Immunological Tolerance – Definition, Mechanism, Types

Immunological tolerance is a state of specific unresponsiveness of the immune system against a particular antigen. In this condition, the immune system does not produce destructive reaction against that antigen. It is a normal protective mechanism of the body.

It helps the immune system to distinguish between self and non-self substances. The immune system can attack foreign pathogens but it does not attack the normal healthy cells and tissues of the body. This condition is referred to as self-tolerance.

Immunological tolerance is important for preventing autoimmune diseases. In autoimmune disease, the immune system reacts against own body cells. So tolerance maintains the balance between immune defence and protection of body tissues.

It is different from general immunosuppression. In immunosuppression, many immune responses are reduced. But in tolerance, only those immune cells which react with the tolerated antigen are inactivated or ignored. Other immune cells remain active and can fight against foreign antigens.

The protective state is mainly maintained by two pathways. These are central tolerance and peripheral tolerance. Central tolerance takes place in primary lymphoid organs such as thymus and bone marrow. In this process, self-reactive T lymphocytes and B lymphocytes are removed or changed during their development.

Peripheral tolerance takes place outside the primary lymphoid organs. It controls the self-reactive lymphocytes which escape from central tolerance and enter into the body. These cells are suppressed, inactivated or prevented from producing harmful immune response.

Immunological tolerance is also important in other normal conditions. It prevents allergic reactions against harmless substances like food and gut microbes. It also helps during pregnancy, where the mother’s immune system does not reject the genetically different developing fetus.

Definition of Immunological Tolerance

Immunological tolerance is the specific unresponsiveness of immune system to a particular antigen. In this condition immune system does not attack own body cells and harmless antigens. It helps to prevent autoimmune diseases.

Tolerance vs Immune Response

• Core objective
  Immune response – It is a state of action. It recognizes and destroys foreign harmful agents.
  Immunological tolerance – It is a state of specific inaction. It ignores self-antigens and harmless antigens.
• Antigen involved
  Immune response – It occurs against foreign antigens. These are present on bacteria, virus and other pathogens.
  Immunological tolerance – It occurs against self-antigens and harmless antigens. These include body tissues, food antigens and fetal antigens.
• Triggering signal
  Immune response – It needs antigen recognition with co-stimulatory signal. Example is CD28 binding with CD80/86.
  Immunological tolerance – It occurs when co-stimulatory signal is absent. CTLA-4 and PD-1 may inhibit the lymphocyte.
• Cellular outcome
  Immune response – Lymphocytes become activated. They undergo clonal expansion and form effector T cells and plasma cells.
  Immunological tolerance – Lymphocytes are deleted, made anergic or changed into regulatory T cells (Tregs).
• Final effect
  Immune response – It produces attack against antigen. It removes pathogen from body.
  Immunological tolerance – It produces no attack against tolerated antigen. It prevents damage of self-tissues.
• Failure result
  Immune response – Failure causes infection and immunodeficiency. Excess response causes tissue damage.
  Immunological tolerance – Failure causes autoimmune diseases, allergy and rejection of fetus during pregnancy.

Importance of Immunological Tolerance

• Prevents autoimmune diseases
  Immunological tolerance is important because it maintains self-tolerance in the body. In this condition immune system does not attack own healthy cells and tissues. Thus it prevents autoimmune diseases and inflammatory diseases.
• Limits tissue damage during infection
  During infection immune system is activated against pathogens. But sometimes excess activation of lymphocytes may injure normal body tissues. Immunological tolerance controls this reaction and helps to reduce tissue damage.
• Prevents reaction against harmless substances
  Some harmless substances like food particles, environmental allergens and normal gut bacteria enter or remain in the body. The immune system should not attack these substances. Tolerance suppresses such destructive immune response and prevents unnecessary allergy and inflammation.
• Protects fetus during pregnancy
  The fetus is genetically different from the mother because it contains paternal antigens also. So mother immune system may recognize it as foreign. Maternal-fetal tolerance prevents rejection of fetus and helps in continuation of pregnancy.
• Important in transplantation
  In organ and tissue transplantation, the graft contains foreign antigens. Immune system may attack and reject the graft. Induction of immune tolerance helps to prevent graft rejection and increase survival of transplanted organ.
• Useful in treatment of immune diseases
  Immunological tolerance is used as an important idea in treatment of allergy and autoimmune diseases. It helps to reduce immune reaction against specific antigen. In this way whole immune system is not suppressed.

