The current presence of hypergammaglobulinemia, autoantibodies, and circulating immune complexes suggests that humoral immunity may contribute to the pathogenesis of sarcoidosis. (CD19+ CD27+ IgD?) and unswitched (CD19+ CD27+ IgD+) memory B cells and coincided with an increased frequency of circulating (CD19+/? CD20? CD27++) plasmablasts. Polyclonal stimulation of sarcoid B cells resulted in reduced expression of activation markers (i.e., CD25, CD69, and CD86), decreased proliferation, and impaired plasma cell differentiation. Baseline expression of p65 in B cells was reduced in 65% of the patients. These results suggest disturbed homeostasis, intrinsic signaling defects, and anergy within the peripheral B-cell compartments of patients with severe chronic sarcoidosis. INTRODUCTION Sarcoidosis is a cell-mediated immunological disorder characterized by granuloma development and the production of inflammatory cytokines by activated macrophages and T cells (29). In spite of the predominant involvement of cellular immunity in the pathogenesis of this disease, sarcoidosis is Rabbit Polyclonal to MMTAG2. frequently associated with hypergammaglobulinemia (28), autoantibody production (66), and circulating immune complexes (18), humoral abnormalities typically found in patients with systemic autoimmunity (63). The clinical and pathological features of sarcoidosis (i.e., multisystemic involvement, arthritis, uveitis, myositis, conjunctivitis, neuritis, response to immunosuppressive therapy, and lymphocytic infiltration in affected tissues and organs) also mimic those of many systemic autoimmune diseases (50), and sarcoidosis has been reported to coexist with systemic lupus erythematosus (SLE), primary Sj?gren’s syndrome (pSS), and rheumatoid arthritis (RA) (62). Thus, a relationship between sarcoidosis and systemic autoimmune diseases has been proposed, and it is postulated that sarcoidosis and connective tissue diseases may share common immunopathogenic mechanisms (67). Sarcoidosis, however, does not meet Witebsky’s criteria for autoimmune illnesses, and for that reason, the addition of sarcoidosis in the band of autoimmune disorders is not generally approved (57). The peripheral B-cell compartments of individuals with systemic autoimmunity are generally modified (51). Different connective cells disorders are correlated with specific adjustments in the peripheral B-cell populations. In SLE, designated reductions in the degrees of Compact disc19+ Compact disc27? na?ve B cells, improved frequencies of Compact disc19+ Compact disc27+memory space B cells, and increased amounts of Compact disc19+/? Compact disc27++ plasma cells had been discovered (46), whereas a predominance of na?ve B cells (with reduced frequencies and total numbers of memory space B cells) and increased frequencies of IgD-expressing memory space B cells (with similar distributions of peripheral na?ve and memory space B cells) were identified in individuals with pSS and RA, (8 respectively, 9, 26). It really is believed these homeostatic adjustments impact a number of B-cell features profoundly, such as for example antigen demonstration, cytokine synthesis, and Ig creation, and these modifications in immune elements are essential towards the pathogenesis of systemic autoimmune illnesses (58). However, regardless of the impressive medical, pathological, and immunological commonalities between sarcoidosis and systemic autoimmune illnesses, the peripheral B-cell area of sarcoidosis individuals is not characterized. Evaluation of B-cell populations in individuals with systemic autoimmunity and healthful individuals generally depends on the manifestation of four surface area markers: Compact disc19, IgD, Compact disc38, and Compact disc27 (51, 58). With this process, two main classifications could be produced with regards to the comparative manifestation of either IgD and Compact disc38 or IgD and Compact disc27 on B cells. Therefore, IgD Compact disc38 staining may be used to determine na?ve cells (Compact disc19+ IgD+ Compact disc38?), triggered na?ve cells (Compact disc19+ IgD+ Compact disc38+), pre-germinal-center cells (Compact disc19+ IgD+ Compact disc38++), centroblasts-centrocytes (Compact disc19+ IgD? Compact disc38++), plasma cells (Compact disc19+ IgD? Compact disc38+++), and memory space cells (Compact disc19+ IgD? Compact disc38?). IgD Compact disc27 staining builds on the idea of Compact disc27 like a marker of memory space B cells to tell apart between memory cells (CD27+) and na?ve cells (CD27?). CD27+ memory cells can be divided into unswitched (IgD+) and class-switched (IgD?) WP1130 memory cells. The various B-cell subpopulations exist in relatively similar ratios in healthy WP1130 individuals (51). Although many studies have shown multiple B-cell homeostatic abnormalities, very little is known regarding B-cell receptor (BCR) signaling in systemic autoimmunity (53). Yet the importance of understanding the regulation of BCR signaling pathways in human autoimmune diseases is underscored by multiple demonstrations WP1130 in animal models that abnormalities in these pathways may result in systemic autoimmunity (27). Transgenic mice deficient in the src family protein tyrosine kinase Lyn develop an SLE-like syndrome with autoantibodies and nephritis (45). Consistent with this observation, a subset of SLE patients have reduced levels of Lyn and.