Autoimmunity and Type I Diabetes

CCMD 793A: Fundamental Integrated Systems FALL, 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 IVbased 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 betterknowledge of self-tolerance mechanisms and how thesemight 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’ssusceptibility to a particular disease.

2 X 2 TABLE

Calculation of Relative Risk:

a x dRelative Risk = _______

b x c

Relative Risk indicates the increased frequency of disease occurrence in personswho express the HLA marker than in those who do not express the marker.

# marker present # marker absentPatients a bControls c 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)

Asp57 on the HLA-DQ chainforms a salt bridge with an Argresidue on the HLA-DQchain and also confers protection from IDDM

Patients with IDDM usually haveSer, Val, or Ala at position 57of HLA-DQ which fails to formsalt bridge with HLA-DQ

HLA-DR3 and HLA-DR4 are markers of IDDM susceptibilityHLA-DR2 is associated with protection against IDDM

Note: The strong association of HLA-DR3/DR4 with IDDM susceptibilityis due to their close linkage with the HLA-DQgene.

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 HLAhaplotypes much more frequently than if HLA genotype did not affect disease.

Other factors implicated in the cause ofautoimmune 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.