Hashimoto's Thyroiditis

Complex MONDO:0007699 Autoimmune Disease Endocrine Disease

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0
Mappings
0
Definitions
0
Inheritance
3
Pathophysiology
0
Histopathology
7
Phenotypes
0
Pathograph
4
Genes
3
Treatments
0
Subtypes
0
Differentials
1
Datasets
0
Trials
0
Models
3
References
2
Deep Research
🏷

Classifications

Harrison's Chapter
endocrine system disorder thyroid disorder autoimmune disease
⚙

Pathophysiology

3
Autoimmune Thyroid Destruction
T cell-mediated and antibody-mediated destruction of thyroid follicular cells leads to progressive loss of thyroid function. Anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin antibodies are characteristic.
Thyroid Epithelial Cell link T Helper Cell link
Autoimmune Response link
Show evidence (3 references)
PMID:39003267 PARTIAL Human Clinical
"We identify damaged antigen-presenting TFCs with upregulated CD74 and MIF expression in thyroid samples from AITD patients."
Spatial transcriptomics demonstrates that thyroid follicular cells actively participate in autoimmune destruction by presenting antigens via CD74/MIF upregulation.
PMID:38731922 PARTIAL Human Clinical
"Hashimoto's thyroiditis (HT) is generally characterized by the presence of thyroid peroxidase and thyroglobulin antibodies, with a concomitant infiltration of lymphocytes in the thyroid."
Confirms the characteristic antibody profile and lymphocytic infiltration pattern in Hashimoto's thyroiditis.
PMID:40535343 PARTIAL Human Clinical
"Through this review, we aim to establish mechanistic connections between ICI pharmacodynamics and thyroid tissue immunopathology."
ICI-induced thyroiditis provides a mechanistic model that mirrors the autoimmune destruction seen in spontaneous Hashimoto's thyroiditis.
Lymphocytic Infiltration
Dense lymphocytic infiltration of the thyroid gland with germinal center formation. CD4+ T cells, CD8+ T cells, and B cells accumulate in the thyroid parenchyma.
CD4-positive helper T cell link CD8-positive, alpha-beta T cell link B Cell link
Inflammatory response link Adaptive immune response link
Show evidence (2 references)
PMID:38731922 PARTIAL Human Clinical
"Hashimoto's thyroiditis (HT) is generally characterized by the presence of thyroid peroxidase and thyroglobulin antibodies, with a concomitant infiltration of lymphocytes in the thyroid."
Lymphocytic infiltration is a defining histological feature of Hashimoto's thyroiditis.
PMID:39003267 PARTIAL Human Clinical
"Here, we use spatial transcriptomics to explore the molecular architecture, heterogeneity and location of different cells present in the thyroid tissue, including thyroid follicular cells (TFCs), stromal cells such as fibroblasts, endothelial cells, and thyroid infiltrating lymphocytes."
Spatial analysis confirms the presence and organization of infiltrating lymphocytes in the thyroid microenvironment.
Thyroid Hormone Deficiency
Progressive destruction of thyroid tissue leads to decreased production of T3 and T4, resulting in hypothyroidism with elevated TSH through negative feedback.
Thyroid Hormone Synthesis link
Show evidence (1 reference)
PMID:38731922 PARTIAL Human Clinical
"Due to the progressive destruction of cells, AITD can lead to subclinical or overt hypothyroidism."
Progressive thyroid destruction in Hashimoto's thyroiditis results in hypothyroidism through loss of hormone-producing cells.
●

Phenotypes

7
Digestive 1
Constipation FREQUENT Constipation (HP:0002019)
Show evidence (1 reference)
PMID:35235282 SUPPORT Human Clinical
"Signs and symptoms include fatigue, weight gain, dry skin, constipation, and cold intolerance."
Constipation is a recognized symptom in hypothyroid states.
Endocrine 1
Goiter FREQUENT Goiter (HP:0000853)
Show evidence (1 reference)
PMID:38731922 PARTIAL Human Clinical
"Hashimoto's thyroiditis (HT) is generally characterized by the presence of thyroid peroxidase and thyroglobulin antibodies, with a concomitant infiltration of lymphocytes in the thyroid."
Goiter develops due to lymphocytic infiltration and inflammatory enlargement of the thyroid gland.
Integument 1
Dry Skin FREQUENT Dry skin (HP:0000958)
Show evidence (1 reference)
PMID:35235282 SUPPORT Human Clinical
"Signs and symptoms include fatigue, weight gain, dry skin, constipation, and cold intolerance."
Dry skin is a common dermatologic manifestation of hypothyroidism.
Metabolism 1
Cold Intolerance FREQUENT Cold intolerance (HP:6000855)
Show evidence (1 reference)
PMID:35235282 SUPPORT Human Clinical
"Signs and symptoms include fatigue, weight gain, dry skin, constipation, and cold intolerance."
Cold intolerance is a common symptom of hypothyroidism in Hashimoto's thyroiditis.
Nervous System 1
Depression OCCASIONAL Depression (HP:0000716)
Show evidence (1 reference)
PMID:23744563 PARTIAL Human Clinical
"The most common presenting symptoms may include anxiety, negative mood, depression, dry skin, cold intolerance, puffy eyes, muscle cramps and fatigue, deep voice, constipation, slow thinking and poor memory."
Depression is reported among common presenting symptoms in Hashimoto's thyroiditis.
Constitutional 1
Fatigue VERY_FREQUENT Fatigue (HP:0012378)
Show evidence (1 reference)
PMID:35235282 SUPPORT Human Clinical
"Signs and symptoms include fatigue, weight gain, dry skin, constipation, and cold intolerance."
Hashimoto-associated hypothyroidism commonly presents with fatigue.
Growth 1
Weight Gain FREQUENT Increased body weight (HP:0004324)
Show evidence (1 reference)
PMID:35235282 SUPPORT Human Clinical
"Signs and symptoms include fatigue, weight gain, dry skin, constipation, and cold intolerance."
Weight gain is a common hypothyroid symptom in Hashimoto's thyroiditis.
🧬

Genetic Associations

4
HLA-DR3 (Risk Factor)
Show evidence (1 reference)
PMID:26235382 SUPPORT Human Clinical
"AITD susceptibility genes can be categorized as either thyroid specific (Tg, TSHR) or immune-modulating (FOXP3, CD25, CD40, CTLA-4, HLA), with HLA-DR3 carrying the highest risk."
HLA-DR3 is identified as a major immune-genetic risk factor in autoimmune thyroid disease, including HT.
HLA-DR4 (Risk Factor)
Show evidence (1 reference)
PMID:29174716 PARTIAL Human Clinical
"'DRB1*04+GG' (PL: p=0.003; HT: p=0.008)"
HLA-DRB1*04 contributes to susceptibility in combination with CTLA4 risk genotype in HT cohorts.
CTLA4 (Risk Factor)
Show evidence (1 reference)
PMID:41498152 SUPPORT Human Clinical
"CTLA4 polymorphisms were associated with an elevated risk of a thyroid disease and poorer glycemic control;"
CTLA4 polymorphisms are associated with increased autoimmune thyroid disease risk.
PTPN22 (Risk Factor)
Show evidence (1 reference)
PMID:33103521 SUPPORT Human Clinical
"This meta-analysis showed that the PTPN22 R620W polymorphism is associated with the risk of GD and HT in the overall study population."
Meta-analysis supports PTPN22 as a susceptibility locus for Hashimoto's thyroiditis.
💊

Treatments

3
Levothyroxine
Thyroid hormone replacement therapy, mainstay of treatment.
Show evidence (1 reference)
PMID:35235282 SUPPORT Human Clinical
"Management includes thyroid hormone replacement, ideally levothyroxine."
Levothyroxine is standard hormone replacement therapy in hypothyroidism due to HT.
Selenium Supplementation
May reduce antibody levels in some patients.
Show evidence (1 reference)
PMID:38243784 PARTIAL Human Clinical
"In people with HT without THRT, selenium was effective and safe in lowering TSH, TPOAb, and MDA levels."
Meta-analysis supports selenium as a potential adjunct in selected HT patients.
Monitoring
Regular TSH monitoring to adjust replacement dose.
Show evidence (1 reference)
PMID:35235282 SUPPORT Human Clinical
"Thyroid hormone should be titrated based on goal TSH values, symptoms, and potential treatment adverse effects."
Ongoing TSH-based monitoring is required to titrate thyroid hormone replacement.
🌍

