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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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
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
Type IV autoimmune disease is mediated by effector T cells.
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.
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.
with susceptibility to autoimmune disease
Position 57 of the HLA-DQ chain affects susceptibility to
insulin-dependent diabetes mellitus (IDDM)
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
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.
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.
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
T Lymphocytes (both CD4+ and CD8+ T cells)
Natural Killer (NK) Cells
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.
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.