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.

-It occurs mainly between the ages of 20-30 years. 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). N