Checkpoints in lymphocyte development and autoimmune disease

Harvard Medical School and Dana Farber Cancer Institute, Boston, Massachusetts, USA.
Nature Immunology (Impact Factor: 24.97). 01/2010; 11(1):14-20. DOI: 10.1038/ni.1794
Source: PubMed

ABSTRACT Antigen receptor-controlled checkpoints in B lymphocyte development are crucial for the prevention of autoimmune diseases such as systemic lupus erythematosus. Checkpoints at the stage of pre-B cell receptor (pre-BCR) and BCR expression can eliminate certain autoreactive BCRs either by deletion of or anergy induction in cells expressing autoreactive BCRs or by receptor editing. For T cells, the picture is more complex because there are regulatory T (T(reg)) cells that mediate dominant tolerance, which differs from the recessive tolerance mediated by deletion and anergy. Negative selection of thymocytes may be as essential as T(reg) cell generation in preventing autoimmune diseases such as type 1 diabetes, but supporting evidence is scarce. Here we discuss several scenarios in which failures at developmental checkpoints result in autoimmunity.

Download full-text


Available from: Harald von Boehmer, Jun 27, 2014
1 Follower
  • Source
    • "Autoimmune diseases, such as rheumatoid arthritis (RA), type 1 diabetes or multiple sclerosis among others, are chronic disorders that result in a significant burden to affected individuals; progressive disability of sufferers with consequent decrease in quality of life has a considerable socioeconomic impact. One of the most widely accepted hypotheses links autoimmunity directly to the emergence of self-specific T cell clones which, having escaped negative selection in the thymus, respond to auto-antigens expressed in the host [1]. In individuals who are not prone to autoimmunity, these T cells are effectively deleted in the periphery [2] by control mechanisms largely relying on the " regulatory cells populations " ; CD1d-restricted Natural Killer T lymphocytes (NKT cells) comprise one of those; these cells are characterised by unique phenotypical and functional features. "
    Clinical Immunology 11/2013; 150(2):140-142. DOI:10.1016/j.clim.2013.11.006 · 3.99 Impact Factor
  • Source
    • "The immune system is finely balanced between providing immune responses against infectious pathogens while remaining tolerant to self-antigen (Goodnow et al., 2010; Kitaura et al., 2007; Schwartz, 2003; Sprent and Surh, 2011; von Boehmer and Melchers, 2010). In optimal immune responses, antigen and costimulatory molecules from activated antigen presenting cells (APCs) or helper T cells induce strong mitogenic signals in naive T or B cells, leading to proliferation and differentiation of effector cells; yet these same stimuli also induce suppressors, such as induced regulatory T (iTreg) cells, to prevent excessive immune pathology. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Lymphocytes provide optimal responses against pathogens with minimal inflammatory pathology. However, the intrinsic mechanisms regulating these responses are unknown. Here, we report that deletion of both transcription factors Egr2 and Egr3 in lymphocytes resulted in a lethal autoimmune syndrome with excessive serum proinflammatory cytokines but also impaired antigen receptor-induced proliferation of B and T cells. Egr2- and Egr3-defective B and T cells had hyperactive signal transducer and activator of transcription-1 (STAT1) and STAT3 while antigen receptor-induced activation of transcription factor AP-1 was severely impaired. We discovered that Egr2 and/or Egr3 directly induced expression of suppressor of cytokine signaling-1 (SOCS1) and SOCS3, inhibitors of STAT1 and STAT3, and also blocked the function of Batf, an AP-1 inhibitor, in B and T cells. Thus, Egr2 and Egr3 regulate B and T cell function in adaptive immune responses and homeostasis by promoting antigen receptor signaling and controlling inflammation.
    Immunity 09/2012; 37(4):685-96. DOI:10.1016/j.immuni.2012.08.001 · 19.75 Impact Factor
  • Source
    • ", 2005 ) , it is reasonable to speculate that the threshold of activation might be altered in WASP - deficient B cells . In the bone marrow , receptor editing is the major mechanism aimed at eliminating self - reactive B cells during differentiation ( Monroe and Dorshkind , 2007 ; von Boehmer and Melchers , 2010 ) by editing autoreactive receptors through secondary rearrangements in light chain loci ( Halverson et al . , 2004 ) . "
    [Show abstract] [Hide abstract]
    ABSTRACT: Wiskott-Aldrich Syndrome (WAS) is a severe X-linked Primary Immunodeficiency that affects 1-10 out of 1 million male individuals. WAS is caused by mutations in the WAS Protein (WASP) expressing gene that leads to the absent or reduced expression of the protein. WASP is a cytoplasmic protein that regulates the formation of actin filaments in hematopoietic cells. WASP deficiency causes many immune cell defects both in humans and in the WAS murine model, the Was(-/-) mouse. Both cellular and humoral immune defects in WAS patients contribute to the onset of severe clinical manifestations, in particular microthrombocytopenia, eczema, recurrent infections, and a high susceptibility to develop autoimmunity and malignancies. Autoimmune diseases affect from 22 to 72% of WAS patients and the most common manifestation is autoimmune hemolytic anemia, followed by vasculitis, arthritis, neutropenia, inflammatory bowel disease, and IgA nephropathy. Many groups have widely explored immune cell functionality in WAS partially explaining how cellular defects may lead to pathology. However, the mechanisms underlying the occurrence of autoimmune manifestations have not been clearly described yet. In the present review, we report the most recent progresses in the study of immune cell function in WAS that have started to unveil the mechanisms contributing to autoimmune complications in WAS patients.
    Frontiers in Immunology 07/2012; 3:209. DOI:10.3389/fimmu.2012.00209
Show more