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1دورية أكاديمية
المؤلفون: Vinuesa, Carola G.1 carola.vinuesa@anu.edu.au, Sanz, Iñaki2, Cook, Matthew C.1,3, Sanz, Iñaki (AUTHOR)
المصدر: Nature Reviews Immunology. Dec2009, Vol. 9 Issue 12, p845-857. 13p. 2 Diagrams, 3 Charts.
مصطلحات موضوعية: *GERMINAL centers, *AUTOIMMUNE diseases, *B cells, *LYMPH nodes, *ANTIGEN presenting cells, *DENDRITIC cells, *ANTIGENS
مستخلص: In germinal centres, somatic hypermutation and B cell selection increase antibody affinity and specificity for the immunizing antigen, but the generation of autoreactive B cells is an inevitable by-product of this process. Here, we review the evidence that aberrant selection of these autoreactive B cells can arise from abnormalities in each of the germinal centre cellular constituents--B cells, T follicular helper cells, follicular dendritic cells and tingible body macrophages--or in the supply of antigen. As the progeny of germinal centre B cells includes long-lived plasma cells, selection of autoreactive B cells can propagate long-lived autoantibody responses and cause autoimmune diseases. Elucidation of crucial molecular signals in germinal centres has led to the identification of novel therapeutic targets. [ABSTRACT FROM AUTHOR]
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2دورية أكاديمية
المؤلفون: Cappione, III., Amedeo1, Anolik, Jennifer H.1, Pugh-Bernard, Aimee1, Barnard, Jennifer1, Dutcher, Paul1, Silverman, Gregg2, Sanz, Iñaki1 IgnacioSanz@urmc.rochester.edu, Cappione, Amedeo 3rd3 (AUTHOR), Sanz, Iñaki (AUTHOR)
المصدر: Journal of Clinical Investigation. Nov2005, Vol. 115 Issue 11, p3205-3216. 12p. 1 Color Photograph, 1 Chart, 5 Graphs.
مصطلحات موضوعية: *SYSTEMIC lupus erythematosus, *ANTIGEN presenting cells, *VASCULAR diseases, *IMMUNE system, *IMMUNOCOMPETENT cells, *CELL populations, *AUTOANTIBODIES, *B cells, *CELL lines, *CELL physiology, *COMPARATIVE studies, *IMMUNITY, *IMMUNOGLOBULINS, *IMMUNOLOGICAL tolerance, *IMMUNOPHENOTYPING, *LYMPHOID tissue, *RESEARCH methodology, *MEDICAL cooperation, *RESEARCH, *RESEARCH funding, *RHEUMATOID arthritis, *SPLEEN, *EVALUATION research
مستخلص: Breach of B cell tolerance is central to the pathogenesis of systemic lupus erythematosus (SLE). However, how B cell tolerance is subverted in human SLE is poorly understood due to difficulties in identifying relevant autoreactive B cells and in obtaining lymphoid tissue. We have circumvented these limitations by using tonsil biopsies to study autoreactive B cells (9G4 B cells), whose regulation is abnormal in SLE. Here we show that 9G4 B cells are physiologically excluded during the early stages of the GC reaction before acquiring a centroblast phenotype. Furthermore, we provide evidence to indicate that an anergic response to B cell receptor stimulation may be responsible for such behavior. In contrast, in SLE, 9G4 B cells progressed unimpeded through this checkpoint, successfully participated in GC reactions, and expanded within the post-GC IgG memory and plasma cell compartments. The faulty regulation of 9G4 B cells was not shared by RA patients. To our knowledge, this work represents the first comparative analysis of the fate of a specific autoreactive human B cell population. The results identify a defective tolerance checkpoint that appears to be specific for human SLE. [ABSTRACT FROM AUTHOR]