Autoimmune Diseases in the Endocrine System -Chan

How do metabolic, nutritional, psychosocial, and genetic factors affect immune responses?

They influence the immune response via endocrine signaling pathways.

How do the endocrine and immune systems communicate?

Through cytokines and hormone receptors; immune cells produce cytokines affecting endocrine function, and both systems express receptors for each other's signals.

What cytokines increase activity of the hypothalamus-pituitary-adrenal (HPA) axis?

IL-1, IL-6, and TNF-α.

What are the functions of the HPA axis?

Energy metabolism, cardiovascular function, and stress response.

What is the role of cortisol in immune modulation?

In physiologic amounts, it boosts immunity and limits inflammation.

What happens when cortisol levels are chronically elevated?

It leads to dysregulation of the HPA axis and may impair immune balance.

What type of autoimmune disorders are most prevalent?

Autoimmune endocrine disorders are the most prevalent.

How are autoimmune diseases classified?

They can be either organ-specific or systemic.

Which autoimmune diseases are systemic?

Systemic lupus erythematosus (SLE), rheumatoid arthritis, and systemic sclerosis (SS).

How are endocrine autoimmune disorders usually classified?

They are typically organ-specific and sometimes cell-type specific.

What is the general mechanism of autoimmune endocrine disease?

Chronic T cell or antibody targeting of specific organs or cell types, leading to hormonal dysfunction.

What role do Th17 cells play in autoimmune endocrine disease?

They maintain and amplify inflammatory reactions.

What is the role of Treg cells in preventing autoimmunity?

Treg cells regulate and suppress autoreactive clones; failure to do so contributes to autoimmunity.

What role does apoptosis play in autoimmune endocrine disorders?

It either fails to eliminate autoreactive lymphocytes or mediates tissue damage.

What is the mainstay of treatment for autoimmune endocrine diseases?

Hormone replacement therapy for hormones lost due to organ damage.

What endocrine organs are commonly affected in autoimmune diseases?

Thyroid (Graves', Hashimoto's), adrenal (Addison’s), pancreas (Type 1 Diabetes), and polyglandular syndromes like APECED.

What is Hashimoto’s thyroiditis?

A chronic autoimmune hypothyroidism; the most common cause of hypothyroidism in the U.S., including during pregnancy.

What autoantibodies are found in Hashimoto’s?

~90% positive for TPO antibodies, ~50% for thyroglobulin antibodies; ~10% negative for both.

What are common manifestations of Hashimoto’s thyroiditis?

Goiter, weight gain, fatigue, depression, dry skin, menstrual issues, oral symptoms like enlarged tongue, thick lips, dysphagia.

What is myxedema?

A severe hypothyroid condition with glycosaminoglycan deposits causing edema-like skin changes.

What kidney dysfunction is seen in Hashimoto’s?

Decreased GFR, plasma flow, and water clearance, leading to hyponatremia and elevated creatine kinase.

What genetic markers are associated with Hashimoto’s thyroiditis?

HLA-DR3, and polymorphisms in PTPN22, CTLA-4, FOXP3.

What does the PTPN22 gene regulate?

Antigen-driven responses via T-cell interferon signaling, affecting tolerance.

What is the function of FOXP3?

Transcription factor crucial for regulatory T-cell activity to prevent autoimmunity.

What is the immune pathogenesis of Hashimoto’s thyroiditis?

Lymphocyte infiltration, cytokine imbalance (↑Th1/Th17, ↓Treg), thyrocyte apoptosis, and autoantibody production.

What cytokines are involved in Hashimoto’s pathogenesis?

Pro-inflammatory: IL-2, IL-12, IL-17, IL-21, IL-22, IFN-γ, TNF-α; Anti-inflammatory: IL-10, TGF-β.

What environmental factors trigger Hashimoto’s?

Infections, smoking, stress, medications (amiodarone, interferon), iodine, iron, selenium, vitamin D, zinc deficiency.

How does excess iodine affect Hashimoto’s?

Increases thyroglobulin immunogenicity, promotes TPO antibody production, and triggers flare-ups.

How does selenium deficiency impact autoimmunity?

Increases T cell activity, cytokine production, reduces regulatory T cells.

What is the primary treatment for Hashimoto’s?

Thyroxine replacement; selenium and vitamin D supplements are beneficial.

What are aggressive treatments for systemic involvement in Hashimoto’s?

Corticosteroids, immunosuppressants (e.g., methotrexate, azathioprine), plasmapheresis.

What cytokine-based interventions are under study for autoimmune endocrine diseases?

