BIO372 : Immunology : Diseases : Lesson

I. Diabetes

1. Disease: insulin-dependent, type I, juvenile-onset diabetes
   • Normal pancreas
     • Most pancreatic cells secrete digestive enzymes
     • Pancreatic beta-cells produce insulin
     • Insulin helps cells absorb glucose from the blood
   • Without insulin
     • Glucose accumulates in the blood
     • Kidneys make excess urine to eliminate glucose - body is dehydrated
     • Cells without glucose break down their own fat and protein for fuel
     • Breakdown of fat produces toxic ketones

2. Involvement of the immune system
   • Inflammation of islet cells: filled with lymphocytes and monocytes
   • Many diabetics have other autoimmune disorders
   • B cells
     • Antibodies against cell surface antigens of islet cells detected in diabetics
     • Infants of diabetic mothers are not diabetic even though maternal antibodies cross the placenta
     • Antibodies injected into healthy rodents do not produce diabetics
   • T cells
     • T cells from the spleen of diabetic rats and mice (animal models) can induce diabetes in healthy rodents
     • T cells are active in the development of diabetes in rats and mice
     • T cells are most prevalent in human insulitis

3. Trigger
   • Hypotheses
     • Hypothesis 1: abnormal substance on the beta cell, e.g., protein encoded by a mutated gene
     • Hypothesis 2: a viral infection of the beta cells displays foreign antigens
     • Hypothesis 3: molecular mimicry - a foreign antigen is similar enough to a self-antigen that the immune system eliminates both
   • Evidence
     • Islet-cell autoantibodies react to self-antigens
     • NOD mice with normal immune systems do not develop insulitis and diabetes
     • Lymphocytes of NOD mice attack islet cells of normal mice
     • Molecular mimicry is involved in other autoimmune disorders, i.e., rheumatic heart disease after a streptococcal infection
     • T cells from mice immunized against bacterial heat-shock proteins induced insulitis in healthy mice
   • Beta cell susceptibility
     • Damaged beta cells display excessive numbers of class I MHC molecules, which display promotes attack by killer T cells
     • The cytokine, interleukin-1 secreted by activated macrophages, is more toxic to beta cells than to other cells
     • Beta cells seem prone to damage by free radicals released by damaged cells and macrophages
   • Vigorous immune attack
     • Overreaction of helper T cells to beta cell autoantigens
     • Natual suppressor system, which should prevent autoimmunity, fails

4. Major histocompatibility complex
   • Class II MHC region on chromosome 6
     • Contains three gene loci: DP, DQ, and DR
     • Each locus codes for a molecule composed of A and B amino acid chains
     • Each locus is polymorphic: there are several alleles of each gene
     • Genes from both parents are expressed: an individual has an MHC molecule from each chromosome
   • Alleles
     • DR1, 3, and 4 alleles are common in diabetics, but DR2 and 5 are not
     • Amino acid in the 57th position in the B chain from the DQ locus is important: diabetes is not associated with a negatively charged aspartic acid but is associated with a non-charged amino acid such as valine or serine
     • Location of the 57th amino acid is in the part of the MHC molecule which binds to an antigen and presents it to a T cell
     • Tightness of the binding depends on the molecular structure determined by the amino acid sequence - affects activation of T cells

5. Hypothesized scenario
   • Foreign antigen elicits an immune response
   • Foreign antigen closely resembles a beta cell antigen, e.g., 64-K protein
   • Class II MHC molecule with tight binding resulting from a "susceptible" allele causes a vigorous and prolonged immune response to the foreign antigen
   • Aroused immune system cells enter the pancreas and react to a self antigen which mimics the foreign antigen

6. Possible action
   • Detect autoantibodies before symptoms of diabetes appear
   • Suppress immune system destruction of beta cells
   • Selectively eliminate T cells sensitive to beta cell antigens

When you have completed this lesson, go on to Review Questions