Choroba hashimoto – Patofizjologia i mechanizm

Choroba hashimoto
Patofizjologia i mechanizm

Choroba Hashimoto to przewlekłe autoimmunologiczne zapalenie tarczycy, charakteryzujące się niszczeniem komórek pęcherzykowych tarczycy przez mechanizmy immunologiczne, w tym aktywację limfocytów T i produkcję przeciwciał przeciwtarczycowych (anty-TPO u >90% pacjentów, anty-Tg u 50-80%). Patogeneza opiera się na utracie tolerancji immunologicznej wobec autoantygenów tarczycy, z kluczową rolą limfocytów T CD8+ i CD4+ (Th1, Th17, Treg), które prowadzą do zapalenia, zwłóknienia i apoptozy tyreocytów. Cytokiny prozapalne (IFN-γ, TNF-α, IL-17, IL-1, IL-18) oraz komponenty inflamasomu nasilają proces zapalny i uszkodzenie komórek tarczycy. Mechanizmy uszkodzenia obejmują cytotoksyczność zależną od przeciwciał (ADCC), apoptozę Fas/FasL oraz cytotoksyczność limfocytów T, co finalnie prowadzi do niedoczynności tarczycy z podwyższonym poziomem TSH i TRH.

Patofizjologia choroby Hashimoto

Choroba Hashimoto, znana również jako przewlekłe autoimmunologiczne zapalenie tarczycy lub przewlekłe limfocytarne zapalenie tarczycy, jest chorobą autoimmunologiczną prowadzącą do niszczenia komórek pęcherzykowych tarczycy poprzez procesy immunologiczne. Ta choroba autoimmunologiczna jest najczęstszą przyczyną niedoczynności tarczycy w krajach rozwiniętych i charakteryzuje się powstawaniem przeciwciał przeciwtarczycowych oraz aktywacją limfocytów T, co prowadzi do postępującego zwłóknienia gruczołu tarczowego.¹ Choroba Hashimoto jest przykładem autoimmunizacji narządowo-specyficznej, prowadzącej do uszkodzenia i niewydolności tarczycy.¹²

Mechanizmy immunologiczne w chorobie Hashimoto

Podstawą patogenezy choroby Hashimoto jest złożona interakcja między czynnikami genetycznymi i środowiskowymi, które prowadzą do przerwania tolerancji immunologicznej wobec antygenów tarczycy. Patofizjologicznie, choroba ta charakteryzuje się naciekami limfocytarnymi i zwłóknieniem w pęcherzykach tarczycy.¹ W rozwoju choroby Hashimoto kluczową rolę odgrywają zarówno komórkowa (zależna od limfocytów T), jak i humoralna (zależna od limfocytów B) odpowiedź immunologiczna.¹²

U osób z chorobą Hashimoto występują poliklonalne przeciwciała specyficzne dla antygenów tarczycy:¹

Przeciwciała przeciwko peroksydazie tarczycowej (anty-TPO): Jest to najczęściej występujące przeciwciało w chorobie Hashimoto, wykrywane u ponad 90% osób z tą chorobą.¹²
Przeciwciała przeciwko tyreoglobulinie (anty-Tg): Obecne u 50-80% osób z chorobą Hashimoto.¹
Przeciwciała przeciwko receptorowi TSH (TSHR Ab): Zidentyfikowano różne typy TSHR Ab, mogą być stymulujące, blokujące lub neutralne. Zdecydowana większość TSHR Ab w chorobie Hashimoto należy do typu blokującego.¹¹

Przeciwciała te mogą nasilać dalsze niszczenie tarczycy poprzez aktywację układu dopełniacza i wywoływanie apoptozy komórek tarczycy.¹ Poziomy przeciwciał anty-TPO mogą korelować ze stopniem nacieku limfocytarnego tarczycy.¹

Rola limfocytów T w patogenezie

Limfocyty T CD8+ odgrywają kluczową rolę w dysfunkcji immunologicznej leżącej u podstaw patogenezy choroby Hashimoto. Te komórki cytotoksyczne infiltrują tkankę tarczycy, powodując zapalenie i niszczenie komórek pęcherzykowych.¹² Limfocyty T CD4+ aktywują inne komórki immunologiczne, zwłaszcza makrofagi i limfocyty B, co prowadzi do produkcji autoprzeciwciał.¹

Różne subpopulacje limfocytów T CD4+, w tym Th1, Th2, Th17 i Treg (regulatorowe limfocyty T), mają różne funkcje, a ich zaburzenie równowagi przyczynia się do patogenezy choroby Hashimoto:¹¹

Limfocyty Th1 są nadmiernie aktywowane w chorobie Hashimoto, promując stan zapalny w tkance tarczycy.¹¹
Limfocyty Treg są kluczowe w promowaniu tolerancji immunologicznej i zapobieganiu nadmiernej odpowiedzi immunologicznej. W chorobie Hashimoto obserwuje się ich zmniejszoną aktywność.¹¹
Limfocyty Th17, które wydzielają cytokinę IL-17, są zwiększone w chorobie Hashimoto, podobnie jak w wielu innych zaburzeniach autoimmunologicznych.¹¹

Zaburzenie równowagi między limfocytami Th17 a Treg wydaje się być bardzo istotne w rozwoju choroby. Stosunek Th17/Treg jest znacząco wyższy u pacjentów z chorobą Hashimoto w porównaniu do zdrowych osób.¹ U pacjentów z chorobą Hashimoto zaobserwowano również niezwykle wysokie poziomy komórek Th17 i powiązanych prozapalnych cytokin zarówno w tkance tarczycy, jak i we krwi obwodowej.¹

Cytokiny i chemokiny w zapaleniu tarczycy

Cytokiny pochodzące z nacieku limfocytarnego odgrywają kluczową rolę w uszkodzeniu komórek tarczycy. Mogą one stymulować same komórki tarczycy do uwalniania mediatorów prozapalnych, tym samym wzmacniając i utrwalając odpowiedź autoimmunologiczną.¹ Cytokiny Th1 produkują IFN-γ i TNF-α, które stymulują tyreocyty do wydzielania chemokin (CXCL10, CXCL9 i CXCL11), co prowadzi do dalszego nasilenia procesu zapalnego.¹

Kolejny prozapalny kaskada została zidentyfikowana w chorobie Hashimoto wraz z odkryciem zwiększonej ekspresji wielu składników inflamasomu (NLRP1, NLRP3, NLRC4, AIM2, ASC i kaspazy-1) oraz związanych z nimi cytokin (IL-18 i IL-1) w tarczycy pacjentów.¹¹ Komponenty te mogą przyczyniać się do dalszego uwalniania cytokin i śmierci komórek poprzez proces piroptoza.¹

