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Is Graves' Disease a Primary Immunodeficiency?

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Is Graves' Disease a Primary Immunodeficiency? Struja et al. BMC Medicine (2017) 15:174 DOI 10.1186/s12916-017-0939-9 REVIEW Open Access Is Graves’ disease a primary immunodeficiency? New immunological perspectives on an endocrine disease Tristan Struja1* , Alexander Kutz1, Stefan Fischli2, Christian Meier3,4, Beat Mueller1,3, Mike Recher3,5† and Philipp Schuetz1,3† Abstract Background: Uncertainty about factors influencing the susceptibility and triggers for Graves’ disease persists, along with a wide variation in the response to anti-thyroid drugs, currently at approximately 50% of non-responders. The aim of this narrative review is to summarize immunological concepts, with a combined endocrine and immunological perspective, to highlight potential new areas of research. Main text: Relevant studies were identified through a systematic literature search using the PubMed and EMBASE databases in March 2016. No cut-offs regarding dates were imposed. We used the terms “Graves’ Disease” or “Basedow” or “thyrotoxicosis” together with the terms “etiology”, “pathophysiology”, “immunodeficiency”, “causality”, and “autoimmunity”. The terms “orbitopathy”, “ophthalmopathy”, and “amiodarone” were excluded. Articles in English, French, German, Croatian, Spanish, and Italian were eligible for inclusion. Conclusions: While concepts such as the impact of iodine, smoking, human leucocyte antigen, infections, and ethnicity are established, new ideas have emerged. Pertaining evidence suggests the involvement of autoimmunity and immunodeficiency in the pathophysiology of Graves’ disease. Recent studies point to specific immunological mechanisms triggering the onset of disease, which may also serve as targets for more specific therapies. Keywords: Graves’ disease, Review, Etiology, Pathophysiology, Primary immunodeficiency Background (Table 1) [1]. The clinical penetrance of PID-associated Primary immunodeficiency diseases (PIDs) are genetic- gene mutations is far below 100% and novel mutations ally determined diseases impacting the normal function may occur during spermatogenesis or during oogenesis, of the immune system due to mutations in immune sys- implying that lack of a familial history does not argue tem genes. More than 250 PID entities have been against PIDs in a patient with autoimmunity. defined to date, with the number rapidly evolving. Many patients with a PID show their first clinical manifestation in adulthood and, in some patients, the PID is never di- Main text agnosed since it is not searched for. PIDs may clinically Literature search and inclusion criteria manifest in both childhood or adulthood and patients Relevant studies were identified through a systematic may present with a susceptibility to infection. However, literature search using the PubMed and EMBASE data- a significant number of PID patients present with auto- bases in March 2016. No cut-offs regarding dates were im- immune disease (AID) alone. The association of PIDs posed. We used the terms “Graves’ Disease” or “Basedow” with AIDs is mechanistically complex and multifactorial or “thyrotoxicosis” together with the terms “etiology”, “pathophysiology”, “immunodeficiency”, “causality”,and * Correspondence: [email protected] “autoimmunity”. The terms “orbitopathy”, “ophthalmopa- † Equal contributors thy”,and“amiodarone” were excluded. Articles in English, 1Medical University Department, Clinic for Endocrinology, Diabetes & Metabolism, Kantonsspital Aarau, Aarau, Switzerland French, German, Croatian, Spanish, and Italian were eli- Full list of author information is available at the end of the article gible for inclusion. © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Struja Table 1 Interplay of autoimmunity and immunodeficiency regarding Graves’ disease Primary immunodeficiency Phenotype Involved Protein/Synapse Gene Mechanism Association with Reference et al. BMC Medicine cell types Graves’ disease Selective IgA Celiac disease, type 1 diabetes B cells Ligation with its receptor (FcαRI) Most commonly Ligation with its receptor ++ [95, 96] deficiency mellitus, impaired mucosal Granulocytes leads to ADCC, granulocyte HLA haplotype 8.1 (FcαRI) leads to ADCC, defense, most common PID degranulation, phagocytosis granulocyte degranulation, and neutrophil oxidative burst phagocytosis and neutrophil oxidative burst Severe combined Recurrent infections, vitiligo, T cells Low expression of CD3γ gene Impaired negative selection +[59] (2017)15:174 immunodeficiency