Expression of B cell receptor-associated signaling molecules in human lupus.
B cell receptor (BcR) signaling requires a tight regulation of several protein tyrosine kinases and phosphatases, and associated co-receptors. Mounting evidence indicates that abnormal BcR signaling, such as occurs in SHP-1 and Lyn-deficient mice, results in production of pathogenic autoantibodies and lupus-like glomerulonephritis, suggesting that altered signaling thresholds could underlie the development of systemic autoimmunity. To test this hypothesis, we investigated expression of BcR-associated signaling molecules in lymphocytes from patients with systemic lupus erythematosus (SLE) during inactive phases of the disease. We found that the transmembrane regulatory protein tyrosine phosphatase CD45 is expressed at abnormal levels. Strikingly, this reduction persisted during four months of follow-up. By contrast, despite its potent role as a regulator of thymus-independent immune responses and of B cell life span, the CD22 co-receptor is expressed at normal levels in B lymphocytes isolated ex vivo from SLE patients. We also noted unusual levels of the cytosolic protein tyrosine kinase Lyn and the protein tyrosine phosphatase SHP-1 in the lymphocytes of the patients. Since in normal B cells Lyn and SHP-1 act in concert within a common negative pathway in which CD45 counteracts SHP-I regulatory role, we propose that this feedback regulatory pathway is crippled to different degrees in human SLE B cells. Break of the balance between positive and negative signaling molecules likely modifies the BcR signaling thresholds. Such alterations, together with other factors, may contribute to the disruption of self-tolerance in this disease.
Huck
S
S
Département d'Immunologie, Institut Pasteur, Paris, France.
Le Corre
R
R
Youinou
P
P
Zouali
M
M
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism; D001402:B-Lymphocytes / Q000201:enzymology / Q000276:immunology; D015815:Cell Adhesion Molecules; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D037102:Lectins; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000201:enzymology / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D017634:Self Tolerance; D051918:Sialic Acid Binding Ig-like Lectin 2; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism
D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; C497867:CD22 protein, human; 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; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D017493:Leukocyte Common Antigens; C516724:PTPN11 protein, human; C509249:PTPN6 protein, human; 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