W tkance tarczycy pacjentów z chorobą Hashimoto wykazano obecność wielu cytokin: IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, IL-14, TNF-α i IFN-γ w komórkach zapalnych i komórkach pęcherzykowych tarczycy.¹ Cytokiny pochodzące z limfocytów T mogą bezpośrednio uszkadzać komórki tarczycy, prowadząc do zaburzeń funkcjonalnych, a także mogą stymulować produkcję tlenku azotu (NO) i prostaglandyny (PG), zwiększając tym samym odpowiedź zapalną w autoimmunologicznej chorobie tarczycy.¹

Mechanizmy uszkodzenia komórek tarczycy

Uszkodzenie komórek tarczycy w chorobie Hashimoto odbywa się poprzez różne mechanizmy immunologiczne:¹

Cytotoksyczność komórkowa zależna od przeciwciał (ADCC)¹
Apoptoza komórek tarczycy zależna od Fas/FasL (tzw. samobójstwo lub bratobójstwo)¹¹
Bezpośredni efekt cytotoksyczny limfocytów CD8+ i CD4+, który jest odpowiednio ograniczony przez MHC-I i MHC-II (tzw. zabójstwo)¹
Szlak egzocytozy ziarnistości (perforyny, granzymy)¹

Mechanizmy humoralne obejmują blokujący efekt przeciwciał przeciwko receptorowi TSH i cytotoksyczny efekt przeciwciał anty-TPO zależny od dopełniacza.¹ Zwiększona apoptoza poprzez Fas-FasL obserwowana jest w komórkach tarczycy znajdujących się w pobliżu naciekających limfocytów i mechanizm ten został opisany jako główny mechanizm niszczenia komórek tarczycy w chorobie Hashimoto.¹

Ostateczne zniszczenie komórek pęcherzykowych tarczycy jest odpowiedzialne za rozwój niedoczynności tarczycy w przewlekłym autoimmunologicznym zapaleniu tarczycy.¹ W wyniku działania tych procesów dochodzi do uszkodzenia gruczołu tarczowego, prowadząc do niewystarczającej produkcji i wydzielania hormonów tarczycy, chociaż początkowo wcześniej utworzona tyroksyna (T4) i trójjodotyronina (T3) mogą „wyciekać” do krążenia z uszkodzonych komórek.¹¹

Czynniki genetyczne w patogenezie choroby Hashimoto

Czynniki genetyczne przyczyniają się w około 70-80% do patogenezy autoimmunologicznej choroby tarczycy, podczas gdy czynniki środowiskowe stanowią około 20-30%.¹¹ Badania bliźniąt wykazały, że chociaż istnieje wyraźna genetyczna predyspozycja do choroby Hashimoto, współczynnik zgodności u bliźniąt jednojajowych wynosi tylko około 50%, co podkreśla, że inne ważne czynniki, takie jak czynniki środowiskowe, odgrywają rolę w patogenezie tej choroby.¹

Geny związane z chorobą Hashimoto obejmują:¹¹

Geny HLA-DR (ludzki antygen leukocytarny), które kontrolują odpowiedź immunologiczną¹¹
Geny regulujące układ immunologiczny, w tym CTLA-4 (antygen 4 cytotoksycznych limfocytów T), PTPN22 (białkowa tyrozynowa fosfataza 22), FOXP3 i CD25 (łańcuch α receptora interleukiny 2)¹¹
Geny specyficzne dla tarczycy, takie jak geny tyreoglobuliny i receptora TSH¹

Badania genomowe (GWAS) zidentyfikowały liczne loci podatności na chorobę Hashimoto. Loci te wspierają rolę czynników zakaźnych w wywoływaniu choroby, zaburzenia sygnalizacji i aktywacji limfocytów T i B oraz specyficzne dla tarczycy ścieżki chorobowe w początkowym etapie i progresji choroby.¹

Czynniki epigenetyczne

Chociaż predyspozycje genetyczne mogą potencjalnie wyjaśnić patogenezę choroby Hashimoto, samo ryzyko genetyczne jest niskie. Jednakże ryzyko to wzrasta, gdy występuje synergizm z pewnymi komponentami lub modyfikacjami epigenetycznymi w regionach regulatorowych, które są zdolne do kontrolowania ekspresji genów.¹

Jednym ze sposobów, w jaki niektóre czynniki środowiskowe i wiele czynników egzystencjalnych może działać, są modyfikacje epigenetyczne, takie jak zmiany w metylacji DNA i modyfikacje histonów na poziomie tkankowym.¹ Choroba Hashimoto może być regulowana epigenetycznie, bez zmian w sekwencji DNA, poprzez różne mechanizmy, które mogą być znaczące w modyfikacji odpowiedzi immunologicznych i funkcji tarczycy.¹

Czynniki środowiskowe w patogenezie choroby Hashimoto

Czynniki środowiskowe mogą wpływać na patogenezę choroby Hashimoto i obejmują:¹¹

Nadmiar jodu: Jest powszechnie wiadomo, że na poziomie populacyjnym przeciwciała tarczycowe i autoimmunologiczna niedoczynność tarczycy są częstsze w obszarach z wystarczającą ilością jodu niż w obszarach z niedoborem jodu.¹ Nadmiar jodu może bezpośrednio blokować syntezę hormonów lub być bezpośrednio toksyczny dla tyreocytów, a także może indukować autoimmunizację w tarczycy poprzez zwiększenie immunogenności cząsteczek tyreoglobuliny i/lub uwalnianie wolnych rodników tlenu poprzez enzymatyczną reakcję peroksydazy tarczycowej.¹ Zwiększone wolne rodniki indukują podwyższoną ekspresję międzykomórkowej cząsteczki adhezyjnej-1.¹
Selen: Jest to niezbędny mikroelement, który odgrywa ważną rolę w chorobach związanych z układem immunologicznym. Niskie poziomy selenu zostały powiązane ze słabą funkcją immunologiczną. W związku z tym postawiono hipotezę, że łagodny niedobór selenu w diecie może sprzyjać autoimmunizacji tarczycy.¹¹
Żelazo: Odgrywa ważną rolę w hemoglobinie i mioglobinie, i jest zaangażowane w wiele ważnych procesów metabolicznych.¹
Cynk: Jest pierwiastkiem śladowym ściśle związanym z metabolizmem tarczycy.¹
Witamina D: Niedobór witaminy D jest jedną z przyczyn choroby Hashimoto; im większy niedobór witaminy D, tym większe prawdopodobieństwo wystąpienia choroby.¹¹
Infekcje: Czynniki zakaźne mogą być bakteryjne, wirusowe i grzybicze.¹
Stres: Stres jako czynnik prowokujący w patogenezie chorób autoimmunologicznych tarczycy jest dobrze znany.¹
Dysbioza jelitowa: Dysbioza jelitowa prowadzi do chorób autoimmunologicznych i zmienia zwykłe tryby trawienia i wchłaniania, funkcjonowanie błony śluzowej i układu immunologicznego.¹ W dysbiozie utracona jest selektywna przepuszczalność ściany jelitowej. Toksyny, produkty niepełnej hydrolizy i inne antygeny, które tworzą obciążenie dla układu immunologicznego, zaczynają przez nią przechodzić. Procesy te prowadzą do nietolerancji pokarmowej, alergii i rozwoju autoimmunizacji.¹
Leki: Nowe leki przeciwnowotworowe, w tym interferon-alfa i inhibitory kinazy tyrozynowej, zostały powiązane z wystąpieniem choroby Hashimoto.¹

