MHC Molecule and Autoimmunity with Examples and Diagrams
MHC molecules, or major histocompatibility complex molecules, are a group of proteins that play a vital role in the immune system. They are found on the surface of most cells in the body and help the immune system to recognize and respond to foreign invaders, such as bacteria, viruses, parasites, and cancer cells.
MHC molecules are encoded by a set of genes called the human leukocyte antigen (HLA) system, which is located on chromosome 6 of the human genome. The HLA system is one of the most diverse and polymorphic gene regions in humans, meaning that there are many different variants or alleles of each gene. This diversity ensures that each individual has a unique set of MHC molecules that can present a wide range of antigens to the immune system.
MHC molecules can be divided into three classes: class I, class II, and class III. Class I and class II molecules are involved in antigen presentation, while class III molecules are involved in other immune functions, such as inflammation and complement activation.
Class I MHC molecules are expressed on almost all nucleated cells in the body and present antigens derived from intracellular sources, such as viral or bacterial proteins. Class I MHC molecules bind to peptides that are generated by the degradation of these proteins in the cytoplasm and transport them to the cell surface. There, they interact with T cells that have a receptor called CD8. CD8+ T cells are also known as cytotoxic T cells or killer T cells because they can destroy infected or abnormal cells by releasing toxic substances.
Class II MHC molecules are expressed mainly on specialized cells called antigen-presenting cells (APCs), such as dendritic cells, macrophages, and B cells. Class II MHC molecules present antigens derived from extracellular sources, such as bacterial toxins or allergens. Class II MHC molecules bind to peptides that are generated by the degradation of these proteins in specialized compartments called endosomes and lysosomes and transport them to the cell surface. There, they interact with T cells that have a receptor called CD4. CD4+ T cells are also known as helper T cells because they can activate other immune cells by releasing cytokines.
The interaction between MHC molecules and T cell receptors is essential for the activation and differentiation of T cells and the initiation of adaptive immune responses. However, this interaction also has implications for self-tolerance and autoimmunity. Self-tolerance is the ability of the immune system to distinguish between self and non-self antigens and avoid attacking healthy tissues. Autoimmunity is the loss of self-tolerance and the development of immune responses against self-antigens, leading to chronic inflammation and tissue damage.
The development of self-tolerance and autoimmunity is influenced by several factors, including genetic predisposition, environmental triggers, and epigenetic modifications. One of the most important genetic factors is the HLA system itself. Certain HLA alleles or combinations of alleles are associated with an increased or decreased risk of developing various autoimmune disorders, such as type 1 diabetes, rheumatoid arthritis, multiple sclerosis, celiac disease, and psoriasis. The exact mechanisms by which HLA genes influence autoimmunity are not fully understood but may involve altered antigen presentation, T cell selection, or regulation.
In this article, we will explore the functions of MHC molecules in more detail and discuss how they are involved in autoimmunity with examples and diagrams. We will also review some of the current research and challenges in this field.
The discovery of MHC molecules dates back to the early 20th century, when scientists were studying the phenomenon of tissue rejection in organ transplantation. They observed that transplanted tissues from genetically different individuals were rejected by the recipient`s immune system, while those from genetically identical individuals (such as identical twins) were accepted. This suggested that there was some genetic factor that determined the compatibility of tissues between individuals.
In 1937, Peter Gorer, a British immunologist, identified four antigens on the surface of red blood cells that were responsible for blood transfusion reactions. He named them A, B, C and D. He also noticed that these antigens were inherited in a Mendelian fashion and were linked to each other on the same chromosome. He speculated that these antigens might be involved in tissue rejection as well.
In 1948, George Snell, an American geneticist, confirmed Gorer`s hypothesis by showing that mice that differed in the A and B antigens also differed in their ability to accept or reject skin grafts from each other. He named the genetic locus that controlled these antigens as H-2 (for histocompatibility-2), and later showed that it was located on chromosome 17. He also discovered that the H-2 locus was very complex and contained multiple genes that encoded different types of antigens.
In 1958, Jean Dausset, a French immunologist, discovered a similar system of antigens in humans, which he called human leukocyte antigens (HLA). He found that these antigens were present on the surface of white blood cells and were also involved in tissue rejection. He also showed that the HLA genes were located on chromosome 6 and were inherited as a haplotype (a set of genes that are inherited together).