Blocking pro-inflammatory cytokines and boosting anti-inflammatory ones.

What is Graves’ disease?

An autoimmune hyperthyroidism; most common in iodine-sufficient areas, especially in women aged 40–50.

What are symptoms of Graves’ disease?

Goiter, proptosis, weight loss, skin lesions, A-fib, SOB, muscle weakness, nervousness.

What is the primary autoantibody in Graves’ disease?

TSH-receptor antibody (TRAb), mimicking TSH and stimulating the thyroid.

What is the isotype of TRAb and its effect?

IgG isotype; leads to hyperthyroidism but does not cause cytotoxicity.

What histological changes occur in Graves’ disease?

Follicular cell hypertrophy and accumulation of thyroglobulin-containing colloid.

What genetic polymorphisms are associated with Graves’ disease?

HLA-DR3, DQA-10501, TSHR, PTPN22, CTLA-4, FOXP3, IL-2RA, CD40.

What does the IL-2RA polymorphism affect?

T-cell response and inflammation regulation.

How is immune tolerance breached in Graves’ disease?

Tregs are insufficient; autoreactive T/B cells survive and stimulate chronic thyroid inflammation.

What role does IFN-γ play in Graves’ thyroid cell inflammation?

Induces HLA class II antigen expression in follicular cells, enhancing T cell activation.

What is Graves’ ophthalmopathy?

Proptosis due to TRAb-stimulated orbital fibroblasts and inflammatory infiltration.

What is pretibial myxedema?

Skin thickening and swelling on shins due to TRAb and immune infiltration.

What infections are linked to triggering Graves’ disease?

Yersinia enterocolitica, EBV, HCV, HSV, CMV.

What is the effect of smoking on Graves’ disease?

Increases risk and severity, especially ophthalmopathy.

What is the link between celiac disease and thyroid autoimmunity?

10× higher prevalence in children with celiac disease.

What are the three main treatments for Graves’ disease?

Radioactive iodine, anti-thyroid drugs, and surgery.

What is the role of genetic predisposition in autoimmune thyroid disease?

Genes like HLA-DR3, FOXP3, CTLA-4, and TSHR polymorphisms influence susceptibility.

What is the mechanism of chronic stimulation in Graves’ disease?

Continuous TRAb presence keeps TSHR activated, sustaining hyperthyroidism.

What are extrathyroidal sites of TSHR expression in Graves’?

Retro-orbit (eyes) and pretibial dermis (shins).

How does TRAb cause ophthalmopathy?

Stimulates orbital fibroblasts, leading to inflammation and tissue expansion.

What triggers pretibial myxedema in Graves’?

TRAb-induced immune infiltration and glycosaminoglycan accumulation in shin skin.

What are environmental risk factors for Graves’?

Infections, smoking, stress, iodine levels, celiac disease.

How does stress impact autoimmune thyroid conditions?

Chronic stress elevates cortisol, which dysregulates immune balance and tolerance.

What is the effect of selenium on autoimmune thyroiditis?

Reduces TPO antibody levels and improves thyroid health.

What nutritional deficiencies contribute to Hashimoto’s?

Iodine excess, iron, selenium, vitamin D, magnesium, zinc deficiencies.

What is the effect of vitamin D on immune function in thyroid autoimmunity?

Prevents excessive B-cell antibody production and supports Treg cells.

What is APECED?

Autoimmune PolyEndocrinopathy-Candidiasis-Ectodermal Dystrophy; a polyglandular autoimmune disorder.

What organs are typically affected in APECED?

Parathyroid, adrenal glands, skin, mucosa, and endocrine pancreas.

What gene mutation is associated with APECED?

AIRE gene mutation.

What is the role of the AIRE gene in immunity?

Facilitates elimination of autoreactive T cells in the thymus.

What cells initiate Hashimoto’s immune response?

Macrophages and dendritic cells accumulate first and release IL-1β and IL-18 to trigger cell death.

What inflammatory process do macrophages activate in Hashimoto’s?

Inflammasome activation leading to pyroptosis.

What happens to Treg levels in Hashimoto’s thyroiditis?

They decrease, allowing pro-inflammatory T cell populations like Th1, Th17, Tfh, and Tc to dominate.

What is the cytokine shift in Hashimoto’s?

Anti-inflammatory cytokines (IL-10, TGF-β) decrease; pro-inflammatory cytokines (IL-2, IL-12, IL-17, IL-21, IL-22, IFN-γ, TNF-α) increase.

What triggers thyrocyte apoptosis in Hashimoto’s?