Czynniki te mogą, poprzez mechanizmy, które nie zostały jeszcze wyjaśnione, zwiększyć podatność na autoimmunologiczne choroby tarczycy. Kluczowym punktem dla rozwoju choroby Hashimoto jest infiltracja tarczycy przez komórki prezentujące antygen (APC), co może być indukowane przez czynniki środowiskowe.¹¹

Zaburzenia tolerancji immunologicznej

Kluczowym mechanizmem leżącym u podstaw rozwoju choroby Hashimoto jest utrata tolerancji immunologicznej na autoantygeny. Tolerancja immunologiczna jest wynikiem procesów zlokalizowanych w tkankach grasicy i pozagrasiczych (określanych odpowiednio jako centralna i obwodowa tolerancja).¹

Utrata immunologicznej samotolerancji leży w centrum patobiologii choroby Hashimoto. Może ona wynikać z:¹

Utraty centralnej tolerancji (tj. zaburzenia eliminacji autoreaktywnych limfocytów T w grasicy)
Dysfunkcji tolerancji obwodowej (tj. zaburzenia apoptozy samoreaktywnych limfocytów T i zahamowania aktywności Tregs)
Zaburzenia anergii

Zgodnie z teorią selekcji klonalnej, we wczesnym etapie rozwoju płodowo-noworodkowego większość autoreaktywnych limfocytów T jest eliminowana w grasicy poprzez selekcję negatywną. Mechanizm ten jest zwykle określany jako centralna tolerancja. Kilka uciekających autoreaktywnych klonów, które migrują do obwodu, jest kontrolowanych przez kilka mechanizmów tolerancji obwodowej, w tym ignorancję (pozostają niereaktywne na stymulację antygenową), anergię, śmierć komórkową indukowaną aktywacją i aktywną supresję przez Tregs.¹

W chorobie Hashimoto, z powodu zaburzonego nadzoru immunologicznego, komórki rozpoznające autoantygeny nie są eliminowane w procesie selekcji i migrują do tkanek obwodowych.¹ Podkreśla się również znaczenie zmniejszonej aktywności regulatorowych limfocytów T i zwiększonej aktywności pomocniczych limfocytów T.¹

Podsumowanie mechanizmów patogenetycznych

Patogeneza choroby Hashimoto obejmuje złożone interakcje między czynnikami genetycznymi, epigenetycznymi i środowiskowymi, które prowadzą do utraty tolerancji immunologicznej na autoantygeny tarczycy. Proces ten rozpoczyna się od aktywacji autoreaktywnych limfocytów T CD4+ specyficznych dla antygenów tarczycy, co prowadzi do rekrutacji limfocytów B i CD8+ do tarczycy.¹

Uczulenie autoreaktywnych limfocytów T CD4+ pomocniczych na antygeny tarczycy inicjuje śmierć tyreocytów poprzez wiele mechanizmów immunologicznych:¹

Śmierć komórek pośredniczona przez cytotoksyczne limfocyty T CD8+
Śmierć komórek pośredniczona przez cytokiny
Wiązanie przeciwciał przeciwtarczycowych

Przeciwciała mogą wiązać się z enzymem peroksydazy tarczycowej, tyreoglobuliną i receptorami TSH, a następnie hamować syntezę hormonów; przeciwciała mogą również wiązać się z nadnerczami, trzustką i komórkami produkującymi kwas (komórki okładzinowe) w żołądku.¹ Gdy układ immunologiczny próbuje zniszczyć gruczoł tarczowy, upośledza zdolność tarczycy do produkcji hormonu tarczycy.¹

Choroba Hashimoto jest pierwszym typem z obniżoną produkcją hormonu tarczycy (TH) i zwiększoną produkcją hormonu stymulującego tarczycę (TSH) i hormonu uwalniającego tyreotropinę (TRH).¹ Ten złożony proces autoimmunologiczny ostatecznie prowadzi do stopniowego niszczenia gruczołu tarczowego i rozwoju niedoczynności tarczycy.¹

Zrozumienie roli znanych loci podatności i określenie brakującej dziedziczności w autoimmunologicznej chorobie tarczycy zapewni wgląd w patogenezę choroby i możliwości przełożenia tych ustaleń na lepsze opcje terapeutyczne.¹

