--- title: "Autoimmunity - Definition, Types, Tolerance, Pathogenesis, Mechanisms" description: "Get Free Biology Notes" url: https://biologynotesonline.com/autoimmunity-definition-types-tolerance-pathogenesis-mechanisms/ --- # Autoimmunity – Definition, Types, Tolerance, Pathogenesis, Mechanisms Autoimmunity is an abnormal condition in which the body immune system react against its own healthy cells and tissues. It means the immune system cannot properly identify self-antigen and foreign antigen. So, the body’s own tissues are attacked like they are infectious agents. Normally, the immune system has a protective mechanism called self-tolerance. This tolerance ... [Read more](https://biologynotesonline.com/autoimmunity-definition-types-tolerance-pathogenesis-mechanisms/) ***Autoimmunity is an abnormal condition in which the body immune system react against its own healthy cells and tissues. It means the immune system cannot properly identify self-antigen and foreign antigen. So, the body’s own tissues are attacked like they are infectious agents.*** Normally, the immune system has a protective mechanism called **self-tolerance**. This tolerance prevents immune cells from reacting against the body own antigens. It helps the immune system to attack only foreign materials like microbes, toxins, and other harmful substances. When **self-tolerance** fails, the **adaptive immune cells** become self-reactive. These cells may include **T-lymphocytes** and **B-lymphocytes**. They recognize normal body tissues as foreign and start immune reaction against them. But presence of autoimmunity does not always produce disease. Low amount of **self-reactive T-cells** or **autoantibodies** may present in many individuals. They remain silent because checkpoint control and homeostatic mechanisms keep them under control. The condition becomes **autoimmune disease** when these self-reactive lymphocytes escape the normal control mechanism. Then they produce tissue injury, organ damage and disturbance of normal function. This is referred to as pathological autoimmunity. The causes of autoimmunity are not due to single factor. It is produced by many factors together. Some of the important factors are **genetic predisposition**, **hormonal influence**, and **environmental triggers**. These factors disturb the normal immune regulation and allow the immune system to attack self tissues. ![Different locations of the body that are affected by autoimmune diseases.](https://biologynotesonline.com/wp-content/uploads/2024/04/image-1565.png)Different locations of the body that are affected by autoimmune diseases. ## Types of Immunological Tolerance **Immunological tolerance** is mainly of two types- - **Central tolerance** - **Peripheral tolerance** ### 1. Central tolerance **Central tolerance** is the first type of immunological tolerance. It develops during early maturation of immune cells. It takes place in primary lymphoid organs. **T-cells** develop in the **thymus**. **B-cells** develop in the **bone marrow**. In this tolerance, the strongly self-reactive lymphocytes are removed or changed. So they cannot attack the body own tissues. The following are the mechanisms of **central tolerance**– **Negative selection or clonal deletion** In this process, developing **T-cells** and **B-cells** are checked against self-antigens. If these cells bind strongly with self-antigens, then they are destroyed. This destruction occurs by programmed cell death or **apoptosis**. This is called **negative selection** or **clonal deletion**. **Receptor editing** **Receptor editing** occurs mainly in developing **B-cells**. If a **B-cell** reacts strongly with self-antigen, then its receptor is changed. This occurs by genetic rearrangement. After receptor editing, if the new receptor does not react with self-antigen, then the **B-cell** is saved. If it still reacts with self-antigen, then it is destroyed. **Regulatory T-cell diversion** Some developing **T-cells** in thymus bind with self-antigens with intermediate affinity. These cells are not always destroyed. They are directed to become **Regulatory T-cells (Tregs)**. These **Tregs** suppress immune reaction. They help to control autoreactive immune cells. ### 2. Peripheral tolerance **Peripheral tolerance** is the second type of immunological tolerance. It acts as the backup system. Central tolerance is not complete always. Some self-reactive lymphocytes may escape from thymus and bone marrow. These escaped cells enter into blood, spleen, lymph nodes and other peripheral tissues. Peripheral tolerance controls these cells. The following are the mechanisms of **peripheral tolerance**– **Anergy** **Anergy** is an inactive state of lymphocyte. It occurs when autoreactive **T-cell** recognizes self-antigen but does not get costimulatory signal. For full activation, the cell needs antigen signal and also second danger signal. Without this second signal, the cell becomes functionally inactive. This inactive condition is called **anergy**. **Exhaustion** **Exhaustion** is progressive loss of function of immune cells. It occurs due to chronic and high dose exposure to antigen. The immune cell becomes weak and cannot work properly. This also helps to reduce harmful immune reaction against self-antigens. **Deletion by apoptosis** Some autoreactive lymphocytes are removed in peripheral tissues. They are killed by extrinsic death pathway. One important pathway is **Fas-Fas ligand (FasL) system**. This pathway induces **apoptosis** and removes harmful self-reactive cells. **Active suppression by regulatory cells** Some regulatory cells suppress the immune response. The important cells are **FOXP3+ Regulatory T-cells (Tregs)** and **Regulatory B-cells (Bregs)**. They release anti-inflammatory cytokines. Example **IL-10**, **TGF-β** and **IL-35**. These cytokines reduce inflammation. They also suppress autoreactive effector cells and reduce their survival signals. **Antigen sequestration or clonal ignorance** In **clonal