Multiple paths to loss of anergy and gain of autoimmunity

University of Colorado, Denver, Colorado, United States
Autoimmunity (Impact Factor: 2.71). 10/2007; 40(6):418-24. DOI: 10.1080/08916930701464723
Source: PubMed


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.

32 Reads
  • Source
    • "CRAC channels are the primary mediators of receptor-activated Ca 2+ entry in lymphocytes, and are functionally identified by their Ca +2 conductance in the cell plasma membrane following reduction in Ca 2+ concentration in the ER. Antigen receptor signals mediate activation of this Ca 2+ entry by triggering ER Ca 2+ depletion (Conrad et al., 2007). The known molecular components of the CRAC mechanism include STIM1 (Liou et al., 2005; Roos et al., 2005; Zhang et al., 2005) and the Ca 2+ selective channel-forming subunit, ORAI1 (Prakriya et al., 2006; Vig et al., 2006; Yeromin et al., 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Ca(2+) acts ubiquitously as a second messenger in transmembrane signal transduction. In lymphocytes, calcium mobilization is triggered by antigen and chemokine receptors, among others, and controls cell functions ranging from proliferation to migration. The primary mechanism of extracellular Ca(2+) entry in lymphocytes is the CRAC influx. STIM1 is a crucial component of the CRAC influx mechanism in lymphocytes, acting as a sensor of low Ca(2+) concentration in the ER and an activator of the Ca(2+) selective channel ORAI1 in the plasma membrane. While STIM1 function has been studied extensively, little is known regarding whether it is differentially expressed and thereby affects the magnitude of calcium mobilization responses. We report here that STIM1 expression differs in murine T and B lymphocytes, and in respective subsets. For example, mature T cells express ∼4 times more STIM1 than mature B cells. Furthermore, we show that through the physiologic range of expression, STIM1 levels determine the magnitude of Ca(2+) influx responses that follow BCR-induced intracellular store depletion. Considered in view of previous reports that differences in amplitude of lymphocyte Ca(2+) mobilization determine alternate biological responses, these findings suggest that differential STIM1 expression may be important determinant of biological responses.
    Molecular Immunology 06/2011; 48(15-16):1851-8. DOI:10.1016/j.molimm.2011.05.006 · 2.97 Impact Factor
  • Source
    • "T and B lymphocytes are responsible for the establishment and maintenance of tolerance as illustrated by the observation that alterations in B cell signaling result in autoimmunity. B cell signaling is modulated by response regulators, such as CD19 (Goodnow 1996; Conrad et al 2007). For example, combined binding of CD19 with the antigen-receptor of B lymphocytes decreases the antigen receptor-stimulation threshold a 100-fold (Carter and Fearon 1992). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Systemic sclerosis (SSc) is a connective disease characterized by features of autoimmunity, vasculopathy, inflammation, and fibrosis. The disease typically starts with Raynaud's phenomenon, followed by skin thickening in the extremities due to inflammation and fibrosis. Fibrosis results from excessive collagen production by fibroblasts, which constitutes the final common pathway of complex cellular interactions including B cells. Several studies have indicated that B cells may play a role in SSc. Lesional skin infiltrates from SSc patients consist of a variety of cells, including eosinophils, neutrophils, lymphocytes, plasma cells, and macrophages. Autoantibodies of several specificities are present in the serum of SSc patients of which antitopoisomerase 1 is the most common, and evidence has been gathered for a potential pathogenic role of some autoantibodies, eg, anti-PDGF antibodies. The blood of SSc patients contains an increased proportion of naïve B cells but a decreased proportion of memory B cells. Furthermore, serum levels of interleukin-6, an important pro-inflammatory cytokine, have been shown to correlate with skin fibrosis. Animal models of SSc have provided more in-depth information on the role of B lymphocytes, eg, through disruption of B cell function. In this review we will discuss the evidence that B cells are involved in the pathogenesis of SSc.
    Targets & therapy 10/2008; 2(3):389-95. DOI:10.2147/BTT.S2806
  • Source

Show more

Similar Publications