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Autoimmunity. A breakdown of mechanisms responsible for tolerance. The auto-reactivity may result in disease. Contents:. General introduction Immunologic pathogenesis involved in autoimmune diseases Proposed mechanisms for induction of autoimmunity Treatment of autoimmune diseases.

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slide1

Autoimmunity

A breakdown of mechanisms responsible for tolerance.

The auto-reactivity may result in disease.

slide2

Contents:

  • General introduction
  • Immunologic pathogenesis involved in autoimmune diseases
  • Proposed mechanisms for induction of autoimmunity
  • Treatment of autoimmune diseases
slide3

Autoimmunity:

An acquired immune reactivity against self antigens.

Autoimmunity can be found in normal persons.

slide4

Autoimmune diseases

Tissue damage caused by autoimmune responses.

The autoantibodies and autoreactive T cells against self antigens exist in all the individuals with autoimmune disease.

effector mechanisms of autoimmune damage
Effector mechanisms of autoimmune damage
  • Specific components:
    • Antibodies
    • T cells
  • Nonspecific components:
    • Complement
    • Phagocytes (PMN and macrophages)
    • NK and other cells
tissues and organs involved
Tissues and organs involved
  • Organ-specific diseases
    • Damage is confined to the organ against which the immune response is mounted
  • Non-organ-specific diseases
    • Immune response against antigens which are not associated with the organ involved
slide10

Immunologic pathogenesis involved in typical autoimmune diseases

  • Direct cellular damage (CDC, Opsonization, ADCC)
  • Stimulatory autoantibodies
  • Blocking autoantibodies
rheumatoid arthritis
Rheumatoid arthritis

Characterized by the presence of rheumatoid factor (antibodies against IgG)

systemic lupus erythematosus

Staining for immune complexes

in lupus nephritis (left) and Anti-renal

basement membrane antibody

In Goodpasture\'s nephritis (right)

Immunofluorescent detection of

antinuclear antibody in the

serum of an SLE patient

Systemic lupus erythematosus
slide20

Proposed mechanisms for induction of autoimmunity

  • Release of sequestered autoantigens
  • Infections (bystander activation, molecular mimicry, epitope spreading)
  • Abnormal immunoregulation
  • Genetic factors
slide21

Release of sequestered antigens

Any tissue antigens that are sequestered from the circulation, and therefore not seen by the developing T cells in the thymus, will not induce self-tolerance.

Exposure of mature T cells to such normally sequestered antigens at a later time might result in their activation.

Myelin basic protein (MBP)

Sperm, lens protein, heart-muscle antigens

slide26

Abnormal immunoregulation

  • Abnormal expression of MHC II molecules
  • Deviation of Th1 and Th2 balance
  • Polyclonal action of B cells and T cells
  • Abnormal expression of Fas/FasL
slide27

Abnormal expression of Fas/FasL

The role of Fas and FasL can be understood by two mouse strains.

One is called MRL/lpr/lpr(Lpr has been identified as a defective Fas gene),

Another is called MRL/gld (mutation of FasL)

slide28

Genetic factors

Most autoimmune diseases are polygenic, and affected individuals inherit genetic polymorphisms that contribute to disease susceptibility.

slide30

Among the genes that are associated with autoimmunity, the strongest associations are with MHC genes, especially class II MHC genes.

slide32

Studies with knockout mice and patients have identified several genes that influence the maintenance of tolerance to self antigens.

slide34

Treatment of autoimmune diseases

  • Ideally, treatment for autoimmune diseases should be aimed at reducing only the autoimmune response while leaving the rest of the immune system intact.
  • To date, this idea has not been reached.
slide35

Methods

  • Immunosuppression
  • T-cell vaccination
  • Peptide blockade
  • Monoclonal antibodies
  • Oral tolerance
slide36

Immunosuppression

  • Nonspecific suppressive drugs: corticosteroids, azathioprine, cyclophosphamide
  • More selective suppressive drugs: cyclosporin A, FK506
  • Thymectomy
  • Plasmapheresis
slide37

T cell vaccination

When irradiated self-reactive T cells are infused to the blood, these T cells apparently elicit regulatory T cells specific for TCR variable-region determinants.

slide38

Proliferation Energy

  • Peptide blockade

altered antigen peptide

slide39

Monoclonal antibodies

  • Anti-CD4
  • Anti-CD25
  • Anti-MHC
  • Anti-TCR
slide41

Inducing tolerance by oral antigen

Mice fed MBP do not develop EAE after subsequent injection of MBP,

However, the human clinical trials are in the early stages.

slide42

Summary

  • Autoimmunity results from a failure of self-tolerance, which mediated by autoantibodies and autoreactive T cells.
  • Autoimmune reactions may be triggered by environmental stimuli, such as infections, in genetically susceptible individuals.
slide43

Indicate whether each of the following statements is true or false. If you think a statement is false, explain why.

a. Th1 cells have been associated with development of autoimmunity.

b. Immunization of mice with IL-12 prevents induction of EAE by injection of myelin basic protein plus adjuvant.

c. The presence of the HLA-B27 allele is diagnostic for ankylosing spondylitis, an autoimmune disease affecting the vertebrae.

d. Individuals with pernicious anemia produce antibodies to intrinsic factor.

e. A defect in the gene encoding Fas can reduce programmed cell death by apoptosis

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