Excessive Cytosolic DNA Fragments as a Potential Trigger of Graves’ Disease: An Encrypted Message Sent by Animal Models

Abstract

Graves’ hyperthyroidism is caused by autoantibodies directed against the thyroid-stimulating hormone receptor (TSHR) that mimic the action of TSH. The establishment of Graves’ hyperthyroidism in experimental animals has proven to be an important approach to dissect the mechanisms of self-tolerance breakdown that lead to the production of thyroid-stimulating TSHR autoantibodies (TSAbs). “Shimojo’s model” was the first successful Graves’ animal model, wherein immunization with fibroblasts cells expressing TSHR and a major histocompatibility complex (MHC) class II molecule, but not either alone, induced TSAb production in AKR/N (H-2k) mice. This model highlights the importance of coincident MHC class II expression on TSHR-expressing cells in the development of Graves’ hyperthyroidism. These data are also in agreement with the observation that Graves’ thyrocytes often aberrantly express MHC class II antigens via mechanisms that remain unclear. Our group demonstrated that cytosolic self-genomic DNA fragments derived from sterile injured cells can induce aberrant MHC class II expression and production of multiple inflammatory cytokines and chemokines in thyrocytes in vitro, suggesting that severe cell injury may initiate immune responses in a way that is relevant to thyroid autoimmunity mediated by cytosolic DNA signaling. Furthermore, more recent successful Graves’ animal models were primarily established by immunizing mice with TSHR-expressing plasmids or adenovirus. In these models, double-stranded DNA vaccine contents presumably exert similar immune-activating effect in cells at inoculation sites and thus might pave the way toward successful Graves’ animal models. This review focuses on evidence suggesting that cell injury-derived self-DNA fragments could act as Graves’ disease triggers.

Targeting B Cells and Plasma Cells in Autoimmune Diseases

“…Memory B cells are formed within germinal centers and differ from naive B cells with respect to several features. While many human and murine memory B cells still express IgM, a significant proportion has already switched to the production of downstream antibody subclasses, mainly IgA and IgGs ( 29 – 31 ). Antigen-mediated crosslinking of membrane IgG provides a much stronger activation signal than IgM ( 32 ), which contributes to the reduced activation threshold observed for memory B cells and their capacity to quickly give rise to antibody-secreting plasma cells ( 33 – 36 ).…”

The Role of the Transcription Factor Nuclear Factor-kappa B in Thyroid Autoimmunity and Cancer

“…Many studies have demonstrated that the main hormones involved in the regulation of thyroid growth and function decrease MHC class I expression, which include thyroid-stimulating hormone (TSH), insulin/ insulin-like growth factor (IGF)-I and hydrocortisone, ( 17 , 29 – 31 ). MHC class I overexpression, as well as MHC class II aberrant expression, on non-immune cells is a feature of autoimmune diseases and thyroid autoimmunity ( 27 , 32 – 37 ). The hormonal regulation of MHC molecules in thyroid cells is considered important for the suppression of autoimmunity during hormonally induced changes in cellular growth and function, which results in enhanced expression of potential thyroid autoantigens, such as thyroglobulin, thyroid peroxidase, and the TSH receptor (TSHR).…”

Graves’ disease with hyperfunctioning thyroid nodule harboring thyroid carcinoma. Case report and literature review

“…При воздействии лиганда (ТТГ, ТСА) происходит диссоциация G-белка с образованием 2 субъединиц -Gα и Gβγ. Передача сигнала внутрь тиреоцита осуществляется в основном за счет субъединицы Gα, а также через вторичную аденилатциклазную сигнальную систему (путь протеинкиназы типа А), в меньшей степени задействуется вторичный сигнальный путь протеинкиназы типа С (для активизации последней требуется больший уровень ТТГ) [15,16,[40][41][42][43].…”

“…В последнее время в связи с рутинным применением генетических исследований и накоплением новых данных, полученных на животных моделях, исследователи вновь заговорили о первичных изменениях в самой ЩЖ как о пусковом механизме БГ [43,51]. В 3 недавних метаанализах определен однонуклеотидный полиморфизм гена TSHR (точечные мутации гена в интроне 1 -rs179247, rs12101255), который имеет сильную корреляцию с БГ [51].…”

“…В другом обзоре продемонстрирована возможность экспрессии аберрантного главного комплекса гистосовместимости II (major histocompatibility complex) на мембране тиреоцита и выполнения им функции антигенпредставляющей клетки [43]. Эти данные также можно экстраполировать на наше клиническое наблюдение.…”