Types of Immunological Tolerance

1. Central tolerance
   Central tolerance is a type of tolerance which occurs in the primary lymphoid organs. It occurs in thymus for T lymphocytes and bone marrow for B lymphocytes. In this process, the immature lymphocytes which react strongly with self-antigens are removed or altered.
2. Peripheral tolerance
   Peripheral tolerance is the tolerance which occurs in peripheral tissues and secondary lymphoid organs. It occurs in spleen, lymph nodes and other tissues. The self-reactive cells which escape from central tolerance are made inactive, deleted or suppressed by regulatory T cells.
3. Maternal-fetal tolerance
   Maternal-fetal tolerance is a special type of tolerance seen during pregnancy. The fetus contains antigens of father also, so it is different from mother. This tolerance prevents the mother immune system from rejecting the fetus.
4. Acquired or induced tolerance
   Acquired tolerance is a type of tolerance which is produced after exposure to a particular antigen. It may be produced experimentally or for treatment purpose. It is important in transplantation, allergy and autoimmune diseases.
5. Dominant tolerance
   Dominant tolerance is the type of T cell tolerance in which harmful immune reaction is actively suppressed. In this condition some cells become regulatory T cells (Tregs). These cells suppress the response of self-reactive lymphocytes.
6. Recessive tolerance
   Recessive tolerance is the type of tolerance where self-reactive cells are directly deleted. This is also called negative selection. It mainly removes those lymphocytes which strongly bind with self-antigen.
7. T-cell tolerance
   T-cell tolerance is the tolerance shown by T lymphocytes. It may occur in thymus or outside thymus. It prevents the activation of those T cells which can attack own body cells.
8. B-cell tolerance
   B-cell tolerance is the tolerance shown by B lymphocytes. It mainly occurs in bone marrow. The self-reactive B cells are removed, inactivated or their receptor is changed by receptor editing.

Mechanism of Central Tolerance

A. Mechanism of T-cell central tolerance

1. Negative selection or clonal deletion
   Negative selection occurs in the thymus. In this process, developing T lymphocytes which bind strongly with self-antigens are removed. These cells are destroyed by apoptosis.
2. Clonal deviation or Treg formation
   Some self-reactive T lymphocytes are not destroyed. They are changed into regulatory T cells (Tregs). These Tregs later suppress harmful immune response against self-antigens.
3. Expression of tissue-restricted antigens
   Special cells of thymus show many self-antigens from different tissues of body. This is controlled by transcription factors like AIRE and FEZF2. Thus developing T cells are checked against organ specific antigens before they leave the thymus.

B. Mechanism of B-cell central tolerance

1. Receptor editing
   Receptor editing occurs in the bone marrow. It is the main mechanism of B-cell central tolerance. The self-reactive B cell rearranges its receptor genes again and forms a new receptor which does not bind with self-antigen.
2. Clonal deletion
   If receptor editing is not successful, the self-reactive B lymphocyte is removed. The cell is destroyed by apoptosis. This prevents harmful B cells from entering into blood circulation.
3. Clonal anergy
   Some B cells bind weakly with small soluble self-antigens. These cells are not destroyed. They become inactive and unresponsive. This condition is called clonal anergy.

Mechanism of Peripheral Tolerance

1. Clonal anergy
   Clonal anergy is a mechanism in which self-reactive T cell or B cell become inactive. It occurs when the cell recognizes self-antigen but second signal is absent. So the cell does not give immune response. This condition is called anergy.
2. Inhibitory receptor action
   Some inhibitory receptors control activation of lymphocytes. CTLA-4 and PD-1 are important receptors in this mechanism. They inhibit the activation of self-reactive cells. Thus the cell remains unresponsive.
3. Clonal deletion
   Clonal deletion is the destruction of self-reactive lymphocytes. It occurs when the cell is repeatedly stimulated by self-antigen. The cell is then killed by apoptosis. This prevents harmful immune reaction.
4. Fas and FasL pathway
   The Fas-FasL pathway is a death pathway. Fas present on the lymphocyte bind with FasL. After this binding, apoptosis is started. As a result the autoreactive cell is removed.
5. Suppression by regulatory T cells
   Regulatory T cells (Tregs) suppress self-reactive immune cells. These cells are present in peripheral tissues. They control the activity of effector lymphocytes. So autoimmune response does not develop.
6. Suppression by cytokines
   Tregs produce some anti-inflammatory cytokines. The important cytokines are IL-10 and TGF-β. These cytokines suppress immune response. They help to maintain peripheral tolerance.
7. Clonal ignorance
   Clonal ignorance is a condition where self-reactive lymphocytes do not react with self-antigen. The antigen may be present in very low amount. It may also bind weakly with the receptor. So the immune cell ignore it.
8. Immune privileged sites
   Some self-antigens are present in protected body sites. These are called immune privileged sites. Example is inside of eye. In these places immune cells cannot easily attack the antigen.

