Cell Receptor Mediated Signaling Checkpoints

Throughout B cell development, lymphocyte survival and selection are determined by the specificity of the hetero-oligomeric BcR, a module that interacts with coreceptors, protein tyrosine kinases (PTKs) and phosphatases (PTPs), adapters, and other proteins to propagate signaling cascades (Reth and Wienands, 1997; Benschop and Cambier, 1999). Since the BcR is responsible for Ag recognition, the transduction events that occur after its ligation mediate interpretation of the magnitude and duration of BcR signaling. In addition to orchestrating the efficient development and subsequent activation of B lymphocytes at several discrete stages during B lineage differentiation, the BcR plays a central role in self-tolerance. During B lymphocyte development, potentially aggressive autore-active B cells must be tolerized at various checkpoints. While studies over the past few years have provided a wealth of new information regarding the selection processes, systemic autoimmune disease is often considered to result from a deficiency in tolerance induction, resulting in failure to eliminate self-reactive lymphocytes. In this scheme, B cells that slip through the mesh of the tolerance safety nets would attack and destroy peripheral tissues. Lupus, for example, would result from rogue B cells reactive to various tissues. Yet, it is clear, from recent work with transgenic systems in which most B cells express receptors directed against self-antigens, that additional mechanisms allow the immune system to control potentially devastating lymphocytes and avoid pathology. Notably, transgenic expression or inactivation of genes encoding certain signaling molecules was found to lead to autoimmune phenomena and to disease, suggesting that a tight balance in BcR signaling pathways is required to prevent pathogenic autoimmune reactions (Hasler and Zouali, 2001; Kammer et al., 2002; Yu et al., 2003; Zouali and Sarmay, 2004).

0 0

Post a comment