Immunology of Endocrine Disease

Question 1

Describe common organ specific and non-organ specific autoimmune disease.

Answer 1

Organ-specific;

• Graves thyroiditis
• Hashimoto thyroiditis

Question 2

Illustrate the multifactorial aetiology of autoimmune disease.

Answer 2

a

Question 3

Describe the immunopathological mechanisms involved in causation of autoimmune disease.

Answer 3

a

Question 4

Illustrate the roles of cell-mediated and humoral immune mechanisms in autoimmune thyroid disease (as an illustration of all autoimmune endocrine disorders).

Answer 4

a

Question 5

Define and classify autoimmune polyendocrine syndromes.

Answer 5

a

Question 6

Illustrate the importance of endocrine autoantibodies as primary pathogenic agents or as secondary non-pathogenic markers of disease.

Answer 6

a

Question 7

Define ‘autoimmunity’.

Answer 7

A immune response against a self-antigen.

Question 8

Define ‘autoimmune diseease’.

Answer 8

Tissue damage or disturbed function resulting from an autoimmune response.

Question 9

Define ‘organ-specific’.

Answer 9

Disease may be restricted to a single organ, usually an endocrine gland.

Question 10

Define ‘non organ-specific’.

Answer 10

• Affect multiple organs
• Associated with autoimmune responses against self-molecules, which are widely distributed throughout the body
• Intracellular molecules involved in transcription and translation

Question 11

Define ‘immunologic tolerance’.

Answer 11

Unresponsiveness to an antigen that is induced by previous exposure to that antigen.

Question 12

Define ‘tolerogens’ (or tolerogenic antigens).

Answer 12

Antigens that induce tolerance.

Question 13

Describe the mechanism of immunological tolerance.

Answer 13

The immune system can generate a diversity of T-cell antigen receptors and immunoglobulin molecules by differential genetic recombination.

This produces many antigen-specific receptors capable of binding to self-molecules.

To avoid autoimmune disease, the T and B cells bearing these self-reactive molecules must be either eliminated or downregulated so that the immune system is made specifically tolerant to self-antigens.

Several mechanisms are involved (central and peripheral tolerance).

A break down of any of the immunological tolerance mechanisms results in autoimmune responses.

Question 14

Describe central tolerance.

Answer 14

Self-tolerance may be induced in immature self-reactive lymphocytes in the generative lymphoid organs.

The thymus plays an important role in eliminating T cells with high affinity to self-antigens.

Bone marrow is important in B cell tolerance.

Question 15

Describe peripheral tolerance.

Answer 15

Mature lymphocytes that recognise self-antigens in peripheral tissues become incapable of activation by re-exposure to that antigen or die by apoptosis.

An important mechanism for the induction of peripheral tolerance is antigen recognition without co-stimulation or “second signals”.

Peripheral tolerance is also maintained by regulatory T cells (Tregs) that actively suppress the activation of lymphocytes specific for self- and other antigens.

Some self-antigens are sequestered from the immune system, and other antigens are ignored.
—> Antigens may be sequestered from the immune system by anatomic barriers, e.g. in testes and eyes, and thus cannot engage antigen receptors.

Question 16

Name the three mechanisms of peripheral tolerance.

Answer 16

• Anergy (functional unresponsiveness)
• Treg Suppression
• Deletion (cell death)

Question 17

Overcoming peripheral tolerance can result from…

Answer 17

• Inappropriate access of self-antigens
• Inappropriate or increased local expression of co-stimulatory molecules
• Alterations in the ways in which self-molecules are presented to the immune system

Question 18

Describe overcoming peripheral tolerance.

Answer 18

More likely to happen when inflammation or tissue damage is present due to the increased activity of proteolytic enzymes –> intra- and extracellular proteins broken down –> high concentrations of peptides (cryptic epitopes) being presented to responsive T cells.

The structures of self-peptides may be altered by viruses, free radicals or ionising radiation, thus bypassing previously established tolerance.

Question 19

Describe the epidemiology of autoimmune disease.