Cells Involved in Immunological Tolerance

A. T lymphocytes

1. Regulatory T cells (Tregs)
   Regulatory T cells (Tregs) are important cells of peripheral tolerance. These cells suppress the self-reactive T cells. They prevent activation and multiplication of harmful effector T cells.
2. Tr1 cells and Th3 cells
   Tr1 cells and Th3 cells are regulatory CD4+ T cells. They produce inhibitory cytokines like IL-10 and TGF-β. These cytokines suppress the immune response.
3. Regulatory γδ T cells
   Regulatory γδ T cells are another suppressive type of T cells. They reduce the harmful immune reaction. They also help in maintaining tolerance.
4. Conventional CD4+ and CD8+ T cells
   CD4+ T cells and CD8+ T cells are normal effector T cells. These cells are controlled by deletion or anergy. So they do not attack the self-tissues.

B. B lymphocytes

1. Immature B cells
   Immature B cells are checked in the bone marrow. The self-reactive B cells are deleted, made anergic or their receptor is edited. This is important for B-cell tolerance.
2. Regulatory B cells (Bregs)
   Regulatory B cells (Bregs) are special B cells. These cells suppress immune response. They help to maintain immunological tolerance.

C. Antigen presenting cells

1. Dendritic cells (DCs)
   Dendritic cells are antigen presenting cells. They present antigen to T cells. Some tolerogenic dendritic cells form Tregs and induce peripheral tolerance.
2. Macrophages
   Macrophages are phagocytic cells. They remove dead apoptotic cells without inflammation. M2 macrophages and decidual macrophages produce anti-inflammatory cytokines.

D. Thymic epithelial cells

1. Medullary thymic epithelial cells (mTECs)
   Medullary thymic epithelial cells (mTECs) are present in the thymus. They show tissue-restricted self-antigens to developing T cells. This occurs with the help of AIRE and FEZF2.

E. Cells of maternal-fetal interface

1. Trophoblast cells
   Trophoblast cells are fetal cells present at maternal-fetal region. They suppress maternal T cell response. They express HLA-G and use IDO to inhibit T cells.
2. Decidual natural killer cells
   Decidual NK cells are present in pregnant uterus. They are less cytotoxic than normal NK cells. They help in placental development and protect the fetus.
3. Decidual stromal cells
   Decidual stromal cells give local signals and cytokines. They help to change maternal T cells into Tregs. Thus they maintain pregnancy tolerance.

F. Other immunosuppressive cells

1. Myeloid-derived suppressor cells (MDSCs)
   Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells. They strongly inhibit T cell response. They act as suppressor cells.
2. Regulatory innate lymphoid cells (ILCs)
   Regulatory innate lymphoid cells are innate immune cells. They control inflammation. They also help in tolerance.
3. Immunosuppressive plasmocytes (ISPCs)
   Immunosuppressive plasmocytes are plasma cells with suppressive role. These cells suppress immune response. They are found in some tolerogenic condition.