ignorance**, self-reactive lymphocytes are present but they do not cause damage. This occurs because some self-antigens are hidden from immune system. They are present in protected sites. Example, eye and brain. These are protected by **blood-retina barrier** and **blood-brain barrier**. So the systemic immune cells cannot easily reach these antigens. This forms immunologically privileged sites. ![Central and peripheral tolerance to self antigens](https://biologynotesonline.com/wp-content/uploads/2024/04/image-1566.png)Central and peripheral tolerance to self antigens ## Immunological Tolerance and Its Role in Preventing Autoimmunity **Immunological tolerance** is a normal physiological condition of immune system. In this condition immune system does not attack the body own **self-antigens**. It protects the healthy cells and tissues from destructive inflammatory reaction. It is an important protective mechanism. It controls the **autoreactive lymphocytes** before they cause tissue damage. Thus, it has major role in prevention of **autoimmunity**. Immunological tolerance is of two types- - **Central tolerance** - **Peripheral tolerance** ### 1. Central tolerance **Central tolerance** takes place during maturation of lymphocytes. It occurs in primary lymphoid organs. **T-cells** mature in the **thymus** and **B-cells** mature in the **bone marrow**. In this process the lymphocytes which strongly react with self-antigens are removed. So these cells cannot enter the blood and peripheral tissues. **T-cell negative selection** In the **thymus**, immature **T-cells** are tested against different self-antigens. These antigens are presented with **MHC molecules**. If the **T-cell** binds strongly with self-antigen, then the cell is destroyed. This is done by programmed cell death or apoptosis. This process is called **negative selection** or **clonal deletion**. **Role of AIRE** **AIRE (autoimmune regulator)** is a transcription factor. It is present in thymus. It helps the thymus to express many tissue-restricted antigens. These antigens are normally found in specific organs. So the thymus can test developing **T-cells** against many body antigens. By this way, harmful self-reactive **T-cells** are removed before they become mature. **B-cell receptor editing** In the **bone marrow**, immature **B-cells** are exposed to self-antigens. If a **B-cell** reacts strongly with self-antigen, then it may change its receptor. This process is called **receptor editing**. In this process the gene rearrangement occurs and a new receptor is formed. If the new receptor is not self-reactive, the cell survives. If receptor editing fails, the **B-cell** is destroyed by **clonal deletion**. ![Central tolerance in B cells – Immature B cells that recognize self antigens in the bone marrow with high avidity (e.g., multivalent arrays of antigens on cells) die by apoptosis or change the specificity of their antigen receptors (receptor editing). Weak recognition of self antigens in the bone marrow may lead to anergy (functional inactivation) of the B cells.](https://biologynotesonline.com/wp-content/uploads/2024/04/image-1567.png)Central tolerance in B cells – Immature B cells that recognize self antigens in the bone marrow with high avidity (e.g., multivalent arrays of antigens on cells) die by apoptosis or change the specificity of their antigen receptors (receptor editing). Weak recognition of self antigens in the bone marrow may lead to anergy (functional inactivation) of the B cells. ### 2. Peripheral tolerance **Peripheral tolerance** is the second line of protection. It acts outside the primary lymphoid organs. It occurs in blood, spleen, lymph nodes and other peripheral tissues. Central tolerance is not complete always. Some self-reactive lymphocytes may escape from thymus and bone marrow. These escaped cells are controlled by peripheral tolerance. The following are the important mechanisms of peripheral tolerance- **Anergy** **Anergy** is the inactive state of lymphocyte. It occurs when lymphocyte recognizes antigen but does not get proper costimulatory signal. For full activation, lymphocyte needs two signals. One is antigen recognition and other is danger or costimulatory signal. If self-reactive **T-cell** or **B-cell** binds with self-antigen without costimulation, then it becomes inactive. It cannot produce immune response. **Deletion by apoptosis** Some autoreactive cells are removed in peripheral tissues. This occurs by apoptosis. Repeated contact with self-antigen may activate death pathway. One important pathway is **Fas-Fas ligand system**. It causes death of harmful self-reactive immune cells. **Active suppression by regulatory cells** Some special cells suppress the immune response. These are **FOXP3+ Regulatory T-cells (Tregs)** and **Regulatory B-cells (Bregs)**. They produce anti-inflammatory cytokines. Example **IL-10** and **TGF-β**. These cytokines reduce inflammation and suppress autoreactive effector cells. They also consume local survival factors. So the autoreactive cells cannot survive properly. **Clonal ignorance** **Clonal ignorance** means the self-reactive lymphocytes are present but they do not react. It happens because they do not meet their target self-antigens. Some self-antigens are hidden in protected sites. Example brain and retina. These are protected by **blood-brain barrier** and **blood-retina barrier**. So the systemic immune cells cannot easily reach these antigens. ![Peripheral tolerance in B cells – B cells that encounter self antigens in peripheral tissues become anergic or die by apoptosis. In some situations, recognition of self antigens may trigger inhibitory receptors that prevent B cell activation.](https://biologynotesonline.com/wp-content/uploads/2024/04/image-1568.png)Peripheral tolerance in B cells – B cells that encounter self antigens in peripheral tissues become anergic or die by apoptosis. In some situations, recognition of self antigens may trigger inhibitory receptors that prevent B cell