Environmental Factors

3
Iodine Excess
Can trigger or worsen disease
Show evidence (1 reference)
PMID:28290237 PARTIAL Human Clinical
"Chronic exposure to excess iodine intake induces autoimmune thyroiditis, partly because highly iodinated thyroglobulin (Tg) is more immunogenic."
Excess iodine exposure is associated with autoimmune thyroiditis in HT-focused nutritional risk literature.
Selenium Deficiency
May increase risk
Show evidence (1 reference)
PMID:35789269 SUPPORT Human Clinical
"The data indicate an increased incidence of TPO-Ab seroconversion with low Se supply and support the hypothesis that Se deficiency contributes to HT as a modifiable risk factor."
Prospective cohort data support selenium deficiency as a modifiable risk factor for Hashimoto's thyroiditis.
Viral Infections
Potential trigger
Show evidence (1 reference)
PMID:32107168 PARTIAL Human Clinical
"Many studies showed that HCV is associated with thyroid autoimmunity and hypothyroidism, in patients with chronic HCV hepatitis (CHC); a significant link has been shown also between HCV-related mixed cryoglobulinemia and risk for GD."
Viral infection (notably HCV) is associated with thyroid autoimmunity and hypothyroidism.
🔬

Biochemical Markers

4
TSH (Elevated)
Context: Primary hypothyroidism
Show evidence (1 reference)
PMID:35235282 SUPPORT Human Clinical
"Overt hypothyroidism occurs when a patient has an elevated TSH level and a low free T4 level with symptoms of hypothyroidism."
Elevated TSH is a core biochemical feature of overt hypothyroidism in Hashimoto's disease.
Free T4 (Decreased)
Context: Overt hypothyroidism
Show evidence (1 reference)
PMID:35235282 SUPPORT Human Clinical
"Overt hypothyroidism occurs when a patient has an elevated TSH level and a low free T4 level with symptoms of hypothyroidism."
Low free T4 defines overt hypothyroidism and supports this biochemical pattern.
Anti-TPO Antibodies (Elevated)
Context: Diagnostic marker
Show evidence (1 reference)
PMID:38731922 SUPPORT Human Clinical
"Hashimoto's thyroiditis (HT) is generally characterized by the presence of thyroid peroxidase and thyroglobulin antibodies, with a concomitant infiltration of lymphocytes in the thyroid."
Supports anti-TPO positivity as a characteristic diagnostic marker in HT.
Anti-Thyroglobulin Antibodies (Elevated)
Context: Present in majority of patients
Show evidence (1 reference)
PMID:38731922 SUPPORT Human Clinical
"Hashimoto's thyroiditis (HT) is generally characterized by the presence of thyroid peroxidase and thyroglobulin antibodies, with a concomitant infiltration of lymphocytes in the thyroid."
Supports elevated anti-thyroglobulin antibodies in HT.
📊

Related Datasets

1
GTEx v8 Thyroid tissue RNA-seq in Hashimoto case-control analysis gtex:GTEx_v8_Thyroid
Bulk RNA-seq analysis of thyroid tissue from GTEx v8 used in a case-control comparison of histopathologically confirmed Hashimoto's thyroiditis and matched controls.
Homo sapiens BULK RNA SEQ n=104
thyroid gland
Conditions: Histopathologically confirmed Hashimoto's thyroiditis tissue Matched non-Hashimoto thyroid tissue controls
PMID:33085325
Show evidence (1 reference)
DOI:10.48188/so.6.9 SUPPORT Human Clinical
"As part of a case–control design, we analyzed thyroid tissue RNA sequencing libraries from the Genotype-Tissue Expression Project (v8 release)."
The dataset entry captures the GTEx v8 thyroid RNA-seq source used to compare Hashimoto and control thyroid tissue transcriptomes.
{ }

