The Autoimmune insulin-dependent Diabetes mellitus:

Major immunologic Features:1- HLA-DR3 and DR4 haplotype expression on the beta cells of the islets of Langerhans.

2-Presence of reactive Autoantibodies directed against multiple antigens of islets beta cells.

3-Monocytic and lymphocytic infiltration of islets of Langerhans.4-Some evidence for partial responses to immunosuppressive therapy.

Mechanism of Autoimmune destruction of islet beta cells:

-Some types of infectious agents: Mumps virus, coxsackievirus types B3 and B4, Rubella virus, CMV, and some strains of influenza.

-Expression of MHC class II on the surface of beta cells.

-Presentation of Autoantigen ; Glutamic acid decarboxylase, and tyrosine phosphatase (IA-2).

-APC (DC) interaction, migration, activation of helper cell.

-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.

Mechanism of Autoimmune destruction of beta cells: .

General Considerations:- Strong association (90%) with MHC class II haplotype

DR3 and DR4 expression.

- Seen almost in individuals under the age of 30 years.

- It occurs predominantly in whites.- Prevalence rate in USA and Europe is 0.25%.

- Males are more commonly affected than females.- No useful diagnostic procedure for autoimmune

response before the appearance of IDDM.

Immunologic diagnosis and clinical features of IDDM:

-Lymphocytic infiltration in the pancreatic islets.-Islets atrophy and glucose intolerance.

-Immunofluorescence staining islet inflammation reveals:1-Expression of HLA-DR on both beta cells and infiltrating lymphocytes.2-CD8-Cytotoxic suppressor phenotype due to monoclonal antibodies staining. 3-Antibodies and complement present on beta cell surface.

-Auto-reactive antibodies localized in vitro: -Anti-Glutamic acid decarboxylase antibodies - Anti- tyrosine phosphatase antibodies.

-Fasting blood glucose greater than 140mg/dl.

-Other diagnostic tests: GTT, and HbA1c.

Adrenal Insufficiency: Addison’s Disease:

Major Immunologic features: -Circulating antibodies against adrenal cells are present.

-Complement is fixed on the surface of adrenal cells.

-It is associated with other autoimmune diseases.

Mechanism of adrenal cell destruction:- Expression of Auto-antigen 21-hydroxylase enzyme by MHC class II on the surface of cell.- Specific APC interaction.

-Migration of APC to the lymph nodes.

-Activation of specific T helper cells.

-Monoclonal B lymphocyte isotype switching.

-Production of Auto-reactive antibodies.

-Attachment to cortical

cell 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.

-The prevalence is relatively low.

-Affect young individuals (30-40 years’ old).

-Female to male ratio is 1.8:1.

-Seen most commonly as part of polyglandular syndrome

( 40% of autoimmune adrenal insufficiency).

-Strong association with HLA-DR3,4 for other 60% of cases.

Immunologic diagnosis and clinical features:

-Microscopy: lymphocytic infiltration.-Immunofluorescence (direct) staining shows: 1-Autoantibodies on the surface of cortical cells. 2-Complement fragments.

-Serum levels of adrenocorticotropic hormone (ACTH) are elevated.-Decreased serum Cortisol level.

-Serology: Detection of serum anti-adrenal cortical cells antibodies in up to 80% of cases by Indirect immunofluorescent.

Autoimmune polyglandular syndromes:Major immunologic features: -Circulating antibodies against multiple endocrine organs.-HLA-DR expression on affected cells.

Type I syndrome:-It occurs in childhood before 10 years.-Oral Candidiasis and hypoparathyroidism (70% of cases).-40-70 % of patients go on to develop adrenal insufficiency. -Minor association with Gonadal failure.

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Type II syndrome:-It occurs mainly between the ages of 20-30 years.-Has a 2:1 female predominance. -familial inheritance of mutant allele.-HLA-DR3 association. -Major criteria: Adrenal failure, Thyroid disease, and IDDM.-Minor: Gonadal failure.

Type III syndrome: -Autoimmune thyroid disease associated with IDDM or Autoimmune Anti-intrinsic factor Abs (gastric disease).