activation. ### Role in preventing autoimmunity Immunological tolerance prevents **autoimmunity** by different ways. It removes self-reactive cells. It makes them inactive. It suppresses their function. It also keeps some self-antigens hidden from immune system. It maintains the difference between **self** and **non-self**. So immune system attacks foreign antigens but does not attack own tissues. When tolerance fails, the self-reactive lymphocytes escape control. They multiply and attack the body own tissues. This causes inflammation, tissue injury and organ dysfunction. This condition is called **autoimmunity**. When it produces disease condition, it is called **autoimmune disease**. ## Mechanisms Responsible for Autoimmunity **Autoimmunity** occurs due to failure of normal immune control. In this condition the immune system starts reaction against body own **self-antigens**. It may be due to genetic, environmental, hormonal and immunological factors. The following are the important mechanisms responsible for **autoimmunity**– **1. Genetic susceptibility** **Genetic susceptibility** has important role in development of autoimmunity. Some inherited gene variants disturb immune regulation. The important genes are **HLA complex** and non-HLA genes like **PTPN22**, **NOD2** and **CTLA4**. These genes affect antigen presentation, lymphocyte activation and tolerance checkpoint. So self-reactive immune cells may escape from normal control. **2. Breakdown of immunological tolerance** **Breakdown of immunological tolerance** is the main mechanism of autoimmunity. Normally **central tolerance** removes self-reactive lymphocytes in **thymus** and **bone marrow**. **Peripheral tolerance** controls escaped self-reactive cells by **anergy**, **apoptosis** and regulatory cells. When these mechanisms fail, **autoreactive T-cells** and **B-cells** survive. They become active and attack own tissues. **3. Molecular mimicry** **Molecular mimicry** occurs when foreign pathogen antigen look similar to body self-antigen. During infection, immune system makes response against the pathogen. But due to similarity, the same immune cells or antibodies react with host tissue also. Thus, the immune response against pathogen becomes cross-reactive. It produces tissue damage and autoimmune reaction. **4. Epitope spreading** **Epitope spreading** is the spreading of immune response from one epitope to other epitopes. At first immune reaction is against one specific epitope. But due to chronic inflammation and tissue injury, more self-antigens are released. Then immune system starts reacting against new epitopes. These may be present in same protein or in other associated proteins. **5. Bystander activation** **Bystander activation** occurs in highly inflammatory condition. Persistent infection or tissue damage produces many inflammatory cytokines. These cytokines activate nearby immune cells in non-specific way. By this way, already present self-reactive **T-cells** or **B-cells** may become active without proper specific antigen recognition. **6. Release of cryptic epitopes** **Cryptic epitopes** are hidden self-peptides. They are normally not exposed to immune system. During chronic inflammation or abnormal antigen processing, these hidden epitopes become exposed. Since they were not seen during immune cell development, immune system may treat them as foreign. This leads to activation of self-reactive lymphocytes and autoimmunity. **7. Superantigens** **Superantigens** are certain bacterial or viral proteins. They bypass normal antigen presentation. They activate large number of **T-cells** or **B-cells** in non-specific manner. This causes massive polyclonal activation. Some dormant autoreactive clones may also become active and produce autoimmune response. **8. Failure of antigen sequestration** Some self-antigens are normally hidden in immunologically protected sites. These sites include **eye**, **brain** and **testes**. They are separated from systemic immune system by physical barriers. Due to trauma or infection, these barriers may break. Then hidden antigens are released into circulation. The immune system identifies them as foreign and starts autoimmune reaction. Example is **sympathetic ophthalmia**. **9. Environmental triggers** Some environmental factors can change self-proteins and make them immunogenic. **Smoking** can increase citrullination of proteins in lungs. In genetically susceptible persons, this may help in development of **rheumatoid arthritis**. **UV radiation** causes cell death and exposes nuclear antigens. This is linked with **systemic lupus erythematosus (SLE)**. **10. Neuroendocrine and hormonal influences** Hormones also influence autoimmunity. Sex hormones like **estrogen** and **prolactin** may increase immune activity. Chronic stress can disturb **hypothalamic-pituitary-adrenal (HPA) axis**. This changes cytokine balance and lowers inflammatory threshold. So the immune system may shift towards self-directed aggressive response. **11. Impaired clearance of apoptotic cells** Normally apoptotic cells are removed by phagocytes. If this clearance is defective, dead cell debris accumulates. These materials may undergo secondary necrosis and release intracellular antigens. These intracellular components act as danger signals. They stimulate autoantibody production and autoimmune inflammation. ## Genetic Factors in Autoimmunity The following are the genetic factors in **autoimmunity**– - **HLA complex**– **Human Leukocyte Antigen (HLA)** complex is the most important genetic factor. Mainly **HLA class II genes** are involved. These genes control presentation of self-peptides to **T-cells**. If presentation becomes abnormal, **autoreactive T-cells** may be activated. **HLA-DRB1 shared epitope** is seen in **rheumatoid arthritis**. **HLA-DR3/DR4** is seen in **Type 1 diabetes**. **HLA-DR2/DR3** is seen in **cutaneous lupus erythematosus**. - **PTPN22**– **PTPN22** is a non-HLA gene. It acts as negative regulator of **T-cell