Programmed Cell Death of Peripheral Blood B Cells Determined by Laser Scanning Cytometry in Sj�gren?s Syndrome with a Special Emphasis on BAFF

Abstract

Functionally impaired B cells play an important role in the pathogenesis of Sjögren's syndrome (SS). The aim of the study was to investigate the apoptosis susceptibility of peripheral blood B cells from patients with SS and the impact of B cell activating factor (BAFF) on the apoptosis capability of these cells in correlation with IgG production. Peripheral blood B cells were isolated and stained for apoptosis markers (Bax, Bcl-2) and members of the TNF-R superfamily, CD95 and CD40. The apoptosis frequency of cells bearing these markers were assessed. Also, the apoptosis capability of cultured B-lymphocytes was investigated in medium alone, with anti-CD95 or with soluble BAFF. Quantitative ELISA was performed to detect plasma levels of sBAFF. Furthermore, the level of circulating B-cell cytokines was measured. BAFF levels were compared between patients with normal and elevated IgG levels. In SS, Bcl-2 positive B cell counts were significantly higher then in controls, also in this population the apoptosis frequency was reduced. Apoptosis within Bax+ and CD40+ B cells were significantly decreased in patients. BAFF induced a significant antiapoptotic effect in SS; also this effect was clearly evident in B cells from SS with hypergammaglobulinaemia. Plasma BAFF levels were significantly higher in SS, mostly in patients with hypergammaglobulinaemia. Plasma B-cell cytokines were raised in SS. In Sjögren's syndrome B cells, a general antiapoptotic tendency might lead to prolonged B-cell survival driven at least partly by elevated levels of BAFF and supposedly by B-cell cytokines. Also, the exaggerated BAFF stimulation might lead to excessive immunoglobulin production. The B-cell apoptosis defects, the increased BAFF levels-correlating with hypergammaglobulinaemia-together with the raised B-cell cytokine levels indicates the disturbed B-cell biology in the disease.

T Lymphocytes in Sjögren’s Syndrome: Contributors to and Regulators of Pathophysiology

“…This is also consistent with autoantibodies found locally and systemically in pSS. B cell activating factor (BAFF), also known as B lymphocyte stimulator (BLyS), is a member of the TNF superfamily that regulates B lymphocyte proliferation, maturation, and survival [89], but is also suggested to be an important factor in both local and systemic autoimmunity [89][90][91]. Local BAFF/BLyS expression by infiltrating T cells and macrophages may be central in the progression of the entire autoimmune process by triggering B cell hyperactivation, autoantibody production, and germinal center (GC) formation [92,93].…”

“…Local BAFF/BLyS expression by infiltrating T cells and macrophages may be central in the progression of the entire autoimmune process by triggering B cell hyperactivation, autoantibody production, and germinal center (GC) formation [92,93]. Enhanced levels of BAFF/BLyS have been demonstrated in rheumatic diseases such as SLE and RA, which are associated with abnormal B cell function and autoantibody production [89][90][91][94][95][96], but with highest BAFF levels seemingly found in pSS patients [94,95]. Moreover, BAFF/BLyS emerged as a potent survival factor for B cell malignancies [89,97].…”

The Roles of the TNF-Family Member B-Cell Activation Factor Belonging to the TNF-Family (BAFF) in Autoimmunity

“…In an investigation of 127 SjS patients, elevated serum levels of BAFF in SjS correlated with anti-SSA and anti-SSB antibodies [90]. Serum BAFF levels in SjS patients with hypergammaglobulinemia were also elevated compared to those of patients with normal IgG levels [91].…”

Treating Sjögren’s syndrome: insights for the clinician

“…Moreover, B-cell hyperactivity is also proven in pSS by the presence of high levels of gammaglobulins, rheumatoid factor and autoantibodies, and has been suggested to be closely related to the development of the systemic extraglandular manifestations [Gottenberg et al 2005]. B-lymphocyte activating factor (BAFF) or B-lymphocyte stimulator (Blys) appears to be cytokine critical for B-cell survival and maturation, and then to have a major role pathogenesis by regulating B-cell activation and autoantibody production in pSS [Szodoray et al 2004]. In fact, BAFF transgenic mice develop a clinical picture manifested by severe sialadenitis, decreased saliva production and destruction of submaxillary glands [Groom et al 2002].…”