Autoimmunity and Type I Diabetes CCMD 793A: Fundamental Integrated SystemsFALL, 2006 James M. Sheil, Ph.D.

Autoantigen - any “self” or autologous protein (or carbohydrate, lipid, nucleic acid) that can trigger an immune response Autoimmunity - the response of the immune system to an autoantigen; results from a breakdown in specific unresponsiveness to “self” antigens known as “self tolerance” (also, “autoimmune response”) Autoimmune disease - accumulation of the pathologic changes that occur as a result of the adverse effects of an autoimmune response; can be difficult to sort out primary from secondary effects AUTOIMMUNITY

Autoimmune Disease Classification Autoimmune diseases are classified as types II, III, and IV based on the immunological effector mechanism mediating the disease and similarities in their tissue damaging effects to related hypersensitivity reactions: Type II autoimmune disease is mediated by antibodies specific for cell surface components or the extracellular matrix. Type III autoimmune disease is mediated by the formation of immune complexes. Type IV autoimmune disease is mediated by effector T cells.

Type II autoimmune diseases

Type III autoimmune diseases

Type IV autoimmune diseases

Mechanisms of Autoimmunity The overriding concern in trying to better understand the mechanisms underlying autoimmunity is to gain a better knowledge of self-tolerance mechanisms and how these might fail… (1) Three main hypotheses concerning the induction and maintenance of self-tolerance: removal and/or silencing of autoreactive lymphocytes antigen-specific T cell regulation idiotype/anti-idiotype network interactions (2) Two main proposed mechanisms for the “breaking” of self-tolerance: increased MHC expression on APCs, and antigenic [molecular] mimicry

GENETIC PREDISPOSITION TO AUTOIMMUNITY The HLA Complex of genes has been strongly implicated in the control of and susceptibility to autoimmune diseases. Relative Risk indicates the degree of association between the expression of one or more HLA alleles and an individual’s susceptibility to a particular disease.

2 X 2 TABLE Calculation of Relative Risk: a x d Relative Risk = _______ b x c Relative Risk indicates the increased frequency of disease occurrence in persons who express the HLA marker than in those who do not express the marker. # marker present # marker absent Patientsa b Controlsc d

Association of HLA genotype and gender with susceptibility to autoimmune disease

EXAMPLE: TYPE I DIABETES Position 57 of the HLA-DQ  chain affects susceptibility to insulin-dependent diabetes mellitus (IDDM)

Asp 57 on the HLA-DQ  chain forms a salt bridge with an Arg residue on the HLA-DQ  chain and also confers protection from IDDM Patients with IDDM usually have Ser, Val, or Ala at position 57 of HLA-DQ  which fails to form salt bridge with HLA-DQ 

HLA-DR3 and HLA-DR4 are markers of IDDM susceptibility HLA-DR2 is associated with protection against IDDM Note: The strong association of HLA-DR3/DR4 with IDDM susceptibility is due to their close linkage with the HLA-DQ  gene.

Figure 13.5 In families where two or more siblings have IDDM, a comparison can be made of the HLA genotypes of affected siblings: Affected siblings share two HLA haplotypes much more frequently than if HLA genotype did not affect disease.

Other factors implicated in the cause of autoimmune disease: Virus infection - latent virus infections can lead to later onset of autoimmunity Altered self components - through modification (i.e. by drugs), degradation of cellular proteins, exposure where they are normally inaccessible Physiological factors - aging, hormonal influences

Possible Causes of Tissue Damage in Autoimmune Disease: Antibodies Complement Immune Complexes T Lymphocytes (both CD4 + and CD8 + T cells) Macrophages Natural Killer (NK) Cells

The role of “autoantibodies” in the pathogenesis of Type I diabetes. Although there is considerable evidence for the presence of such antibodies (of different types), their role in the pathogenesis of Type I diabetes is unclear. Of particular importance is whether these antibodies play a causative role or whether they are induced as a secondary consequence of the resulting pathological tissue damage that occurs throughout disease pathogenesis.

The role of CD4+ and CD8+ T cells in the pathogenesis of Type I diabetes. It is clear that both CD4+ and CD8+ T cells appear in the vicinity of pancreatic islet lesions during the course of prediabetic and diabetic onset stages in the pathogenesis of IDDM. There has been much controversy, however, whether and how both CD4+ and CD8+ T cells might serve as autoreactive effectors in the pathogenesis of Type I diabetes.

The role of virus infection in the pathogenesis of Type I diabetes. Considerable evidence (including “molecular mimicry” studies) suggests that a virus infection may serve as the underlying basis for the pathogenesis of IDDM. It is unclear how such a virus infection mechanism may be involved in the initial and/or later stages of IDDM.

The identification of potential target antigens for antibodies and T cells in Type I diabetes. A number of “self” antigens have been proposed as targets for autoantibodies and autoreactive T cells involved in the pathogenesis of IDDM. It is unclear how and/or why these normally tolerated “self” antigens become autoantigens in IDDM.