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Activation of thyroid antigen-reactive B cells in recent onset autoimmune thyroid disease patients.

ABSTRACT: Autoimmune thyroid disease (AITD), including Hashimoto's thyroiditis (HT) and Graves' disease (GD), is the most common autoimmune disorder in the United States, affecting over 20 million people. At the time of diagnosis, both HD and GD are characterized by the accumulation of B and T lymphocytes in the thyroid gland and production of autoantibodies targeting the thyroid, indicating that a breach in tolerance of autoreactive lymphocytes has occurred. However, few studies have sought to understand the underlying pathogenesis of AITD that ultimately leads to production of autoantibodies and loss of thyroid function. In this study, we analyzed the phenotype of thyroid antigen-reactive B cells in the peripheral blood of recent onset and long standing AITD patients. We found that in recent onset patients thyroid antigen-reactive B cells in blood no longer appear anergic, rather they express CD86, a marker of activation. This likely reflects activation of these cells leading to their production of autoantibodies. Hence, this study reports the early loss of anergy in thyroid antigen-reactive B cells, an event that contributes to development of AITD.

SUBMITTER: Smith MJ

PROVIDER: S-EPMC5902436 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Activation of thyroid antigen-reactive B cells in recent onset autoimmune thyroid disease patients.

Smith Mia J MJ Rihanek Marynette M Coleman Brianne M BM Gottlieb Peter A PA Sarapura Virginia D VD Cambier John C JC

Journal of autoimmunity 20171209

Autoimmune thyroid disease (AITD), including Hashimoto's thyroiditis (HT) and Graves' disease (GD), is the most common autoimmune disorder in the United States, affecting over 20 million people. At the time of diagnosis, both HD and GD are characterized by the accumulation of B and T lymphocytes in the thyroid gland and production of autoantibodies targeting the thyroid, indicating that a breach in tolerance of autoreactive lymphocytes has occurred. However, few studies have sought to understand ...[more]

PMID: 29233566

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Project description:ImportanceAutoimmune thyroid disease ([AITD] including hypothyroidism and hyperthyroidism) is the most common organ-specific autoimmune disorder and is more prevalent among patients with rheumatoid arthritis (RA). Real-world studies on when and how this increased risk of AITD develops, in association with the time before or after the onset of RA, are lacking.ObjectiveTo estimate the risk of thyroxine-treated AITD among patients with RA at different time points before and after the diagnosis of RA.Design, setting, and participantsA nationwide register-based case-control and cohort study was conducted between January 1, 2006, and June 30, 2013, with a maximum follow-up time of 7 years before and 8 years after diagnosis of RA. The study used the Swedish Rheumatology Quality Register and linkage to other nationwide registers to identify 8090 adults with new-onset RA and a random population-based sample of 80 782 referents matched by age, sex, and residential area. Statistical analysis was performed from July 1, 2015, to June 30, 2017.ExposuresPresence of AITD in the participants in the case-control design and RA in the participants in the cohort design.Main outcomes and measuresPrevalence and relative risk of incident AITD before (odds ratios) and after (hazard ratios) diagnosis of RA compared with the population as reference.ResultsThere were 8090 patients with RA (5529 women and 2561 men; mean [SD] age, 58.3 [15.2] years) and 80?782 population-based participants as reference who were identified. By the time of diagnosis of RA, the prevalence of AITD was 10.3% among the patients with RA (n?=?832) vs 7.1% among the controls (5725 of 80?350) (odds ratio, 1.5; 95% CI, 1.4-1.7). This increased risk of AITD developed during the 5 years (range, 2-5 years) before diagnosis of RA (odds ratio, 1.5; 95% CI, 1.2-1.8) and peaked by the time of diagnosis of RA (range, 0-3 months before diagnosis of RA) (odds ratio, 5.3; 95% CI, 3.7-7.6). From diagnosis of RA and onward, the risk of developing AITD decreased (range, 2-5 years after diagnosis of RA) (hazard ratio, 0.7; 95% CI, 0.5-1.0).Conclusions and relevanceCompared with the general population, Swedish patients with RA appear to have a higher prevalence of thyroxine-treated AITD at diagnosis of RA and an increased incidence of AITD during the 5-year period before diagnosis of RA. After diagnosis of RA, the risk of developing AITD is suggested to decrease below the expected rate. Besides temporal changes in diagnostic intensity, this pattern of risk raises the question whether AITD may influence the pathogenesis of RA (or vice versa) and, conversely, the question whether antirheumatic therapies may prevent AITD.

Project description:Anti-phospholipid syndrome (APS) and systemic lupus erythematosus (SLE) are autoimmune diseases characterized by autoantibody production and autoantibody-related pathology. Anti-phospholipid antibodies (aPL) are found in all patients with APS and in 20-30% of individuals with SLE. aPL recognize a number of autoantigens, but the primary target in both APS and SLE is ?2-glycoprotein I (?2GPI). The production of IgG aPL in APS and SLE, as well as the association of aPL with certain MHC class II molecules, has led to investigation of the role of ?2GPI-reactive T helper (Th). ?2GPI-reactive CD4 Th cells have been associated with the presence of aPL and/or APS in both primary APS and secondary APS associated with SLE, as well as in SLE patients and healthy controls lacking aPL. CD4 T cells reactive with ?2GPI have also been associated with atherosclerosis and found within atherosclerotic plaques. In most cases, the epitopes targeted by autoreactive ?2GPI-reactive CD4 T cells in APS and SLE appear to arise as a consequence of antigenic processing of ?2GPI that is structurally different from the soluble native form. This may arise from molecular interactions (e.g., with phospholipids), post-translational modification (e.g., oxidation or glycation), genetic alteration (e.g., ?2GPI variants), or molecular mimicry (e.g., microbiota). A number of T cell epitopes have been characterized, particularly in Domain V, the lipid-binding domain of ?2GPI. Possible sources of negatively charged lipid that bind ?2GPI include oxidized LDL, activated platelets, microbiota (e.g., gut commensals), and dying (e.g., apoptotic) cells. Apoptotic cells not only bind ?2GPI, but also express multiple other cellular autoantigens targeted in both APS and SLE. Dying cells that have bound ?2GPI thus provide a rich source of autoantigens that can be recognized by B cells across a wide range of autoantigen specificities. ?2GPI-reactive T cells could potentially provide T cell help to autoantigen-specific B cells that have taken up and processed apoptotic (or other dying) cells, and subsequently present ?2GPI on their surface in the context of major histocompatibility complex (MHC) class II molecules. Here, we review the literature on ?2GPI-reactive T cells, and highlight findings supporting the hypothesis that these T cells drive autoantibody production in both APS and SLE.

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Activation of thyroid antigen-reactive B cells in recent onset autoimmune thyroid disease patients.

Publications

Activation of thyroid antigen-reactive B cells in recent onset autoimmune thyroid disease patients.

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