Checkpoints in lymphocyte development and autoimmune disease

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


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.

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Available from: Harald von Boehmer, Jun 27, 2014
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    • "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. "

    Full-text · Article · Nov 2013 · Clinical Immunology
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    • "Class switch recombination (CSR) occurs via an intrachromosomal deletional process while maintaining the original V(D)J assembly (Kenter 2012). The failure to assemble V(D)J exons or signal through the B-cell receptor (BCR) creates a block in the developmental progression of pro-B cells (Jankovic et al. 2004; von Boehmer and Melchers 2010). However, the strict ontological separation of V(D)J joining and CSR may break down under some circumstances (Milili et al. 1991; Rolink et al. 1996; Weller et al. 2001; Dudley et al. 2002; Mao et al. 2004; Han et al. 2007; Ueda et al. 2007; Scheeren et al. 2008; Kuraoka et al. 2009; Wesemann et al. 2011). "
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    ABSTRACT: V(D)J joining is mediated by RAG recombinase during early B-lymphocyte development in the bone marrow (BM). Activation-induced deaminase initiates isotype switching in mature B cells of secondary lymphoid structures. Previous studies questioned the strict ontological partitioning of these processes. We show that pro-B cells undergo robust switching to a subset of immunoglobulin H (IgH) isotypes. Chromatin studies reveal that in pro-B cells, the spatial organization of the Igh locus may restrict switching to this subset of isotypes. We demonstrate that in the BM, V(D)J joining and switching are interchangeably inducible, providing an explanation for the hyper-IgE phenotype of Omenn syndrome.
    Preview · Article · Nov 2013 · Genes & development
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    • "The table summarizes some of the various agents/events that may downregulate or upregulate thyroid autoantibodies (both TPO and Tg-Ab) in both euthyroid individuals and those with active thyroid disease. Abstracted from [35–47, 49–55]. "
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    ABSTRACT: Autoantibodies to thyroglobulin and thyroid peroxidase are common in the euthyroid population and are considered secondary responses and indicative of thyroid inflammation. By contrast, autoantibodies to the TSH receptor are unique to patients with Graves' disease and to some patients with Hashimoto's thyroiditis. Both types of thyroid antibodies are useful clinical markers of autoimmune thyroid disease and are profoundly influenced by the immune suppression of pregnancy and the resulting loss of such suppression in the postpartum period. Here, we review these three types of thyroid antibodies and their antigens and how they relate to pregnancy itself, obstetric and neonatal outcomes, and the postpartum.
    Full-text · Article · Apr 2013 · Journal of Thyroid Research
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