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Materiały źródłowe

#1 Hashimoto Thyroiditis – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK459262/
Hashimoto thyroiditis, also known as chronic autoimmune thyroiditis or chronic lymphocytic thyroiditis, is an autoimmune disease that leads to the destruction of thyroid follicular cells through immune-mediated processes. This autoimmune condition is the most common cause of hypothyroidism in developed countries and is characterized by the formation of antithyroid antibodies and T-cell activation, which result in progressive fibrosis of the thyroid gland. […] Hashimoto thyroiditis is an autoimmune disease that destroys thyroid follicular cells through cell- and antibody-mediated immune processes. This disease is also known as chronic autoimmune thyroiditis and chronic lymphocytic thyroiditis. Hashimoto thyroiditis is the most common cause of hypothyroidism in developed countries. The pathophysiology of this disease involves the formation of antithyroid antibodies and T-cell activation that attack the thyroid tissue, causing progressive fibrosis.
#1 Clinical Relevance of Environmental Factors in the Pathogenesis of Autoimmune Thyroid Disease
https://www.e-enm.org/journal/view.php?doi=10.3803/enm.2016.31.2.213
Genetic factors contribute for about 70% to 80% and environmental factors for about 20% to 30% to the pathogenesis of autoimmune thyroid disease (AITD). […] Autoimmune thyroid diseases (AITD) like Graves disease and Hashimoto disease are complex diseases in which autoimmunity against thyroid autoantigens develop against a certain genetic background, provoked by exposure to environmental factors. […] The implication is that the proportion of environmental factors in the immunopathogenesis of AITD is limited, in the order of 20% to 30%. […] The Amsterdam AITD cohort is a 5-year follow-up study in a population at risk for AITD, namely in healthy women with one or more 1st or 2nd degree relatives with proven AITD. […] Independent risk factors for the occurrence of overt hyper- or hypothyroidism in the Amsterdam AITD cohort were baseline TSH, baseline TPO-Ab, and family background of AITD.
#1 Hashimoto Thyroiditis – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK459262/
The presence of lymphocytic infiltration and fibrosis in the thyroid follicles are characteristic of Hashimoto thyroiditis. Both cellular (T-cell mediated) and humoral (B-cell mediated) immune responses have essential roles in the pathogenesis of this disorder. […] Individuals with Hashimoto thyroiditis have the following polyclonal antibodies specific to thyroid antigens: Thyroid peroxidase antibody: This is the most common antibody found in Hashimoto thyroiditis. These are found in over 90% of individuals with Hashimoto thyroiditis. Thyroglobulin antibody: This is present in 50% to 80% of the individuals with Hashimoto thyroiditis. TSH receptor antibody (TSHR Ab): Various types of TSHR Ab have been identified. These can be stimulating, blocking, or neutral. A vast majority of TSHR Ab in Hashimoto thyroiditis is the blocking type. Rarely can individuals with Hashimoto thyroiditis have TSHR-stimulating antibodies, which can also result in thyroid eye disease. This might also explain why few individuals with Hashimoto thyroiditis switch to Graves disease.
#1 Hashimoto’s thyroiditis – Wikipedia
https://en.wikipedia.org/wiki/Hashimoto%27s_thyroiditis
Hashimoto’s thyroiditis is thought to be due to a combination of genetic and environmental factors. […] Hashimoto’s thyroiditis is a T-lymphocyte mediated attack on the thyroid gland. T helper 1 cells trigger macrophages and cytotoxic lymphocytes to destroy thyroid follicular cells, while T helper 2 cells stimulate the excessive production of B cells and plasma cells which generate antibodies against the thyroid antigens, leading to thyroiditis. […] The three major antibodies are: Thyroid peroxidase Antibodies (TPOAb), Thyroglobulin Antibodies (TgAb), and Thyroid stimulating hormone receptor Antibodies (TRAb), with TPOAb and TgAb being most commonly implicated in Hashimoto’s. […] They are hypothesized to develop as a result of thyroid damage, where T-lymphocytes are sensitized to residual thyroid peroxidase and thyroglobulin, rather than as the initial cause of thyroid damage.
#1 Hashimoto Thyroiditis: Practice Essentials, Background, Etiology
https://emedicine.medscape.com/article/120937-overview
Hashimoto thyroiditis is part of the spectrum of autoimmune thyroid diseases (AITDs) and is characterized by the destruction of thyroid cells by various cell- and antibody-mediated immune processes. […] Although the initiating process in Hashimoto thyroiditis is not well understood, genetic and environmental factors play a role in the pathogenesis. […] Antibodies binding to and blocking the thyroid-stimulating hormone (TSH) receptor, thyrotropin receptor blocking antibodies (TBII) have also been described and may contribute to impairment in thyroid function. The result is inadequate thyroid hormone production and secretion, although initially, preformed thyroxine (T4) and triiodothyronine (T3) may „leak” into the circulation from damaged cells. […] Genes demonstrated to play a role in the pathogenesis of Hashimoto thyroiditis include those related to immune response and thyroid function. The human leukocyte antigen (HLA) complex, containing genes that control the immune response, has been associated with development of the condition.
#1 Hashimoto’s thyroiditis – Wikipedia
https://en.wikipedia.org/wiki/Hashimoto%27s_thyroiditis
However, they may exacerbate further thyroid destruction by binding the complement system and triggering apoptosis of thyroid cells. […] TPO antibody levels may correlate with the degree of lymphocyte infiltration of the thyroid. […] The pathophysiology of autoimmune thyroiditis is not well understood. However, once the disease is established, its core processes have been observed. […] Gross morphological changes within the thyroid are seen in the general enlargement, which is far more locally nodular and irregular than more diffuse patterns (such as that of hyperthyroidism). […] Hypothyroidism is caused by replacement of follicular cells with parenchymatous tissue. […] Partial regeneration of the thyroid tissue can occur, but this has not been observed to normalize hormonal levels.
#1 Hashimoto Thyroiditis – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK459262/
CD8+ T cells are a central part of the immune dysfunction underlying the pathogenesis of Hashimoto thyroiditis. These cytotoxic cells infiltrate the thyroid tissue, causing inflammation and destruction of the follicular cells. CD4+ T cells activate other immune cells, especially macrophages and B cells, which lead to the production of autoantibodies. Different subsets of CD4+ T cells, including Th1, Th2, Th17, and Tregs (regulatory T cells), have various functions, and their imbalance contributes to the pathogenesis of Hashimoto thyroiditis. Th1 is upregulated in Hashimoto thyroiditis, promoting inflammation in the thyroid tissue. Tregs are critical in promoting immune tolerance and avoiding excessive immune responses. Tregs are downregulated in Hashimoto thyroiditis.
#1 Hashimoto Thyroiditis | Treatment & Management | Point of Care
https://www.statpearls.com/point-of-care/22579
Different subsets of CD4+ T cells, including Th1, Th2, Th17, and Tregs (regulatory T cells), have various functions, and their imbalance contributes to the pathogenesis of Hashimoto thyroiditis. […] Th1 is upregulated in Hashimoto thyroiditis, promoting inflammation in the thyroid tissue. Tregs are critical in promoting immune tolerance and avoiding excessive immune responses. Tregs are downregulated in Hashimoto thyroiditis.
#1 An update on the pathogenesis of Hashimotoâs thyroiditis