Cytokines in Immunological Tolerance

• Interleukin-10 (IL-10) – IL-10 is a strong anti-inflammatory cytokine. It is secreted by regulatory T cells (Tregs) and some macrophages. It decreases MHC and co-stimulatory molecules like CD80/CD86 on antigen presenting cells. So inflammatory T cells are not activated.
• Transforming Growth Factor-beta (TGF-β) – TGF-β is secreted by Tregs and decidual macrophages. It converts normal T cells into regulatory T cells. It also maintains suppressive nature of Tregs. It suppresses the multiplication of effector T cells.
• Interleukin-35 (IL-35) – IL-35 is an inhibitory cytokine. It is produced by Tregs. It suppresses inflammatory Th1 and Th17 cells. It also helps in formation and increase of more Tregs.
• Interleukin-2 (IL-2) – IL-2 is needed for survival of Tregs. Tregs have high affinity IL-2 receptor (CD25). They take up IL-2 from the surrounding. So autoreactive effector T cells get less survival signal.
• Interleukin-13 (IL-13) – IL-13 is also involved in regulatory condition. It helps to reduce inflammation. It may help to restore immune tolerance during some tolerogenic response.
• CCL2 – CCL2 is a regulatory chemokine. It is increased in some tolerance producing therapies. It helps to control inflammation and supports immune tolerance.

Immune Checkpoints in Tolerance

• CTLA-4 – CTLA-4 is an inhibitory checkpoint of T cells. It works mainly in secondary lymphoid organs. It binds with CD80/CD86 (B7) on antigen presenting cells. This binding prevents CD28 from getting co-stimulatory signal. So the T cell does not become fully active and becomes anergic.
• CTLA-4 in Tregs – CTLA-4 is present on regulatory T cells (Tregs). These cells use CTLA-4 for suppressing other T cells. Tregs remove B7 molecules from antigen presenting cells. So other T cells cannot get activation signal.
• PD-1 – PD-1 is another inhibitory receptor of T cells. It acts mainly in peripheral tissues. It controls the already activated effector T cells. It binds with PD-L1 and PD-L2 and then reduces the immune response.
• PD-1 signaling – After binding with its ligand, PD-1 brings inhibitory molecules like SHP-2. These molecules stop early TCR signaling. So the T cell cannot survive, divide and release cytokines properly. It also helps in maintaining induced Tregs.
• LAG-3 – LAG-3 is a co-inhibitory receptor. It binds with MHC class II on antigen presenting cells. It is used by Tregs to inhibit dendritic cells. As a result T cell priming is reduced.
• TIGIT – TIGIT is an inhibitory molecule found more on Tregs. It suppresses inflammatory Th1 and Th17 cells. So harmful immune response is controlled.
• TIM-3 – TIM-3 is an inhibitory receptor. It is present on some special Tregs. These Tregs have strong suppressive function. They help in maintaining immune tolerance.

Factors Affecting Immunological Tolerance

1. Antigen affinity and avidity
   Antigen affinity and avidity affect the development of tolerance. When lymphocyte receptor bind strongly with self-antigen, the cell may be deleted or receptor may be edited. When binding is weak, the cell may become anergic or it may ignore the antigen.
2. Antigen valence and form
   The form of antigen also affects tolerance. Multivalent self-antigens present on cell surface usually cause receptor editing or clonal deletion in B cells. Small soluble self-antigens usually make the cell inactive. This condition is called anergy.
3. Antigen dose
   The dose of antigen is an important factor. Very low or very high amount of antigen may produce tolerance. But some amount of antigen may stimulate immune response. So the concentration of antigen decide whether tolerance or immune response will occur.
4. Co-stimulatory signals
   Activation of T cell needs antigen recognition and second signal. The second signal is called co-stimulatory signal. Example is binding of CD28 with B7. If this signal is absent, the T cell becomes inactive and anergic.
5. Inhibitory receptors
   Some receptors inhibit the activation of lymphocytes. CTLA-4 and PD-1 are important inhibitory receptors. When these receptors act, the self-reactive lymphocyte does not become active. Thus tolerance is maintained.
6. Age
   Age also affects immunological tolerance. In old age, the thymus becomes reduced in structure and function. So central tolerance and negative selection may become weak. The body may increase regulatory T cells to control this condition.
7. Sex and hormones
   Sex hormones affect the mechanism of tolerance. In males, androgen receptor activity increases AIRE expression in the thymus. This helps in showing more tissue-restricted self-antigens. Females have higher risk of autoimmunity due to hormonal and tolerance differences.
8. Developmental timing
   Tolerance is easily produced during fetal and neonatal life. At this stage immune system is not fully mature. If foreign antigen enters during this time, the body may accept it as self. This produces long lasting acquired tolerance.
9. Anatomical location
   Some self-antigens are present in protected body sites. These sites are called immune privileged sites. Example is inside of the eye. Immune cells do not normally meet these antigens, so they are ignored by immune system.
10. Nature of antigen exposure
    The time and way of antigen exposure also affects tolerance. Continuous exposure to self-antigen may make lymphocytes inactive or deleted. Sudden exposure with inflammation may produce immune response. So the condition of antigen presentation is important.

