Tolerance and Autoimmune diseases

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Tolerance and Autoimmune Diseases:

Tolerance and Autoimmune Diseases By: Dr. Iman Hussein Shehata

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Autoimmune disease occurs when a specific adaptive immune response is mounted against self antigens

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Once an immune response develops against self antigens, it is almost impossible to eliminate the (self) antigen completely as would occur in a normal conventional immune response. As a result, effector immune pathways cause tissue damage, change of cell function and/or chronic inflammatory injury.


TOLERANCE Tolerance : refers to the: specific immunological no reactivity to an antigen. The most important form of tolerance is non-reactivity to self antigens . Failure of tolerance to self antigens (self-tolerance) results in autoimmune diseases .


MECHANISMS OF SELF-TOLERANCE Tolerance is generated at 2 levels: Central tolerance : which develops primarily in fetal life and occurs in the primary lymphoid organs ( the bone marrow and the thymus). Peripheral tolerance : which develops postnatally to deal with self-reactive cells in the periphery that have escaped central tolerance .

Central Tolerance :

Central Tolerance During development in primary lymphoid organs, immature B and T lymphocytes that encounter, recognize and interact with high affinity with self antigens, are deleted by apoptosis ( clonal deletion ). This process is called negative selection and ensures that self-reactive B and T lymphocytes are removed from the immune cell repertoire before entering the periphery

Peripheral Tolerance:

Peripheral Tolerance Self-reactive B and T lymphocytes that have escaped central tolerance encounter several checkpoints in the periphery to prevent their activation. Several mechanisms are involved in this process: Anergy : A state of metabolic arrest. It occurs when a lymphocyte receives an antigenic signa l in the absence of costimulation .

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2. Ignorance : T cells reactive to self antigen not encountered in the thymus will mature and migrate to the periphery, but they may never encounter the appropriate antigen because it is sequestered in inaccessible tissues. Autoimmune lymphocytes are kept in ignorance by sequestration of autoantigens behind cellular or vascular barriers. Such cells may die out for lack of stimulus. Many autoantigens are normally held in sites that are inaccessible to circulating lymphocytes e.g. the brain tissue and the eye lens.

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Immunologic ignorance also refers to the occurrence of small numbers of low avidity autoreactive T cells existing in the presence of low levels of presented self peptides without becoming activated to respond.

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3. Regulation : Subsets of T cells inhibit the effector functions of other lymphocytes, e.g. self-reactive cells. Such cells are termed regulatory T cells. Suppression by regulatory T cells probably occurs through secretion of 1- inhibitory cytokines, such as transforming growth factor-β (TGF-β) or IL-10, 2-or may involve direct inhibition.

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4.Homeostatic control : Occurs by expression of cytotoxic T lymphocyte antigen 4 (CTLA-4 ) on activated T lymphocytes as an alternative to CD28 . A normal immune response requires interaction between CD28 on T cells and its corresponding ligand , B7.1 and B7.2, on antigen presenting cells, thus providing costimulation for the T cell. Interaction with CTLA-4, instead of CD28, results in T cell inhibition.

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A second form of homeostatic control occurs due to lack of T cell help for autoreactive B cells . As a result, autoreactive B cells do not get stimulated In addition, some autoimmune diseases have been shown to be associated with a skew in the immune response towards the predominance of a TH1 or TH2 response . This may be attributed to the cytokine imbalance that is associated with such a switch.

Figure showing Major Mechanisms of Tolerance Induction:

Figure showing Major Mechanisms of Tolerance Induction

Etiology of Autoimmunity:

Etiology of Autoimmunity While theoretically, it is possible for anyone to develop an autoimmune disease, it seems that some individuals are more at risk than others. Although the trigger for the development of autoimmune disease is not well-defined, several environmental and genetic fact ors have been shown to play a role.

1. Genetic Factors :

1. Genetic Factors All autoimmune diseases probably have some genetic components. Thus susceptibility to autoimmunity may occur via genes that influence tolerance, apoptosis or inflammatory responses . Many studies have shown a close association between certain MHC genotypes and the occurrence of certain autoimmune diseases

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Several other genes may play a role in increasing the susceptibility to autoimmune diseases. Inherited homozygous deficiency of the early proteins of the classical pathway of complement (C1, C4, or C2) is very strongly associated with the development of systemic lupus erythematosus (SLE). The mechanism of this association is unknown but may involve the abnormal processing of immune complexes in the absence of a functional classical complement pathway.