In 1969, Baruj Benacerraf, a Venezuelan-American immunologist, discovered another function of the HLA antigens: they were essential for the activation of T cells, a type of immune cell that recognizes and kills foreign invaders. He showed that T cells could only recognize antigens that were presented by HLA molecules on the surface of antigen-presenting cells (APCs), such as macrophages or dendritic cells. He also found that different HLA molecules could present different types of antigens to different subsets of T cells.
In 1974, Rolf Zinkernagel and Peter Doherty, two Australian immunologists, demonstrated the molecular mechanism of how T cells recognize antigens presented by MHC molecules. They showed that T cells have receptors (TCRs) that bind to both the antigen and the MHC molecule on the APCs. They also showed that T cells can only recognize antigens presented by MHC molecules that match their own (self-MHC), and not those from other individuals (non-self-MHC). This explained why transplanted tissues from non-self-MHC donors were rejected by the recipient`s immune system.
In 1980, Snell, Dausset and Benacerraf were awarded the Nobel Prize in Physiology or Medicine for their discoveries of the MHC molecules and their role in immune recognition and response. Since then, many more genes and molecules have been identified within the MHC complex, which is now known as the major histocompatibility complex (MHC). The MHC is divided into three classes: class I, class II and class III. Class I and II molecules are involved in antigen presentation to T cells, while class III molecules encode other proteins involved in immune regulation. The MHC is also highly polymorphic, meaning that there are many different variants (alleles) of each gene within the population. This diversity ensures that each individual has a unique set of MHC molecules that can present a wide range of antigens to their immune system.
The MHC molecules are not only important for immune defense against foreign pathogens, but also for immune tolerance to self-tissues. The process of thymic selection ensures that only those T cells that can recognize self-MHC molecules without reacting to self-antigens are allowed to mature and circulate in the body. However, sometimes this process fails and some T cells become autoreactive, meaning that they attack self-tissues instead of foreign invaders. This can lead to autoimmune disorders, such as type 1 diabetes, multiple sclerosis or rheumatoid arthritis. The association between certain MHC alleles and autoimmune disorders has been extensively studied and is one of the main topics of this article.
The main function of the MHC molecules is to bind and present peptide fragments of proteins from within or outside the cell to T cells or NK cells, which can then eliminate or neutralize the threat . This process is called antigen presentation and it helps the immune system to recognize and respond to foreign antigens or pathogens .
There are two primary classes of MHC molecules: MHC class I and MHC class II, and they have different roles and characteristics :
|MHC class||Expression||Peptide source||Peptide length||T cell type|
|MHC I||All nucleated cells||Endogenous antigens (from inside the cell)||8-11 amino acids||CD8+ cytotoxic T cells|
|MHC II||Antigen-presenting cells (APCs) such as macrophages, dendritic cells and B cells||Exogenous antigens (from outside the cell)||13-25 amino acids||CD4+ helper T cells|
MHC I molecules are designed to enable the body to recognize infected cells and tumor cells and destroy them with cytotoxic T cells. They bind peptides from endogenous antigens, such as viral proteins or mutated proteins, that are generated in the cytoplasm and degraded by proteasomes. The peptides are then transported to the endoplasmic reticulum, where they bind to MHC I molecules and are delivered to the cell surface. There, they can be recognized by cytotoxic T cells that have specific receptors for both the peptide and the MHC I molecule. If the peptide is foreign or abnormal, the cytotoxic T cell will kill the presenting cell.
MHC II molecules are designed to enable the body to activate helper T cells that can coordinate the immune response against extracellular pathogens such as bacteria or parasites. They bind peptides from exogenous antigens, such as bacterial proteins or toxins, that are taken up by phagocytosis or endocytosis by APCs. The antigens are then degraded in lysosomes, where they bind to MHC II molecules and are delivered to the cell surface. There, they can be recognized by helper T cells that have specific receptors for both the peptide and the MHC II molecule. If the peptide is foreign or abnormal, the helper T cell will secrete cytokines that can stimulate other immune cells, such as B cells, macrophages or cytotoxic T cells.