Answer 19

• 3% of the population
• Clustering within families
• Peak onset: 15-65 years (except type 1 DM)
• Almost all types are more common in women (except ankylosing spondylitis)

Question 20

Describe the aetiology of autoimmune disease.

Answer 20

Genetic factors;

• Clusters within families
• Alleles of MHC

Environmental factors

Infections;

• Molecular mimicry
• Upregulation of co-stimulation
• Antigen breakdown and presentation changes
• ?Increased incidence in animals held in germ free conditions

Drugs;

• Molecular mimicry
• Genetic variation in drug metabolism

UV radiation;

• Triggers skin inflammation
• Modification of self-antigen

Question 21

Describe the treatment of autoimmune diseases.

Answer 21

Suppression of the damaging immune response;

• Before irreversible tissue damage
• Early detection is a challenge
• Problem with specificity of treatments and toxicity

Replacement of the function of the damaged organ;

• Hypothyroidism
• Insulin-dependent diabetes mellitus

Question 22

Describe the classification of diabetes.

Answer 22

Type 1 (Juvenile-onset, insulin-dependent diabetes);

• Ketoacidosis
• Inadequate insulin secretion
• Lymphocytic infiltration of the islets of Langerhans with specific destruction of beta cells
• Aetiology: Autoimmune destruction, genetic factors, viral infections

Type 2 (maturity onset, noninsulin-dependent diabetes);

• More common
• Middle age
• Non-ketotic coma (occasional)
• Normal or increased insulin secretion
• Reduction of cell surface receptors to insulin
• Genetic factors
• Evidence against autoimmunity

Question 23

Describe the aetiology of type 1 diabetes.

Answer 23

Autoimmune destruction;

• Circulatory antibodies to islet cells
• Patients prone to develop other organ specific autoimmune diseases

Genetic factors;

• Association with certain HLA types
• Environmental factors play a role too (40% concordance in twins in comparison to 100% in Type 2)

Viral infection;

• Antibodies to certain viruses are high in patients
• Viruses may act as triggers for autoimmune destruction e.g. coxsackie B, mumps

Question 24

Describe the complications of diabetes.

Answer 24

Large blood vessels;
- Accelerates atheroma leading to MI, CVS disease, ischaemic limbs

Small blood vessels;

• Endothelial cells and basal lamina damage
• Retinopathy
• Nephropathy

Peripheral nerves;
- Neuropathy

Neutrophils;
- Susceptibility to infection

Pregnancy;

• Preeclamptic toxaemia
• Large babies
• Neonatal hypoglycaemia

Skin;

• Necrobiosis lipoidica diabeticorum
• Granumolma annulare
• Gangrene of extremities

Question 25

Describe the structure and secretion of the thyroid gland.

Answer 25

• Follicles lines by cuboidal cells
• Proteinaceous stores secretions
• Synthesis of T3 and T4 under negative feedback by TSH (anterior pituitary)
• C-cells scattered throughout the gland that secrete calcitonin

Question 26

Name the diseases of the thyroid gland.

Answer 26

Secretory malfunction;

• Hyperthyroidism
• Hypothyroidism

Swelling of the entire gland = goitre

Solitary masses;

• Nodular goitre
• Adenoma
• Carcinoma

Question 27

Name the causes of hyperthyroidism.

Answer 27

• Graves thyroiditis
• Functioning adenoma
• Toxic nodular goitre
• Exogenous thyroid hormone (rare)
• Ectopic secretion by ectopic thyroid tissue or tumours

Question 28

Briefly describe Graves thyroiditis and its histology.

Answer 28

• Most common cause of thyrotoxicosis
• Usually associated with a diffuse goitre
• Increased vascularity

Histologically;

• Hyperplasia of the acinar epithelium
• Reduction of stored colloid
• Local accumulations of lymphocytes with lymphoid follicle formation

Question 29

Describe the pathophysiology of Graves thyroiditis.

