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Immunology of Endocrine Disease

Autoimmune Endocrine Disorders

Disease of Endocrine Glands caused by Autoimmu nity
Immune System err in its response, Targets body’s tissues and cells
Attacks any target of Endocrine Glands
• Endocrine cells
• Hormones
• Hormone Receptors
Most Autoimmune Endocrine disorders target single organs
• Adrenal Gland – Addison’s Disease
• Pancreas’s Islet of Langerhans – Type I Diabetes
In Multiple Autoimmune Endocrine Disorders, ≥ 2 glands are affected
Autoimmune Endocrine disor ders
Hashimoto’s Thyroiditis
Graves’ Disease
Addison’s Disease (Adrenal Gland Insufficien cy)
Autoimmune Hypophysitis (Pituitary Gland Insufficiency)
Autoimmune Oophritis (Ovarian Insufficiency)
Insulin Dependent (Type 1 DM)(IDDM)
Autoimmune Hypoparathyroidism
Testicular Insufficiency
Premature Ovarian Failure
Autoimmune Thyroid disorders
(most common autoimmune end ocrine disorder)
Hypothyroidism – Under-Functioning Thyroid
Hyperthyroidism – Over-Functioning Thyroid
Results of Autoimmune Disorder
Destruction of ≥ 1 glands
(Failure to produce hormones – eg. Hashimoto’s disease, IDMM)
Abnormal Growth of an Organ
Changes in Organ Function (eg. Grave’s disease)

Development of Autoimmune Endocrine Disease

Aberrant expression of Class II HLA molecules on Endocrine Cell Membrane
↓
Recognized by Autoreactive T, B Cells
↓
Destruction of Endocrine Cells
Molecular Mimicry
By Cross Reactive Microbial Antigens
Stimulate Autoreactive B, T Cells
Result in Loss of Tolerance to an Autoantigen

Dysregulation of Cytokine Network

(eg. IFN γ upregulate MHC Class II surface
Lead to Activation of Autoreactive T cells)
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Pathogenic Role in Autoimmune in AIED

T Lymphocytes B Lymphocytes
Subsets of T cells – CD4, CD8 cells Hallmark
CD4 divided into Th0, Th1, Th2 Production of Auto-Antibodies directed against Organ-Specific Antigen
Th0 by stimulation with Antigen, Co-Stimulatory Signals, Differentiate into Auto-Antibodie s in Pathogenesi s of Disease
• Th1 (Secrete IL-2, IFN γ) Graves’ disease – Thyroid-Stimulating Hormone Receptor
• Th2 (Secrete IL-4, IL-5, IL-10) Type I Diabetes – Glutamic Acid
Auto-Antibodie s for Type 1 DM
Islet Cell Antibody
Anti-GAD65 Antibody
Anti-Insulin Antibody
B cell receptor on surface of B Cell
Bind, Internalize Antigens
↓
Process, Present on Class II MHC Molecules to Helper T-Cells
↓
T-B Cell Interactions in presence of Co-Stimulatory Molecules
Lead to Production of Autoantibodies

Important to have
• Engagement of TCR (TCR Signal)
• Co-stimulatory Signals
Co-Stimulatory Molecules
• CD28 (on T-cell ) ←→ B7
• CD40L (on T-cell) ←→ CD40
Absence of Co-Stimulatory Signals
• T-cell Unresponsiveness (Anergy)
• Apoptosis (Programmed Cell Death) = Deletion