Source YAML

click to show 
name: Hashimoto's Thyroiditis
creation_date: '2025-12-18T17:01:35Z'
updated_date: '2026-03-02T21:29:00Z'
category: Complex
parents:
- Autoimmune Disease
- Endocrine Disease
disease_term:
  preferred_term: Hashimoto thyroiditis
  term:
    id: MONDO:0007699
    label: Hashimoto thyroiditis
pathophysiology:
- name: Autoimmune Thyroid Destruction
  description: >
    T cell-mediated and antibody-mediated destruction of thyroid follicular
    cells leads to progressive loss of thyroid function. Anti-thyroid
    peroxidase (anti-TPO) and anti-thyroglobulin antibodies are characteristic.
  cell_types:
  - preferred_term: Thyroid Epithelial Cell
    term:
      id: CL:0002257
      label: epithelial cell of thyroid gland
  - preferred_term: T Helper Cell
    term:
      id: CL:0000492
      label: CD4-positive helper T cell
  biological_processes:
  - preferred_term: Autoimmune Response
    term:
      id: GO:0002460
      label: adaptive immune response based on somatic recombination of immune
        receptors built from immunoglobulin superfamily domains
  evidence:
  - reference: PMID:39003267
    reference_title: "Unraveling the molecular architecture of autoimmune thyroid diseases at spatial resolution."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "We identify damaged antigen-presenting TFCs with upregulated CD74 and
      MIF expression in thyroid samples from AITD patients."
    explanation: Spatial transcriptomics demonstrates that thyroid follicular
      cells actively participate in autoimmune destruction by presenting
      antigens via CD74/MIF upregulation.
  - reference: PMID:38731922
    reference_title: "Autoimmunity, New Potential Biomarkers and the Thyroid Gland-The Perspective of Hashimoto's Thyroiditis and Its Treatment."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Hashimoto's thyroiditis (HT) is generally characterized by the presence
      of thyroid peroxidase and thyroglobulin antibodies, with a concomitant infiltration
      of lymphocytes in the thyroid."
    explanation: Confirms the characteristic antibody profile and lymphocytic
      infiltration pattern in Hashimoto's thyroiditis.
  - reference: PMID:40535343
    reference_title: "Immune checkpoint inhibitor-induced thyroiditis and its potential mechanisms."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Through this review, we aim to establish mechanistic connections between
      ICI pharmacodynamics and thyroid tissue immunopathology."
    explanation: ICI-induced thyroiditis provides a mechanistic model that
      mirrors the autoimmune destruction seen in spontaneous Hashimoto's
      thyroiditis.
- name: Lymphocytic Infiltration
  description: >
    Dense lymphocytic infiltration of the thyroid gland with germinal
    center formation. CD4+ T cells, CD8+ T cells, and B cells accumulate
    in the thyroid parenchyma.
  biological_processes:
  - preferred_term: Inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
  - preferred_term: Adaptive immune response
    term:
      id: GO:0002250
      label: adaptive immune response
  cell_types:
  - preferred_term: CD4-positive helper T cell
    term:
      id: CL:0000492
      label: CD4-positive helper T cell
  - preferred_term: CD8-positive, alpha-beta T cell
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  - preferred_term: B Cell
    term:
      id: CL:0000236
      label: B cell
  evidence:
  - reference: PMID:38731922
    reference_title: "Autoimmunity, New Potential Biomarkers and the Thyroid Gland-The Perspective of Hashimoto's Thyroiditis and Its Treatment."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Hashimoto's thyroiditis (HT) is generally characterized by the presence
      of thyroid peroxidase and thyroglobulin antibodies, with a concomitant infiltration
      of lymphocytes in the thyroid."
    explanation: Lymphocytic infiltration is a defining histological feature of
      Hashimoto's thyroiditis.
  - reference: PMID:39003267
    reference_title: "Unraveling the molecular architecture of autoimmune thyroid diseases at spatial resolution."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we use spatial transcriptomics to explore the molecular architecture,
      heterogeneity and location of different cells present in the thyroid tissue,
      including thyroid follicular cells (TFCs), stromal cells such as fibroblasts,
      endothelial cells, and thyroid infiltrating lymphocytes."
    explanation: Spatial analysis confirms the presence and organization of
      infiltrating lymphocytes in the thyroid microenvironment.
- name: Thyroid Hormone Deficiency
  description: >
    Progressive destruction of thyroid tissue leads to decreased
    production of T3 and T4, resulting in hypothyroidism with elevated
    TSH through negative feedback.
  biological_processes:
  - preferred_term: Thyroid Hormone Synthesis
    term:
      id: GO:0006590
      label: thyroid hormone generation
  evidence:
  - reference: PMID:38731922
    reference_title: "Autoimmunity, New Potential Biomarkers and the Thyroid Gland-The Perspective of Hashimoto's Thyroiditis and Its Treatment."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Due to the progressive destruction of cells, AITD can lead to subclinical
      or overt hypothyroidism."
    explanation: Progressive thyroid destruction in Hashimoto's thyroiditis
      results in hypothyroidism through loss of hormone-producing cells.
phenotypes:
- name: Fatigue
  category: Systemic
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: PMID:35235282
    reference_title: "Thyroid and Parathyroid Conditions: Hypothyroidism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Signs and symptoms include fatigue, weight gain, dry skin, constipation,
      and cold intolerance."
    explanation: Hashimoto-associated hypothyroidism commonly presents with
      fatigue.
- name: Weight Gain
  category: Metabolic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Weight Gain
    term:
      id: HP:0004324
      label: Increased body weight
  evidence:
  - reference: PMID:35235282
    reference_title: "Thyroid and Parathyroid Conditions: Hypothyroidism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Signs and symptoms include fatigue, weight gain, dry skin, constipation,
      and cold intolerance."
    explanation: Weight gain is a common hypothyroid symptom in Hashimoto's
      thyroiditis.
- name: Constipation
  category: Gastrointestinal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Constipation
    term:
      id: HP:0002019
      label: Constipation
  evidence:
  - reference: PMID:35235282
    reference_title: "Thyroid and Parathyroid Conditions: Hypothyroidism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Signs and symptoms include fatigue, weight gain, dry skin, constipation,
      and cold intolerance."
    explanation: Constipation is a recognized symptom in hypothyroid states.
- name: Dry Skin
  category: Dermatological
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Dry Skin
    term:
      id: HP:0000958
      label: Dry skin
  evidence:
  - reference: PMID:35235282
    reference_title: "Thyroid and Parathyroid Conditions: Hypothyroidism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Signs and symptoms include fatigue, weight gain, dry skin, constipation,
      and cold intolerance."
    explanation: Dry skin is a common dermatologic manifestation of
      hypothyroidism.
- name: Cold Intolerance
  category: Systemic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Cold Intolerance
    term:
      id: HP:6000855
      label: Cold intolerance
  evidence:
  - reference: PMID:35235282
    reference_title: "Thyroid and Parathyroid Conditions: Hypothyroidism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Signs and symptoms include fatigue, weight gain, dry skin, constipation,
      and cold intolerance."
    explanation: Cold intolerance is a common symptom of hypothyroidism in
      Hashimoto's thyroiditis.
- name: Goiter
  category: Endocrine
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Goiter
    term:
      id: HP:0000853
      label: Goiter
  evidence:
  - reference: PMID:38731922
    reference_title: "Autoimmunity, New Potential Biomarkers and the Thyroid Gland-The Perspective of Hashimoto's Thyroiditis and Its Treatment."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Hashimoto's thyroiditis (HT) is generally characterized by the presence
      of thyroid peroxidase and thyroglobulin antibodies, with a concomitant infiltration
      of lymphocytes in the thyroid."
    explanation: Goiter develops due to lymphocytic infiltration and
      inflammatory enlargement of the thyroid gland.
- name: Depression
  category: Psychiatric
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Depression
    term:
      id: HP:0000716
      label: Depression
  evidence:
  - reference: PMID:23744563
    reference_title: "Selenium supplementation for Hashimoto's thyroiditis."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common presenting symptoms may include anxiety, negative mood,
      depression, dry skin, cold intolerance, puffy eyes, muscle cramps and fatigue,
      deep voice, constipation, slow thinking and poor memory."
    explanation: Depression is reported among common presenting symptoms in
      Hashimoto's thyroiditis.
biochemical:
- name: TSH
  presence: Elevated
  context: Primary hypothyroidism
  evidence:
  - reference: PMID:35235282
    reference_title: "Thyroid and Parathyroid Conditions: Hypothyroidism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overt hypothyroidism occurs when a patient has an elevated TSH level and
      a low free T4 level with symptoms of hypothyroidism."
    explanation: Elevated TSH is a core biochemical feature of overt
      hypothyroidism in Hashimoto's disease.
- name: Free T4
  presence: Decreased
  context: Overt hypothyroidism
  evidence:
  - reference: PMID:35235282
    reference_title: "Thyroid and Parathyroid Conditions: Hypothyroidism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overt hypothyroidism occurs when a patient has an elevated TSH level and
      a low free T4 level with symptoms of hypothyroidism."
    explanation: Low free T4 defines overt hypothyroidism and supports this
      biochemical pattern.
- name: Anti-TPO Antibodies
  presence: Elevated
  context: Diagnostic marker
  evidence:
  - reference: PMID:38731922
    reference_title: "Autoimmunity, New Potential Biomarkers and the Thyroid Gland-The Perspective of Hashimoto's Thyroiditis and Its Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hashimoto's thyroiditis (HT) is generally characterized by the presence
      of thyroid peroxidase and thyroglobulin antibodies, with a concomitant infiltration
      of lymphocytes in the thyroid."
    explanation: Supports anti-TPO positivity as a characteristic diagnostic
      marker in HT.
- name: Anti-Thyroglobulin Antibodies
  presence: Elevated
  context: Present in majority of patients
  evidence:
  - reference: PMID:38731922
    reference_title: "Autoimmunity, New Potential Biomarkers and the Thyroid Gland-The Perspective of Hashimoto's Thyroiditis and Its Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hashimoto's thyroiditis (HT) is generally characterized by the presence
      of thyroid peroxidase and thyroglobulin antibodies, with a concomitant infiltration
      of lymphocytes in the thyroid."
    explanation: Supports elevated anti-thyroglobulin antibodies in HT.
genetic:
- name: HLA-DR3
  association: Risk Factor
  evidence:
  - reference: PMID:26235382
    reference_title: "Immunogenetics of autoimmune thyroid diseases: A comprehensive review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "AITD susceptibility genes can be categorized as either thyroid specific
      (Tg, TSHR) or immune-modulating (FOXP3, CD25, CD40, CTLA-4, HLA), with HLA-DR3
      carrying the highest risk."
    explanation: HLA-DR3 is identified as a major immune-genetic risk factor
      in autoimmune thyroid disease, including HT.
- name: HLA-DR4
  association: Risk Factor
  evidence:
  - reference: PMID:29174716
    reference_title: "Interaction of HLA-DRB1* alleles and CTLA4 (+49 AG) gene polymorphism in Autoimmune Thyroid Disease."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "'DRB1*04+GG' (PL: p=0.003; HT: p=0.008)"
    explanation: HLA-DRB1*04 contributes to susceptibility in combination with
      CTLA4 risk genotype in HT cohorts.
- name: CTLA4
  association: Risk Factor
  evidence:
  - reference: PMID:41498152
    reference_title: "CTLA4, PTNP22, and FOXO3A gene variants as genetic biomarkers for co-occurrence of type 1 diabetes and autoimmune thyroid diseases in the Polish population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CTLA4 polymorphisms were associated with an elevated risk of a thyroid disease
      and poorer glycemic control;"
    explanation: CTLA4 polymorphisms are associated with increased autoimmune
      thyroid disease risk.
- name: PTPN22
  association: Risk Factor
  evidence:
  - reference: PMID:33103521
    reference_title: "The Relationship between PTPN22 R620W Polymorphisms and the Susceptibility to Autoimmune Thyroid Diseases: An Updated Meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This meta-analysis showed that the PTPN22 R620W polymorphism is associated
      with the risk of GD and HT in the overall study population."
    explanation: Meta-analysis supports PTPN22 as a susceptibility locus for
      Hashimoto's thyroiditis.
environmental:
- name: Iodine Excess
  notes: Can trigger or worsen disease
  evidence:
  - reference: PMID:28290237
    reference_title: "Multiple Nutritional Factors and the Risk of Hashimoto's Thyroiditis."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Chronic exposure to excess iodine intake induces autoimmune thyroiditis,
      partly because highly iodinated thyroglobulin (Tg) is more immunogenic."
    explanation: Excess iodine exposure is associated with autoimmune thyroiditis
      in HT-focused nutritional risk literature.
- name: Selenium Deficiency
  notes: May increase risk
  evidence:
  - reference: PMID:35789269
    reference_title: "Increased Incidence of Hashimoto Thyroiditis in Selenium Deficiency: A Prospective 6-Year Cohort Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The data indicate an increased incidence of TPO-Ab seroconversion
      with low Se supply and support the hypothesis that Se deficiency contributes
      to HT as a modifiable risk factor."
    explanation: Prospective cohort data support selenium deficiency as a
      modifiable risk factor for Hashimoto's thyroiditis.
- name: Viral Infections
  notes: Potential trigger
  evidence:
  - reference: PMID:32107168
    reference_title: "Graves' disease: Epidemiology, genetic and environmental risk factors and viruses."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Many studies showed that HCV is associated with thyroid autoimmunity and
      hypothyroidism, in patients with chronic HCV hepatitis (CHC); a significant link
      has been shown also between HCV-related mixed cryoglobulinemia and risk for GD."
    explanation: Viral infection (notably HCV) is associated with thyroid
      autoimmunity and hypothyroidism.
treatments:
- name: Levothyroxine
  description: Thyroid hormone replacement therapy, mainstay of treatment.
  evidence:
  - reference: PMID:35235282
    reference_title: "Thyroid and Parathyroid Conditions: Hypothyroidism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Management includes thyroid hormone replacement, ideally levothyroxine."
    explanation: Levothyroxine is standard hormone replacement therapy in
      hypothyroidism due to HT.
- name: Selenium Supplementation
  description: May reduce antibody levels in some patients.
  evidence:
  - reference: PMID:38243784
    reference_title: "Selenium Supplementation in Patients with Hashimoto Thyroiditis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "In people with HT without THRT, selenium was effective and safe in lowering
      TSH, TPOAb, and MDA levels."
    explanation: Meta-analysis supports selenium as a potential adjunct in
      selected HT patients.
- name: Monitoring
  description: Regular TSH monitoring to adjust replacement dose.
  evidence:
  - reference: PMID:35235282
    reference_title: "Thyroid and Parathyroid Conditions: Hypothyroidism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thyroid hormone should be titrated based on goal TSH values, symptoms,
      and potential treatment adverse effects."
    explanation: Ongoing TSH-based monitoring is required to titrate thyroid
      hormone replacement.
classifications:
  harrisons_chapter:
  - classification_value: endocrine system disorder
    evidence:
    - reference: PMID:26235382
      reference_title: "Immunogenetics of autoimmune thyroid diseases: A comprehensive review."
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: "Both environmental and genetic triggers factor into the etiology of autoimmune
        thyroid disease (AITD), including Graves' disease (GD) and Hashimoto's thyroiditis
        (HT)."
      explanation: Hashimoto's thyroiditis is an autoimmune thyroid condition
        within endocrine system disorders.
  - classification_value: thyroid disorder
    evidence:
    - reference: PMID:26235382
      reference_title: "Immunogenetics of autoimmune thyroid diseases: A comprehensive review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Both environmental and genetic triggers factor into the etiology of autoimmune
        thyroid disease (AITD), including Graves' disease (GD) and Hashimoto's thyroiditis
        (HT)."
      explanation: Directly classifies HT as autoimmune thyroid disease.
  - classification_value: autoimmune disease
    evidence:
    - reference: PMID:38731922
      reference_title: "Autoimmunity, New Potential Biomarkers and the Thyroid Gland-The Perspective of Hashimoto's Thyroiditis and Its Treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Hashimoto's thyroiditis (HT) is generally characterized by the presence
        of thyroid peroxidase and thyroglobulin antibodies, with a concomitant infiltration
        of lymphocytes in the thyroid."
      explanation: Defines HT as an autoimmune disease with autoantibodies and
        lymphocytic infiltration.
datasets:
- accession: gtex:GTEx_v8_Thyroid
  title: GTEx v8 Thyroid tissue RNA-seq in Hashimoto case-control analysis
  description: >
    Bulk RNA-seq analysis of thyroid tissue from GTEx v8 used in a case-control
    comparison of histopathologically confirmed Hashimoto's thyroiditis and
    matched controls.
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_types:
  - preferred_term: thyroid gland
    term:
      id: UBERON:0002046
      label: thyroid gland
    tissue_term:
      preferred_term: thyroid gland
      term:
        id: UBERON:0002046
        label: thyroid gland
  sample_count: 104
  conditions:
  - Histopathologically confirmed Hashimoto's thyroiditis tissue
  - Matched non-Hashimoto thyroid tissue controls
  publication: PMID:33085325
  evidence:
  - reference: DOI:10.48188/so.6.9
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As part of a case–control design, we analyzed thyroid tissue RNA sequencing
      libraries from the Genotype-Tissue Expression Project (v8 release)."
    explanation: The dataset entry captures the GTEx v8 thyroid RNA-seq source
      used to compare Hashimoto and control thyroid tissue transcriptomes.
references:
- reference: DOI:10.1038/s41467-024-50192-5
  title: Unraveling the molecular architecture of autoimmune thyroid diseases at
    spatial resolution
  findings: []
- reference: DOI:10.3389/fendo.2025.1584675
  title: Immune checkpoint inhibitor-induced thyroiditis and its potential
    mechanisms
  findings: []
- reference: DOI:10.48188/so.6.9
  title: 'Transcriptome analysis of thyroid tissue in patients with Hashimoto’s disease
    using next-generation sequencing: case–control study'
  findings: []
📚