IFN-γ and TNF-α.

What is the role of B cells in Hashimoto’s pathogenesis?

They present autoantigens and produce autoantibodies that mediate complement-mediated cytotoxicity.

How does iodine affect thyroid autoimmunity?

Excess iodine increases immunogenicity of thyroglobulin and TPO, triggering apoptosis and antibody production.

How does iron deficiency contribute to Hashimoto’s?

Increases immunogenicity of TPO and thyroglobulin.

What effect does selenium deficiency have in Hashimoto’s?

Increases T cell activity and TNF-α levels while decreasing regulatory T cells.

What does vitamin D deficiency do in Hashimoto’s?

Promotes differentiation of B cells into antibody-producing plasma cells.

What are some environmental toxins linked to thyroid autoimmunity?

Chemical solvents and radiation.

What medications are associated with Hashimoto’s thyroiditis?

Amiodarone and interferon.

What is the standard pharmacologic treatment for Hashimoto’s?

Thyroxine (T4) replacement therapy.

What are immune-suppressing treatments used in severe autoimmune thyroiditis?

Corticosteroids combined with methotrexate, azathioprine, cyclophosphamide, cyclosporine, etc.

What treatment is used in serious brain or kidney autoimmune disease?

Plasmapheresis to remove antibodies from the blood

What are potential cytokine-based treatments for autoimmune thyroid diseases?

Blocking pro-inflammatory cytokines and enhancing anti-inflammatory cytokine production.

What immune mechanism is defective in Graves' disease allowing autoreactive cells to persist?

Failure of central and peripheral deletion of autoreactive T and B cells.

What cytokines enhance HLA class II expression in thyroid follicular cells in Graves’?

Interferons.

What is the significance of HLA class II expression on thyroid follicular cells?

Enhances presentation of TSH-R to autoreactive T cells.

What are the effects of chronic TSHR activation in Graves' disease?

Sustained thyroid hormone production and gland enlargement.

How do orbital fibroblasts contribute to Graves’ ophthalmopathy?

TRAb activates fibroblasts, causing inflammation and tissue remodeling behind the eyes.

Why is pretibial myxedema localized to the shins?

Due to TSHR expression on dermal fibroblasts and localized immune infiltration.

What is the overall impact of pro-inflammatory cytokines in Graves' disease?

They perpetuate inflammation and autoantigen presentation, sustaining autoimmune stimulation.

What are the three main treatments for Graves' disease?

Radioactive iodine, anti-thyroid drugs, and surgery.

What are two other names for Type 1 diabetes?

Insulin-dependent diabetes and juvenile diabetes.

At what ages does Type 1 diabetes most commonly develop?

It often develops in children, teens, and young adults, but can occur at any age.

What is the underlying cause of Type 1 diabetes?

Destruction of insulin-producing beta cells in the islets of Langerhans within the pancreas.

What are the classic symptoms of Type 1 diabetes?

Polyuria (frequent urination), polydipsia (increased thirst), polyphagia (increased hunger), weight loss, extreme fatigue, and blurry vision.

What was the first strong evidence for the autoimmune pathogenesis of Type 1 diabetes?

The detection of islet-reactive autoantibodies.

What are insulin autoantibodies (IAA)?

Autoantibodies directed against insulin.

What are islet cell antibodies (ICA)?

Antibodies targeting cytoplasmic proteins in pancreatic beta cells.

What is the significance of GAD-65 antibodies in Type 1 diabetes?

They are autoantibodies against glutamic acid decarboxylase in beta cells, supporting autoimmune etiology.

What is the role of i2A antibodies in Type 1 diabetes?

They are antibodies that target the protein tyrosine phosphatase i2A, an enzyme involved in insulin secretion. These antibodies impair insulin production by attacking this regulatory protein.

What does the presence of two or more islet autoantibodies suggest?

Asymptomatic Type 1 diabetes may be developing.

What HLA haplotypes are associated with increased risk for Type 1 diabetes?

HLA-DQA1, HLA-DQB1, and HLA-DRB1.

What genetic insulin-related variation increases the risk of Type 1 diabetes?

A high number of tandem repeated (VNTR) regions in the insulin gene.

What type of immune-mediated disease is Type 1 diabetes mellitus?

It is a T-cell dependent immune-mediated disease.

What type of immune cells are found in pancreatic lesions in T1D?

T-cells are present in the inflammatory lesions.

Why does Type 1 diabetes develop in terms of immune regulation?

Due to defects in central and peripheral immunological tolerance mechanisms.