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AUTOTOLERANCE AND AUTOIMMUNITY. The problem of self-nonself discrimination. The immune system responds to many foreign (microbial) antigens but not to self antigens Developing lymphocytes express a large number of antigen receptors, not biased by specificity

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Autotolerance and autoimmunity




Autotolerance and autoimmunity

The problem of self-nonself discrimination

  • The immune system responds to many foreign (microbial) antigens but not to self antigens

  • Developing lymphocytes express a large number of antigen receptors, not biased by specificity

  • Therefore, all individuals produce lymphocytes with the ability to recognize self antigens

  • Self antigens have access to the immune system

  • Therefore, self-reactive lymphocytes must be selected against (eliminated or inactivated) to prevent autoimmunity

Autotolerance and autoimmunity

Immunological tolerance

  • Definition:

    • specific unresponsiveness to an antigen that is induced by exposure of lymphocytes to that antigen (implies antigen specificity, in contrast to “non-specific immunosuppression”)

  • Significance:

    • All individuals are tolerant of their own antigens (self-tolerance); breakdown of self-tolerance results in autoimmunity

    • Therapeutic potential: Inducing tolerance may be exploited to prevent graft rejection, treat autoimmune and allergic diseases, and prevent immune responses in gene therapy, perhaps stem cell transplantation

Autotolerance and autoimmunity

Central and peripheral tolerance

The principal fate

of lymphocytes that

recognize self antigens

in the generative organs

is death (deletion), BUT:

Some B cells may change

their specificity (called

“receptor editing”)

Some T cells may

differentiate into

regulatory (suppressor)

T lymphocytes

Autotolerance and autoimmunity

Mechanisms of unresponsiveness to self antigens

  • Central tolerance: Immature self-reactive lymphocytes that recognize self antigens in generative (“central”) lymphoid organs die by apoptosis; other fates

  • Peripheral tolerance: Mature self-reactive lymphocytes that recognize self antigens in peripheral tissues are inactivated (anergy), killed (deletion) or suppressed

  • “Clonal ignorance”: Mature self-reactive lymphocyte clones do not encounter or respond to self antigens

  • In normal individuals it is not known which self antigens induce tolerance by which mechanism

Autotolerance and autoimmunity

Central T cell tolerance

Autotolerance and autoimmunity

Deletion of self-reactive T cells in the thymus:

how are self antigens expressed in the thymus?

AIRE (autoimmune regulator) is a putative transcription factor

that stimulates thymic expression of many self antigens, which were thought to be restricted to peripheral tissues

Discovered as the genetic cause of a human autoimmune disease (APS-1)

Autotolerance and autoimmunity

Consequences of AIRE mutation

  • Human disease: autoimmune polyendocrinopathy with candidiasis and ectodermal dysplasia (APECED), also called autoimmune polyendocrine syndrome (APS-1)

    • Associated gene identified by positional cloning, named AIRE (“autoimmune regulator”)

Autotolerance and autoimmunity

Central tolerance: fates of immature self-reactive lymphocytes

  • Induced by antigen in generative lymphoid organs (thymus for T cells, bone marrow for B cells), and high-affinity (“strong”) recognition of the antigens (dangerous lymphocytes)

  • Immature lymphocytes undergo apoptosis upon encounter with antigens (negative selection)

    • Eliminates high-affinity self-reactive (potentially most dangerous) lymphocytes

  • Some self-reactive T cells that encounter self antigens in the thymus develop into regulatory T cells and immature B cells in the bone marrow change their receptors (rendered harmless)

Autotolerance and autoimmunity





Peripheral tolerance

T cell


Normal T cell



T cells





Off signals



T cell



cell death)


