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