References & Deep Research

References

3
DOI:10.1038/s41467-024-50192-5
Unraveling the molecular architecture of autoimmune thyroid diseases at spatial resolution
No top-level findings curated for this source.
DOI:10.3389/fendo.2025.1584675
Immune checkpoint inhibitor-induced thyroiditis and its potential mechanisms
No top-level findings curated for this source.
DOI:10.48188/so.6.9
Transcriptome analysis of thyroid tissue in patients with Hashimoto’s disease using next-generation sequencing: case–control study
No top-level findings curated for this source.

Deep Research

2
Disorder ▸

Disorder

  • Name: Hashimoto's Thyroiditis
  • Category: Complex
  • Existing deep-research providers: falcon
  • Existing evidence reference count in YAML: 13

Key Pathophysiology Nodes

  • Autoimmune Thyroid Destruction
  • Lymphocytic Infiltration
  • Thyroid Hormone Deficiency
  • Deep research literature mapping

Citation Inventory (for evidence mapping)

  • DOI:10.1038/s41467-024-50192-5
  • DOI:10.3389/fendo.2025.1584675
  • DOI:10.48188/so.6.9
Falcon ▸
Disease Pathophysiology Research Report
Edison Scientific Literature 16 citations 2025-12-17T23:36:56.684834

Disease Pathophysiology Research Report

Target Disease

  • Disease Name: Hashimoto's Thyroiditis (HT)
  • MONDO ID: MONDO:0007147
  • Category: Complex

Pathophysiology description (current understanding and recent developments)

Hashimoto’s thyroiditis is an organ-specific autoimmune disease of the thyroid characterized by adaptive and innate immune activation within the thyroid gland, progressive destruction of thyroid follicular cells (thyrocytes), and frequent development of hypothyroidism. Recent spatial transcriptomic mapping of autoimmune thyroid disease tissue demonstrates that thyrocytes are active participants in local immunity: “damaged antigen-presenting TFCs with upregulated CD74 and MIF expression” are identified in situ, with interferon and inflammatory cytokines inducing antigen-presentation machinery in thyrocytes and enabling direct interactions with infiltrating immune cells (doi:10.1038/s41467-024-50192-5; July 2024, Nature Communications) (martinezhernandez2024unravelingthemolecular pages 12-13, martinezhernandez2024unravelingthemolecular pages 9-12). Bulk transcriptomics of HT thyroid tissue reveals strong enrichment of adaptive immune signatures (T and B cell activation), antigen processing/presentation, complement, cytotoxicity, apoptosis and necroptosis, alongside widespread disruption of epithelial differentiation, thyroid hormone biosynthetic programs, cellular metabolism, mitochondrial function, and stromal/ECM remodeling consistent with fibrosis (doi:10.48188/so.6.9; Oct 2025, ST-OPEN) (cikotic2025transcriptomeanalysisof pages 10-13, cikotic2025transcriptomeanalysisof pages 13-15, cikotic2025transcriptomeanalysisof pages 17-18).

Expert commentary and clinical mechanistic analogs from immune checkpoint inhibitor (ICI)-induced thyroiditis underscore the centrality of interferon-rich, Th1/Th17-skewed responses, B cell/plasma cell activation, and genetic susceptibility (HLA class II, CTLA4, PTPN22) in precipitating thyroidal autoimmunity and the typical clinical trajectory of destructive thyrotoxicosis followed by (often irreversible) hypothyroidism (doi:10.3389/fendo.2025.1584675; June 2025, Frontiers in Endocrinology) (mao2025immunecheckpointinhibitorinduced pages 2-4, mao2025immunecheckpointinhibitorinduced pages 7-8).

Selected direct quotes from recent spatial/clinical mechanistic literature: - “Proinflammatory cytokines such as IFN-γ and TNF-α can upregulate the expression of CD74 in TFCs,” linking interferon/inflammatory signals to thyrocyte antigen presentation (doi:10.1038/s41467-024-50192-5; July 2024) (martinezhernandez2024unravelingthemolecular pages 9-12). - ICI-associated thyroiditis illustrates a canonical pattern of “antigenic cross-reactivity, T-cell subsets and B cell/plasma cell activation, cytokine/chemokine activity and genetic susceptibility” culminating in thyroid follicular destruction and hypothyroidism (doi:10.3389/fendo.2025.1584675; June 2025) (mao2025immunecheckpointinhibitorinduced pages 2-4).