Thyroid Autoimmune Disease
Hashimoto’s Thyroiditis Grave’s Disease
Organ-specific Autoimmune disorder Autoimmune disorders of unknown cause
Unknown cause Presents as Thyrotoxicosis with a Diffuse goiter
rd th
Results in Progressive Destruction of Thyroid Most common in 3 , 4 decades of life
Female Predominance Female ↑
1/10 Middle-Aged Women Occur in 0.1-0.5% of general population
Elderly, Children (can also be affected) Strong associations with
Families with History of Whites
Autoimmune Thyroid Disease DR3 Bw35
Associated with DQβ Bw46
SLE DQa
Chronic Active Hepatitis
Dermatitis Herpetiformis Immunopathogenesis
Scleroderma Presence of an autoantibody that
Strong Associations with recognizes TSH Receptor
HLA DR4 Mediates stimulation of receptor
HLA DR5 (eg. Grave’s disease)
Inhibition of receptor activation by TSH
Immunopathogenesis (Unclear)
Cellular Immunity Clinical Features
Antibody-Dependent Cytotoxicity Uniformly Enlarged Diffuse Goiter
Clinical Features Signs of Hyperthyroidism
Euthyroidism (Early disease) • Tremor
Clinical Hyperthyroidism • Tachycardia
(due to Inflammatory Breakdown of Thyroid Follicles • Heat Intolerance
with release of Thyroid Hormone) • Nervousness
Hypothyroidism (Late disease) • Warm Moist Skin
(due to Progressive Destruction of Opthalmopathy
Thyroid Gland) • Lid Lag
• Proptosis
Dermopathy
• Pretibial area (Myxedema)
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Primary Hypothyroidism Transient Thyroiditis Syndromes
Most common cause of Hypothyroidism in Adults Self limited Thyroiditis syndrome with transient immune activity against Thyroid
Female ↑ Subacute Thyroiditis Post Partum Thyroiditis
40 – 60 y/o Caused by Viral Infection of Thyroid Gland Occurs in 5-8% of Pregnant Women
Atrophy from unrecognized Thyroiditis with resulting Acute Phase Characterized by
Progressive Destruction of Gland Gland may be Painful Development of Transient Thyrotoxicosis
st
Lab Investigations Antithyroid Antibodies may be present Hypothyroidism during 1 3 months of post partum
Asians ↑ TSH ↑ T4 Significant % develop Chronic Thyroid Dysfunction
↓ Thyroid Hormones Thyrotoxic Assocation with
Immunologic Features Progressive Euthyroid, Hypothyroid periods HLA-DR3 Haplotype
Lymphocytic infiltration of Thyroid Gland Then Thyroid Function Normalize HLA-DR5 Haplotype
Anti-Thyroid Antibodies (>80% of patients) Feature
Treatment Silent Thyroiditis without Pain
Lifelong Thyroid Hormone replacement Immunologic Features Immunologic Features
Antibodies to Thyroid Peroxidase Antibodies to Thyroid Peroxidase
(both – Transient, Low Titer in Subacute Thyroiditis) (both – Transient, Low Titer in Subacute Thyroiditis)
Thyroid Stimulating Antibodies
Treatment Treatment (clinically Hypothyroid)
(Thyroid Function back to Normal within few months) (Thyroid Function back to Normal within few months)
Anti-Inflammatory drugs Thyroid Hormone Replacement

Immunologic Features Immunologic Diagnosis (Identification of Abs)

Presence of Circulating Autoantibodies to
• Thyroglobulin
• Thyroid Microsomal Antigen
(Thyroid Peroxidase)
Lymphocytic Infiltration in Thyroid Gland
(mainly B cells, CD4 T cells)
↑ Apoptosis of Thyroid Cells
↓ Free T3, T4
↑ TSH
Treatment
Thyroid Hormone Replacement Therapy (T4)
(Hypothyroidism)
Thyroidectomy (unusually Large, Painful gland)
+ve Thyroid-Binding Inhibitory Immunoglobulins (TBI)
+ve Thyroid Stimulating Antibody (TSAb)
2 different assay methods
Measurement of degree of inhibition of binding to
labelled TSH Receptor (TBII)
Measurement of cAMP production in cultured thyroid
cells (TSAb)
↑ Free T3, T4
↓ TSH
Treatment
Prophylthiouracil, Methimazole
• Inhibit Thyroid Hormone Production
• ↓ Size, Vascularity of Goiter
Suppressive doses of Thyroid Hormone + Anti Thyroid
Drugs (long term remission)
Radioactive Iodine 131I Therapy
Complete surgical removal of gland
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Pancreas Autoimmune Disease Adrenal Autoimmune Disease

Insulin-Dependent Diabetes Mellitus (IDDM) Addison’s Disease

Autoimmune disease Most common form of Adrenal Insufficiency
rd th
Destruction of Insulin-producing β cells of pancreatic Islets of Langerhans Occurs in 3 and 4 decade of life
Results in Deficiency of Insulin Female ↑
rd
Occurs in 3 decade of life Part of a Polyglandular Syndrome
Peak age of onset – 10 – 14 y/o Associated with
Common in Whites HLA-DR3
Male ↑ HLA-DR4
Caused by
Classification of Diabetes Mellitus Destruction of Adrenal Cortices
Type I DM Results in Chronic Adrenocortical Insufficiency
Type II DM Leading Causes
Gestational DM Autoimmune Destruction
Undiagnosed with Diabetes – 5.2 million
Clinical Features
Type I DM (IDDM) Hypotension
Develop due to Destruction of Pancreatic β cells Anorexia
Type IA (Autoimmune) Type IB Malaise
HLA-DR3 Uncommon Hyperpigmentation
HLA-DR4 Non-Autoimmune Salt Wasting