The expression of MHC molecules is increased by cytokines produced during both innate and adaptive immune responses, such as interferons and tumor necrosis factor . This enhances the antigen presentation and the immune recognition of infected or abnormal cells .
The diversity of MHC molecules is achieved by three mechanisms: (1) an organism`s MHC repertoire is polygenic (via multiple, interacting genes); (2) MHC expression is codominant (from both sets of inherited alleles); (3) MHC gene variants are highly polymorphic (diversely varying from organism to organism within a species) . This ensures that each individual can present a wide range of peptides from different sources and respond to various pathogens .
The diversity of MHC molecules also determines donor compatibility for organ transplant, as well as one`s susceptibility to autoimmune diseases . If the donor and recipient have different MHC molecules, their immune systems may recognize each other`s cells as foreign and reject them . On the other hand, if the individual has certain MHC molecules that can bind self-peptides or mimic foreign peptides, their immune system may attack their own tissues and cause autoimmune disorders .
MHC class I and II molecules are two types of cell surface proteins that bind and present antigens to T cells, initiating an immune response. However, they have several differences in their structure, function and distribution. Here are some of the main differences between them:
|MHC Class I||MHC Class II|
|Present on almost all nucleated cells, including platelets||Mainly found on antigen-presenting cells (APCs) such as B cells, dendritic cells, macrophages and activated T cells|
|Encode by HLA-A, HLA-B and HLA-C genes||Encoded by HLA-D region genes|
|Consist of one membrane-spanning alpha chain and one beta-2 microglobulin chain||Consist of two membrane-spanning chains, alpha and beta|
|Bind peptides of 8-11 amino acids derived from endogenous (cytosolic) proteins||Bind peptides of 12-25 amino acids derived from exogenous (extracellular) proteins|
|Peptide loading takes place in the endoplasmic reticulum with the help of TAP, tapasin, ERp57 and calreticulin||Peptide loading takes place in specialized vesicular compartments with the help of invariant chain and HLA-DM|
|Recognized by CD8 co-receptors on cytotoxic T cells||Recognized by CD4 co-receptors on helper T cells|
|Involved in killing infected or abnormal cells||Involved in activating B cells and other immune cells|
The following diagram illustrates the differences between MHC class I and II molecules:
Thymic selection is a crucial process that occurs in the thymus during the development of T cells. It ensures that only mature and functional T cells are released into the peripheral immune system, while eliminating those that are potentially harmful or useless.
Thymic selection involves two main steps: positive selection and negative selection. Both steps depend on the interaction between the T cell receptor (TCR) and the self-peptide-MHC complex on the surface of thymic epithelial cells (TECs) or dendritic cells (DCs).
Positive selection occurs in the cortex of the thymus, where immature T cells (thymocytes) express both CD4 and CD8 co-receptors (double-positive thymocytes). These thymocytes encounter self-peptide-MHC complexes on cortical TECs. Only those thymocytes that can bind to these complexes with a low to moderate affinity are allowed to survive and proceed to the next stage of development. This ensures that the T cells are able to recognize self-MHC molecules, which are essential for antigen presentation in the periphery. The surviving thymocytes also undergo lineage commitment, where they downregulate either CD4 or CD8 depending on whether they recognize MHC class I or II molecules, respectively. Thus, they become single-positive thymocytes.
Negative selection occurs in the medulla of the thymus, where single-positive thymocytes encounter self-peptide-MHC complexes on medullary TECs or DCs. These complexes represent a wider range of self-antigens than those in the cortex, including some that are expressed only in specific tissues (tissue-restricted antigens). Thymocytes that bind to these complexes with a high affinity are induced to undergo apoptosis (programmed cell death). This eliminates potentially autoreactive T cells that could cause damage to self-tissues in the periphery. Some thymocytes that bind to these complexes with a moderate affinity are spared from apoptosis and instead differentiate into regulatory T cells (Tregs), which play a role in suppressing immune responses and maintaining tolerance.
The outcome of thymic selection is a repertoire of mature and functional T cells that are self-MHC restricted (able to recognize self-MHC molecules) and self-tolerant (not reactive to self-antigens). These T cells exit the thymus and circulate in the blood and lymphatic system, where they can encounter foreign antigens and mount adaptive immune responses.