Reasons for Breakdown or Failure of Immunological Tolerance

1. Imperfect central selection
   Central tolerance is not fully complete process. Some self-reactive T cells and B cells may escape from thymus and bone marrow. These cells enter into blood and later may produce autoimmune reaction.
2. Genetic mutations
   Mutation in some regulatory genes can break tolerance. Mutation in AIRE gene prevents proper showing of tissue-specific antigens in thymus. Mutation in CTLA-4 gene removes the inhibitory control on T-cell activation.
3. Defect in cell death pathway
   Some self-reactive cells are normally removed by apoptosis. If Fas or FasL genes are defective, these cells are not destroyed properly. So harmful lymphocytes survive and attack the body tissues.
4. Aging or thymic involution
   In old age, the thymus becomes smaller and less active. The expression of self-antigens also become reduced. So negative selection of developing T cells becomes weak and autoreactive cells may escape.
5. Molecular mimicry
   Molecular mimicry occurs when antigen of bacteria or virus is similar to self-antigen of body. The immune system reacts against pathogen antigen. But the same antibody or lymphocyte may also attack own tissues due to similarity.
6. B-cell hypermutation
   During immune response, B cells change their receptor by hypermutation. This process helps to improve binding with pathogen. But sometimes a harmless B cell may become self-reactive after mutation.
7. Low avidity escape
   Some T cells bind weakly with self-antigen during thymic testing. Because binding is weak, they are not deleted. Later in peripheral tissues, these cells may recognize self-antigen and produce harmful reaction.
8. Antigen modification
   Some self-antigens may be changed in structure after formation. This is called post-translational modification. Modified self-antigen may be recognized as foreign and immune response may start against it.
9. Late expression of self-antigens
   Some self-antigens are not expressed during early development. So they are not shown in thymus when T cells are educated. Later when these antigens appear, immune system may not tolerate them.
10. Disruption of maternal-fetal tolerance
    During pregnancy, tolerance is needed between mother and fetus. If regulatory T cells are reduced or abnormal antibodies are present, this tolerance may break. It may cause pregnancy problems like miscarriage and pre-eclampsia.
11. Release of sequestered antigens
    Some self-antigens are hidden in immune privileged sites like inside of the eye. Normally immune cells do not contact them. If trauma releases these antigens into blood, immune system may attack them and tolerance is broken.

Results of Breakdown or Failure of Immunological Tolerance

• Autoimmune diseases
  Breakdown of immunological tolerance mainly results in autoimmune diseases. In this condition immune system attack own body tissues. Examples are rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes and multiple sclerosis.
• Allergic reactions
  Failure of peripheral tolerance may produce allergic reaction. The immune system reacts against harmless environmental antigens. It may cause asthma, food allergy and other allergic diseases.
• Pregnancy complications
  Breakdown of maternal-fetal tolerance affects pregnancy. Mother immune system may treat the fetus as foreign body. It may result in unexplained infertility, repeated miscarriage, pre-eclampsia and Rh disease.
• Tissue and organ damage
  Self-reactive T cells, B cells and autoantibodies attack normal tissues. This produces inflammation and injury in the organs. It may destroy thyroid function or may cause adrenal insufficiency.
• Severe genetic autoimmune syndromes
  Major defect in central or peripheral tolerance causes severe autoimmune syndromes. Examples are Autoimmune Polyendocrine Syndrome type 1 (APS-1) and Immunodysregulation Polyendocrinopathy Enteropathy X-linked (IPEX) syndrome. These diseases affect many organs.
• Chronic inflammatory diseases
  Loss of immune regulation causes continuous activation of lymphocytes. This produces long term inflammation in the body. It may contribute to diseases like inflammatory bowel disease.
• Formation of autoantibodies
  When tolerance fails, B cells may produce antibodies against self-antigens. These antibodies are called autoantibodies. They bind with own cells and tissues and start harmful immune reaction.
• Loss of normal immune balance
  Immunological tolerance maintains balance between defence and self-protection. When it fails, this balance is lost. The immune system becomes harmful to the same body which it normally protects.