Answer 29

• Organ-specific autoimmune disease
• Autoantibody (IgG) (LATS) binds to thethyroidepithelial cells and mimics the action of TSH
• LATS stimulates the function and growth ofthyroidfollicular epithelium

Question 30

Describe the signs of Graves thyroiditis.

Answer 30

• Diffuse goitre
• Exophthalmos
• Pretibial myxoedema (accumulation of mucopolysaccharides in the deep dermis of the skin)
• Finger clubbing

Question 31

Describe cretinism.

Answer 31

If hypothyroidism is present in the new-born, physical growth and mental development are impaired, sometimes irreversibly (cretinism).

Cretinism may be endemic in geographical areas where the diet contains insufficient iodine for thyroid hormone synthesis.

Sporadic cases are usually due to a congenital absence of thyroid tissue, or to enzyme defects blocking hormone synthesis.

Question 32

Briefly describe Hashimoto thyroiditis and its histology.

Answer 32

• Most common cause of acquired hypothyroidism in adults
• Female preponderance
• Certain HLAs are commonly found in affected individuals
• May initially cause thyroid enlargement but later atrophy and fibrosis
• In early stages: damage to thyroid follicles –> release of thyroglobulin –> transient thyrotoxicosis

Histologically:

• Dense infiltration by lymphocytes and plasma cells, with lymphoid follicle formation
• Colloid content is reduced
• Thyroid epithelial cells show a characteristic change in which they enlarge and develop eosinophilic granular cytoplasm due to proliferation of mitochondria (called Askanazy cells, Hürthle cells or oncocytes)
• In advanced cases, there may be fibrosis

Question 33

What two antibodies are found in the serum of patients with Hashimoto thyroiditis, and what are their origin?

Answer 33

• One reacting with thyroid peroxidase
• The other reacting with thyroglobulin

These autoantibodies are probably formed locally by the plasma cells infiltrating the thyroid, and are possibly the result of a loss of specific suppressor T-lymphocytes.

Question 34

Define ‘autoimmune polyendocrine syndromes’,

Answer 34

A diverse group of clinical conditions characterised by functional impairment of multiple endocrine glands due to loss of immune tolerance.

Frequently include conditions such as alopecia, vitiligo, celiac disease, and autoimmune gastritis with vitamin B12deficiency that affect non-endocrine organs.

Question 35

Describe the aetiology and pathophysiology of autoimmune polyendocrine syndromes.

Answer 35

Aetiology;

• Can occur in patients from early infancy to old age
• new components of a given syndrome can appear throughout life
• Variation in the frequencies and patterns of autoimmunity in affected patients and their families
• Combination of genetic susceptibility and environmental factors

Pathophysiology;

• Circulating autoantibodies and lymphocytic infiltration of the affected tissues or organs
• Eventually leading to organ failure

Question 36

Describe autoimmune polyendocrine syndrome type 1.

Answer 36

• APS-1, AKA autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy
• Rare autosomal recessive disease
• Caused by mutations in the autoimmune regulator gene (AIRE).

Question 37

Describe the epidemiology of autoimmune polyendocrine syndrome type 1.

Answer 37

1:100,000 in most countries, with a higher prevalence in some countries.

Question 38

Describe the clinical features of autoimmune polyendocrine syndrome type 1.

Answer 38

At least two of three cardinal components during childhood;

• Chronic mucocutaneous candidiasis
• Hypoparathyroidism
• Primary adrenal insufficiency (Addison’s disease)

Other typical components;

• Enamel hypoplasia
• Enteropathy with chronic diarrhea or constipation
• Primary ovarian insufficiency (approximately 60% of women with APS-1 before they reach 30 years of age)

Less frequent components;

• Bilateral keratitis (accompanied by severe photophobia)
• Periodic fever with rash
• Autoimmunity-induced hepatitis, pneumonitis, nephritis, exocrine pancreatitis, and functional asplenia

Rare findings;

• Retinitis
• Metaphyseal dysplasia
• Pure red-cell aplasia
• Polyarthritis