https://pmc.ncbi.nlm.nih.gov/articles/PMC8049926/
The relationship between goitrous and atrophic forms of autoimmune thyroiditis has long been debated, particularly the question of whether the former simply progresses to the latter, as opposed to these being two discrete entities. […] Regulatory T cell (Treg) are now well established as having a critical role in preventing autoimmunity. Several types have been identified, broadly classed as natural or thymic Tregs (CD4+ CD25+Foxp3+), previously shown to be abnormal in HT, and induced Treg subsets which differentiate in the periphery in response to specific antigen. An increase in CD4+CD69+Foxp Tregs but with diminished function has been reported in HT, and a decrease in both number and function of CD4+CD49+LAG-3+IL-10+ Treg type 1 cells has also been found. These changes have been identified using peripheral blood samples and also occur in Graves disease. It seems that the relationship between Treg and HT is complex by the time disease is fully established, but future detailed studies, especially using thyroid-derived lymphocytes, could identify the sequence of immunoregulatory failure that leads to autoimmune thyroid disease.
#1 An update on the pathogenesis of Hashimotoâs thyroiditis
https://pmc.ncbi.nlm.nih.gov/articles/PMC8049926/
In terms of thyroid cell injury, cytokines derived from the lymphocytic infiltrate play a key role, including their ability to stimulate the thyroid cells themselves to release proinflammatory mediators, thus amplifying and perpetuating the autoimmune response. Previous studies have shown that blood and thyroid Th17 cells which secrete the cytokine IL-17 are increased in HT, as in many other autoimmune disorders, but a recent study has reported finding an additional source of IL-17 in the thyroid follicular cells themselves in HT. […] A further proinflammatory cascade has been identified in HT with the finding of increased expression of multiple inflammasome components (NLRP1, NLRP3, NLRC4, AIM2, ASC, and caspase-1) and their associated cytokines (IL-18 and IL-1) in the thyroid of patients, as well as identification of inflammasome component release by thyroid cell stimulated in vitro with the IFN- and tumour necrosis factor-, which may in turn contribute to further cytokine release and cell death through pyroptosis. […] The PD-1/PD ligand-1 axis has also been investigated. This pathway plays a major role in suppressing adaptive immunity in a variety of settings, including the immune response by tumour cells, and as we have seen, blockade can result in autoimmune disease.
#1 Role of the T and B lymphocytes in pathogenesis of autoimmune thyroid diseases | Thyroid Research | Full Text
https://thyroidresearchjournal.biomedcentral.com/articles/10.1186/s13044-018-0046-9
In peripheral blood and thyroid inflammatory environment in patients with AITD, especially HT, higher concentration of Th17 and their excreted cytokines were observed. […] Considerable impact on progress of AITD have an imbalance between Th17 lymphocytes and Tregs, which seems to be very important in development of the disease. […] The Th17/Treg ratio was remarked significantly higher in patients with HT compared with healthy controls and the correlation between the levels of GITRL and the proportion of Th17 cells was found positive. […] In patients suffering from HT, there have been also discovered unusually high levels of Th17 cells and Th-17-associated proinflammatory cytokines both in thyroid tissue and/or in peripheral blood which has been confirmed in subsequent assays. […] Altogether, it is clear that Th17 lymphocytes play a key role in development and progress of AITD, which makes them plausible potential aims for innovative immunosuppressive treatment.
#1 Cellular and molecular basis of thyroid autoimmunity in: European Thyroid Journal Volume 11 Issue 1 (2022)
https://etj.bioscientifica.com/view/journals/etj/11/1/ETJ-21-0024.xml
The mechanisms triggering the cascade of events leading to AITD involve the interplay between environmental factors (e.g. viral infection), epigenetic/genetic predispositions, and microbiome of which dysfunction contributes to the loss of immune tolerance, activation of autoreactive lymphocytes, and inflammation, leading to the damage of thyrocytes and clinical AITD. […] The common mechanism involved in the initiation and acceleration of the inflammatory processes in AITD is the Th1-cytokine/chemokine axis. Th1 cells produce IFNG and TNFA which stimulate thyrocytes (in HT and GD) and retroorbital cells in thyroid eye disease to secrete chemokines (CXCL10, CXCL9, and CXCL11). […] The mechanisms by which most SNPs in the AITD-linked genes contribute to thyroid autoimmunity are mostly unknown, with a few notable exceptions. The AITD-related SNPs can influence translation efficiency, transcriptional repression, or alternative splicing of the affected genes (CD40, TSHR, and FLT3).
#1
https://link.springer.com/article/10.1007/s40618-020-01477-1
A further proinflammatory cascade has been identified in HT with the finding of increased expression of multiple inflammasome components (NLRP1, NLRP3, NLRC4, AIM2, ASC, and caspase-1) and their associated cytokines (IL-18 and IL-1) in the thyroid of patients, as well as identification of inflammasome component release by thyroid cell stimulated in vitro with the IFN- and tumour necrosis factor-, which may in turn contribute to further cytokine release and cell death through pyroptosis. […] The PD-1/PD ligand-1 axis has also been investigated. This pathway plays a major role in suppressing adaptive immunity in a variety of settings, including the immune response by tumour cells, and as we have seen, blockade can result in autoimmune disease.
#1 The role of the immune system and cytokines involved in the pathogenesis of autoimmune thyroid disease (AITD) | MikoÅ | Endokrynologia Polska
https://journals.viamedica.pl/endokrynologia_polska/article/view/38191
Autoimmune thyroid disease (AITD) is the most common organ-specific autoimmune disorder. AITD development occurs due to loss of immune tolerance and reactivity to thyroid autoantigens: thyroid peroxidase (TPO), thyroglobulin (TG) and thyroid stimulating hormone receptor (TSHR). This leads to infiltration of the gland by T cells and B cells that produce antibodies specific for clinical manifestations of hyperthyroidism in Graves disease (GD) and chronic autoimmune thyroiditis (cAIT). […] In addition, T cells in Hashimotos thyroiditis induce apoptosis in thyroid follicular cells, leading ultimately to the destruction of the gland. Cytokines are involved in the pathogenesis of thyroid diseases working in both the immune system and directly targeting the thyroid follicular cells. They are involved in the induction and effector phase of the immune response and inflammation, playing a key role in the pathogenesis of autoimmune thyroid disease. The presence of multiple cytokines has been demonstrated: IL-1alpha, IL-1b, IL-2, IL-4 , IL-6, IL-8, IL-10, IL-12, IL-13, IL-14, TNF-alpha and IFN-gamma within the inflammatory cells and thyroid follicular cells. Finally, cytokines derived from T cells can directly damage thyroid cells, leading to functional disorders and may also stimulate the production of nitric oxide (NO) and prostaglandin (PG), thus increasing the inflammatory response in AITD.
#1 Hormones.gr
http://www.hormones.gr/841/article/an-overview-of-the-pathogenesis-of%E2%80%A6.html
