Dec 04 2009 12:00am

By Carlo Chizzolini

Abstract

Purpose of Review:

A better comprehension of the interactions between cells of the adaptive immune system with fibroblasts and endothelial cells is required to understand abnormal extracellular matrix deposition, development of pathologic fibrosis, and vasculopathy.

Recent Findings:

Skin T cells with high IL-4 production potential and peripheral blood T cells preferentially expressing chemokine receptors associated with Th2 functions are found in individuals with active systemic sclerosis. Animal models indicate that Th2 cells and IL-13 can induce muscular hypertrophy in pulmonary arterial vasculature. In bleomycin-induced fibrosis, B cells produce fibrogenic cytokines upon interaction of an endogenous ligand (hyaluronan) with toll-like receptor-4. In the sclerodermatous graft versus host model, the lack of tumor necrosis factor-production by CD4+ T cells is permissive for fibrosis development. Dermal fibrosis and capillary loss typical of systemic sclerosis can be reversible after high-dose immunosuppression and hematopoietic stem cell transplantation.

Summary:

Although immunosuppressive strategies to treat patients with systemic sclerosis and allied conditions are largely disappointing, thus indicating a permissive rather than causative role of immunoinflammatory events characteristic of the disease, new findings stress that cells of the adaptive immune system play important roles in assisting fibrogenesis and vascular abnormalities. This may help in identifying efficacious strategies aimed at their control.

IntroductionSystemic sclerosis (SSc) is thought to be an autoimmune disease. In favor of this contention is the presence of high affinity autoantibodies [immunoglobulin G (IgG) isotype] targeting characteristic autoantigens and possible clinical overlap with other collagen vascular diseases, including systemic lupus erythematosus and rheumatoid arthritis. However, no animal model in which the disease can be induced by vaccination with a particular autoantigen or by passive transfer of antibodies, B cells, or T cells is at hand. Thus, the relationship between a subverted immune response and the pathogenesis of SSc remains largely undefined. Furthermore, it is still unclear whether early events leading to SSc are primitively characterized by alterations of the vascular compartment or inflammatory responses due to perturbation of the immune system. In other words, it is not clear whether fibrosis is induced by endothelial cells or by T and B cell abnormalities. Recent evidence, albeit indirect, is tipping the balance in favor of a hierarchical predominant role of the immune response in inducing SSc and will be reviewed here.

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