POLYGENIC AUTOIMMUNE TRAITS - LYN, CD22, AND SHP-1 ARE LIMITING ELEMENTS OF A BIOCHEMICAL PATHWAY REGULATING BCR SIGNALING AND SELECTION

A B lymphocyte hyperactivity syndrome resembling systemic lupus erythe matosus characterizes mice lacking the src-family kinase Lyn, Lyn is n ot required to initiate a cell antigen receptor (BCR) signaling but is an essential inhibitory component. lyn(-/-) B cells have a delayed bu t increased calcium flux and exaggerated negative selection responses in the presence of antigen and spontaneous hyperactivity in the absenc e of antigen. As in invertebrates, genetic effects of loci with only o ne functional allele can be used to analyze signaling networks in mice , demonstrating that negative regulation of the BCR is a complex quant itative trait in which Lyn, the coreceptor CD22, and the tyrosine phos phatase SHP-1 are each limiting elements. The biochemical basis of thi s complex trait involves a pathway requiring Lyn to phosphorylate CD22 and recruit SHP-1 to the CD22/BCR complex.