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Autoimmunity and Type I Diabetes. CCMD 793A: Fundamental Integrated Systems FALL, 2006 James M. Sheil, Ph.D. . AUTOIMMUNITY. Autoantigen - any “self” or autologous protein (or carbohydrate, lipid, nucleic acid) that can trigger an immune response.

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Autoimmunity and Type I Diabetes

CCMD 793A: Fundamental Integrated Systems FALL, 2006

James M. Sheil, Ph.D.


AUTOIMMUNITY

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


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.





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 ofRelative Risk:

    a x d

    Relative Risk = _______

    b x c

    # marker present# marker absent

    Patients a b

    Controls c d

    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.


    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)


    Patients with IDDM usually have

    Ser, Val, or Ala at position 57

    of HLA-DQb which fails to form

    salt bridge with HLA-DQa

    Asp57 on the HLA-DQb chain

    forms a salt bridge with an Arg

    residue on the HLA-DQa chain

    and also confers protection

    from IDDM


    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-DQb 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.


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