Biological and Clinical Significance of Immunological Tolerance

• Prevention of autoimmune diseases
  Immunological tolerance maintains self-tolerance in the body. The immune system recognize own antigens and does not attack them. Thus it prevents harmful autoimmune response against healthy tissues.
• Limiting tissue damage
  During infection immune system becomes active against pathogens. But excess activation of lymphocytes can damage normal tissues also. Immunological tolerance controls this reaction and reduces collateral tissue injury.
• Tolerance to harmless substances
  Food particles, environmental allergens and commensal bacteria are harmless substances. The immune system should not attack them. Tolerance prevents unnecessary immune response against these antigens.
• Protection of fetus
  During pregnancy fetus is genetically different from mother. So mother immune system may recognize it as foreign. Maternal-fetal tolerance prevents rejection of fetus and helps in continuation of pregnancy.
• Prevention of graft rejection
  In transplantation, the graft contain foreign antigens. Immune system may attack the transplanted organ or tissue. Induced immune tolerance helps to prevent graft rejection.
• Treatment of autoimmune diseases
  Restoration of antigen-specific tolerance is useful in autoimmune diseases. It may help in diseases like multiple sclerosis, rheumatoid arthritis and type 1 diabetes. In this treatment harmful immune response is reduced against specific self-antigen.
• Treatment of allergic diseases
  Tolerance is clinically important in allergy. It can suppress immune reaction against food allergens and environmental allergens. Thus it is useful in treatment of food allergy and other allergic disorders.
• Use in advanced therapies
  Immune tolerance is important in stem cell transplantation and gene therapy. It prevents unwanted immune reaction against introduced cells or genetic products. So it supports better survival of these therapies.
• Development of new tolerogenic therapy
  New therapies are developed to retrain immune system. These include tolerogenic nanoparticle vaccines and engineered CAR-Tregs. These methods try to restore specific immune tolerance without suppressing whole immunity.

Disorders Related to Defective Tolerance

A. Autoimmune diseases

1. Rheumatoid arthritis (RA) – Rheumatoid arthritis is an autoimmune disease of joints. Immune cells attack the joint tissue. The joint becomes inflamed. Pain and destruction of joint occurs slowly.
2. Systemic lupus erythematosus (SLE) – SLE is a systemic autoimmune disease. Here autoantibodies are formed. These antibodies attack own body antigens and many organs such as skin, kidney, joints and blood may be involved.
3. Multiple sclerosis (MS) – Multiple sclerosis is autoimmune disease of central nervous system. The immune response is directed against nerve covering. So conduction of nerve impulse becomes disturbed. Weakness and nervous symptoms are produced.
4. Type 1 diabetes mellitus – Type 1 diabetes occurs due to immune destruction of pancreatic beta cells. These beta cells secrete insulin. When they are destroyed, insulin becomes deficient.
5. Autoimmune thyroid diseases – Autoimmune thyroid diseases include Graves’ disease and Hashimoto’s thyroiditis. The thyroid gland is attacked by immune system. So thyroid function may increase or decrease.
6. Myasthenia gravis (MG) – Myasthenia gravis is a disease of neuromuscular junction. Antibodies bind with muscle receptors. As a result, nerve signal cannot act properly on muscle. Muscle weakness occurs.
7. Celiac disease – Celiac disease is related with immune reaction against gluten. Gluten acts as the triggering antigen. The main damage is seen in small intestine.
8. Other autoimmune diseases – Primary biliary cholangitis, Crohn’s disease, systemic sclerosis and autoimmune gastritis are also related with defective tolerance. In these diseases self tissues are not tolerated. They are attacked by immune system.

B. Severe genetic autoimmune syndromes

1. Autoimmune polyendocrinopathy syndrome type 1 (APS-1 / APECED) – APS-1 occurs due to mutation in AIRE gene. In this condition self-antigens are not shown properly in thymus. So central tolerance becomes defective and many endocrine organs are affected.
2. CTLA-4 haploinsufficiency with autoimmune infiltration (CHAI disease) – CHAI disease occurs due to mutation in CTLA-4 gene. The inhibitory brake of T cells becomes weak. Effector T cells become highly active. These cells infiltrate different organs.
3. Autoimmune lymphoproliferative syndrome (ALPS) – ALPS occurs due to mutation in Fas or FasL genes. The self-reactive T cells are not removed by apoptosis. So these cells survive. Lymph node enlargement and autoantibody formation is seen.
4. IPEX syndrome – IPEX syndrome occurs due to mutation in FOXP3 gene. Regulatory T cells (Tregs) are defective. So immune suppression is not done properly and severe autoimmune disease develops.