In the last few years, evidence was also accumulated supporting the concept that INF- inducible chemokines, such as CXCL10, play an important role in the initial stages of thyroid autoimmunity. When stimulated by INF-, thyroid follicular cells secrete CXCL10, which in turn recruits into the thyroid Th1 lymphocytes expressing CXCR3 and secreting INF-, thus establishing a loop which reinforces and maintains the autoimmunity process. […] […] Cell damage mechanisms in thyroid autoimmunity involve: antibody dependent cell-mediated cytotoxicity (ADCC); Fas/FasL-mediated apoptosis of thyroid cells (so-called suicide or fratricide); the direct cytotoxic effect of CD8+ and CD4+ cells, which is MHC-I and MHC-II restricted, respectively (also so-called homicide); and the granule-exocytosis pathway (perforins, granzymes). Lymphokine-activated killer cells are also involved. Humoral mechanisms include the thyroid stimulating or TSH blocking effect of TSH-R antibodies and the complement-mediated cytotoxic effect of TPO-antibodies. The eventual destruction of thyroid follicular cells is responsible for the development of hypothyroidism in chronic autoimmune thyroiditis. […]
#1 Autoimmune Hashimotoâs Thyroiditis and Hypothyroidism: Novel Aspects | IntechOpen
https://www.intechopen.com/chapters/80671
Increased apoptosis may be involved in the mechanism of thyroid cells destruction in Hashimoto thyroiditis. Cytotoxic T lymphocytes destroy target cells inducing an apoptosis mechanism. Increased apoptosis via Fas-FasL is observed in thyroid cells which are near the infiltrating lymphocytes and this mechanism has been described as a major thyroid cell destruction mechanism in Hashimoto thyroiditis.
#1 Hashimotoâs Thyroiditis (Hashimotoâs Disease) | Doctor
https://patient.info/doctor/hashimotos-thyroiditis
In this condition, typically there is aggressive destruction of thyroid cells by various cell- and antibody-mediated immune processes (in contrast to the stimulatory effect seen in Graves’ disease). It is not yet understood why this occurs. […] The major environmental triggers of autoimmune thyroid disease include iodine, medications, infection, smoking and diet. Patients’ iron levels (particularly in menstruating women), vitamin D status and selenium intake (in areas of iodine deficiency/excess) are important. […] Antibodies binding to and blocking the thyroid-stimulating hormone (TSH) receptor have been described and may contribute to further impairment in thyroid function. […] The result is inadequate thyroid hormone production and secretion, although initially both preformed thyroxine (T4) and triiodothyronine (T3) may 'leak’ into the circulation from damaged cells. […] The goitrous form (rather than atrophic) is associated with HLA-DR5. […] Twin studies indicate that there is about 70% genetic contribution to autoimmune thyroid disease.
#1 Clinical Relevance of Environmental Factors in the Pathogenesis of Autoimmune Thyroid Disease
https://www.e-enm.org/journal/view.php?doi=10.3803%2FEnM.2016.31.2.213
Genetic factors contribute for about 70% to 80% and environmental factors for about 20% to 30% to the pathogenesis of autoimmune thyroid disease (AITD). […] Autoimmune thyroid diseases (AITD) like Graves disease and Hashimoto disease are complex diseases in which autoimmunity against thyroid autoantigens develop against a certain genetic background, provoked by exposure to environmental factors. […] The implication is that the proportion of environmental factors in the immunopathogenesis of AITD is limited, in the order of 20% to 30%. […] The Amsterdam AITD cohort is a 5-year follow-up study in a population at risk for AITD, namely in healthy women with one or more 1st or 2nd degree relatives with proven AITD. […] Independent risk factors for the occurrence of overt hyper- or hypothyroidism in the Amsterdam AITD cohort were baseline TSH, baseline TPO-Ab, and family background of AITD.
#1 Hormones.gr
https://www.hormones.gr/840/article/article.html
Hashimotos thyroiditis (HT), a common thyroid disease, is now recognized as an autoimmune thyroid disorder (AITD). […] Although the exact etiology is not as yet known, HT is thought to arise from an interaction between genetic susceptibility factors, epigenetic effects and various environmental triggers (e.g. iodine, infection). […] Twin studies showed epidemiological evidence for genetic susceptibility to HT. […] To date, several loci have been associated with Hashimotos disease, such as HLA-DR, immune-regulatory genes (CD40, CTLA-4, PTPN22, FOXP3 and CD25) and thyroid-specific genes (thyroglobulin and thyroid-stimulating hormone [TSH] receptor). […] Even with identical twins the concordance rate was only about 50%, emphasizing that other important factors such as environmental factors play roles in the pathogenesis of HT.
#1 Genetic and epigenetic markers in Hashimoto’s thyroiditis (Review)
https://www.spandidos-publications.com/10.3892/ije.2025.24
Specific gene variants, particularly in the HLA region and the genes outside the HLA, involved in immune function, can be traced back to be the genetic risk for HT. […] HT is marked by a particular type of immune-mediated inflammation that targets the thyroid. […] The thyroid gland is one of the organs most affected by autoimmune processes; numerous patients with HT seek medical advice on lifestyle changes and dietary modifications in order to improve and maintain their thyroid function. […] Disruptive inflammation and self-immune reactions against thyroid connective tissues lead to the continuous destruction of thyroid follicles, resulting in their inefficiency to perform their function of thyroid hormone synthesis. […] Hypothyroidism is a common condition of thyroid hormone deficiency, which is readily diagnosed and managed; however, if left untreated, it can be potentially fatal in severe cases. […] The clinical characteristics of Hashimoto’s disease are a result of the interplay and interaction of the genetic and environmental components that underlie and provoke the disease.
#1 Pathology Outlines – Hashimoto thyroiditis
https://www.pathologyoutlines.com/topic/thyroidhashimotosthyroiditis.html
Prototype of autoimmune disease presenting with goiter, elevated circulating antithyroid antibodies, often with hypothyroidism […] Histopathologically diffuse lymphoplasmacytic infiltration, lymphoid follicle formation, follicular atrophy, oncocytic metaplasia and fibrosis […] Breakdown of immune tolerance […] Genetic susceptibility […] Environmental factors […] Autoantibodies against thyroglobulin, thyroid peroxidase (TPO) and antithyroid stimulating hormone (TSH) receptor […] CD8+ T cell mediated cytotoxicity, cytokine mediated cell death and antibody dependent cell mediated cytotoxicity […] Multifactorial; immunological, genetic and environmental […] Polymorphisms in human leukocyte antigen (HLA) genes […] Polymorphisms in genes involved in immune regulation, including cytotoxic T lymphocyte associated antigen 4 (CTLA4), protein tyrosine phosphatase 22 (PTPN22) and interlukin 2 receptor Î± chain (IL2RA) […] Decrease in Tregs […] Hashitoxicosis: transient thyrotoxicosis due to follicle destruction in Hashimoto thyroiditis […] IgG4 related variant shows a more aggressive clinical course, with more severe and treatment resistant hypothyroidism.
#1 GWAS in autoimmune thyroid disease: redefining our understanding of pathogenesis | Nature Reviews Endocrinology
https://www.nature.com/articles/nrendo.2013.56
Susceptibility loci identified by GWAS support a role for viral triggering of disease, disrupted T-cell and B-cell signalling and activation, and thyroid-specific disease pathways in AITD onset and progression. […] Understanding the role of known susceptibility loci and determining missing heritability in AITD will provide insights into disease pathogenesis and opportunities to translate these findings into improved therapeutic options.
#1 Molecular Mechanisms in Autoimmune Thyroid Disease
https://www.mdpi.com/2073-4409/12/6/918
