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. "
    Clinical Immunology 11/2013; 150(2):140-142. DOI:10.1016/j.clim.2013.11.006 · 3.67 Impact Factor
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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.
    Journal of Thyroid Research 04/2013; 2013(1):182472. DOI:10.1155/2013/182472
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    • "Broken down of immune tolerance often leads to auto-reactive T-cell activation, which is pivotal for the development of autoimmune diseases, including Type 1 diabetes (T1D) [1], [2]. Foxp3+ regulatory T cells (Treg) play a critical role in maintaining self-tolerance, and co-transfer of Treg with pathogenic effector cells can prevent autoimmune disease development [3]–[5]. "
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    ABSTRACT: Foxp3(+) regulatory T cells (Treg) play a crucial role in regulating immune tolerance. The use of Treg to restore immune tolerance is considered an attractive novel approach to inhibit autoimmune disease, including type 1 diabetes (T1D), and to prevent rejection of organ transplants. In view of the goal of developing autologous Treg-based cell therapy for patients with long-term (>15 years) T1D, it will be necessary to expand a sufficient amount of functional Treg in vitro in order to study and compare Treg from T1D patients and healthy subjects. Our results have demonstrated that there is a comparable frequency of Treg in the peripheral blood lymphocytes (PBLs) of patients with long-term T1D relative to those in healthy subjects; however, Th1 cells, but not Th17 cells, were increased in the T1D patients. Further, more Treg in PBLs from T1D patients than from healthy subjects expressed the CD45RO(+) memory cell phenotype, suggesting they were antigen-experienced cells. After isolation, Treg from both T1D patients and healthy subjects were successfully expanded with high purity. Although there was no difference in Helios expression on Treg in PBLs, in vitro expansion led to fewer Helios-expressing Treg from T1D patients than healthy subjects. While more Th1-like Treg expressing IFN-γ or TNF-α were found in the PBLs of T1D patients than healthy controls, there was no such difference in the expanded Treg. Importantly, expanded Treg from both subject groups were able to suppress autologous or allogeneic CD8(+) effector T cells equally well. Our findings demonstrate that a large number of ex vivo expanded functional Treg can be obtained from long-term T1D patients, although fewer expanded Treg expressed a high level of Helios. Thus, based on the positive outcomes, these potent expanded Treg from diabetic human patients may be useful in treating T1D or preventing islet graft rejection.
    PLoS ONE 02/2013; 8(2):e56209. DOI:10.1371/journal.pone.0056209 · 3.23 Impact Factor
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