receptor** and **B-cell receptor** signaling. Mutation in this gene disturb normal immune control. The important variant is **R620W (1858C>T)**. It increases risk of **rheumatoid arthritis**, **systemic lupus erythematosus (SLE)** and **Type 1 diabetes**. - **CTLA-4**– **CTLA-4** is an immune checkpoint gene. It normally stops excess **T-cell activation**. It helps in **peripheral tolerance**. When polymorphism occurs in this gene, the control over T-cell is reduced. So self-reactive T-cells may remain active. It is related with **Type 1 diabetes** and **autoimmune thyroid disease**. - **FOXO-3**– **FOXO-3** is a transcription factor. It is involved in immune regulation, apoptosis and oxidative stress response. Polymorphism in this gene can change immune tolerance. It may increase susceptibility to **autoimmune thyroid disease**. - **NOD2**– **NOD2** gene has role in mucosal immunity. It helps to maintain mucosal **Regulatory T-cells (Tregs)**. Mutation in **NOD2** causes defective **NF-κB** activation. It also causes early death of protective **Tregs**. So intestinal immune control becomes weak. It is involved in bowel lesions of **Crohn’s disease**. - **Interferon genes**– Some genes control nucleic acid sensing and **interferon** response. These include **TREX1**, **IRF5**, **ITGAM** and **TYK2**. Mutation in these genes disturb removal of cytosolic DNA. Interferon response also become abnormal. This may lead to lupus type autoimmunity like **cutaneous lupus erythematosus**. - **Epistasis**– **Epistasis** means one gene affect the function of another gene. In autoimmune disease, many genes act together. So disease risk becomes more high. Example, high risk **HLA** alleles with **INS**, **CTLA4** and **PTPN22** variants increase risk of childhood **Type 1 diabetes**. - **Epigenetic change**– **Epigenetic change** means change in gene expression without changing DNA sequence. It includes abnormal **DNA hypomethylation** and altered **microRNA** expression. These changes disturb normal immune function. So tolerance may break and **autoimmunity** can develop. ## Environmental Factors Triggering Autoimmunity The following are the environmental factors triggering **autoimmunity**– - **Infection**– **Viruses** and **bacteria** are important environmental triggers of **autoimmune diseases**. Pathogens may activate immune system by **molecular mimicry**, **bystander activation** and **epitope spreading**. In this condition immune response against microbes may also attack the body own healthy tissues. - **UV radiation**– **Ultraviolet radiation**, mainly **UVB**, causes apoptosis of skin cells. During this process hidden nuclear **autoantigens** are released outside the cell. These antigens act as danger signal and increase pro-inflammatory cytokines and **interferons**. It is related with **cutaneous lupus erythematosus** and **systemic lupus erythematosus (SLE)**. - **Smoking and pollutants**– **Cigarette smoking** increases autoimmune risk, mainly in genetically susceptible person. In **rheumatoid arthritis**, smoking increases **citrullination** of proteins in lung tissues and these changed proteins become immunogenic. In **lupus**, smoking is related with severe skin lesions and poor response to treatment. Environmental pollutants also produce chronic inflammation and disturb immune tolerance. - **Physical trauma**– Physical injury or surgical trauma can break the barrier of protected body sites. Antigens from **eye**, **brain** and other privileged sites may enter into lymph nodes and blood. Immune system may treat these antigens as foreign. Example, penetrating injury of eye may cause **sympathetic ophthalmia**, where autoimmune attack occurs in both eyes. - **Stress**– Psychological and emotional stress can trigger autoimmunity in susceptible person. Chronic stress affects **hypothalamic-pituitary-adrenal (HPA) axis** and autonomic nervous system. It causes hormonal imbalance and lowers inflammatory threshold. Then immune system may produce aggressive cytokine response. - **Drugs**– Some medicines may induce autoimmune reaction. Example, certain **diuretics**, **anti-TNF agents** and blood pressure medicines. These drugs may bind with self-proteins and form new antigens, called **hapten formation**. They may also cause cell toxicity, disturb tolerance checkpoint and alter gene expression by epigenetic changes. - **Diet and microbiome**– Diet, nutrients and gut microbes are important in immune tolerance. **Vitamin D** helps in normal immune regulation. Healthy gut bacteria produce **short-chain fatty acids**, which promote protective **Regulatory T-cells (Tregs)**. But altered diet response or disturbed gut microbiome may produce inflammatory condition and trigger bowel or systemic autoimmune disorders. ## Autoantigens and Autoantibodies **Autoantigens**– **Autoantigens** are normal body **self molecules**. Present in healthy cells and tissues. But immune system wrongly take it as foreign antigen. It may be **protein**, **nucleic acid** or complex cellular structure. Reaction against it produce autoimmune damage. **Autoantibodies**– **Autoantibodies** are antibodies formed against body own antigen. These are formed by **autoreactive B-cells** and plasma cells. It binds with **autoantigens**. Then immune reaction starts against own tissue. **Damage by autoantibodies** - **Type II reaction**– Autoantibody binds with antigen on cell surface or extracellular matrix. Then complement activation occurs. Phagocytosis also occurs. The cell is damaged or destroyed. In some cases antibody binds with receptor. It may stimulate receptor or block receptor work. - **Type III reaction**– Autoantibody binds with soluble autoantigen. It forms **immune complex**. The complex circulate in blood. It deposit in blood vessel, joint and kidney. After deposition local inflammation occurs. Tissue damage is produced. **Systemic examples** - **Rheumatoid arthritis**– In **rheumatoid arthritis (RA)**, main autoantigens are **citrullinated