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Furthermore, abnormalities in genes encoding proteins involved in the regulation of lymphocyte apoptosis, including Fas (CD95) and Fas ligand , are strongly associated with the development of SLE

2.Host Factors:

2.Host Factors Many autoimmune diseases display a sex bias. For example, several conditions are more common in females including systemic lupus erythematosus , Grave’s disease and multiple sclerosis. Furthermore, many autoimmune diseases that are more common in females show peak incidence during the active childbearing age at which maximal production of the female sex hormones occurs

3.Environmental Factors :

3.Environmental Factors Environmental agents have been shown to trigger several autoimmune diseases although a permissive genetic background is also needed. 1- Infection is strongly implicated because it may disrupt peripheral tolerance in several ways . For example, infection may result in breakdown of vascular or cellular barriers resulting in exposure of self antigens to the immune system. Bacterial products may also induce a superantigen effect , leading to inappropriate (self-reactive) T cell s

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local inflammation in response to an infectious agent may trigger expression of MHC molecules and costimulatory molecules on tissue cells, inducing an autoimmune response. Some infections induce autoimmunity through molecular mimicry , where a pathogen antigen induces a response cross-reacting with self. The classic example is rheumatic fever following infection with Streptococcus pyogenes . Antibodies to Streptococcal antigen bind host heart tissue and can damage it .

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2. Damage to an immunologically privileged site can also induce an autoimmune response. E.g. in the disease sympathetic ophthalmia , trauma to one eye releases the sequestered eye antigens to the surrounding tissues, making them accessible to T cells. As a result, the effector T cells attack the traumatized eye and infiltrate to attack the healthy eye.

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3. Alteration of self molecules sufficiently for it to become immunogenic may additionally occur and account for autoimmunity, for example, chemical, radiation or drug-induced autoimmune syndromes.

Mechanisms of damage in autoimmune diseases :

Mechanisms of damage in autoimmune diseases The disease may be organ specific Graves' disease, Goodpasture’s syndrome, autoimmune hemolytic anemia or systemic SLE rheumatoid arthritis

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The mechanisms of tissue damage in autoimmune diseases can occur due to any of the hypersensitivity reactions. Some common autoimmune diseases classified according to the immunopathologic mechanism of tissue damage.

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Disease Self antigen Consequence Type II antibody to cell-surface or matrix antigens Acute rheumatic fever Streptococcal cell wall antigens, antibodies cross-react with cardiac muscle Myocarditis, arthritis Autoimmune hemolytic anemia Rh blood group, I antigen Destruction of RBCs and anemia Myasthenia gravis α chain of nicotinic acetylcholine receptor Progressive weakness Graves' disease Thyroid-stimulating hormone receptor Thyroid over-activity Goodpasture’s syndrome Collagen type IV of glomerular basement membrane Glomerulonephritis and pulmonary hemorrhage Type III Immune complex disease Systemic lupus erythematosus DNA, ribosomes Glomerulonephritis , vasculitis, arthritis Type IV T cell-mediated disease Insulin-dependent diabetes mellitus Pancreatic β-cell antigen β-cell destruction Rheumatoid arthritis Synovial joint antigen Joint inflammation and destruction


DIAGNOSIS OF AUTOIMMUNE DISEASES Diagnosis of autoimmune diseases is based on symptoms and signs . Detection of antibodies and/or T cells reactive against antigens of tissues and cells involved . Antibodies against cell/tissue associated antigens are detected by immunofluorescence . Antibodies against soluble antigens are normally detected by ELISA or radioimmunoassay . In some cases, a biological /biochemical assay may be used (e.g., Graves diseases, pernicious anemia ).


TREATMENT OF AUTOIMMUNE DISEASES General : immunosuppressive (and anti-inflammatory drugs Metabolic : may be useful in some disorders, such as antithyroid drugs in Grave’s disease. Induction of antigen-specific tolerance , e.g. by vaccines . Vaccines may be effective in a minority of persons at high risk for autoimmunity against a known self antigen (e.g., the siblings of patients with autoimmune diabetes). Immunomodulation (to suppress the activity of autoreactive cells), e.g. by costimulation blockade: e.g. using antibodies to block CD28-dependent T cell costimulation .

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