Block in




T cell

Autotolerance and autoimmunity

T cell anergy

From Abbas, Lichtman and Pillai. Cellular and Molecular Immunology 6th ed, 2007

Autotolerance and autoimmunity

“Activation-induced cell death”: death of mature

T cells upon recognition of self antigens


Autotolerance and autoimmunity

Regulatory T cells

From Abbas, Lichtman and Pillai. Cellular and Molecular Immunology 6th ed, 2007

Autotolerance and autoimmunity

Tolerance in B lymphocytes

  • Central tolerance:

    • Deletion of immature cells by high-affinity antigen recognition in the bone marrow

    • Some immature cells may change their antigen receptors when they encounter antigens in the bone marrow (“receptor editing”)

  • Peripheral tolerance:

    • Anergy

    • Exclusion from lymphoid follicles, death because of loss of survival signals

Autotolerance and autoimmunity


Frequency: 5% of population

The most Reumatoid arthritis

frequent Graves disease

diseases Type I diabetes mellitus

Pernicious anemia

Systemic lupus erithematosus

Multiple sclerosis

Autotolerance and autoimmunity


  • Definition: immune response against self (auto-) antigen, by implication pathologic

  • General principles:

    • Pathogenesis: The development of autoimmunity reflects a combination of susceptibility genes and environmental triggers (usually infections)

    • Different autoimmune diseases may be systemic or organ-specific; may be caused by different types of immune reactions (antibody- or T cell-mediated)

  • Problems in understanding pathogenesis of human autoimmune diseases:

    • Failure to identify target antigens, heterogeneous disease manifestations, disease may present long after initiation

Autotolerance and autoimmunity



- MHC genes

- non MHC genes

Environmental factors

- infection

- drugs


Autotolerance and autoimmunity

Genetic basis of autoimmunity -- 1

  • Genetic predisposition of autoimmune diseases

    • Increased incidence in twins (more in monozygotic)

    • Identification of disease-associated genes by breeding and genomic approaches

  • Multiple genes are associated with autoimmunity

    • Most human autoimmune diseases are multigenic

    • Single gene mutations and mouse knockouts reveal critical pathways

Autotolerance and autoimmunity

Genetic basis of autoimmunity -- 2

  • MHC genes

    • Major genetic association with autoimmune diseases (relative risk of disease in individuals with particular HLA haplotypes)

    • Disease-associated alleles are present in normal individuals

  • Non-MHC genes:

    • Many loci identified by whole genome association and linkage studies

    • Most are chromosomal locations; actual genes and roles in disease are largely unknown

Autotolerance and autoimmunity

Genetic basis of autoimmunity -- 3

  • Genome wide association studies are being done to define genes

    • Crohn’s disease:

      • NOD-2: microbial sensor in intestinal epithelial and other cells

      • IL-23 receptor: involved in TH17 responses

    • Rheumatoid arthritis, others:

      • PTPN-22 (tyrosine phosphatase): may control kinase-dependent lymphocyte activation

    • Multiple sclerosis:

      • CD25 (IL-2 receptor): required for maintenance of regulatory T cells

    • Difficult to define pathways and target them for therapies

Autotolerance and autoimmunity

Infections predispose to autoimmunity

Genes encoding antigen receptor

specific for a myelin antigen

Transgenic mouse with

myelin-specific T cells

Pathogen-free mouse colony

Normal mouse colony

CNS disease

No disease

Autotolerance and autoimmunity

Infections and autoimmunity

  • Infections trigger autoimmune reactions

    • Clinical prodromes, animal models

    • Autoimmunity may develop after infection is eradicated (i.e. the autoimmune disease is precipitated by infection but is not directly caused by the infection)

    • Some autoimmune diseases are prevented by infections (type 1 diabetes, multiple sclerosis, others? -- increasing incidence in developed countries): mechanism unknown; similar protection suggested for asthma

      • The “hygiene hypothesis”

Autotolerance and autoimmunity

Immune-mediated inflammatory diseases

  • Immune-mediated inflammatory diseases develop because the normal controls on immune responses fail

  • These diseases often become self-perpetuating

  • The phenotype of the disease is determined by the nature of the immune response

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