proteins**. Example **fibrin** and **enolase**. These are targeted by **anti-cyclic citrullinated peptide antibody (ACPA)**. **Rheumatoid factor (RF)** is also present. It reacts with **IgG Fc region**. - **SLE**– In **systemic lupus erythematosus (SLE)**, main autoantigens are nuclear materials. These are **double stranded DNA (dsDNA)**, **histones**, **Smith (Sm) antigen** and **La/Ro ribonucleoproteins**. These are targeted by **antinuclear antibody (ANA)** and **anti-dsDNA antibody**. **Organ specific examples** - **Skin**– In blistering disease, autoantigens are cell adhesion proteins and basement membrane proteins. **Desmoglein 1** and **Desmoglein 3** are targeted in **pemphigus vulgaris** and **pemphigus foliaceus**. **BP180** and **BP230** are targeted in **bullous pemphigoid**. **Collagen VII** is targeted in **epidermolysis bullosa acquisita**. - **Thyroid**– In **Hashimoto’s thyroiditis**, **thyroid peroxidase (TPO)** and **thyroglobulin** are targeted. Thyroid cells are damaged. So hypothyroidism occurs. In **Graves’ disease**, **TSH receptor** is targeted. The receptor is stimulated. So hyperthyroidism occurs. - **Gastrointestinal tract**– In **autoimmune gastritis**, **H+, K+-ATPase** or proton pump is targeted. It affects parietal cells of stomach. In **celiac disease** and **dermatitis herpetiformis**, **transglutaminases (TG2, TG3)** are targeted by **IgA autoantibodies**. - **Nervous system and muscle**– In **multiple sclerosis**, **myelin basic protein (MBP)** and **myelin oligodendrocyte glycoprotein (MOG)** are autoantigens. In **myasthenia gravis**, **acetylcholine receptor** is targeted. Neuromuscular transmission is blocked. Muscle weakness occurs. ## Cytokines and Immune Mediators in Autoimmunity The following are the important cytokines and immune mediators in **autoimmunity**– **Cytokines** are chemical messengers of immune system. In autoimmune disease their normal balance is disturbed. Inflammatory signals become more and regulatory signals become less. So chronic inflammation and tissue destruction occurs. - **Interferons**– **Interferons (IFNs)** are strong immune activating cytokines. **IFN-α**, **IFN-β** and **IFN-λ** produce antiviral type inflammatory response. This type of response is common in **lupus**. **IFN-γ** is produced by **Th1 cells**. It activates macrophages and brings cytotoxic lymphocytes to the damaged tissue. - **TNF-α**– **Tumor Necrosis Factor-alpha (TNF-α)** is a powerful inflammatory cytokine. It increases immune reaction and tissue injury. Its high level is seen in many autoimmune diseases. So **anti-TNF** therapy is used to block its effect. - **IL-1 and IL-6**– **IL-1** and **IL-6** are pro-inflammatory interleukins. They support survival and increase of **T-cells** and **B-cells**. They lower the inflammatory threshold. They also help in autoantibody formation and long immune activation. - **IL-17**– **IL-17** is produced by **Th17 cells**. It mainly recruits neutrophils. These neutrophils enter the tissue and produce strong sterile inflammation. It is important in many autoimmune and hypersensitivity reactions. - **IL-21**– **IL-21** helps **B-cells** to come at inflammatory site. It also supports local autoantibody production. Due to this autoimmune reaction is continued in the tissue. - **Regulatory cytokines**– **IL-10**, **TGF-β** and **IL-35** are suppressor cytokines. These are produced by **Regulatory T-cells (Tregs)** and **Regulatory B-cells (Bregs)**. They reduce autoreactive effector cells. They maintain **immunological tolerance**. - **CXCL8**– **CXCL8** is also called **IL-8**. It attracts neutrophils to affected tissue. It also activates them. Then neutrophils release inflammatory enzymes and local tissue damage occurs. - **CXCL9, CXCL10 and CXCL11**– These are chemokines produced by stressed cells. In **lupus**, keratinocytes of skin may release them. They attract **T-cells**, macrophages and **plasmacytoid dendritic cells (pDCs)**. Thus inflammatory cycle is maintained. - **BAFF**– **B-cell Activating Factor (BAFF)** helps in maturation and survival of **B-cells**. In autoimmune disease, it allows autoreactive **B-cells** to survive. These cells then produce harmful autoantibodies. - **Granzymes and perforin**– **Granzyme B** and **perforin** are cytotoxic mediators. They are released by **CD8+ T-cells**, **Natural Killer cells** and some dendritic cells. They induce apoptosis of healthy body cells. So tissue damage is produced. - **Histamine and leukotrienes**– **Histamine** and **leukotrienes** are vasoactive mediators. They are released mainly from mast cells. They increase vascular permeability and tissue edema. Thus they help in local inflammatory environment. ## Classification of Autoimmune Disorders The classification of **autoimmune disorders** are as follows- ### Anatomical classification - **Organ specific**– In this type, immune system attack one organ or one tissue only. The autoantigens are mostly tissue restricted. Examples are **Type 1 diabetes** where **pancreatic beta cells** are damaged. **Graves’ disease** and **Hashimoto’s thyroiditis** affect **thyroid gland**. **Autoimmune gastritis** affect stomach. **Vitiligo** affect skin. - **Systemic**– In this type, immune reaction is not limited to one organ. Autoantigens are present in many cells of body. So many tissues and organs are damaged. Examples are **Systemic lupus erythematosus (SLE)**, **Rheumatoid arthritis**, **Sjögren’s syndrome** and **Dermatomyositis**. ### Pathophysiological classification - **Type IIa cytotoxic**– In this type, **IgG** or **IgM antibodies** bind with cell surface antigen or extracellular matrix antigen. Then complement activation occurs. Phagocytosis and cytotoxicity also occur. Examples are **Autoimmune hemolytic anemia** and **Goodpasture’s disease**. - **Type IIb cell stimulating**– In this type, autoantibodies act on cell receptor. It may stimulate the receptor or block the receptor. In **Graves’ disease**, receptor stimulation occurs. In **Myasthenia gravis**, receptor blocking occurs. - **Type III immune complex**– In this type, soluble antigen and antibody combine and form **immune complexes**. These complexes circulate in blood and deposit in kidney, skin or joints. Then complement activation and neutrophil damage occurs. Examples are **SLE glomerulonephritis** and **Rheumatoid arthritis synovitis**. - **Type IV cell mediated**– In this type, damage is caused by **T-cells**. It is delayed type reaction. **Th1 type** reaction is seen in **Type 1 diabetes**. **Th2 type** reaction may occur in some autoimmune reactions. **CD8+ cytotoxic T-cell** reaction is seen in **viral induced myocarditis**. **T-cell and neutrophil type** reaction also occur in some lesions. ### McGonagle spectrum classification - **Pure autoinflammatory**– In this group, disease is mainly due to abnormal activation of **innate immune system**. There is no clear autoreactive T-cell response or high titre autoantibody. Many are monogenic disease. Examples are **Familial Mediterranean fever (FMF)** and **TNF receptor-associated periodic syndrome (TRAPS)**. - **Classical autoimmune**– In this group, there is breakdown of **adaptive immune self-tolerance**. **HLA class II** association is strong. Autoreactive **B-cells** and **T-cells** increase. High titre autoantibodies are present. Examples are **SLE**, **Graves’ disease** and **Type 1 diabetes**. - **Mixed intermediate**– In this group, both autoinflammatory and autoimmune features are present. Innate immune trigger and adaptive immune response act together. These are mostly polygenic conditions. Examples are **Rheumatoid arthritis**, **Crohn’s disease**, **Psoriasis** and **Ankylosing spondylitis**. ## Pathogenesis of Autoimmune Diseases The pathogenesis of **autoimmune diseases** are as follows- ### Genetic Factors - **HLA variants**– **Human Leukocyte Antigen (HLA)** genes are the strongest genetic factors. These genes control presentation of self-peptides to **T-cells**. If self-peptide presentation become abnormal, then autoreactive immune response may start. - **Non-HLA genes**– Some non-HLA genes also take part in autoimmunity. These include **PTPN22**, **CTLA4** and **NOD2**. Mutation in these genes disturb immune regulation. So central and peripheral tolerance may not work properly. - **Epigenetic change**– **Epigenetic change** means change in gene expression without change in DNA sequence. It includes abnormal **DNA methylation** and altered **microRNA** expression. These changes disturb normal immune function and help in autoimmunity. ### Immunological Mechanisms - **Molecular mimicry**– In this process, foreign pathogen antigen become similar with body own antigen. Immune system first reacts against pathogen. But due to similarity it also attack self tissue. Thus autoimmune reaction is started. - **Epitope spreading**– In this process, immune response first start against one epitope. Later due to chronic inflammation, more self-antigens are released. Then immune response spread to other epitopes of same molecule or associated protein. - **Bystander activation**– Infection or tissue damage produce high inflammatory condition. Many cytokines are released at that site. These cytokines activate silent self-reactive immune cells without specific antigen recognition. - **Cryptic epitopes**– **Cryptic epitopes** are hidden self-peptides. Normally these are not exposed to immune system. During chronic inflammation protein processing may change. Then hidden epitopes become exposed and immune system take them as foreign. - **Antigen sequestration failure**– Some antigens are normally hidden in protected sites like **eye** and **brain**. Trauma or infection may break these barriers. Then hidden antigen enter blood and lymph node. Immune system reacts against it. Example is **sympathetic ophthalmia**. ### Environmental Triggers - **Microbial infection**– **Viruses** and **bacteria** are important triggers of autoimmunity. They may start disease by **molecular mimicry**, **bystander activation** and **epitope spreading**. So infection act as first stimulus in many autoimmune diseases. - **UV radiation**– **Ultraviolet radiation** causes apoptosis of skin cells. If dead cells are not cleared properly, cellular debris accumulate. Nuclear autoantigens are exposed. This is important in pathogenesis of **lupus**. - **Smoking**– **Cigarette smoking** increases oxidative stress. It also increases **citrullination** of proteins in lungs. These changed proteins become immunogenic. It increases risk of **rheumatoid arthritis** in genetically susceptible person. - **Drugs**– Some drugs can produce drug induced autoimmunity. They may bind with self-proteins and form new antigens. This is called **hapten formation**. Some drugs also cause cell toxicity or disturb immune tolerance. ### Hormonal and Neuroendocrine Factors - **Sex hormones**– Autoimmune diseases are more common in females. **Estrogen** can change signaling pathway of activated **T-cells**. It lowers inflammatory threshold and helps in disease onset. - **Chronic stress**– Chronic stress activates **hypothalamic-pituitary-adrenal (HPA) axis** and autonomic nervous system. It causes hormonal imbalance. Then immune system produce more self-directed cytokines. Peripheral tolerance may break and autoimmunity develops. ## Diagnosis of Autoimmune Disorders The diagnosis of **autoimmune disorders** are done by different laboratory tests. These tests are used to find inflammation, **autoantibodies** and genetic susceptibility. **1. Initial tests**– **Complete blood count (CBC)** and **comprehensive metabolic panel (CMP)** are done first. These tests give general idea about blood cells, liver function, kidney function and other basic body condition. It is used as first laboratory work-up. **2. Inflammatory markers**– **ESR**, **CRP** and **ferritin** are tested to detect inflammation. These are acute phase reactants. Their level may increase during active autoimmune disease. Sometimes **ceruloplasmin**, **fibrinogen**, **haptoglobin** and **albumin** are also checked. **3. Autoantibody test**– **ELISA** is commonly used to detect circulating **autoantibodies**. In **rheumatoid arthritis**, **Rheumatoid factor (RF)** and **anti-CCP** are tested. In **systemic lupus erythematosus (SLE)**, **ANA** and **anti-dsDNA** are tested. **ANCA** is tested in diseases like **Wegener granulomatosis** and **microscopic polyangiitis**. **4. Immunofluorescence**– **Direct immunofluorescence (DIF)** and **indirect immunofluorescence (IIF)** are used to detect antibodies and complement. **DIF** shows deposits present directly in tissue like skin and mucous membrane. **IIF** shows circulating antibodies present in blood. It is useful in autoimmune blistering disease and cutaneous lupus. **5. Flow cytometry**– **Flow cytometry** is used to count and study immune cell population. It identifies cells by cell surface markers. It helps to know which immune cells are increased, decreased or abnormal. **6. Genetic typing**– **Genetic test** and **HLA typing** are used because many autoimmune diseases have genetic link. **PCR** and **gel electrophoresis** may be used for this. **HLA-B27** is associated with **ankylosing spondylitis**. **HLA-DRB1** is associated with **rheumatoid arthritis**. ## Prevention and Management of Autoimmunity The following are the prevention and management of **autoimmunity**– ### Prevention strategies - **Smoking cessation**– Smoking should be stopped. It can reduce risk of some autoimmune diseases like **rheumatoid arthritis**. It is more important in genetically susceptible person. - **UV protection**– Excess **UV light** exposure should be avoided. Proper photoprotection is used. It helps to prevent onset and flare of **cutaneous lupus erythematosus** and **systemic lupus erythematosus (SLE)**. - **Stress management**– Chronic stress should be controlled. Stress activates neuroendocrine pathway. It lowers inflammatory threshold. So stress control may help to prevent immune imbalance and reactivation of disease. - **Diet and nutrition**– Balanced diet is important. Disease specific trigger should be avoided. Example, **gluten** is avoided in **celiac disease**. **Vitamin D** and probiotics may help in immune tolerance and metabolic control. - **Trauma care**– Proper care of tissue injury and surgery is needed. It prevents release of hidden antigens. Penetrating eye injury should be managed quickly to prevent **sympathetic ophthalmia**. ### Standard medical management - **Corticosteroids**– **Corticosteroids** are used to suppress acute immune response. Example **prednisone** and **prednisolone**. These may be given systemic or topical. It quickly reduces inflammation. - **Immunosuppressive drugs**– These drugs are used for long term control and to reduce steroid side effects. Examples are **methotrexate**, **azathioprine**, **mycophenolate mofetil**, **cyclosporine** and **cyclophosphamide**. - **Biologic therapy**– **Biologic drugs** target selected immune pathway. They do not suppress whole immune system like general drugs. Examples are **TNF-α inhibitors** such as **infliximab**, **adalimumab**, **etanercept**. **Rituximab** removes B-cells. **Belimumab** blocks **BAFF**. - **Plasmapheresis and IVIG**– **Plasmapheresis** is used to remove harmful autoantibodies from blood. **Intravenous immunoglobulin (IVIG)** is used in severe cases as supportive immune treatment. These are used when disease is serious or not controlled. - **Side effect control**– Long term treatment needs monitoring. Immunosuppressive drugs may cause infection and other problems. **Calcium** and **Vitamin D** are used for osteoporosis prevention. Blood sugar should be checked. Infection surveillance is also needed. ### Advanced and emerging therapies - **Small molecule inhibitors**– These are newer oral drugs. They block inflammatory signals inside the cell. Examples are **JAK/STAT pathway inhibitors** and **SYK inhibitors**. **Deucravacitinib** is one such drug. - **Antigen specific therapy**– This therapy tries to control only harmful autoimmune response. **Decoy peptides** may neutralize harmful autoantibodies. Therapeutic peptide vaccines may restore immune tolerance without full immune suppression. - **Adoptive cell transfer**– In this method, patient own regulatory immune cells are taken. They are increased in laboratory and given back to the body. **Tregs** or engineered **CAR-Tregs** may suppress autoimmune attack. - **Stem cell and gene therapy**– **Autologous hematopoietic stem cell transplantation (HSCT)** is used to reset the defective immune system. Gene therapy is also studied to correct genetic defects which disturb immune regulation. ## Clinical Significance of Autoimmunity The following are the clinical significance of **autoimmunity**– - **High burden**– **Autoimmune diseases** affect large number of people worldwide. Its prevalence is increasing day by day. So it is an important health problem. - **Silent autoimmunity**– Presence of **self-reactive lymphocytes** or **autoantibodies** does not always mean disease. Many time it remain clinically silent. Disease occur only when these cells escape normal control and produce tissue damage. - **Organ damage**– Uncontrolled autoimmune reaction causes chronic inflammation. It damages tissues and reduce normal function of organ. Example, **rheumatoid arthritis (RA)** causes cartilage and bone damage. **Systemic lupus erythematosus (SLE)** may damage kidney. **Sympathetic ophthalmia** may cause permanent blindness. - **Female predominance**– Autoimmune diseases are more common in women. It shows the role of sex hormones in immune response. **Estrogen** and other hormonal factors may increase immune activity and disease tendency. - **Wide involvement**– Autoimmunity may affect single organ or many organs. In organ specific disease, one organ is mainly affected, such as pancreas in **Type 1 diabetes** and thyroid in **Graves’ disease**. In systemic disease, many organs are