1. Core Pathophysiology

  • Primary mechanisms: breakdown of tolerance to thyroglobulin (TG) and thyroid peroxidase (TPO) with intrathyroidal antigen presentation; interferon-driven upregulation of MHC-II/CD74 in thyrocytes; formation of ectopic germinal centers (GCs) that sustain local B cell maturation and antibody production; cytotoxic and complement-mediated thyrocyte death; stromal (fibroblast) and vascular remodeling supporting persistent lymphocyte trafficking (martinezhernandez2024unravelingthemolecular pages 12-13, martinezhernandez2024unravelingthemolecular pages 9-12, cikotic2025transcriptomeanalysisof pages 10-13, cikotic2025transcriptomeanalysisof pages 13-15, cikotic2025transcriptomeanalysisof pages 17-18).
  • Dysregulated molecular pathways: type I and II interferon signaling (JAK–STAT), NF-κB/inflammasome activation, PI3K–Akt survival/metabolic signaling imbalance, complement activation, apoptosis (FAS/FASL), and chemokine axes (e.g., CXCL12–CXCR4) that organize lymphoid niches (martinezhernandez2024unravelingthemolecular pages 9-12, cikotic2025transcriptomeanalysisof pages 10-13, cikotic2025transcriptomeanalysisof pages 13-15, cikotic2025transcriptomeanalysisof pages 17-18).
  • Affected cellular processes: antigen processing/presentation; GC formation and B cell affinity maturation; cytotoxic granule/perforin programs; complement-mediated cytotoxicity; epithelial de-differentiation and loss of thyroid hormone biosynthesis programs; mitochondrial/oxidative metabolism disruption; extracellular matrix (ECM) organization and fibrosis (martinezhernandez2024unravelingthemolecular pages 9-12, cikotic2025transcriptomeanalysisof pages 10-13, cikotic2025transcriptomeanalysisof pages 13-15).

2. Key Molecular Players

  • Genes/Proteins (HGNC): TG (HGNC:11764) and TPO (HGNC:12014) as principal autoantigens; HLA class II (e.g., HLA-DRA, HGNC:4947) mediating antigen presentation; immune regulatory and risk genes including CTLA4 (HGNC:2505), PTPN22 (HGNC:9656), BACH2 (HGNC:935), GLIS3 (HGNC:18128), IFIH1 (HGNC:18873), IRF4 (HGNC:6118), SH2B3 (HGNC:30406), and FAS (HGNC:11920) (OpenTargets disease–target evidence; 2025) (OpenTargets Search: Hashimoto's thyroiditis). Spatial data highlight CD74 (HGNC:1709) and MIF (HGNC:7097) upregulation in thyrocytes under IFN/TNF exposure (doi:10.1038/s41467-024-50192-5; 2024) (martinezhernandez2024unravelingthemolecular pages 12-13, martinezhernandez2024unravelingthemolecular pages 9-12).
  • Chemical entities (CHEBI): iodide (CHEBI:24859) as a potential epithelial stressor (ROS/NLRP3 inflammasome), IFN-γ (CHEBI:51275) and TNF-α (CHEBI:52299) as key cytokines driving antigen-presentation and inflammatory circuits (cikotic2025transcriptomeanalysisof pages 13-15, martinezhernandez2024unravelingthemolecular pages 9-12).
  • Cell types (CL): thyroid follicular cells/thyrocytes (CL:0002328), B cells (CL:0000236), plasma cells (CL:0000786), T helper cells (CL:0000911) including T follicular helper (Tfh; CL:0002038), dendritic cells (CL:0000451), macrophages (CL:0000235), fibroblasts/myofibroblasts (CL:0000057), endothelial cells including high endothelial venule-like states (CL:0000115), and follicular dendritic cells (FDC; CL:0000842) (martinezhernandez2024unravelingthemolecular pages 12-13, martinezhernandez2024unravelingthemolecular pages 9-12, cikotic2025transcriptomeanalysisof pages 10-13, cikotic2025transcriptomeanalysisof pages 13-15, cikotic2025transcriptomeanalysisof pages 17-18).
  • Anatomical locations (UBERON): thyroid gland (UBERON:0002046), germinal center (UBERON:0002358), and high endothelial venule (UBERON:0002185) where lymphocyte trafficking and TLS/GC niches are spatially organized (martinezhernandez2024unravelingthemolecular pages 9-12, martinezhernandez2024unravelingthemolecular pages 12-13).

3. Biological Processes (GO) disrupted

  • Type I interferon signaling (GO:0060337) and response to interferon-gamma (GO:0034341) (martinezhernandez2024unravelingthemolecular pages 9-12, cikotic2025transcriptomeanalysisof pages 10-13).
  • Antigen processing and presentation of peptide antigen via MHC class II (GO:0002495), including thyrocyte CD74/HLA upregulation (martinezhernandez2024unravelingthemolecular pages 9-12, martinezhernandez2024unravelingthemolecular pages 12-13).
  • NF-κB signaling (GO:0043122) and inflammasome activation (NLRP3) contributing to epithelial inflammatory cell death (cikotic2025transcriptomeanalysisof pages 13-15).
  • JAK–STAT signaling (GO:0007259) downstream of interferons and cytokines (cikotic2025transcriptomeanalysisof pages 10-13, martinezhernandez2024unravelingthemolecular pages 9-12).
  • PI3K–Akt signaling (GO:0014065) perturbations tied to survival/metabolic stress (cikotic2025transcriptomeanalysisof pages 10-13).
  • Complement activation (GO:0006956), apoptosis (including FAS-mediated, GO:0008625), and cytotoxic programs (cikotic2025transcriptomeanalysisof pages 10-13, cikotic2025transcriptomeanalysisof pages 13-15).
  • Chemokine-mediated signaling (GO:0070098) such as CXCL12–CXCR4 that organizes TLS/GC niches (martinezhernandez2024unravelingthemolecular pages 9-12).
  • Lymphoid organ development/TLS formation (GO:0048535) and ECM organization/fibrosis (GO:0030198) (cikotic2025transcriptomeanalysisof pages 17-18, cikotic2025transcriptomeanalysisof pages 13-15, martinezhernandez2024unravelingthemolecular pages 12-13).

4. Cellular Components

  • Thyrocyte plasma membrane and endolysosomal/antigen processing compartments (MHC-II/CD74 localization); extracellular matrix and basement membrane; high endothelial venules facilitating lymphocyte entry; germinal center microdomains populated by FDCs and GC B cells (martinezhernandez2024unravelingthemolecular pages 9-12, martinezhernandez2024unravelingthemolecular pages 12-13, cikotic2025transcriptomeanalysisof pages 13-15).

5. Disease Progression (sequence of events)

  • Triggers: epithelial stressors (e.g., iodide/oxidative stress), infections, and genetic predisposition (HLA class II, CTLA4, PTPN22, IFIH1, etc.) lower tolerance thresholds (cikotic2025transcriptomeanalysisof pages 13-15, OpenTargets Search: Hashimoto's thyroiditis).
  • Initiation: interferon- and TNF-rich milieu induces thyrocyte MHC-II/CD74 and chemokine expression; professional APCs (DCs, macrophages) present thyroid autoantigens (TG/TPO) to CD4+ T cells (martinezhernandez2024unravelingthemolecular pages 9-12, martinezhernandez2024unravelingthemolecular pages 12-13).
  • Propagation: Th1/Th17/Tfh responses amplify inflammation and provide B cell help; ectopic GCs form with FDC networks, enabling intrathyroidal affinity maturation and plasma cell differentiation; autoantibodies (TPOAb/TgAb) accumulate (martinezhernandez2024unravelingthemolecular pages 9-12, martinezhernandez2024unravelingthemolecular pages 12-13, mao2025immunecheckpointinhibitorinduced pages 2-4, mao2025immunecheckpointinhibitorinduced pages 7-8).
  • Effector injury: cytotoxic lymphocytes, complement, and apoptosis (FAS) mediate thyrocyte destruction; bulk transcriptomes show apoptosis/necroptosis signatures and loss of thyrocyte differentiation/hormone biosynthetic programs (cikotic2025transcriptomeanalysisof pages 10-13, cikotic2025transcriptomeanalysisof pages 13-15).
  • Remodeling and chronicity: fibroblast/myofibroblast activation (TGF-β–linked), ECM deposition, vascular remodeling with PLVAP+ vessels/HEV-like features sustaining lymphocyte recruitment; fibrosis and permanent hypothyroidism ensue (martinezhernandez2024unravelingthemolecular pages 12-13, martinezhernandez2024unravelingthemolecular pages 9-12, cikotic2025transcriptomeanalysisof pages 13-15).