AITD is triggered by a variety of factors (genetic, nongenetic, epigenetic, and environmental). Among the susceptibility genes associated with the immune system, the following stand out: HLA-DR3; PTPN22; CD40; FOXP3; CTLA-4; and IL-2RÎ±, although thyroid-specific susceptibility genes have been described (TSHR, Tg, and TPO). Some SNPs in these genes play key roles that help explain (at least in part) the increased risk for AITD. […] Although genetic susceptibility can potentially explain the pathogenesis of AITD, the genetic risk by itself is low; however, this risk is increased when there is synergism with some components or epigenetic modifications in the regionâs regulators that are capable of controlling the gene expression. […] Environmental factors can be infectious and noninfectious and, in turn, nutritional and nonnutritional. These factors can, by mechanisms not yet elucidated, increase the susceptibility to AITD. However, the key point for the development of AITD is the infiltration of the thyroid by APCs, which may be induced by environmental factors.
#1 The Immunopathogenesis of Chronic Autoimmune Thyroiditis One Century after Hashimoto in: European Thyroid Journal Volume 1 Issue 4 (2013)
https://etj.bioscientifica.com/view/journals/etj/1/4/ETJ343834.xml
One way in which some environmental and many existential factors may operate is through epigenetic modifications, such as changes in DNA methylation and histone modification, at the tissue level. […] The early observation of experimental autoimmune thyroiditis being precipitated by 3-methylcholanthrene has been reprised by the demonstration of thyroid peroxidase autoantibodies and lymphocytic thyroiditis in rats given polychlorinated biphenyls, widely used compounds which have known effects as endocrine disruptors. […] Being a woman rather than a man increases the risk of Hashimoto thyroiditis 8-fold, making this the greatest known risk factor by some margin. […] Although huge strides have been made in our understanding of the causes of Hashimoto thyroiditis since its original description, the genetic and non-genetic factors which are involved in its aetiology are far more complex than could be imagined even a decade ago.
#1 Genetic and epigenetic markers in Hashimoto’s thyroiditis (Review)
https://www.spandidos-publications.com/10.3892/ije.2025.24
Consequently, HT may experience epigenetic regulation which differs from the normal DNA sequence, although the DNA does not change. […] The factor that modifies gene expression in heritable thyroid disorders is rich in epigenetic mechanisms, and it operates through a variety of mechanisms, which may be significant in the modification of immune responses and thyroid function. […] The present review provides an overview of currently existing evidence on the genetic and epigenetic mechanisms of HT. […] The present review aimed to not only provide explanations of the possible disease-causal pathways of the disease, but also to enhance the understanding of the pre-existing and causative factors of the disease. […] HT is a complex disease combining genetic and epigenetic factors affecting autoimmunity development; it is well known as a susceptibility factor for the development of other autoimmune diseases.
#1 Pathogenesis Markers of Hashimoto’s DiseaseâA Mini Review
https://www.imrpress.com/journal/FBL/27/10/10.31083/j.fbl2710297/htm
Environmental factors can also influence the pathogenesis of HT. […] Iodine plays an important role in endocrine diseases, especially thyroid diseases. […] Selenium is an essential micronutrient that plays an important role in immune-related diseases. […] Iron plays an important role in hemoglobin and myoglobin, and it is involved in many important metabolic processes. […] Zinc is a trace element closely related to thyroid metabolism. […] Vitamin D deficiency is one of the causes of HT, whereby the greater the vitamin D deficiency, the greater the likelihood of HT. […] Because HT is an autoimmune disease characterized by thyroid-specific autoantibodies, inflammatory infiltration of T and B cells is the main pathogenesis. […] The cytokines affecting HT are produced by subsets of Th1, Th2, and Th3 cells that participate in HT cellular and humoral immunity. […] The pathogenesis of HT is further clarified by understanding the familial correlation with other diseases. […] HT is an autoimmune disease caused by a variety of factors, such as environmental factors, genetic susceptibility, and immune factors.
#1 Hashimoto’s disease – Symptoms & causes – Mayo Clinic
https://www.mayoclinic.org/diseases-conditions/hashimotos-disease/symptoms-causes/syc-20351855
Hashimoto’s disease is an autoimmune disorder affecting the thyroid gland. […] In Hashimoto’s disease, immune-system cells lead to the death of the thyroid’s hormone-producing cells. […] Hashimoto’s disease is an autoimmune disorder. The immune system creates antibodies that attack thyroid cells as if they were bacteria, viruses or some other foreign body. The immune system wrongly enlists disease-fighting agents that damage cells and lead to cell death. […] What causes the immune system to attack thyroid cells is not clear. The onset of disease may be related to: Genetic factors, Environmental triggers, such as infection, stress or radiation exposure, Interactions between environmental and genetic factors.
#1 Clinical Relevance of Environmental Factors in the Pathogenesis of Autoimmune Thyroid Disease
https://www.e-enm.org/journal/view.php?doi=10.3803%2FEnM.2016.31.2.213
Iodine intake It is well known that at a population level thyroid antibodies and autoimmune hypothyroidism are more common in iodine-replete areas than in iodine-deficient areas. […] Low selenium levels have been associated with poor immune function. Thus it has been hypothesized that mild nutritional selenium deficiency may promote thyroid autoimmunity. […] The mechanism of action of these protective effects of alcohol remain poorly understood. […] The plausible theory then is that Y. enterocolitica ompF (outer membrane porin F) is involved in the production of TSH receptor antibodies and the pathogenesis of Graves disease through molecular mimicry. […] Stress as a provocative factor in the pathogenesis of Graves disease is well known. […] A cross-sectional analysis of the Amsterdam AITD cohort at baseline indicated a lower frequency of estrogen use in euthyroid women with TPO-Ab as compared to TPO-Ab negative women. […] The advice to stop smoking should be given always to every subject. […] Taken together, preventive interventions to diminish the risk of AITD are few, not always feasible, and probably of limited efficacy.
#1 Hormones.gr
https://www.hormones.gr/840/article/article.html
Although excess intake of iodine directly blocks hormone synthesis or is directly toxic to thyrocytes, iodine can induce autoimmunity in the thyroid by increasing the immunogenicity of thyroglobulin molecules and/or releasing free oxygen radicals via the enzymatic reaction of thyroid peroxidase. […] The increased free radicals induce an elevated expression of intracellular adhesion molecule-1. […] The characteristic histopathologic changes of HT include diffuse lymphoplasmacytic infiltration, lymphoid follicle formation with germinal centers, a varying degree of fibrosis, parenchymal atrophy and the presence of large follicular cells with abundant granular eosinophilic cytoplasm, so-called Hrthle, oxyphilic or Askanazy cells. […] Increased expression of Th1-related cytokines such as IFNg, interleukin-2 and CD25 reportedly occurs in intrathyroidal T cells from patients with HT.
#1 Hashimoto Thyroiditis: Practice Essentials, Background, Etiology
https://emedicine.medscape.com/article/120937-overview