Autoimmunity is a condition in which the immune system mistakenly attacks the body`s own cells and tissues, causing inflammation and damage. Normally, the immune system can distinguish between self and non-self antigens, which are molecules that trigger an immune response. However, in autoimmune disorders, the immune system fails to recognize some self antigens as harmless and produces antibodies or T cells that target them. This results in a chronic state of inflammation and tissue injury that can affect various organs and systems.
There are many factors that can contribute to the development of autoimmunity, such as genetic predisposition, environmental triggers, infections, hormonal changes, and stress. Some of the common environmental triggers include drugs, chemicals, toxins, dietary components, and microbiota. Some of the common infections that can induce autoimmunity include Epstein-Barr virus, cytomegalovirus, hepatitis C virus, human immunodeficiency virus, and Helicobacter pylori. Some of the common hormonal changes that can influence autoimmunity include pregnancy, menopause, and thyroid disorders.
Autoimmune disorders are classified into two main types: organ-specific and systemic. Organ-specific autoimmune disorders affect only one organ or tissue type, such as type 1 diabetes mellitus (affecting the pancreas), Hashimoto`s thyroiditis (affecting the thyroid), and multiple sclerosis (affecting the central nervous system). Systemic autoimmune disorders affect multiple organs or tissues, such as systemic lupus erythematosus (affecting the skin, joints, kidneys, blood cells, and other organs), rheumatoid arthritis (affecting the joints and other tissues), and Sjögren`s syndrome (affecting the salivary glands, lacrimal glands, and other exocrine glands).
Autoimmune disorders are diagnosed based on clinical symptoms, physical examination, laboratory tests, and imaging studies. Some of the common laboratory tests include autoantibody tests, which detect the presence of specific antibodies against self antigens; complement tests, which measure the level of complement proteins that are involved in inflammation; and inflammatory markers tests, which measure the level of substances that indicate inflammation in the body. Some of the common imaging studies include ultrasound, X-ray, computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET), which can reveal structural or functional abnormalities in affected organs or tissues.
Autoimmune disorders are treated with various medications that aim to suppress or modulate the immune system, reduce inflammation, relieve symptoms, and prevent complications. Some of the common medications include corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), immunosuppressants, biologics, and monoclonal antibodies. In some cases, surgery may be required to remove damaged organs or tissues or to replace them with artificial devices or transplants. In addition to medications and surgery, lifestyle modifications such as diet, exercise, stress management, and avoiding triggers can also help improve the quality of life of people with autoimmune disorders.
Autoimmune disorders are conditions where the immune system attacks the body`s own tissues, causing inflammation and damage. The exact causes of autoimmune disorders are not fully understood, but genetic factors play a key role. Among the most important genetic factors are the major histocompatibility complex (MHC) genes, also known as human leukocyte antigen (HLA) genes in humans .
MHC genes encode molecules that present antigens (peptides derived from foreign or self-proteins) to T cells, which are specialized immune cells that can recognize and eliminate infected or abnormal cells. MHC molecules are divided into two classes: MHC class I and MHC class II. MHC class I molecules present antigens to cytotoxic T cells, which can kill infected or cancerous cells. MHC class II molecules present antigens to helper T cells, which can activate other immune cells and produce inflammatory cytokines .
The MHC genes are highly polymorphic, meaning that there are many different variants (alleles) of each gene in the population. This diversity ensures that the immune system can recognize a wide range of antigens and respond to various pathogens. However, some MHC alleles may also predispose individuals to autoimmune disorders by presenting self-antigens to T cells, leading to a loss of self-tolerance and an attack on healthy tissues .
The association between MHC alleles and autoimmune disorders has been established by various methods, such as genetic linkage studies, genome-wide association studies (GWAS), and functional studies. Table 1 shows some examples of autoimmune disorders and their associated MHC alleles .
|Autoimmune disorder||Associated MHC alleles|
|Type 1 diabetes||HLA-DR3, HLA-DR4|
|Multiple sclerosis||HLA-DR2, HLA-DR4|
|Celiac disease||HLA-DQ2, HLA-DQ8|
|Systemic lupus erythematosus||HLA-DR2, HLA-DR3|
Table 1: Examples of autoimmune disorders and their associated MHC alleles.