atopic dermatitis, ITP, AH, AITD T cell receptor in thymus Autoimmune Autoimmunity and polyclonal T cells Intra-thymic apoptosis via FASL Heterogeneous (1) Molecular mimicry or +[62–64] lymphoproliferative lymphocyte accumulation to its receptor FAS (CD95) and mutations of FAS (2) Slowing down of syndrome with lymphadenopathy subsequent activation of signaling pathway apoptosis and/or exposure and splenomegaly caspases 8 and 3 with impaired of apoptosis related T cell apoptosis autoantigens IPEX Immune dysregulation (eczema), Treg cells Loss of essential FOXP3 on X Greatly reduced Treg ++ [65] syndrome polyendocrinopathy (T1DM), Thymus transcription factor chromosome cell number enteropathy IPEX-like IPEX-like Treg cells IL-2-receptor-α CD25 deficiency Normal Treg in numbers +/– [67–70] phenotype chain (CD25) due to autosomal but deficient stimulation by recessive mutations defective IL-10 expression Common variable Various autoimmune diseases APCs CTLA-4 binds to CD80/CD86 (B7) CTLA-4 germline Treg cells increased, +[71, 75] immunodeficiency (ITP, AIHA, psoriasis, AITD, arthritis) Treg cells on APCs, leading to lower mutations with but dysfunctional and antibody deficiencies, B cells levels of co-stimulatory B7, incomplete (decreased CTLA-4 organ infiltration (bone marrow, Naïve T cells failure to activate CD28 penetrance ligand binding) kidney, brain, liver, spleen) by (the ligand for B7) granulomatous-lymphocytic on T cells infiltration Systemic lupus Recurrent infections; cutaneous, Macrophages MFG-E8 (mice) and Homozygous Impaired debris removal, +[76–79] erythematosus discoid lupus most common complement nonsense and -like presentation, malar rash, Apoptotic B factor C1q missense autoantibodies against C1q oral ulcers, recurrent cells mutations on correlates with thyroid fever and vasculitis chromosome 1p function in AITD (C1q) Common variable See above APCs BAFF BAFF (SNPs Higher levels stimulate B ++ [102–104, immunodeficiency Treg cells BAFF-R rs1041569 & cell survival, increase of 106, 107] B cells P21R variant rs2893321) TR antibody levels naïve T cells P21R (TNF-RSF13C allele) Hyper-IgM Elevated serum IgM, but deficiency APCs CD40 Autosomal Upregulation of CD40 +[5, 14, syndrome in IgG/A/E, recurrent respiratory T cells recessive CD40 on thyrocytes, increased 54, 108] and gastrointestinal infections B cells gene mutations co-stimulatory effects with pyogenic bacteria and Thyrocytes and immunoglobulin opportunistic organisms class switching Page 2 of 15 (e.g., P. jirovecii) Table 1 Interplay of autoimmunity and immunodeficiency regarding Graves’ disease (Continued) Struja Common variable Decreased Higher ICAM-1, [109, et al. BMC Medicine immunodeficiency methylation decreased B cell 120, 121] See above APCs Miscellaneous of various genes class switching +/– Treg cells B cells Naïve T cells Skewed X- Wiskott–Aldrich syndrome: Thymus Miscellaneous Genes for Reduced thymic ++ [118, 119] (2017)15:174 chromosome PID with eczema, T cells Wiskott–Aldrich expression of X inactivation thrombocytopenia, B cells syndrome protein, chromosome-dependent and diarrhea CD40L or the IL-2 self-antigens primes receptor-γ chain inadequate T cell apoptosis Trisomy 21 Down syndrome: Thymus IFN-γ AIRE and FOXP3 on Increased production ++ [51, 53, 66] increased susceptibility T cells X chromosome of IFN-γ with to leukemia, but reduced augmented Th1 incidence of solid tumors responses Reduced activity of Treg cells ADCC antibody dependent cellular cytotoxicity, AIHA autoimmune hemolytic anemia, AITD autoimmune thyroid disease, AH autoimmune hepatitis, APC antigen presenting cell, BAFF B-lymphocyte activating factor, CD cluster of differentiation, CTLA cytotoxic T-lymphocyte-associated protein, FasL type-II transmembrane protein of TNF family, FOXP3 forkhead box P3, HLA human leukocyte antigen, IL interleukin, IFN interferon, IPEX immunodysregulation polyendocrinopathy enteropathy X-linked, ITP immune thrombocytopenic purpura, MFG-E8 Milk fat globule epidermal growth factor 8, PID primary immunodeficiency, T1DM type 1 diabetes mellitus, TR thyrotropin related Page 3 of 15 Struja et al. BMC Medicine (2017) 15:174 Page 4 of 15 Immunologic view on exogenous factors associated with GD may be due to genetic variations and/or exposure Graves’ disease (GD) to local factors, but immigrants from lower risk re- In iodine-sufficient areas, GD is the most common cause gions acquire a similar risk over time as people in the of primary hyperthyroidism in the younger population new area of residence [11]. Analyses of National [2].
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