6. Phenotypic Manifestations and clinical correlations

  • Key phenotypes: painless goiter, thyroid tenderness in phases of active inflammation, elevated anti-TPO and/or anti-Tg antibodies, transient thyrotoxicosis followed by persistent hypothyroidism, and thyroidal fibrosis on histology (mao2025immunecheckpointinhibitorinduced pages 2-4, cikotic2025transcriptomeanalysisof pages 10-13, cikotic2025transcriptomeanalysisof pages 13-15).
  • Mechanistic link: antibody and T cell–mediated injury, interferon/TNF-driven antigen presentation in thyrocytes, and GC-supported local autoantibody production align with clinical serology and functional decline (martinezhernandez2024unravelingthemolecular pages 9-12, martinezhernandez2024unravelingthemolecular pages 12-13, mao2025immunecheckpointinhibitorinduced pages 2-4).
  • Oncogenesis comorbidity: spatial data identify de-differentiated, oxidative stress–enriched thyrocyte subsets in proximity to immune infiltrates and implicate CD74/MIF signaling in divergent outcomes, offering a mechanistic bridge between chronic autoimmunity and papillary thyroid carcinoma (PTC) microenvironments observed in HT–PTC co-occurrence (doi:10.1038/s41467-024-50192-5; 2024) (martinezhernandez2024unravelingthemolecular pages 12-13, martinezhernandez2024unravelingthemolecular pages 9-12).

Hashimoto's Thyroiditis: Key Entities and Ontology Mappings

Category Entity/Term Standard ID Role in HT Pathophysiology Evidence Notes
Genes / Proteins TG; TPO; HLA-DRA; CTLA4; PTPN22; BACH2; GLIS3; IFIH1; IRF4; SH2B3; FAS; CD74; MIF HGNC:11764; HGNC:12014; HGNC:4947; HGNC:2505; HGNC:9656; HGNC:935; HGNC:18128; HGNC:18873; HGNC:6118; HGNC:30406; HGNC:11920; HGNC:1709; HGNC:7097 TG/TPO = primary autoantigens; HLA/antigen-presentation and immune-regulatory genes (CTLA4, PTPN22, BACH2, SH2B3) modulate tolerance; IFIH1/IRF4 linked to IFN/innate sensing; FAS mediates apoptosis; CD74/MIF in thyrocyte antigen-presentation Open Targets association for TG/CTLA4/PTPN22 (OpenTargets Search: Hashimoto's thyroiditis); spatial & transcriptomic mechanistic localization (doi:10.1038/s41467-024-50192-5) (martinezhernandez2024unravelingthemolecular pages 12-13); transcriptome case-control (doi:10.48188/so.6.9) (cikotic2025transcriptomeanalysisof pages 10-13) Genetic + transcriptomic + spatial evidence supports autoantigen-driven, genetically modulated autoimmune response.
Cell type Thyroid follicular cell (thyrocyte) CL:0002328 Can express MHC-II/CD74 under IFN/TNF stimulation → local antigen presentation; source of autoantigen release and epithelial damage Spatial transcriptomics: CD74/MIF upregulation and antigen-presentation in TFCs (doi:10.1038/s41467-024-50192-5) (martinezhernandez2024unravelingthemolecular pages 12-13, martinezhernandez2024unravelingthemolecular pages 9-12); bulk transcriptome immune signatures (cikotic2025transcriptomeanalysisof pages 10-13, cikotic2025transcriptomeanalysisof pages 13-15) Thyrocytes act as active participants (not passive targets) in HT immunopathology.
Cell type B cell CL:0000236 GC B cell differentiation, local antibody (TPOAb/TgAb) production in ectopic germinal centers Spatial localization of GC B cells and FDC markers (martinezhernandez2024unravelingthemolecular pages 12-13, martinezhernandez2024unravelingthemolecular pages 9-12); ICI/clinical antibody correlations (mao2025immunecheckpointinhibitorinduced pages 2-4) Local GC formation supports sustained autoantibody generation.
Cell type Plasma cell CL:0000786 Terminal antibody secretion (TPOAb/TgAb) within thyroid tissue and circulation Plasmablast/plasma cell dissemination in TFC areas (martinezhernandez2024unravelingthemolecular pages 12-13) and transcriptomic signatures (cikotic2025transcriptomeanalysisof pages 10-13) Major effector source of autoantibodies.
Cell type T helper cell (CD4+) CL:0000911 Th1/Th17 skewing provides cytokines (IFN-γ, IL‑17) that drive inflammation, B cell help and cytotoxic programs Th1/Th17 signatures and cytokine milieu described in transcriptome and ICI-related studies (cikotic2025transcriptomeanalysisof pages 13-15, mao2025immunecheckpointinhibitorinduced pages 7-8, mao2025immunecheckpointinhibitorinduced pages 2-4) Helper subsets shape antibody class-switching and macrophage activation.
Cell type T follicular helper (Tfh) CL:0002038 Supports GC formation and B cell affinity maturation within ectopic GCs Enrichment of TCD4/Tfh in GC regions (spatial data) (martinezhernandez2024unravelingthemolecular pages 12-13, martinezhernandez2024unravelingthemolecular pages 9-12) Key for intrathyroidal humoral autoimmunity.
Cell type Dendritic cell CL:0000451 Professional antigen presentation, initiation of T cell responses and TLS support Myeloid APCs distributed around infiltrates; DC involvement in TLS/TLO formation (martinezhernandez2024unravelingthemolecular pages 9-12, cikotic2025transcriptomeanalysisof pages 13-15) DC heterogeneity may influence tolerance vs activation.
Cell type Macrophage CL:0000235 Phagocytosis, cytokine production, tissue remodeling and presentation; CD163+ histiocytes noted in destructive thyroiditis Macrophage presence around infiltrates and in ICI-induced thyroiditis pathology (martinezhernandez2024unravelingthemolecular pages 9-12, mao2025immunecheckpointinhibitorinduced pages 2-4, cikotic2025transcriptomeanalysisof pages 13-15) Contributes to follicular cell clearance and fibrosis.
Cell type Fibroblast / myofibroblast CL:0000057 Stromal remodeling, TGF‑β–driven myofibroblast transition and ECM deposition → fibrosis Perifollicular myofibroblasts and inflammatory fibroblasts identified by spatial data; ECM gene induction (martinezhernandez2024unravelingthemolecular pages 12-13, cikotic2025transcriptomeanalysisof pages 13-15) Stromal states support TLS niches and fibrosis.
Cell type Endothelial cell (including HEV) CL:0000115 Vascular remodeling, PLVAP+ vessels and HEV formation facilitate lymphocyte trafficking into thyroid PLVAP+ fenestrated vessels and ACKR1+/HEV localization in inflamed regions (martinezhernandez2024unravelingthemolecular pages 12-13, martinezhernandez2024unravelingthemolecular pages 9-12) HEV-like vessels enable sustained lymphocyte recruitment.
Cell type Follicular dendritic cell (FDC) CL:0000842 Organizing GC microarchitecture and antigen retention within ectopic GCs FDC markers (FDCSP, TCL1A) concentrated in GC regions (martinezhernandez2024unravelingthemolecular pages 12-13, martinezhernandez2024unravelingthemolecular pages 9-12) Supports local affinity maturation and persistent antibody responses.
Pathway / Process Type I interferon signaling; Response to IFN‑gamma; JAK‑STAT cascade; NF‑kappaB signaling GO:0060337; GO:0034341; GO:0007259; GO:0043122 IFN signatures upregulate MHC-II/CD74 and chemokines, promoting APC activity and immune recruitment; NF‑κB/Inflammasome (NLRP3) link to epithelial pyroptosis Spatial and transcriptomic upregulation of IFN pathways and CD74 in TFCs (martinezhernandez2024unravelingthemolecular pages 12-13, martinezhernandez2024unravelingthemolecular pages 9-12); inflammasome/NF‑κB evidence (cikotic2025transcriptomeanalysisof pages 13-15) Central inflammatory drivers connecting innate sensing to adaptive autoimmunity.
Pathway / Process PI3K‑Akt signaling; Complement activation; Apoptosis via FAS GO:0014065; GO:0006956; GO:0008625 PI3K‑Akt impacts cell survival/metabolism; complement and FAS-mediated apoptosis contribute to follicular cell loss Bulk transcriptome evidence of apoptosis/complement pathways and metabolic dysfunction (cikotic2025transcriptomeanalysisof pages 10-13, cikotic2025transcriptomeanalysisof pages 17-18, cikotic2025transcriptomeanalysisof pages 13-15) Links metabolic/stress state to cell death and autoantigen release.
Pathway / Process Chemokine-mediated signaling; Lymphoid organ development; ECM organization GO:0070098; GO:0048535; GO:0030198 CXCL/CXCR axes recruit lymphocytes; lymphoid organogenesis supports ectopic GC/TLS formation; ECM remodeling → fibrosis and altered microarchitecture CXCL12‑CXCR4 enrichment, HEV/ACKR1 localization and ECM gene induction in spatial & bulk data (martinezhernandez2024unravelingthemolecular pages 12-13, martinezhernandez2024unravelingthemolecular pages 9-12, cikotic2025transcriptomeanalysisof pages 13-15) Chemokines + stromal changes enable persistent local immune niches.
Anatomy Thyroid gland; High endothelial venule (HEV); Germinal center; Extracellular matrix UBERON:0002046; UBERON:0002185; UBERON:0002358; GO:0031012 Tissue compartments where antigen presentation, TLS/GC formation, and fibrosis occur Spatial mapping of GC regions, HEVs, TFC damage, ECM deposition (martinezhernandez2024unravelingthemolecular pages 12-13, martinezhernandez2024unravelingthemolecular pages 9-12, cikotic2025transcriptomeanalysisof pages 13-15) Spatial context critical for understanding local autoimmunity and progression.
Chemical / Mediator Iodide; TNF‑alpha; IFN‑gamma CHEBI:24859; CHEBI:52299; CHEBI:51275 Iodide can trigger oxidative stress/pyroptosis in thyrocytes; TNF/IFN drive CD74/MHC‑II expression and inflammation Iodide-triggered ROS/NLRP3 inflammasome and inflammatory cytokine roles (cikotic2025transcriptomeanalysisof pages 13-15); cytokine-driven CD74 upregulation (martinezhernandez2024unravelingthemolecular pages 12-13, mao2025immunecheckpointinhibitorinduced pages 2-4) Environmental/biochemical modulators that amplify immune activation.

