Multiple paths to loss of anergy and gain of autoimmunity
ABSTRACT B cells and autoimmunity: cells of the immune system have the capacity to recognize/neutralize a myriad array of disease-causing pathogens, while simultaneously minimizing damage to self tissue. Obvious breakdowns in this ability to distinguish between self and non-self are evident in multiple forms of autoimmune disease, where B and T cells mount damaging attacks on cells and organs. B cells may directly damage tissue by producing pathogenic antibodies that bind self antigen, fix complement or form immune complexes. Recent evidence also suggests B cells indirectly induce autoimmunity by concentrating low avidity self antigen through the B cell receptor and presenting self-peptides to autoreactive T cells. B cells may also initiate autoimmunity when provided sufficient help from autoreactive T cells that have escaped deletion in the thymus. Here, we will review the role of anergy in maintenance of tolerance and how alterations in the normal balance of positive and negative signals may contribute to the development of autoimmune disease in mouse models and humans.
Free Radical Biology and Medicine 11/2011; 51. DOI:10.1016/j.freeradbiomed.2011.10.282 · 5.71 Impact Factor
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ABSTRACT: Protein Kinase C delta (PKCδ) deficiency causes autoimmune pathology in humans and mice and is crucial for the maintenance of B cell homeostasis. However, the mechanisms underlying autoimmune disease in PKCδ deficiency remain poorly defined. Here we address the antigen-dependent and -independent roles for PKCδ in B cell development, repertoire selection and antigen responsiveness. We demonstrate that PKCδ is rapidly phosphorylated downstream of both the B cell receptor (BCR) and the B cell activating factor (BAFF) receptor. We find that PKCδ is essential for antigen-dependent negative selection of splenic transitional B cells and is required for activation of the pro-apoptotic Ca(2+)-Erk pathway that is selectively activated during B cell negative selection. Unexpectedly, we also identify a previously unrecognized role for PKCδ as a proximal negative regulator of BCR signaling that substantially impacts survival and proliferation of mature follicular B cells. As a consequence of these distinct roles, PKCδ deficiency leads to the survival and development of a B cell repertoire that is not only aberrantly autoreactive but also hyperresponsive to antigen stimulation.Molecular and Cellular Biology 02/2014; DOI:10.1128/MCB.01699-13 · 5.04 Impact Factor