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

Classification of Diabetes o Type 1: insulin deficiency due to beta cells destruction. - Type 1A: autoimmune destruction. - Type 1B: no evidences of autoimmunity. o Type 2: insulin deficiency or resistance (more common).

Major immunologic Features: HLA-DR3 and DR4 haplotype Expression of MHC class II on the beta cells of the islets of Langerhans. Presence of autoantibodies directed against multiple antigens of 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: Molecular mimicry or direct damage: Mumps virus, Coxsackievirus (B3 &B4), Rubella, CMV, and some strains of influenza virus. Formation of antibodies against autoantigens: Glutamic acid decarboxylase, and insulinoma associated proteins (a member of tyrosine phosphatase family). Complement activation and beta cell destruction.

N APC (dendritic cells) interaction, migration, activation of helper cell. Specific T lymphocyte response; mainly CD8 cells, and some CD4 and NK cells inside the pancreatic islets. FasL-mediated killing of beta cells and release of more autoantigens. Direct cytotoxicity to beta cells; killing, release of more autoantigen. Isotype switching of B lymphocytes and production of more autoantibodies.

General Considerations: Strong association (90%) with haplotype DR3 & DR4 and MHC class II expression (familial tendency but no inheritance; more common in some countries). Seen almost in individuals < 30 years with one peak at 4-6 years and another one at 10 years old. An 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.

Diagnosis of Type-1 Diabetes Mellitus: Metabolic tests: Fasting blood glucose: ≥ 126 mg/dl in more than one occasion. Random venous plasma glucose ≥ 200 mg/dl Glucose Tolerance test (GTT): ≥ 200 mg/dl Glycated hemoglobin (A1C) ≥ 6.5%.

N Immunologic diagnosis of IDDM: Lymphocytic infiltration in the islets. Islets atrophy. Islet immunofluorescence staining reveals: ▫ Detection of MHC II on both beta cells and infiltrating lymphocytes. ▫ CD8-cytotoxic\suppressor phenotype. ▫ Antibodies and complement present on beta cell surface. Detection of autoantibodies in vitro: ▫ Anti-Glutamic acid decarboxylase antibodies. ▫ Anti- tyrosine phosphatase antibodies.

Adrenal Insufficiency: Autoimmune 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 21-hydroxylase enzyme by MHC class II cells (an enzyme involved in cleavage and subsequent hydroxylation of steroids). Specific APC interaction and migration to the regional lymph nodes. Activation of specific T helper cells. Monoclonal B lymphocyte isotype switching and production of auto-reactive antibodies which will Interact with the cortical cells surface leading to complement fixation & cellular destruction.

General Considerations: Addison’s disease (autoimmune) is the most common form of adrenal insufficiency, accounting for 70-80% of all cases. Relatively low prevalence (4\100,000). 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, HLA-DR4 (60% of cases).

Some Clinical Features: Symptoms: fatigue, muscle weakness, weight loss due to anorexia, difficulty in standing up, anxiety, vomiting, diarrhea, sweating, changes in mood, and joint and muscle pains. Signs: 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. ( due to high levels of ACTH & MSH)

Diagnosis: Decreased serum cortisol level. Elevated serum levels of adrenocorticotropic hormone (ACTH) (no negative feed back). Immunologic diagnosis: Microscopy: lymphocytic infiltration in adrenal cortex. Immunofluorescence staining of cortical cells: ▫ Autoantibodies. ▫ Complement fragments. Serology: ▫ Detection of serum anti-adrenal cortical cells antibodies (esp. anti 21-hydroxylase) in up to 80% of cases by Indirect immunofluorescence.

Kennedy is one of the famous Addison's disease patients

Autoimmune Polyglandular Syndromes:

Autoimmune polyglandular syndromes: Major immunologic features: ▫ Circulating autoantibodies against multiple endocrine organs. ▫ HLA-DR expression by 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 years Has 2:1 female predominance. Familial inheritance of mutant allele. HLA-DR3 association. Major criteria: Adrenal failure (100%) Thyroid disease 70% (hypo or hyperthyroidism) and/or IDDM 50%. Minor criteria: Gonadal failure.

Type III Polyglandular Syndrome: Autoimmune thyroid disease associated with: IDDM or pernicious anemia not associated with adrenal insufficiency.