The B1a (CD5+) B-cells are the primary producers of natural antibodies that are self-reactive and polyreactive but usually non-pathogenic. However, in some circumstances, B1a B-cells contribute substantially to the immunopathogenesis of chronic systemic autoimmune diseases such as rheumatoid arthritis (RA), Sjogren's syndrome and systemic lupus erythematosus (SLE). B1a B-cells are a critical arm of the innate immune system and provides the first line of defense against a variety of bacterial and viral infections. The most prevalent B-cell malignancy, chronic lymphocytic leukemia (CLL) is CD5+ B-cell in origin. Curiously, HIV patients with progressive disease have paucity of CD5+ B-cells;in contrast, seropositive individuals with non-progressive disease have normal levels of B1a B-cells. This suggests the possibility that natural antibodies produced by CD5+ B-cells may be protective in HIV. The role of CD5 in the development, function and/or persistence of B1a B-cells remains an unresolved and controversial question. Since CD5 can negatively regulate signals initiated when the B-cell antigen receptor (BCR) is engaged by antigen, it is believed that its primary role in B1a B-cells is to control B-cell receptor activation from responding pathogenically to self antigen. However, this dogma is challenged by the fact that that CD5-/- mice do not develop spontaneous autoimmune disease. Our recent studies have led to that discovery that a major and probably dominant role of CD5, in addition to its inhibitory activity, is to promote survival. The survival activity of CD5 is mediated its unique interaction with CK2, a serine/threonine kinase that is a major positive regulator of multiple cellular prosurvival signaling cascades. In a counterpoint to the prosurvival activity mediated by activation of CK2, CD5 also has an immunoreceptor tyrosine inhibitory motif (ITIM) necessary for negative regulation of B-cell activation. The ITIM domain also provides prosurvival signals by attenuating B-cell activation and therefore activation-induced cell death. We suggest that CD5 regulates the B-cell response by two independent but complimentary pathways. To test this model, we have generated by gene targeting approach mice expressing CD5 with selective inability to activate the CD5-CK2 dependent prosurvival signaling cascade and mice lacking CD5-ITIM dependent negative regulatory activity. Using these unique animal models, and the new model we propose to develop, we will be in a position to (1) determine the role of CD5 in the development of B1a B-cells and its contribution to autoimmunity, (2) elucidate how CD5 regulates B-cell responses to T-independent antigens and T-dependent antigens and (3) dissect the molecular mechanism of CD5-dependent survival and inhibitory signals in normal B-cells. These studies using the novel animal models will enable us to resolve CD5 biology in B-cells. An important outcome of the proposed studies will be a major advancement in our understanding of regulatory pathways in innate B-cell responses to bacterial and viral pathogens and the development of targeting approaches for treatment of autoimmune diseases and leukemia.
CD5+ B-Cells (B1a) B-cells are important in innate immunity, shaping the adaptive immune repertoire and in the immunopathogenesis of autoimmune diseases. The role of CD5 in the development of B-cells has been extensively interrogated, but remains unresolved;the goal of this proposal is to fill this gap in our understanding.
|McGuire, Donald J; Rowse, Amber L; Li, Hao et al. (2014) CD5 enhances Th17-cell differentiation by regulating IFN-Ã½Ã½ response and RORÃ½Ã½t localization. Eur J Immunol 44:1137-42|
|FenutrÃa, Rafael; Martinez, Vanesa G; SimÃµes, InÃªs et al. (2014) Transgenic expression of soluble human CD5 enhances experimentally-induced autoimmune and anti-tumoral immune responses. PLoS One 9:e84895|
|Liu, Yudong; Holdbrooks, Andrew T; De Sarno, Patrizia et al. (2014) Therapeutic efficacy of suppressing the Jak/STAT pathway in multiple models of experimental autoimmune encephalomyelitis. J Immunol 192:59-72|
|Harms, Ashley S; Cao, Shuwen; Rowse, Amber L et al. (2013) MHCII is required for Î±-synuclein-induced activation of microglia, CD4 T cell proliferation, and dopaminergic neurodegeneration. J Neurosci 33:9592-600|
|Naves, Rodrigo; Singh, Simer P; Cashman, Kevin S et al. (2013) The interdependent, overlapping, and differential roles of type I and II IFNs in the pathogenesis of experimental autoimmune encephalomyelitis. J Immunol 191:2967-77|
|Qin, Hongwei; Yeh, Wen-I; De Sarno, Patrizia et al. (2012) Signal transducer and activator of transcription-3/suppressor of cytokine signaling-3 (STAT3/SOCS3) axis in myeloid cells regulates neuroinflammation. Proc Natl Acad Sci U S A 109:5004-9|
|Rowse, Amber L; Naves, Rodrigo; Cashman, Kevin S et al. (2012) Lithium controls central nervous system autoimmunity through modulation of IFN-Î³ signaling. PLoS One 7:e52658|
|Sestero, Christine M; McGuire, Donald J; De Sarno, Patrizia et al. (2012) CD5-dependent CK2 activation pathway regulates threshold for T cell anergy. J Immunol 189:2918-30|
|Aleman-Muench, German R; Mendoza, Valentin; Stenvers, Kaye et al. (2012) Betaglycan (TÃ½Ã½RIII) is expressed in the thymus and regulates T cell development by protecting thymocytes from apoptosis. PLoS One 7:e44217|
|Axtell, Robert C; Raman, Chander (2012) Janus-like effects of type I interferon in autoimmune diseases. Immunol Rev 248:23-35|
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