Transcript Autoimmune Insulin-dependent diabetes mellitus (Type 1): (IDDM

Autoimmune Insulin-dependent diabetes mellitus
(Type 1): (IDDM-type 1)
-IDDM is a type of diabetes that results from autoimmune
destruction of insulin-producing pancreatic beta cells of
the islets of Langerhans.
-Incidence varies from (8 to 17) per 100,000 in Northern
Europe and USA (Highest in Scandinavia: 35 per
100,000) to a very low of 1 per 100,000 in Japan and
China.
Causes of beta-cells destruction:
IDDM type 1 is induced by one or more of the following:
1-Getetic susceptibility:
-Type 1 IDDM is a polygenic disease; more then one
gene could be involved in establishment of this type.
-The strongest gene IDDM1 (on one locus or more;
dominant or recessive) that located in the MHC Class II
gene region on chromosome 6 at region 6p21.
- IDDM2 locus on chromosome 11 ( 11p15).
-The expression of HLA-DR 3,4 haplotype by beta cells.
N
2-The Viral infection of beta cells:
-Some types of viruses could cause virus-triggered
autoimmune response against the infected beta cells;
due to antigenic cross-reactivity.
Example: Coxsackievirus types B3 and B4, Rubella virus.
3-Environmental factors:
-Allergies against chemicals or drugs that change the
antigenic nature of beta-cell surface proteins.
Major immunologic Features of IDDM type 1:
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:
coxsackievirus types B3 and B4, Rubella virus, CMV,
Mumps virus, 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) , engulfment of Autoantigen, migration to
pancreatic lymph nodes, activation of helper cell.
N
-Isotype switching of B lymphocytes.
- Circulating anti-GAD, Tyrosine phosphatase
autoantibodies.
-Specific T lymphocyte response; mainly CD8 cells
, and some CD4 and NK cells inside the pancreatic islets.
-Direct cytotoxicity to Beta cells by:
1-ADDC Mechanism.
2-FasL-mediated killing of beta cells.
Mechanism of Autoimmune destruction of beta cells:
N
Immunologic and diagnostic features of IDDM Type 1:
A- Immunofluorescent microscopy (monoclonal
antibodies staining) reveals:
1-Expression of HLA-DR3,4 on both beta cells and
infiltrating lymphocytes.
2-CD8-Cytotoxic suppressor phenotype.
3-Antibodies and complement present on beta cells.
B-Serology:
Detection of autoantibodies in patient serum is a
diagnostic feature for type 1 but NOT type 2.
N
-The Auto-reactive antibodies are :
1-Anti-Glutamic acid decarboxylase antibodies.
2-Anti- tyrosine phosphatase antibodies.
-These autoantibodies could be localized in vitro.
C-Biochemistry:
-Fasting plasma Glucose: at or above 7.00mmol/L
(126 mg/dl).
-GTT: Plasma glucose at or above 11.1 mmol/L
(200 mg/dl).
-HbA1c: At or above 6.5%
Adrenal Insufficiency: Addison’s Disease:
Adrenal insufficiency: the glands do not produce
adequate amount of steroid hormones (primary Cortisol),
but may include impaired production of aldosterone.
Cortisol is produced by adrenal cortex in response to
stress and low level of glucocorticoids.
Cortisol is a strong Anti-inflammatory agent that inhibits
Cellular and humoral immunity.
N
Cortisol down-regulates the production of large group of
Interleukins (IL-2,IL-4,5,6); this results in suppression of
TH subset-2 which has a major function in activation of Blymphocytes.
So Cortisol is used mainly to treat diseases associated
with antibodies –mediated immune response
(Rheumatoid diseases, and allergies).
In Biochemistry:
Regulation of Glucose metabolism (gluconeogenesis).
n
Types of Adrenal insufficiency:
1-Primary:
-70-80% of cases are due to autoimmune adrenal
disease (Addison’s disease).
-Other cases are due to congenital adrenal hyperplasia.
2-Secondary:
-Impairment of the pituitary gland or hypothalamus.
Causes of Adrenal insufficiency:
-Chronic: Mainly the Addison’s disease.
Others: Tuberculosis, hemochromatosis, and
Adrenoleukodystrophy.
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.
-Strong association with HLA-DR3,4 for 60% of cases.
Mechanism of adrenal cell destruction:
- Expression of Auto-antigen 21-hydroxylase enzyme by
MHC class II on the surface of cell.
- Specific APC interaction.
n
-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.
Diagnostic features of Addison’s disease:
-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.
-Increased serum potassium.
-Serology:
Detection of anti-21 hydroxylase antibodies in serum.
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).