Etiology Laborato ry Findings

Viral Infection (eg. Mumps virus) ↑ Adrenocorticotropic Hormone (ACTH)
Viral Infection Lack of Corticol response to ACTH administration
↓
Inflammatory response to β cells of Islets Immunological Features
↓
Islet cells Destruction Circulating Antibodies against Adrenal Cortical Cells (IF)
↓ Complement is Fixed on Surface of Adrenal Cells
Insulin Deficiency
Genetic Susceptibility Treatment
HLA-DR3 Corticosteroid Hormone Replacement
HLA-DR4

Immunological Features
Monocytic, Lymphocytic Infiltration of Islets of Langerhans
+ve for Anti-Glutamic Acid Decarboxylase Antibody
+ve Islet Cells Antibody
+ve Anti-Insulin Autoantibody (IAA) (Type IA Disease)
HLA-DR expression on β cells
↑ Apoptosis of β cells

Diagnosis
Clinical Signs, Symptoms
Hyperglyc aemia
Osmotic Diuresis (Polyuria, Polydypsia)
Insulin Deficiency
↓
Utilization of Fats for Fuel
↓
Metabolism of Fatty Acids
↓
Ketoacids Production
↓
Ketonuria
Ketonaemia
Ketoacidosis with Cerebral Edema
Unexplained Weight Loss
↑HbA1c (Glycosylated Hb conc)
Severe impairment of Insulin Secretion
Fasting C-peptide (Proinsulin) not detectable
Presence of Islet Cell Autoantibodies against Autoantigens
Insulin
Glutamic Acid Decarboxylase
ICA

Treatment
Oral Hypoglycaemia drugs (Normalize Blood Glucose level)
Insulin replacement
Islet Cell Transplantation (future)
Immunosuppressive therapy
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Autoimmune Polyglandular Syndromes

Autoimmune Polyendocrine Syndromes

Heterog enous group of Rare Diseases
Characterised by
Autoimmune activity against > 1 endocrine organs
Non-endocrine organs (can also be affected)
3 Autoimmune Polyendocrine Syndromes
Immunological Features
Circulating Antibodies against Multiple Endocrine Organs
Evidence of HLA-DR expression on affected cells
Genetic susceptibility to Autoimmune

Syndrome
Type I Type II Type III
(Mucocutaneous Candidiasis Endocrinopathy) (Schmidt’s Syndrome)
Major Criteria Major Criteria Major Criteria
Candidiasis Adrenal Failure Thyroid Disease
Adrenal Failure Thyroid Disease
Hypoparathyroidism IDDM
Minor Criteria Minor Criteria Minor Criteria
Gonadal Failure Gonadal Failure IDDM
Alopecia Vitiligo Gastric Disease
Malabsorption Nonendocrine AD Neuroendocrine AD
Chronic Hepatitis
Epidemiology Epidemiology Epidemiology
Female ↑ Female ↑ Least Well Characterized
Childhood < 10 y/o 20 – 30 y/o Most Common disorder
Female ↑
Most common associations Idiopathic Addison’s Disease with presence of Presence of Autoimmune Thyroid Disease with other AID
Candidiasis (>70%) Diabetes IDDM
Hypoparathyroidism (>70%) Thyroid Disease Gastric Disease
Adrenal Insufficiency (40 – 70%) Both (Diabetes, Thyroid Disease) Non-Endocrine AID (eg. Myasthenia Gravis)
Other associations Gonadal Failure (↓% of cases) Associated with HLA
Chronic Active Hepatitis Association with HLA-DR3
Alopecia Areata Familial – Mode of Inheritance is Unknown
Pernicious Anaemia
Gonadal Failure
Pathogenesis (Unknown)
Fungal Infection (cell-mediated immunity defect)
Auto-Antibodies are seen
Not associated with HLA Haplotype