The mechanism by which MHC alleles contribute to autoimmune disorders is not fully elucidated, but it may involve several factors, such as:
- The affinity of the MHC molecule for self-antigens, which may affect the threshold of T cell activation and tolerance induction.
- The repertoire of T cell receptors (TCRs) that can bind to the MHC-peptide complex, which may influence the diversity and specificity of the T cell response.
- The expression level and regulation of the MHC molecule on different cell types, which may modulate the availability and presentation of antigens.
- The interaction of the MHC molecule with other molecules, such as co-stimulatory receptors, cytokine receptors, or natural killer (NK) cell receptors, which may affect the activation or inhibition of immune cells.
Understanding the role of MHC alleles in autoimmune disorders may help to identify biomarkers for diagnosis, prognosis, and treatment response. It may also provide insights into the pathogenesis and potential therapies for these conditions .
There are many types of autoimmune disorders that affect different organs and systems in the body. Some of the most common ones are:
- Type 1 diabetes: This is a condition where the immune system destroys the insulin-producing cells in the pancreas, leading to high blood sugar levels and various complications. Symptoms include increased thirst, urination, hunger, weight loss, fatigue, and blurred vision. Treatment involves taking insulin injections or using an insulin pump to regulate blood sugar levels .
- Rheumatoid arthritis: This is a chronic inflammatory disease that affects the joints, causing pain, swelling, stiffness, and reduced mobility. It can also affect other organs such as the skin, eyes, lungs, heart, and blood vessels. The immune system produces antibodies that attack the synovial membrane that lines the joints, causing inflammation and damage. Treatment options include medications that suppress the immune system or reduce inflammation, physical therapy, and surgery .
- Psoriasis: This is a skin condition that causes red, scaly patches to form on various parts of the body, especially the elbows, knees, scalp, and lower back. It can also affect the nails and joints. The immune system triggers an abnormal growth of skin cells that accumulate on the surface of the skin, causing inflammation and itching. Treatment options include topical creams, light therapy, oral or injectable medications that modulate the immune system or reduce inflammation .
- Multiple sclerosis: This is a neurological disease that affects the central nervous system, which consists of the brain and spinal cord. The immune system attacks the protective layer of myelin that covers the nerve fibers, causing inflammation and damage. This disrupts the transmission of nerve impulses between the brain and other parts of the body, leading to symptoms such as vision problems, numbness, tingling, weakness, fatigue, balance issues, and cognitive impairment. Treatment options include medications that modify the immune system or reduce inflammation, physical therapy, and symptom management .
- Celiac disease: This is a digestive disorder that occurs when the immune system reacts to gluten, a protein found in wheat, barley, rye, and some oats. The immune system damages the lining of the small intestine, impairing its ability to absorb nutrients from food. Symptoms include diarrhea, bloating, abdominal pain, weight loss, anemia, osteoporosis, and skin rashes. Treatment involves following a strict gluten-free diet .
These are just some examples of autoimmune disorders. There are many more that affect different parts of the body in different ways. The exact causes of autoimmune disorders are not fully understood, but they may involve genetic factors, environmental triggers, infections, or hormonal changes. There is no cure for autoimmune disorders, but treatments can help manage symptoms and prevent complications.
MHC molecules are essential for the immune system to recognize and eliminate foreign antigens. They are also involved in the development and selection of T cells in the thymus. However, sometimes the immune system fails to distinguish between self and non-self antigens, leading to autoimmune disorders. Autoimmune disorders are characterized by chronic inflammation and tissue damage in various organs. Some of the common examples of autoimmune disorders are multiple sclerosis, rheumatoid arthritis, type 1 diabetes, systemic lupus erythematosus, psoriasis, dermatomyositis, and celiac disease. These disorders have complex etiologies that involve genetic, environmental, and immunological factors. There is no permanent cure for most of these disorders, but treatments can help to reduce symptoms and complications. Further research is needed to understand the mechanisms of autoimmunity and to develop novel therapies that can restore immune tolerance and prevent organ damage.
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