Hashimoto thyroiditis has a markedly higher clustering of other autoimmune diseases, including pernicious anemia, adrenal insufficiency, celiac disease, and type 1 diabetes mellitus. […] The development of Hashimoto thyroiditis may be influenced not only by inherent predisposition but also by environmental factors. […] Insufficient dietary intake of selenium may lead to worsening of the condition. […] Emerging anticancer medications, including interferon-alpha and tyrosine kinase inhibitors, have been linked to the onset of Hashimoto thyroiditis. […] A study by Mazokopakis et al indicated that an association may exist between vitamin D deficiency and the development of Hashimoto thyroiditis.
#1
https://iej.zaslavsky.com.ua/index.php/journal/article/view/95
There is a steady increase in the incidence of Hashimotos autoimmune thyroiditis worldwide. […] The etiology and pathogenetic mechanisms of its development are unknown. It is believed that the cause may be increasing and rapidly changing antigenic load on the immune system by environmental triggers such as the nature and quality of food, intestinal dysbacteriosis, bacterial, viral and fungal infections. […] Due to the action of several of these factors or one of them, the intestinal immune system loses the ability to identify antigens that come with food and mistakenly begins to produce antibodies to body tissues. Leading importance in the development of this process is given to intestinal dysbacteriosis. […] The review analyzes the literature data on the importance of dysbacteriosis and the intestinal immune system in the development of autoimmunity and Hashimotos thyroiditis.
#1
https://iej.zaslavsky.com.ua/index.php/journal/article/view/95
Intestinal dysbacteriosis leads to autoimmune diseases and changes the usual modes of digestion and absorption, the functioning of the mucous membrane and the immune system. […] Intestinal dysbacteriosis causes a violation of the functional density of its mucous membrane. […] In dysbacteriosis, the selective permeability of the intestinal wall is lost. Toxins, products of incomplete hydrolysis and other antigens that create a load on the immune system begin to pass through it. These processes lead to food intolerance, allergies and the development of autoimmunity.
#1 Cellular and molecular basis of thyroid autoimmunity in: European Thyroid Journal Volume 11 Issue 1 (2022)
https://etj.bioscientifica.com/view/journals/etj/11/1/ETJ-21-0024.xml
The key mechanism behind AITD development is the loss of immune tolerance to autoantigens. Immune tolerance is the result of processes localized in the thymic and extrathymic tissues (referred as a central and peripheral tolerance, respectively). […] The loss of immune self-tolerance lies in the center of AITD pathobiology. It may result from the loss of central tolerance (i.e. disturbed deletion of autoreactive T cells in the thymus), dysfunction of peripheral tolerance (i.e. impaired apoptosis of self-reactive T cells and inhibition of the activity of Tregs), and disturbed anergy. […] The key stage in AITD development is the thyroidal accumulation of APCs expressing MHC class II molecules. The infiltration of thyroid by APC (in particular, dendritic cells and macrophages) may be triggered by inflammation resulting from viral or bacterial infection or the exposure of thyroid cells to toxins.
#1 Hormones.gr
http://www.hormones.gr/841/article/an-overview-of-the-pathogenesis-of%E2%80%A6.html
According to the clonal selection theory, in the early stage of fetal-neonatal development most auto-reactive T-cells are eliminated within the thymus by negative selection. This mechanism is usually referred to as central tolerance. The few escaped auto-reactive clones that migrate to the periphery are controlled by several mechanisms of peripheral tolerance involving ignorance (they remain non-responsive to antigenic stimulation), anergy, activation-induced cell death, and active suppression by Tregs. […] […] The role of genetics is suggested by the high frequency of autoimmune thyroid diseases affecting family members and by a significantly higher concordance of autoimmune thyroid diseases in monozygotic (HT = 55%; GD = 35%) compared to dizygotic (HT = 0%; GD = 3%) twins. The fact that concordance is not 100% in monozygotic twins indicates that environmental factors also play an important role in the etiology of autoimmune thyroid diseases. […]
#1 The Role of the Immune System in the Course of Hashimotoâs Thyroiditis: The Current State of Knowledge
https://www.mdpi.com/1422-0067/25/13/6883
In Hashimoto’s thyroiditis, due to impaired immune surveillance, cells recognizing autoantigens are not eliminated in the selection process and migrate to peripheral tissues. […] The importance of decreased regulatory T cell activity and increased helper T cell activity is also emphasized. […] The attack of these cells results in damage to the thyroid parenchyma, inflammation, fibrosis, reduced hormone production, and glandular hypofunction. […] Cytokines lead to the destruction of thyrocytes via many mechanisms at various stages of disease development. […] The pathogenesis of Hashimoto’s thyroiditis involves the involvement of cytokines produced by cells of the immune system, such as Th1, Th2, Th3, and Th17, which influence both cellular and humoral immunity. […] The studies assessed in this review have proven that IL-2 and TNF-Î± have variable effects, contributing to both the progression and decrease in the severity of the disease.
#1 Pathophysiology, Clinical Presentation and Diagnosis | Hashimoto’s Disease
https://u.osu.edu/hashimotosdisease2019/pathophysiology-and-clinical-presentation/
Hashimotos disease is a form of autoimmune disease that destroys thyroid cells by cell and antibody-mediated immune processes (Hashimoto Disease, 2019). […] The leading cause of hypothyroidism is due to the disruption of the thyroid gland (Hashimoto Disease, 2019). Sodium iodide symporter (an intrinsic plasma membrane glycoprotein that mediates the active transport of iodide in the thyroid gland) can take up toxins to the thyroid follicles where free radicals are generated. Free radicals then activate immune responses and sensitize immune cells to thyroid proteins. […] Sensitization of autoreactive CD4+ T-helper cells to thyroid antigens initiates the death of thyrocytes by multiple immunologic mechanisms: 1. CD8+ cytotoxic T cell-mediated cell death; 2. cytokine-mediated cell death; and 3. binding of antithyroid antibodies. The antibodies can bind to thyroid peroxidase enzyme, thyroglobulin, and TSH receptors, then inhibit hormone synthesis; the antibodies may also bind to adrenal glands, pancreas, and acid-producing cells (parietal cells) of the stomach. When your immune system tries to destroy your thyroid gland, it impairs your thyroids ability to produce thyroid hormone. […] Hashimoto disease is the primary type with reduced production of thyroid hormone (TH) and increased the production of thyroid-stimulating hormone (TSH) and thyrotropin-releasing hormone (TRH).
#2 Hashimoto Thyroiditis | Treatment & Management | Point of Care
https://www.statpearls.com/point-of-care/22579
Hashimoto thyroiditis is an autoimmune disease that destroys thyroid follicular cells through cell- and antibody-mediated immune processes. […] The pathophysiology of this disease involves the formation of antithyroid antibodies and T-cell activation that attack the thyroid tissue, causing progressive fibrosis. […] Both cellular (T-cell mediated) and humoral (B-cell mediated) immune responses have essential roles in the pathogenesis of this disorder. […] Individuals with Hashimoto thyroiditis have the following polyclonal antibodies specific to thyroid antigens: Thyroid peroxidase antibody: This is the most common antibody found in Hashimoto thyroiditis. […] CD8+ T cells are a central part of the immune dysfunction underlying the pathogenesis of Hashimoto thyroiditis. […] CD4+ T cells activate other immune cells, especially macrophages and B cells, which lead to the production of autoantibodies.