Autoimmune Insulin Dependent Diabetes Mellitus(Type 1 Diabetes Mellitus):

Major immunologic Features:•HLA-DR3 and DR4 haplotype expression

on the beta cells of the islets of Langerhans.•Presence of reactive Autoantibodies

directed against multiple antigens of islets beta cells.•Monocytic and lymphocytic infiltration of

islets of Langerhans.•Some evidence of partial response to

immunosuppressive therapy.

Mechanism of Autoimmune destruction of islet beta cells:•Some viruses (molecular mimicry): Mumps,

Coxsackievirus (B3 &B4), Rubella, CMV, and some strains of influenza virus. •Expression MHC class II on the surface of

beta cells. •Presentation of Autoantigens: Glutamic acid

decarboxylase, and tyrosine phosphatase, and insulinoma associated proteins (IA-2).•APC (DC) interaction, migration, activation of

helper cell.

N

•Specific T lymphocyte response; mainly CD8 cells, and some CD4 and NK cells inside the pancreatic islets.•Isotype switching of B lymphocytes.•Direct cytotoxicity to Beta cells; killing,

release of Autoantigen.•FasL-mediated killing of beta cells

(apoptosis).

Mechanism of Autoimmune destruction of beta cells: • N

General Considerations:• Strong association (90%) with MHC class

II haplotype DR3 & DR4 expression (familial tendency but no inheritance).

• Seen almost in individuals < 30 years.• The only autoimmune disease that does

not show higher incidence in females.• subjects who are at high risk for type 1

diabetes can be identified using immune, genetic, and metabolic markers.

Immunologic diagnosis of IDDM:•Lymphocytic infiltration in the islets.•Islets atrophy and glucose intolerance.•Islet immunofluorescence staining reveals:▫Detection of HLA-DR on both beta cells and infiltrating lymphocytes.▫CD8-cytotoxic\suppressor phenotype▫Antibodies and complement present on beta cell surface.

N

•Detection of autoantibodies in vitro:Anti-Glutamic acid decarboxylase antibodies

Anti-tyrosine phosphatase antibodies•Fasting blood glucose: greater than

126mg/dl.•Other diagnostic tests:

Glucose Tolerance Test (GTT)Glycated hemoglobin (HbA1c) to identify plasma glucose concentration

Adrenal Insufficiency: Addison’s Disease

Major Immunologic features:

•Presence of circulating antibodies against adrenal cells.

•Fixation of complement on the surface of adrenal cells.

•Associated with other autoimmune diseases.

Mechanism of adrenal cell destruction:•Expression of Auto-antigen 21-

hydroxylase enzyme (this enzyme is involved in the side-chain cleavage and subsequent hydroxylation of steroids) by MHC class II.•Specific APC interaction and migration to

the regional lymph nodes.•Activation of specific T helper cells.•Monoclonal B lymphocyte isotype

switching.

N

•Production of Auto-reactive antibodies•Interaction with the cortical cells

surface.•Complement fixation.• cellular destruction.

General Considerations: •Addison’s disease is the most common form

of adrenal insufficiency, accounting for 70-80% of all cases.•Relatively low prevalence.•Affect young individuals (30-40 years’ old).•Female to male ratio is 1.8:1.•Seen commonly as part of polyglandular

syndrome type1 or 2 (40% of autoimmune adrenal insufficiency).•Strong association with HLA-DR3,4 for the

other 60% of cases.

Immunologic diagnosis•Microscopy: lymphocytic infiltration in

adrenal cortex.•Immunofluorescence staining of cortical

cells shows:▫ Autoantibodies.▫ Complement fragments.

•Decreased serum Cortisol level.•Elevated serum levels of

adrenocorticotropic hormone (ACTH) (no negative feed back)

•Serology: ▫ Detection of serum anti-adrenal

cortical cells antibodies in up to 80% of cases by Indirect immunofluorescence.

Some Clinical Features: •The most common symptoms are fatigue,

muscle weakness, weight loss, difficulty in standing up, anxiety, nausea, vomiting, diarrhea, sweating, changes in mood, and joint and muscle pains. •Postural hypotension and

hyperpigmentation of the skin, especially in sun-exposed areas, darkening of the palmar creases, recent scars, borders of the lips, and genital skin. (ACTH is similar to melanin stimulating hormone “MSH”)

Kennedy is one of the famous Addison's disease patients

Autoimmune polyglandular syndromes:

•Major immunologic features: ▫Circulating antibodies against multiple endocrine organs.▫HLA-DR expression on affected cells.• Three types

Type I Polyglandular Syndrome

•Occurs in childhood ≤ 10 •Chronic mucocutaneous candidiasis

(70% of cases)•Hypoparathyroidism (70% of cases).•Adrenal insufficiency (40-70 %).•Minor association with gonadal

failure.

Type II Polyglandular Syndrome:•Occurs mainly between the ages of 20-30 years•Has 2:1 female predominance. •Familial inheritance of mutant allele.•HLA-DR3 association. •Major criteria: •Adrenal failure•Thyroid disease (Hypo or hyperthyroidism)•IDDM.•Minor criteria: Gonadal failure.

Type III Polyglandular Syndrome:

•Autoimmune thyroid disease associated with:

IDDM or pernicious anemia (autoimmune anti-intrinsic factor antibodies) • not associated with adrenal

insufficiency.