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Autoimmune endocrine disease
Published in Philip E. Harris, Pierre-Marc G. Bouloux, Endocrinology in Clinical Practice, 2014
Terry J. Smith, Laszlo Hegedüs
The etiologies of Hashimoto’s thyroiditis and GD remain uncertain, but they are likely the result of both genetic and acquired factors.3 Perhaps our best clues about the relative importance of each derive from twin studies in which GD affects either one or both monozygotic twins.9 Those studies point to about a 30% genetic contribution. Frequently, the HLA-DR3 genotype is found in these patients. Several candidate susceptibility genes have been proposed as being associated with thyroid autoimmunity. Among these genes are CTLA-4, CD40, PTPN22, and FCRL3.10 The evidence for each being involved in the pathogenesis of disease has been reviewed extensively elsewhere. Importantly, no convincing evidence yet exists for any of these candidates targeting individuals for disease-specific manifestations associated with either GD or Hashimoto’s thyroiditis. Thus, factors other than those arising from genetic makeup might provide disease-specific susceptibility. With regard to the nongenetic factors, stress, diet, pollutants, and infectious agents have all been mentioned, but the successful identification of specific factors as causative in GD remains an unmet objective. Nonetheless, tobacco smoking has been identified as a major risk factor for developing GD.11 In a study of monozygotic twins both of whom smoked, the twin with the greater exposure to cigarettes was more likely to manifest GD.
Genetic analysis of IgG4-related disease
Published in Modern Rheumatology, 2020
Umemura et al. [28] recruited a total of 59 AIP patients and 97 controls together with 62 CCP, none of whom had increased IgG4 levels. In this analysis, they focused on Fcγ receptor-like gene3 (FCRL3) which showed associations with rheumatoid arthritis, systemic lupus erythematosus and autoimmune thyroiditis in the Japanese population [29,30]. They genotyped four SNPs in FCRL3 and found a suggestive association between –110 SNP and AIP (χ2 = 8.12, p = .017). Interestingly, they also found that serum level of IgG4 significantly positively correlated with the number of susceptible alleles (–110, r2 = 0.094, p = .014) in patients with AIP. No association between the HLA DRB1*04:05-DQB1*04:01 haplotype and FCRL3 –110 alleles was found in this study indicating that they play different roles in the AIP pathogenesis.
CRISPR and personalized Treg therapy: new insights into the treatment of rheumatoid arthritis
Published in Immunopharmacology and Immunotoxicology, 2018
Fatemeh Safari, Safar Farajnia, Maryam Arya, Habib Zarredar, Ava Nasrolahi
Within inflamed joints, TNF-α inhibits Treg suppressive activity with different mechanisms. TNF-α exerts its inhibitory effects via TNF receptor II (TNFRII) which overexpressed on the surface of Tregs in the inflammatory situation. TNF-α downregulates the expression of Foxp3 through TNFRII signaling pathway in both natural Tregs (nTregs) also called thymus Treg (tTreg) and adaptive Tregs41. In the other mechanism, TNF-α by activating canonical NF-kB pathway (signaling via TNFRII), induces a pro-inflammatory phenotype. In this mechanism, the expression of Foxp3 is not affected. In addition, TNF-α makes an influence on the immunological synapse (IS) formation between Tregs and APCs which results in the inhibition of Treg suppressive activity42. Fc receptor-like 3 (FcRL3) is a suspected autoimmune susceptibility gene that negatively regulates TCR signaling. It expresses on a population of nTregs but not Teffs and reduces suppressive activity43.
Update on Fc receptor-like (FCRL) family: new immunoregulatory players in health and diseases
Published in Expert Opinion on Therapeutic Targets, 2018
Davood Rostamzadeh, Tohid Kazemi, Zahra Amirghofran, Mahdi Shabani
The inhibitory effects of FCRL3 on BCR signaling have been studied in same approach using hybrid FCRL3 protein. Kochi et al. indicated that FCRL3 potentially inhibits BCR-mediated signaling through binding of SHP-1 to the intracellular domain of FCRL3 [62]. FCRL3 chimeric protein exhibited inhibitory potential for BCR-mediated tyrosine phosphorylation and calcium mobilization, when colligated with BCR, too [62].