Immunological Tolerance

Immunological toleranceImmunological tolerance is a state of is a state ofunresponsiveness that is specific for a unresponsiveness that is specific for a particular antigen; it is induced by prior particular antigen; it is induced by prior exposure to that antigen. exposure to that antigen.

Tolerance prevents harmful reactivity against the Tolerance prevents harmful reactivity against the body’s own tissues. body’s own tissues. natural tolerance central tolerance natural tolerance central tolerance acquired tolerance peripheral tolerance acquired tolerance peripheral tolerance

Central toleranceCentral tolerance is the process wherebyis the process wherebyimmature T and B cells acquire tolerance to self immature T and B cells acquire tolerance to self antigens during maturation within the primary antigens during maturation within the primary lymphoid organs / tissues ( thymus and bone lymphoid organs / tissues ( thymus and bone marrow). It involves the elimination of cells with marrow). It involves the elimination of cells with receptors for self antigens.receptors for self antigens. Peripheral tolerancePeripheral tolerance is the process whereby is the process wherebymature T and B cells acquire tolerance to selfmature T and B cells acquire tolerance to selfantigens in peripheral tissues through antigens in peripheral tissues through elimination , lack of co-stimulatory signals.elimination , lack of co-stimulatory signals.

Immunologic features of toleranceImmunologic features of toleranceIt is an antigen-induced, active processLike immunologic memory, it is antigen specificLike immunologic memory, it can exist in B cells, T cells or bothIt is easier to induce and lasts longer in T cells than in B cell

Ⅱ Ⅱ Factors affecting toleranceFactors affecting tolerance 1. The role of antigen1. The role of antigenFactors which affect response

Favor immune response

Favor tolerance

Physical form of antigen

Route of injection

Dose of antigen

Large, aggregated, complex molecules, properly processed

Subcutaneous or intramuscular

Optimal dose

soluble, aggregate-free, simple small molecules, not processed

Oral or intravenous

Very large or very small dose

2. the role of host2. the role of host

Factors that affect response

Favor immune response

Favor tolerance

Age of responding animal

Differentiation state of cells

Fully differentiated; memory T & B cells

Older, immuno-logically mature

Newborn (mice), immunologically immature

Relative undifferentiated B cell with only IgM, T cells in the thymic cortex

ⅢⅢ..Mechanism of tolerance inductionMechanism of tolerance induction 1. Clonal deletion

Thymus: negative selectionBone marrow: IgM+, IgD- B cells encountering self antigen

2. Clonal anergy (T cell anergy, B cell anergy)Lack of co-stimulatory (B7) molecules Exposure to large amounts of antigen (high zone tolerance) Improper antigen presentationLack of antigenic stimulus (low zone tolerance)

3. Suppressor T cells 4. Immunological privileged sites (brain, anterior chamber of the eye and testes)

Ⅳ Clinic significance of immunological tolerance ⒈induce and maintain immunological tolerance prevent and cure hypersensitivity diseases cure autoimmune diseases prevent transplantation rejection reaction 2.stop immunological tolerance cure infectious diseases cure tumor

Autoimmunity andautoimmune diseases

Autoimmunity is defined as an acquired immune reactivity against self antigens.

This response usually produces autoantibodies and autoreactive T cells

Failure of immune tolerance

Autoimmunity Classification

Can be classified into clusters that are either organ specific or systemic

Examples of Organ SpecificExamples of Organ Specific

Lungs of a patient with Goodpasture’s

Vitiligo (melanocyte damage)

Hashimoto’s disease (thyroiditis)

Examples of Systemic Autoimmunity

SLE

Factors contributing to the development of Factors contributing to the development of autoimmune diseaseautoimmune disease

1. Autoimmune diseases are multifactorial including age, genetics, gender, infections and

the nature of the autoantigen.

2. Age and gender: Autoantibodies are more prevalent in older people and women have a greater risk than men for developing a autoimmune disease.

Sex-based differences in autoimmunitySex-based differences in autoimmunityDifferences can be traced to sex hormones - hormones circulate throughout the body and alter

immune response by influencing gene expression - (in general) estrogen can trigger autoimmunity and

testosterone can protect against itDifference in immune response - ♀ produce a higher titer of antibodies and mount

more vigorous immune responses than ♂ - ♀ have a slightly higher cortisol secretion than ♂ - ♀ have higher levels of CD4+ T-cells and serum

IgM

Nature Immunology  2, 777 - 780 (2001)

Sex differences in autoimmunity

Females are much more likely to develop autoimmune illness

Estrogens and AutoimmunityEstrogens and Autoimmunity

3. Genetic factors: Particular HLA genes are associated with certain autoimmune diseases.

There have been numerous disease associated genes or disease “susceptibility” genes linked to autoimmunity

4. Infections: Many infectious agents have been linked to particlular autoimmune diseases and may be important in their etiology.

5. Nature of the autoantigens: Target antigens are often highly conserved proteins, such as heat shock proteins (HSPs), stress proteins, enzymes, or their substrates.

