MECHANISMS OF AUTOIMMUNITY

(Cellular and Molecular Immunology A.K. Abbas et al, ch 15)

AHMET VARIS

AUTOIMMUNITY•The term autoimmunity is often

erroneously used for any disease in which immune reactions accompany tissue injury, even though it may be difficult or impossible to establish a role for immune responses against self antigens in causing these disorders.

Immunologic Abnormalities Leading to Autoimmunity

•Defective tolerance or regulation.▫Failure of the mechanisms of self-tolerance in T

or B cells, leading to an imbalance between lymphocyte activation and control, is the underlying cause of all autoimmune diseases

▫There are four known causes for this; Negative selection of T and B cells Defective numbers and functions of regulatory T

lymphocytes Defective apoptosis of mature self-reactive

lymphocytes Inadequate function of inhibitory receptors

Immunologic Abnormalities Leading to Autoimmunity

•Abnormal display of self antigens.▫Increased expression and persistence of self

antigens that are normally cleared.

•Inflammation or an initial innate immune response.▫ By activating APCs, which overcomes

regulatory mechanisms and results in excessive T cell activation. (why T cells are imp.)

Genetic Basis of Autoimmunity• Mostly complex polygenic• Genome-wide association studies, linkage

analyses in families, and interbreeding studies in animals have revealed some of the common variations (polymorphisms) of genes that may contribute to different autoimmune diseases.

• Three main group of genes▫ Association of MHC alleles with autoimmunity▫ Polyphormism in Non-HLA genes▫ Inherited single-gene abnormalities

MHC alleles with autoimmunity

• The strongest group that associate with autoimmunity

• The realtion between HLA and autoimmunity shows how impotant T cells.

• But HLA allele is not, by itself, the cause of the disease

Polyphormism in Non-HLA genes• Associated with various

autoimmune diseases and may contribute to failure of self-tolerance or abnormal activation of lymphocytes

• Combinations of multiple inherited genetic polymorphisms interacting with environmental factors induce the immunologic abnormalities that lead to autoimmunity.

• Epigenetic changes also affect the diseases onset.

Inherited single-gene abnormalities

• Genes encoding complement proteins: Without complement activation circulating immune complexes and apoptotic cell bodies accumulate in blood

• FcγRIIB: Cause failure to control antibody-mediated feedback inhibition of B cells.

Role of Infections and Other Environmental Influences in Autoimmunity

•Infections

▫Bystander activation: The infection results in the activation of wrong T cells

▫Molecular mimicry: Infectious microbes may contain antigens that cross-react with self antigens, so immune responses to the microbes may result in reactions against self antigens.

•Other Environmental Influences

▫Anatomic alterations in tissues, caused by inflammation (possibly secondary to infections), ischemic injury, or trauma, may lead to the exposure of self antigens that are normally concealed from the immune system

▫Hormonal influences play a role in some autoimmune diseases.

REFERENCES• Mitchell Kronenberg & Alexander Rudensky, 2005, Regulation

of immunity by self-reactive T cells, doi:10.1038/nature03725• Kazuhiko YAMAMOTO, 2004, Mechanisms of Autoimmunity,

JMAJ 47(9): 403–406• Kornblum HI, Introduction to neural stem cells,  2007

Feb;38(2 Suppl):810-6.• Wobus AM, Boheler KR, Embryonic stem cells: prospects for

developmental biology and cell therapy, Physiol Rev. 2005 Apr;85(2):635-78.

• Book: Cellular and Molecular Immunology. 8th edition. Abul K Abbas

• Book: Basic Immunology:Functions and Disorders of the Immune System, 4th edition, Abul K Abbas