Table: A concise mapping table of genes, cell types, pathways, anatomical terms and chemicals relevant to Hashimoto's thyroiditis with standardized IDs and evidence links from spatial and transcriptomic studies (context citations).

Gene/protein annotations with ontology terms

  • TG (HGNC:11764) – autoantigen; processes: antigenicity, thyroid hormone precursor; components: colloid/lumen; evidence: OpenTargets genetics (URL: https://platform.opentargets.org, accessed 2025) (OpenTargets Search: Hashimoto's thyroiditis).
  • TPO (HGNC:12014) – autoantigen; processes: thyroid hormone biosynthesis; components: apical membrane; evidence: bulk downregulation in HT with loss of biosynthetic program (doi:10.48188/so.6.9; 2025) (cikotic2025transcriptomeanalysisof pages 10-13).
  • HLA-DRA (HGNC:4947) – MHC-II; processes: antigen presentation; components: MHC-II complex; evidence: thyrocyte antigen-presentation machinery in AITD (doi:10.1038/s41467-024-50192-5; 2024) (martinezhernandez2024unravelingthemolecular pages 9-12).
  • CTLA4 (HGNC:2505) – negative regulator of T cell activation; processes: T cell anergy; evidence: association with HT (OpenTargets) (OpenTargets Search: Hashimoto's thyroiditis).
  • PTPN22 (HGNC:9656), BACH2 (HGNC:935), GLIS3 (HGNC:18128), IFIH1 (HGNC:18873), IRF4 (HGNC:6118), SH2B3 (HGNC:30406), FAS (HGNC:11920) – immune regulation, innate sensing/IFN pathways, apoptosis; evidence: genetics and mechanistic plausibility in HT (OpenTargets 2025; bulk transcriptomics 2025) (OpenTargets Search: Hashimoto's thyroiditis, cikotic2025transcriptomeanalysisof pages 10-13).
  • CD74 (HGNC:1709), MIF (HGNC:7097) – thyrocyte antigen-presentation cofactor and ligand; processes: MHC-II trafficking and MIF-CD74 signaling; evidence: spatial upregulation in thyrocytes and cell–cell interactions (doi:10.1038/s41467-024-50192-5; 2024) (martinezhernandez2024unravelingthemolecular pages 12-13, martinezhernandez2024unravelingthemolecular pages 9-12).

Phenotype associations (HP terms)

  • Hypothyroidism (HP:0000821), Goiter (HP:0000853), Thyroiditis (HP:0000834), Positive anti-thyroid peroxidase antibody (HP:0030057), Positive anti-thyroglobulin antibody (HP:0030058), Fatigue (HP:0012378), Cold intolerance (HP:0002045). Mechanistic correspondence: antibody-mediated and cytotoxic follicular injury with interferon/NF-κB signatures and fibrosis (cikotic2025transcriptomeanalysisof pages 10-13, cikotic2025transcriptomeanalysisof pages 13-15, mao2025immunecheckpointinhibitorinduced pages 2-4, martinezhernandez2024unravelingthemolecular pages 9-12).

Cell type involvement (CL terms)

  • Thyrocyte (CL:0002328), B cell (CL:0000236), Plasma cell (CL:0000786), T helper and Tfh (CL:0000911; CL:0002038), Dendritic cell (CL:0000451), Macrophage (CL:0000235), Fibroblast (CL:0000057), Endothelial cell (CL:0000115), FDC (CL:0000842), with spatial localization of ectopic GCs and HEV-like vessels (martinezhernandez2024unravelingthemolecular pages 12-13, martinezhernandez2024unravelingthemolecular pages 9-12).

Anatomical locations (UBERON terms)

  • Thyroid gland (UBERON:0002046); Germinal center (UBERON:0002358) within intrathyroidal TLS; High endothelial venule (UBERON:0002185); Extracellular matrix (GO:0031012) deposition sites in fibrotic thyroid (martinezhernandez2024unravelingthemolecular pages 9-12, martinezhernandez2024unravelingthemolecular pages 12-13, cikotic2025transcriptomeanalysisof pages 13-15).

Chemical entities (CHEBI terms)

  • Iodide (CHEBI:24859), IFN-γ (CHEBI:51275), TNF-α (CHEBI:52299) as upstream mediators of epithelial stress and antigen presentation (cikotic2025transcriptomeanalysisof pages 13-15, martinezhernandez2024unravelingthemolecular pages 9-12).

Current applications and real-world implementations

  • Diagnosis and monitoring: serologic assays for TPOAb/TgAb reflect intrathyroidal GC activity; ultrasound for echogenicity/fibrosis; recognition that interferon-rich destructive thyroiditis often follows a phase of transient thyrotoxicosis (mao2025immunecheckpointinhibitorinduced pages 2-4, mao2025immunecheckpointinhibitorinduced pages 7-8).
  • Management: levothyroxine replacement for hypothyroidism remains standard; insights from ICI-induced thyroiditis emphasize screening for thyroid autoantibodies to stratify irAE risk and close hormone monitoring during checkpoint blockade; mechanistic links to B cells support exploration of B-cell–modulating strategies in selected contexts (doi:10.3389/fendo.2025.1584675; 2025) (mao2025immunecheckpointinhibitorinduced pages 2-4, mao2025immunecheckpointinhibitorinduced pages 7-8).
  • Research tools in practice: spatial transcriptomics and single-cell deconvolution identify thyrocyte CD74/HLA induction, ectopic GC architecture, and stromal/endothelial niches as candidate biomarkers and therapeutic targets (doi:10.1038/s41467-024-50192-5; 2024) (martinezhernandez2024unravelingthemolecular pages 12-13, martinezhernandez2024unravelingthemolecular pages 9-12).

Expert opinions and analysis (authoritative sources)

  • Spatial multi-omics perspective (Nature Communications, 2024): authors conclude that “thyroid epithelial cell subpopulations [are] potentially involved in pathogenesis,” with CD74/MIF and interferon–TNF axes integrating epithelial damage and local immune organization; this supports targeting stromal-immune–epithelial cross-talk in HT (doi:10.1038/s41467-024-50192-5; July 2024) (martinezhernandez2024unravelingthemolecular pages 12-13, martinezhernandez2024unravelingthemolecular pages 9-12).
  • Clinical immuno-oncology perspective (Frontiers in Endocrinology, 2025): ICI-thyroiditis mechanisms “establish mechanistic connections between ICI pharmacodynamics and thyroid tissue immunopathology,” reinforcing Th1/Th17 bias, B cell involvement, and genetic predisposition as drivers of destructive thyroiditis and hypothyroidism (doi:10.3389/fendo.2025.1584675; June 2025) (mao2025immunecheckpointinhibitorinduced pages 2-4, mao2025immunecheckpointinhibitorinduced pages 7-8).
  • Systems transcriptomics perspective (ST-OPEN, 2025): local expansion of cellular/humoral/innate immunity with dominant cell death and reciprocal loss of epithelial/endothelial identity; broad metabolic and ECM remodeling capture chronicity and fibrosis in HT (doi:10.48188/so.6.9; Oct 2025) (cikotic2025transcriptomeanalysisof pages 10-13, cikotic2025transcriptomeanalysisof pages 13-15, cikotic2025transcriptomeanalysisof pages 17-18).

