Multiple checkpoints control the survival and activation of auto-reactive B cells. The discovery of the TNF family cytokine BAFF has been crucial to understanding peripheral B cell tolerance mechanisms. Homeostatic levels of BAFF are tightly regulated to maintain tolerance in the periphery. Chronically increased levels of BAFF lead to the survival of autoreactive B cells. Autoimmune patients display elevated serum BAFF levels. BAFF Tg mice model this situation with systemically high levels of BAFF and the subsequent development of two separate but related autoimmune syndromes; systemic lupus erythematosus (SLE) and Sj??gren???s syndrome (SS). The work conducted in this thesis further investigates the defects in tolerance down-stream of self-reactive B cell survival, which may contribute to autoimmune disease development in BAFF Tg mice. Expansion of the Marginal zone (MZ) B cell population correlates with the pathogenesis of several models of autoimmune disease. BAFF Tg mice are unique in that they not only display an increased splenic MZ B cell population, but also MZ B cells are found in the salivary glands of mice developing SS. The examination of genes differentially regulated between MZ and Follicular (Fo) B cells led to the investigation of sphingosine-1-phosphate receptor biology. The expression of S1P receptors was shown to be required for the positioning of MZ B cells in the spleen. Chronic BAFF stimulation alters the retention of MZ B cells through the alteration of S1P receptors and decreased integrin activation. The alteration of S1P receptors and increased ligand sensitivity leads to the accumulation of MZ B cells in the inflamed salivary glands of BAFF Tg mice. This works provides a potential mechanism for the tissue specificity seen in systemic autoimmune disease. The provision of T cell help to auto-reactive B cells is thought to underlie the development of SLE. BAFF Tg mice deficient in T cells surprisingly developed an SLE-like disease indistinguishable from that of BAFF Tg mice. Autoimmunity in BAFF Tg mice did however require signals through the toll-like receptor (TLR)-associated signalling adaptor, MyD88, which controlled the production of pathogenic autoantibodies. Therefore, autoimmunity in BAFF Tg mice results from altered B cell tolerance, which requires TLR signalling and is independent of T cell help. It is likely that autoimmune patients with elevated levels of BAFF show a similar basis for disease.

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 6 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 4 uppsatser.

Diss. (sammanfattning) Uppsala : Sveriges lantbruksuniv. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 4 uppsatser.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2006. / Härtill 4 uppsatser.

Tez (Tıpta Uzmanlık) - Süleyman Demirel Üniversitesi, Tıp Fakültesi, Nükleer Tıp Anabilim Dalı, 2007. / Bibliyografya var.