Autoimmunity A breakdown of mechanisms responsible for tolerance

Autoimmunity A breakdown of mechanisms responsible for tolerance. The auto-reactivity may result in disease.

Contents: l General introduction l Immunologic pathogenesis involved in autoimmune diseases l Proposed mechanisms for induction of autoimmunity l Treatment of autoimmune diseases

Autoimmunity: An acquired immune reactivity against self antigens. Autoimmunity can be found in normal persons.

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 Ø Specific components: ØAntibodies ØT cells Ø Nonspecific components: ØComplement ØPhagocytes (PMN and macrophages) ØNK and other cells

Tissues and organs involved Ø Organ-specific diseases ØDamage is confined to the organ against which the immune response is mounted Ø Non-organ-specific diseases ØImmune response against antigens which are not associated with the organ involved

Tissues and organs involved

Immunologic pathogenesis involved in typical autoimmune diseases 1. Direct cellular damage (CDC, Opsonization, ADCC) 2. Stimulatory autoantibodies 3. Blocking autoantibodies

Type II hypersensitivity role of complement and phagocytes

Anti microsomal antibodies in Hashimoto’s disease

Goodpasture’s syndrome

Insulin-dependent diabetes mellitus

Grave’s disease

Myasthenia gravis the mechanism

Rheumatoid arthritis Characterized by the presence of rheumatoid factor (antibodies against Ig. G)

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

Multiple Sclerosis

Proposed mechanisms for induction of autoimmunity l Release of sequestered autoantigens l Infections (bystander activation, molecular mimicry, epitope spreading) l Abnormal immunoregulation l Genetic factors

l 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

l Infection (Bystander activation)

l. Infection (Molecular mimicry)

Epitope spreading

l Abnormal immunoregulation Ø Abnormal expression of MHC II molecules Ø Deviation of Th 1 and Th 2 balance Ø Polyclonal action of B cells and T cells Ø Abnormal expression of Fas/Fas. L

Abnormal expression of Fas/Fas. L The role of Fas and Fas. L can be understood by two mouse strains. One is called MRL/lpr (Lpr has been identified as a defective Fas gene), Another is called MRL/gld (mutation of Fas. L)

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

Susceptibility loci for autoimmune diseases

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

Examples of HLA-linked immunologic Diseases

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

Examples of Gene mutations that results in autoimmunity

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

Methods l Immunosuppression l T-cell vaccination l Peptide blockade l Monoclonal antibodies l Oral tolerance

l Immunosuppression üNonspecific suppressive drugs: corticosteroids, azathioprine, cyclophosphamide üMore selective suppressive drugs: cyclosporin A, FK 506 üThymectomy üPlasmapheresis

l 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.

l Peptide blockade Proliferation Energy altered antigen peptide

l Monoclonal antibodies üAnti-CD 4 üAnti-CD 25 üAnti-MHC üAnti-TCR

l 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.

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

Indicate whether each of the following statements is true or false. If you think a statement is false, explain why. a. Th 1 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-B 27 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