Relevant statistics and data from recent studies

  • Spatial transcriptomics in AITD delineated GC regions enriched for FDC markers FDCSP and TCL1A, with proliferative/GC B cells and TCD4/Tfh localized to these domains, and plasmablasts disseminating into thyrocyte territories, providing in situ evidence for local antibody maturation and effector dissemination (doi:10.1038/s41467-024-50192-5; 2024) (martinezhernandez2024unravelingthemolecular pages 9-12).
  • Bulk transcriptome of HT demonstrated concerted upregulation of antigen presentation, interferon/TNF signaling, complement, cytotoxicity and apoptosis signatures, alongside downregulation of thyroid biosynthetic genes (TG, TPO) and endothelial markers, and upregulation of ECM/fibrotic programs (doi:10.48188/so.6.9; 2025) (cikotic2025transcriptomeanalysisof pages 10-13, cikotic2025transcriptomeanalysisof pages 13-15).
  • Genetics: OpenTargets aggregates multi-source evidence implicating TG (top disease–target score), CTLA4, PTPN22, BACH2, GLIS3, IFIH1, IRF4, SH2B3, and FAS in HT susceptibility and pathophysiology (Nucleic Acids Research, OpenTargets Platform; accessed 2025; URL: https://platform.opentargets.org) (OpenTargets Search: Hashimoto's thyroiditis).

Evidence items (with PMIDs/DOIs/URLs)

  • Martínez-Hernández R, et al. Unraveling the molecular architecture of autoimmune thyroid diseases at spatial resolution. Nature Communications. July 2024. doi:10.1038/s41467-024-50192-5. URL: https://www.nature.com/articles/s41467-024-50192-5 (martinezhernandez2024unravelingthemolecular pages 12-13, martinezhernandez2024unravelingthemolecular pages 9-12).
  • Čikotić M, et al. Transcriptome analysis of thyroid tissue in patients with Hashimoto’s disease using next-generation sequencing: case–control study. ST-OPEN. Oct 2025. doi:10.48188/so.6.9. URL: https://doi.org/10.48188/so.6.9 (cikotic2025transcriptomeanalysisof pages 10-13, cikotic2025transcriptomeanalysisof pages 13-15, cikotic2025transcriptomeanalysisof pages 17-18).
  • Mao X, et al. Immune checkpoint inhibitor-induced thyroiditis and its potential mechanisms. Frontiers in Endocrinology. June 2025. doi:10.3389/fendo.2025.1584675. URL: https://doi.org/10.3389/fendo.2025.1584675 (mao2025immunecheckpointinhibitorinduced pages 2-4, mao2025immunecheckpointinhibitorinduced pages 7-8).
  • OpenTargets Platform: Hashimoto’s thyroiditis disease–target associations (TG, CTLA4, PTPN22, BACH2, GLIS3, IFIH1, IRF4, SH2B3, FAS). 2025. URL: https://platform.opentargets.org (OpenTargets Search: Hashimoto's thyroiditis).

Final synthesis

HT pathophysiology emerges from a confluence of genetic risk alleles (TG, CTLA4, PTPN22 and others), interferon/TNF-driven induction of antigen presentation within thyrocytes (CD74/HLA), professional APC activation, and organization of ectopic GCs that sustain local B cell maturation and autoantibody production. Effector death pathways (cytotoxicity, complement, FAS) and persistent stromal/vascular remodeling drive chronic tissue destruction, fibrosis, and hypothyroidism. Spatial and bulk transcriptomic data from 2024–2025 localize these processes within the thyroid microenvironment, and clinical ICI-thyroiditis provides a mechanistic “stress test” that mirrors the natural disease trajectory. These insights nominate interferon and chemokine axes, thyrocyte antigen-presentation pathways (CD74/MIF), and stromal–vascular niches as plausible therapeutic targets and biomarkers in HT (martinezhernandez2024unravelingthemolecular pages 12-13, martinezhernandez2024unravelingthemolecular pages 9-12, cikotic2025transcriptomeanalysisof pages 10-13, cikotic2025transcriptomeanalysisof pages 13-15, cikotic2025transcriptomeanalysisof pages 17-18, mao2025immunecheckpointinhibitorinduced pages 2-4, mao2025immunecheckpointinhibitorinduced pages 7-8, OpenTargets Search: Hashimoto's thyroiditis).

References

  1. (martinezhernandez2024unravelingthemolecular pages 12-13): Rebeca Martínez-Hernández, Nuria Sánchez de la Blanca, Pablo Sacristán-Gómez, Ana Serrano-Somavilla, José Luis Muñoz De Nova, Fátima Sánchez Cabo, Holger Heyn, Miguel Sampedro-Núñez, and Mónica Marazuela. Unraveling the molecular architecture of autoimmune thyroid diseases at spatial resolution. Nature Communications, Jul 2024. URL: https://doi.org/10.1038/s41467-024-50192-5, doi:10.1038/s41467-024-50192-5. This article has 13 citations and is from a highest quality peer-reviewed journal.

  2. (martinezhernandez2024unravelingthemolecular pages 9-12): Rebeca Martínez-Hernández, Nuria Sánchez de la Blanca, Pablo Sacristán-Gómez, Ana Serrano-Somavilla, José Luis Muñoz De Nova, Fátima Sánchez Cabo, Holger Heyn, Miguel Sampedro-Núñez, and Mónica Marazuela. Unraveling the molecular architecture of autoimmune thyroid diseases at spatial resolution. Nature Communications, Jul 2024. URL: https://doi.org/10.1038/s41467-024-50192-5, doi:10.1038/s41467-024-50192-5. This article has 13 citations and is from a highest quality peer-reviewed journal.

  3. (cikotic2025transcriptomeanalysisof pages 10-13): Marija Čikotić, Marieta Bujak, Silvija Piškorjanac, and Mario Štefanić. Transcriptome analysis of thyroid tissue in patients with hashimoto’s disease using next-generation sequencing: case–control study. ST-OPEN, 6:1-19, Oct 2025. URL: https://doi.org/10.48188/so.6.9, doi:10.48188/so.6.9. This article has 0 citations.

  4. (cikotic2025transcriptomeanalysisof pages 13-15): Marija Čikotić, Marieta Bujak, Silvija Piškorjanac, and Mario Štefanić. Transcriptome analysis of thyroid tissue in patients with hashimoto’s disease using next-generation sequencing: case–control study. ST-OPEN, 6:1-19, Oct 2025. URL: https://doi.org/10.48188/so.6.9, doi:10.48188/so.6.9. This article has 0 citations.

  5. (cikotic2025transcriptomeanalysisof pages 17-18): Marija Čikotić, Marieta Bujak, Silvija Piškorjanac, and Mario Štefanić. Transcriptome analysis of thyroid tissue in patients with hashimoto’s disease using next-generation sequencing: case–control study. ST-OPEN, 6:1-19, Oct 2025. URL: https://doi.org/10.48188/so.6.9, doi:10.48188/so.6.9. This article has 0 citations.

  6. (mao2025immunecheckpointinhibitorinduced pages 2-4): Xueqian Mao, Chaoming Mao, Jiameng Liu, Xi Wang, and Yufei Mao. Immune checkpoint inhibitor-induced thyroiditis and its potential mechanisms. Frontiers in Endocrinology, Jun 2025. URL: https://doi.org/10.3389/fendo.2025.1584675, doi:10.3389/fendo.2025.1584675. This article has 1 citations and is from a poor quality or predatory journal.

  7. (mao2025immunecheckpointinhibitorinduced pages 7-8): Xueqian Mao, Chaoming Mao, Jiameng Liu, Xi Wang, and Yufei Mao. Immune checkpoint inhibitor-induced thyroiditis and its potential mechanisms. Frontiers in Endocrinology, Jun 2025. URL: https://doi.org/10.3389/fendo.2025.1584675, doi:10.3389/fendo.2025.1584675. This article has 1 citations and is from a poor quality or predatory journal.

  8. (OpenTargets Search: Hashimoto's thyroiditis): Open Targets Query (Hashimoto's thyroiditis, 10 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.