C. Pregnancy and reproductive complications

1. Recurrent spontaneous abortion – It occurs due to failure of maternal-fetal tolerance. The fetus is not tolerated properly by mother immune system. Fetal tissues may be attacked. Repeated miscarriage occurs.
2. Unexplained infertility – In some cases local tolerance becomes defective. The embryo is not accepted properly in uterus. Implantation is affected and infertility may occur.
3. Pre-eclampsia – Pre-eclampsia is associated with abnormal immune reaction against placenta. Maternal immune regulation is disturbed. So pregnancy complication is produced.
4. Rh disease – Rh disease is also called hemolytic disease of newborn. Maternal antibodies attack fetal RBCs. This occurs due to reaction against fetal blood antigen.
5. Placental abruption – Placental abruption may occur when maternal-fetal immune balance is disturbed. The placenta separates from uterus before normal time. It is a serious pregnancy condition.
6. Endometriosis – Endometriosis is related with immune dysfunction. Endometrial tissue grows outside uterus. Improper immune regulation helps the tissue to survive there.

D. Allergic and hypersensitivity disorders

1. Asthma – Asthma occurs due to failure of tolerance against inhaled allergens. The airway gives unwanted immune reaction. Inflammation occurs and breathing becomes difficult.
2. Food allergy – Food allergy occurs when tolerance to food antigen fails. Harmless food protein is recognized as harmful. Allergic reaction is produced.
3. Atopic diseases – Atopic diseases are related with abnormal Th2 and IgE mediated response. Harmless environmental allergens are attacked. Allergy and hypersensitivity occurs.

Danger theory model

Danger theory model is a model of immunological tolerance. It was proposed by Polly Matzinger in 1994. This model was given as an alternative idea to the old self and non-self theory.

According to this theory, immune system does not only see whether antigen is self or foreign. It mainly responds to danger. When the body cells are injured, stressed or necrotic, they release danger signals. These signals are called DAMPs or damage-associated molecular patterns.

These danger signals act like alarm for the immune system. They activate antigen presenting cells (APCs). After activation, these cells present antigen and start immune response against the harmful condition.

If there is no tissue damage, immune response is not produced. During normal apoptosis, cells die in a controlled way and danger signals are not released. So the immune system remains tolerant.

This theory explains why healthy self-tissues are not attacked. It also explains why harmless non-self antigens like food and environmental particles are ignored. They do not produce cell damage, so no danger signal is formed.

Danger Theory vs Self-Marker Theory

• Main basis – Self-marker theory is based on self and non-self recognition. Danger theory is based on danger signal or tissue damage.
• Triggering factor – In self-marker theory, foreign antigen is the main trigger. In danger theory, damaged, stressed or necrotic cell is the main trigger.
• Immune activation – In self-marker theory, immune system becomes active when antigen is not recognized as self. In danger theory, immune system becomes active when DAMPs are released from injured cells.
• Tolerance formation – In self-marker theory, tolerance is formed by learning self-antigens during early development. In danger theory, tolerance is present when no danger signal is produced.
• View about foreign antigen – In self-marker theory, foreign antigen is usually treated as harmful. In danger theory, foreign antigen is not always harmful, if it does not cause tissue injury.
• View about self-antigen – In self-marker theory, self-antigen is normally tolerated. In danger theory, self-antigen may be attacked if it is present with danger signal.
• Role of apoptosis – In self-marker theory, apoptosis is mainly related with deletion of self-reactive cells. In danger theory, normal apoptosis does not produce danger signal, so tolerance is maintained.
• Role of APCs – In self-marker theory, APCs present antigen mainly for self or non-self recognition. In danger theory, APCs are activated by danger signals and then immune response starts.
• Proposed by – Self-marker theory was mainly proposed by Frank Macfarlane Burnet and Frank Fenner. Danger theory was proposed by Polly Matzinger in 1994.
• Simple difference – Self-marker theory says immune system attacks according to identity of antigen. Danger theory says immune system attacks according to damage produced in tissue.

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