6. Drugs and autoimmune reactions: Certain drugs can initiate autoimmune reactions by unknow mechanisms, e.g. patients receiving procainamide develop SLE-like symptoms and have anti-nuclear antibodies.

Molecular Mechanisms of AutoimmunityMolecular Mechanisms of Autoimmunity

What could go wrong here?

How is autoimmunity induced?

Molecular Mechanisms of AutoimmunityMolecular Mechanisms of Autoimmunity

Cross-reactivity (molecular and viral mimicry)

Viral and nonviral peptides can mimic self-peptides and induce autoimmunity

Cross-reactivityCross-reactivity

Rheumatic fever is a classic example of molecular mimicry

Molecular Mechanisms of AutoimmunityMolecular Mechanisms of Autoimmunity

Release of sequestered antigen

Immunological privileged sites: brain, anterior chamber of the eye and testes

e.g. antibodies in blood can attack myelin basic

protein if blood-brain barrier is breached.

Molecular Mechanisms of AutoimmunityMolecular Mechanisms of AutoimmunityInappropriate MHC expression Type I diabetes: pancreatic β cells express

abnormally high levels of MHC I and MHC II (?)MHC II – APC only! This may hypersensitize Th cells to β cell peptides.

Normal Pancreas Pancreas with Insulitis

Molecular Mechanisms of AutoimmunityMolecular Mechanisms of Autoimmunity

Polyclonal B cell activation by viruses and bacteria

If B cells reactive to self-peptides are

activated, autoimmunity can occur.

Example: Epstein-Barr virus, which is the cause of infectious mononucleosis.

Myasthenia gravisMyasthenia gravis

Disease marked by progressive weakness and loss of muscle control

Classified as a “B cell” diseaseAutoantibodies against nicotinic acetylcholine

receptors

DiabetesDiabetes Disease in

which the body does not produce or properly use insulin

“ T cell” disease

T cells attack and destroy pancreatic beta cells

Multiple sclerosis

MS patients can have autoantibodies and/or self reactive T cells which are responsible for the demyelination

Grave’s diseaseGrave’s disease

•Production of thyroid hormones is regulated by thyroid-stimulating hormones (TSH)•The binding of TSH to a receptor on thyroid cells activates adenylate cyclase and stimulates the synthesis of two thyroid hormones: thyroxine and triiodothyronine•A person with Grave’s Disease makes auto-antibodies to the receptor for TSH. The binding of these auto-antibodies to the receptor mimics the normal action of TSH, without the regulation, leading to overstimulation of the thyroid•The auto-antibodies are called long-acting thyroid stimulating hormones

Grave’s DiseaseGrave’s Disease•Beta-blockers such as propranolol are often used to treat symptoms of rapid heart rate, sweating, and anxiety until the hyperthyroidism is controlled. •Hyperthyroidism is treated with antithyroid medications, radioactive iodine or surgery.•Both radiation and surgery result in the need for lifelong use of replacement thyroid hormones, because these treatments destroy or remove the gland.

Autoimmune anemiasAutoimmune anemias Pernicious anemia

What is it? - deficiency in vitamin B12

What causes it?- auto-antibodies to intrinsic factorWhat happens? - B12 remains in the stomach and is excretedTreatment

- treated with injections of B12

Hemolytic anemia- results from monoclonal antibodies to normal RBC constituents- antibodies coat the erythrocytes, causing clumping, lysis, and premature clearance by the spleen- can be induced by an “offending” agent (parasite, drug, or toxin) that adheres to the RBC- Drug-induced hemolytic anemia- drug binds to RBC’s and causes them to become antigenic- antibodies that develop from the drug recognize these cells and they are lysed

Rheumatoid arthritis (RA)

Cause is unknown!Affects 1-2% of worldwide populationPatients are 75% women, between 40-60 years

of age Rheumatoid factor (Rf): antibodies to IgG

Treatment of autoimmune diseases

I. Current therapies- aimed at reducing symptoms by providing non-specific suppression of the immune system

II. Experimental therapeutic approaches - try to induce specific immunity

I. Current therapies Immunosuppressive drugs

- corticosteroids, azathioprine - slows the proliferation of lymphocytes Cyclosporin A

- blocks signal transduction mediated by the TCR (inhibits only antigen-activated T cells while sparing non-activated ones)

Thymectomy- removal of thymus from patients with myasthenia gravis

Plasmapheresis- removes antigen-antibody complexes for a short-term reduction in symptoms

II. Experimental therapeutic approachesII. Experimental therapeutic approaches T-cell vaccination

- autoimmune T-cell clones elicit regulator T-cells that are specific for the TCR on the autoimmune T-cells- results in suppression of the autoimmune cells

Peptide blockade of MHC molecules- a synthetic peptide is used to bind in place of the regular peptide on the MHC- induces a state of clonal anergy in the autoimmune T-cells

(Experimental Therapies continued)

Monoclonal-antibody treatment - monoclonal antibody against the IL-2 receptor

blocks activated Th-cells - blockage of preferred TCRs with monoclonal

antibodies - monoclonal antibody against an MHC molecule that

is associated with autoimmunity while sparing the others Oral antigens

- tend to induce tolerance- still in early clinical trials