The combined effect of BCL-2 over-expression and E2F2 deficiency induces an autoimmune syndrome in non-susceptible mouse strain C57BL/6.

Multiple evidences support the notion that cell-cycle deregulation or apoptosis alterations can lead to autoimmune syndrome (AIS). Inactivation of the cell-cycle regulator E2F2 or over-expression of the anti-apoptotic Bcl-2 protein induces spontaneously an AIS in certain mouse strains. In the present study, we have examined the contribution of the genetic background on the development of autoimmunity after E2F2 gene inactivation, and the effect that a simultaneous inactivation of the E2F2 gene and over-expression of the Bcl-2 gene in B cells has on lymphoid homeostasis and autoimmunity. We show that E2F2(- / - ) mice carrying wild-type levels of Bcl-2 do not develop AIS when they are in a non-pro-autoimmune background (C57BL/6). However, mice harboring both genetic alterations concomitantly develop late AIS characterized by the presence of serum anti-nuclear antibodies, double and single strand anti-DNA antibodies, and the development of a mild glomerulonephritis with mesangial immunoglobulins, mainly IgA, deposits. These results suggest that alterations in cell-cycle and cell survival are critical contributing factors for the development of autoimmunity.

Giant cell arteritis and polymyalgia rheumatica: role of cytokines in the pathogenesis and implications for treatment.

OBJECTIVE: To summarize the contribution of cytokines to pathogenesis, clinical manifestations and prognosis of polymyalgia rheumatica (PMR) and giant cell arteritis (GCA). METHODS: MEDLINE database search for studies published between 1980 and April 2008. RESULTS: PMR and GCA are characterized by a hyperproduction of IL-6. The role of other circulating cytokines in their pathogenesis remains unclear. Cytokine mRNA in the arterial wall of GCA can distinguish different clinical subgroups of patients. The profile of T cell-derived cytokines in GCA suggests that it is a Th1-driven disease. The scarce number of studies makes difficult to evaluate the exact contribution of cytokine polymorphisms to their pathogenesis. Small studies have suggested the utility of TNF antagonists in patients with refractory PMR and GCA. However, these data have not been confirmed in controlled studies in patients with recent onset disease. CONCLUSION: Further studies are needed to evaluate the role of circulating cytokines in PMR and GCA. The study of tissue cytokines has provided important insights into the mechanisms implicated in the local inflammatory response that occurs in GCA. The important advance in the knowledge of the role of cytokines in PMR and GCA will have clear implications for treatment.