Graves' disease: Clinical manifestations, immune pathogenesis (cytokines and chemokines) and therapy

Antonelli, Alessandro; Fallahi, Poupak; Elia, Giusy; Ragusa, Francesca; Paparo, Sabrina Rosaria; Ruffilli, Ilaria; Patrizio, Armando; Gonnella, Debora; Giusti, Claudia; Virili, Camilla; Centanni, Marco; Shoenfeld, Yehuda; Ferrari, Silvia

doi:10.1016/j.beem.2020.101388

Cited by 92 publications

(86 citation statements)

References 79 publications

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Section: Introductionmentioning

confidence: 99%

“…Graves disease and Hashimoto thyroiditis are common autoimmune diseases (AIDs) in which autoantibodies interfere with the function of the thyroid gland, in the former causing hyperthyroidism and in the latter hypothyroidism [ 1 , 2 ]. Consequently, the disease mechanisms are different; in Graves disease an antibody (thyroid-stimulating immunoglobulin) mimics the function of thyroid stimulating hormone (TSH), and thus an excessive production of thyroid hormones ensues [ 1 , 2 ]. The initial phase of Hashimoto thyroiditis is characterized by lymphocytic infiltration into thyroid follicles followed by their gradual destruction; antibodies against thyroid peroxidase or thyroglobulin are often found but whether they contribute to the disease mechanism or are consequences thereof remains unestablished [ 1 , 3 ].…”

Section: Introductionmentioning

confidence: 99%

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Familial risks between Graves disease and Hashimoto thyroiditis and other autoimmune diseases in the population of Sweden

Thomsen

Sundquist

et al. 2020

Journal of Translational Autoimmunity

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Genetic and family studies have indicated that Graves disease and Hashimoto thyroiditis have a heritable component which appears to be shared to some extend also with some other autoimmune diseases (AIDs). In the present nation-wide study we describe familial risk for Graves disease and Hashimoto thyroiditis identified from the Swedish Hospital Discharge Register (years 1964 through 2012) and the Outpatient Register (2001 through 2012). Family relationships were obtained from the Multigeneration Register and cancers from the Cancer Registry. Familial standardized incidence ratios (SIRs) were calculated for 29,005 offspring with Graves disease and for 25,607 offspring with Hashimoto thyroiditis depending on any of 43 AIDs in parents or siblings. The concordant familial risks for Graves disease and Hashimoto thyroiditis were 3.85 and 4.75, higher for men than for women. The familial risks were very high (11.35, Graves and 22.06, Hashimoto) when both a parent and a sibling were affected. Spousal familial risks were higher for Hashimoto thyroiditis (1.98/1.93) than for Graves disease (1.48/1.50). For Graves disease, 24 discordant AIDs showed a significant association; for Hashimoto thyroiditis, 20 discordant associations were significant. All significant discordant associations were positive for the two thyroid AIDs, with the exception of Hashimoto thyroiditis with Reiter disease. Overall 8 associations were significant only for Graves disease and 6 Hashimoto thyroiditis. The overall high concordant familial risks for Graves disease and Hashimoto thyroiditis suggest a strong genetic contribution to the familial risk. Significant familial associations among more than half of the 43 AIDs attest to the extensive polyautoimmunity among thyroid AIDs.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Familial risks between Graves disease and Hashimoto thyroiditis and other autoimmune diseases in the population of Sweden

Thomsen

Sundquist

et al. 2020

Journal of Translational Autoimmunity

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“…Although GD can occur at any age and in both genders, it is more frequently observed in women in the 4–5th decade of life ( 1 ). The ultimate event is the continuous activation of the TSH-R on thyroid follicular cells by TRAb ( 8 , 9 ). This dysregulated and continuous thyroid stimulation causes hyperthyroidism and, frequently, thyroid enlargement (goiter) ( 10 , 11 ).…”

