B cells from patients with systemic lupus erythematosus display abnormal antigen receptor-mediated early signal transduction events.
To understand the molecular mechanisms that are responsible for the B cell overactivity that is observed in patients with SLE, we have conducted experiments in which the surface immunoglobulin (sIg)-mediated early cell signaling events were studied. The anti-sIgM-mediated free intracytoplasmic calcium ([Ca2+]i) responses were significantly higher in SLE B cells compared with responses of normal individuals and to those of patients with other systemic autoimmune rheumatic diseases. The anti-IgD mAb induced [Ca2+]i responses were also higher in lupus B cells than in controls. The magnitude of anti-sIgM-mediated Ca2+ release from intracellular stores was also increased in B cells from SLE patients compared with normal controls. The amount of inositol phosphate metabolites produced upon crosslinking of sIgM was slightly higher in patients with lupus than in normal controls, although the difference was not statistically significant. In contrast, the degree of anti-sIgM-induced protein tyrosine phosphorylation was obviously increased in lupus patients. Our study demonstrates clearly for the first time that SLE B cells exhibit aberrant early signal transduction events, including augmented calcium responses after crosslinking of the B cell receptor and increased antigen-receptor-mediated phosphorylation of protein tyrosine residues. Because the above abnormalities did not correlate with disease activity or treatment status, we propose that they may have pathogenic significance.
Liossis
S N
SN
Department of Clinical Physiology, Walter Reed Army Institute of Research, Washington, DC 20307-5100, USA.
Kovacs
B
B
Dennis
G
G
Kammer
G M
GM
Tsokos
G C
GC
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001402:B-Lymphocytes / Q000276:immunology / Q000502:physiology*; D002118:Calcium / Q000097:blood; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology / Q000502:physiology; D007295:Inositol Phosphates / Q000378:metabolism; D007700:Kinetics; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D012016:Reference Values; D015398:Signal Transduction
D000911:Antibodies, Monoclonal; D007075:Immunoglobulin M; D007295:Inositol Phosphates; D011947:Receptors, Antigen, B-Cell; D002118:Calcium