Signalling pathways in B cells: implications for autoimmunity.
Following investigations of the pathogenic role of autoantibodies in rheumatic diseases, preclinical and clinical studies suggest a more central role of B cells in the maintenance of the disease process beyond just being precursors of (auto)antibody-producing plasma cells. Detailed analyses have implicated a number of surface molecules and subsequent downstream signalling pathways in the regulation of the events induced by BCR engagement. In this review, we discuss the potential role of molecules involved in altered B cell longevity, especially molecules involved in apoptosis (bcl-2, bcl-x, mutations in the Fas/Fas-L pathway), as well as molecules that might alter activation thresholds of B cells (CD19, CD21, CD22, lyn, SHP, SHIP-1) in the development of autoimmunity. Although focused on intrinsic B cell abnormalities, the complexity of interactions of B cells with other immune cells also makes it possible that increased B cell activation can be induced by distortions in the interaction with other cells. Further delineation of these alterations of B cell function in autoimmune conditions will allow development of more precise B cell-directed therapies beyond drastic B cell depletion, with the potential to improve the risk-benefit ratio of the treatments of autoimmune diseases.
Dörner
T
T
Institute of Transfusion Medicine, Charite University Medicine Berlin, Coagulation Unit, Germany. thomas.doerner@charite.de
Lipsky
P E
PE
D000818:Animals; D015703:Antigens, CD; D018941:Antigens, CD19 / Q000502:physiology; D000954:Antigens, Surface / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000502:physiology; D001327:Autoimmune Diseases / Q000276:immunology / Q000628:therapy; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D007113:Immunity, Innate; D008213:Lymphocyte Activation; D061026:Programmed Cell Death 1 Receptor; D017464:Receptors, Complement 3d / Q000502:physiology; D017452:Receptors, IgG / Q000502:physiology; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
D015703:Antigens, CD; D018941:Antigens, CD19; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D017464:Receptors, Complement 3d; D017452:Receptors, IgG; D051918:Sialic Acid Binding Ig-like Lectin 2