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 erythematosus characterizes mice lacking the src-family kinase Lyn. Lyn is not required to initiate B cell antigen receptor (BCR) signaling but is an essential inhibitory component. lyn-/- B cells have a delayed but increased calcium flux and exaggerated negative selection responses in the presence of antigen and spontaneous hyperactivity in the absence of antigen. As in invertebrates, genetic effects of loci with only one functional allele can be used to analyze signaling networks in mice, demonstrating that negative regulation of the BCR is a complex quantitative trait in which Lyn, the coreceptor CD22, and the tyrosine phosphatase SHP-1 are each limiting elements. The biochemical basis of this complex trait involves a pathway requiring Lyn to phosphorylate CD22 and recruit SHP-1 to the CD22/BCR complex.
Cornall
R J
RJ
Howard Hughes Medical Institute and Department of Microbiology and Immunology, Stanford University, Palo Alto, California 94305, USA.
Cyster
J G
JG
Hibbs
M L
ML
Dunn
A R
AR
Otipoby
K L
KL
Clark
E A
EA
Goodnow
C C
CC
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001324:Autoantigens / Q000378:metabolism; D015551:Autoimmunity / Q000235:genetics*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015815:Cell Adhesion Molecules; D005260:Female; D047908:Intracellular Signaling Peptides and Proteins; D037102:Lectins; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009113:Muramidase / Q000276:immunology; D010641:Phenotype; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D019655:Quantitative Trait, Heritable; D011828:Radiation Chimera; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D051918:Sialic Acid Binding Ig-like Lectin 2; D015398:Signal Transduction; D019061:src-Family Kinases / Q000172:deficiency / Q000235:genetics / Q000276:immunology*
D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D001324:Autoantigens; C497868:Cd22 protein, mouse; D015815:Cell Adhesion Molecules; D047908:Intracellular Signaling Peptides and Proteins; D037102:Lectins; D011947:Receptors, Antigen, B-Cell; D051918:Sialic Acid Binding Ig-like Lectin 2; D019061:src-Family Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse; C509248:Ptpn6 protein, mouse; D009113:Muramidase