Section: Current Understanding Of the Pathogenesis Of Graves' Diseasementioning

confidence: 99%

“…This dysregulated and continuous thyroid stimulation causes hyperthyroidism and, frequently, thyroid enlargement (goiter) ( 10 , 11 ). As for other autoimmune disorders, GD likely results from the breakdown in the immune tolerance mechanisms, both at systemic (peripheral blood) and local (tissue) levels ( 8 , 9 ). Failure of T regulatory (T reg) cell activity, proliferation of autoreactive T and B cells, and enhanced presentation of TSH-R (due to increased HLA-D affinity for TSH-R, more immunogenic TSH-R haplotype, or increased exposure of TSH-R peptide) drive the development of the disease ( 12 , 13 ).…”

Section: Current Understanding Of the Pathogenesis Of Graves' Diseasementioning

confidence: 99%

Immunological Drivers in Graves' Disease: NK Cells as a Master Switcher

et al. 2020

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Graves' disease (GD) is a common autoimmune cause of hyperthyroidism, which is eventually related to the generation of IgG antibodies stimulating the thyrotropin receptor. Clinical manifestations of the disease reflect hyperstimulation of the gland, causing thyrocyte hyperplasia (goiter) and excessive thyroid hormone synthesis (hyperthyroidism). The above clinical manifestations are preceded by still partially unraveled pathogenic actions governed by the induction of aberrant phenotype/functions of immune cells. In this review article we investigated the potential contribution of natural killer (NK) cells, based on literature analysis, to discuss the bidirectional interplay with thyroid hormones (TH) in GD progression. We analyzed cellular and molecular NK-cell associated mechanisms potentially impacting on GD, in a view of identification of the main NK-cell subset with highest immunoregulatory role.

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“…Clinical manifestations are linked to hyperthyroidism and to the autoimmune process. GD-associated signs and symptoms can vary markedly, influencing the overall well-being (5,6).…”

Section: Introductionmentioning

confidence: 99%

Cytokines as Targets of Novel Therapies for Graves’ Ophthalmopathy

et al. 2021

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Graves’ disease (GD) is an organ-specific autoimmune disorder of the thyroid, which is characterized by circulating TSH-receptor (TSH-R) stimulating antibodies (TSAb), leading to hyperthyroidism. Graves’ ophthalmopathy (GO) is one of GD extra-thyroidal manifestations associated with the presence of TSAb, and insulin-like growth factor-1 receptor (IGF-1R) autoantibodies, that interact with orbital fibroblasts. Cytokines are elevated in autoimmune (i.e., IL-18, IL-6) and non-autoimmune hyperthyroidism (i.e., TNF-α, IL-8, IL-6), and this could be associated with the chronic effects of thyroid hormone increase. A prevalent Th1-immune response (not related to the hyperthyroidism per se, but to the autoimmune process) is reported in the immune-pathogenesis of GD and GO; Th1-chemokines (CXCL9, CXCL10, CXCL11) and the (C-X-C)R3 receptor are crucial in this process. In patients with active GO, corticosteroids, or intravenous immunoglobulins, decrease inflammation and orbital congestion, and are considered first-line therapies. The more deepened understanding of GO pathophysiology has led to different immune-modulant treatments. Cytokines, TSH-R, and IGF-1R (on the surface of B and T lymphocytes, and fibroblasts), and chemokines implicated in the autoimmune process, are possible targets of novel therapies. Drugs that target cytokines (etanercept, tocilizumab, infliximab, adalimumab) have been tested in GO, with encouraging results. The chimeric monoclonal antibody directed against CD20, RTX, reduces B lymphocytes, cytokines and the released autoantibodies. A multicenter, randomized, placebo-controlled, double-masked trial has investigated the human monoclonal blocking antibody directed against IGF-1R, teprotumumab, reporting its effectiveness in GO. In conclusion, large, controlled and randomized studies are needed to evaluate new possible targeted therapies for GO.

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Graves' disease: Clinical manifestations, immune pathogenesis (cytokines and chemokines) and therapy

Cited by 92 publications

References 79 publications

Familial risks between Graves disease and Hashimoto thyroiditis and other autoimmune diseases in the population of Sweden

Familial risks between Graves disease and Hashimoto thyroiditis and other autoimmune diseases in the population of Sweden

Immunological Drivers in Graves' Disease: NK Cells as a Master Switcher

Cytokines as Targets of Novel Therapies for Graves’ Ophthalmopathy

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