affected, such as **SLE** and **RA**. - **Diagnostic difficulty**– Diagnosis of autoimmune disease is not always easy. Symptoms may be different in different patients. So clinical features, inflammatory markers like **CRP** and **ESR**, and autoantibody tests like **ANA**, **RF** and **anti-CCP** are used together. - **Disease progression**– One autoimmune disease may increase risk of another autoimmune disease. In chronic disease, immune response may spread to new antigens. This is called **epitope spreading**. Due to this disease may become progressive and difficult to control. - **Treatment problem**– There is no fixed cure for most autoimmune diseases. Treatment is often long term. **Corticosteroids**, **immunosuppressive drugs** and **biologic agents** are used to control inflammation. But these drugs may cause infection risk, bone loss and organ toxicity. ## Examples of Autoimmune Disorders The following are the examples of **autoimmune disorders**– - **Rheumatoid arthritis (RA)**– It is a systemic autoimmune disease. It mainly affects joints. Chronic inflammation causes pain, swelling and joint damage. - **Systemic lupus erythematosus (SLE)**– It is a systemic autoimmune disease. It may affect skin, kidney, joints, blood and nervous system. **ANA** and **anti-dsDNA antibodies** are commonly present. - **Type 1 diabetes mellitus**– It is an organ specific autoimmune disease. Immune system damages the **pancreatic beta cells**. So insulin production becomes low. - **Sjögren’s syndrome**– It affects mainly salivary and lacrimal glands. Dry mouth and dry eyes are common features. - **Multiple sclerosis (MS)**– It affects central nervous system. Immune reaction damages **myelin sheath**. So nerve conduction becomes disturbed. - **Celiac disease**– It is gluten induced autoimmune disease. It affects small intestine. **Transglutaminase** is the main autoantigen. - **Graves’ disease**– It affects thyroid gland. Autoantibodies stimulate **TSH receptor**. So hyperthyroidism occurs. - **Hashimoto’s thyroiditis**– It is autoimmune thyroid disease. **TPO** and **thyroglobulin** are targeted. Thyroid damage causes hypothyroidism. - **Crohn’s disease**– It is chronic inflammatory bowel disease. It can affect any part of gastrointestinal tract. Immune dysregulation and intestinal inflammation occurs. - **Scleroderma**– It is autoimmune connective tissue disease. Skin thickening and fibrosis are common. Internal organs may also be affected. - **Psoriasis and psoriatic arthritis**– **Psoriasis** affects skin. **Psoriatic arthritis** affects joints. Both are related with abnormal immune activation. - **Ankylosing spondylitis**– It mainly affects spine and sacroiliac joint. It is associated with **HLA-B27**. - **Myasthenia gravis**– It affects neuromuscular junction. Autoantibodies block **acetylcholine receptor**. Muscle weakness occurs. - **Guillain-Barré syndrome**– It affects peripheral nerves. It may occur after infection. Weakness and paralysis may develop. - **Autoimmune hemolytic anemia**– Autoantibodies attack red blood cells. It causes hemolysis and anemia. - **Goodpasture syndrome**– Autoantibodies attack basement membrane of lung and kidney. It causes lung bleeding and kidney damage. - **Pemphigus vulgaris and pemphigus foliaceus**– These are autoimmune blistering diseases. **Desmogleins** are targeted. Skin and mucous membrane blisters occur. - **Bullous pemphigoid**– It is blistering disease of skin. **BP180** and **BP230** are targeted. Tense blisters are formed. - **Dermatitis herpetiformis**– It is related with gluten sensitivity. **Transglutaminase** is targeted. It causes itchy skin lesions. - **Autoimmune hepatitis**– Immune system attacks liver cells. Chronic liver inflammation and liver damage occurs. - **Autoimmune adrenalitis**– It is also called **Addison’s disease**. Immune system damages adrenal cortex. Cortisol and aldosterone production becomes low. - **Giant cell arteritis**– It is autoimmune inflammation of large and medium arteries. Temporal artery is commonly involved. - **Rheumatic fever**– It occurs after **streptococcal infection**. Due to molecular mimicry, immune reaction may damage heart, joints and other tissues. - **Primary biliary cirrhosis**– It is autoimmune disease of bile ducts. Small intrahepatic bile ducts are damaged. Cholestasis and liver injury occur. - **Immune thrombocytopenic purpura**– Autoantibodies attack platelets. Platelet count decreases. Bleeding tendency occurs. - **Sympathetic ophthalmia**– It may occur after injury of one eye. Retinal antigens are exposed. Autoimmune attack may affect both eyes. - **Autoimmune uveitis**– It is autoimmune inflammat ![Pathogenesis of acute rheumatic fever](https://biologynotesonline.com/wp-content/uploads/2024/04/image-1569.png)Pathogenesis of acute rheumatic fever ![Pathogenesis of Multiple Sclerosis](https://biologynotesonline.com/wp-content/uploads/2024/04/image-1571.png)Pathogenesis of Multiple Sclerosis ![Pathogenesis of Rheumatoid Arthritis](https://biologynotesonline.com/wp-content/uploads/2024/04/image-1572.png)Pathogenesis of Rheumatoid Arthritis ![Pathogenesis of Rheumatoid Arthritis II (with Callout)](https://biologynotesonline.com/wp-content/uploads/2024/04/image-1573.png)Pathogenesis of Rheumatoid Arthritis II (with Callout) ![Immune Response in Type I Diabetes](https://biologynotesonline.com/wp-content/uploads/2024/04/image-1574.png)Immune Response in Type I Diabetes ![Symptoms of Systemic Lupus Erythematosus (SLE)](https://biologynotesonline.com/wp-content/uploads/2024/04/image-1575.png)Symptoms of Systemic Lupus Erythematosus (SLE) ![The IL-23_IL-17 Axis in Psoriasis](https://biologynotesonline.com/wp-content/uploads/2024/04/image-1576.png)The IL-23_IL-17 Axis in Psoriasis ![Immune Response in IBD](https://biologynotesonline.com/wp-content/uploads/2024/04/image-1577.png)Immune Response in IBD ## References - *A Proposed Classification of the Immunological Diseases – PMC*. 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