Chapter 3: Nature of Antigens and the Major Histocompatibility Complex PDF

# Chapter 3: Nature of Antigens and the Major Histocompatibility Complex ## Relationship of Antigens to the Host - **Autoantigens** are antigens that belong to the host and do not evoke an immune response under normal circumstances. - **Alloantigens** are from other members of the host’s species a...

# Chapter 3: Nature of Antigens and the Major Histocompatibility Complex ## Relationship of Antigens to the Host - **Autoantigens** are antigens that belong to the host and do not evoke an immune response under normal circumstances. - **Alloantigens** are from other members of the host’s species and are capable of eliciting an immune response. They are relevant in tissue transplantation and blood transfusions. - **Heteroantigens** are from other species such as animals, plants, or microorganisms. - **Heterophile antigens** are heteroantigens that exist in unrelated plants or animals but are either identical or closely related in structure. Antibodies against one antigen will cross-react with the other. An example is human blood Group A and B antigens, which are related to bacterial polysaccharides. ## Major Histocompatibility Complex - For years, scientists searched for immune response genes that could explain the differences in how individuals respond to antigens. - Immune response is linked to a group of molecules originally referred to as human leukocyte antigens (HLAs). - These molecules were first defined by a study discovering a response to circulating white blood cells (WBCs) - They are now known as MHC molecules because they determine whether transplanted tissue is histocompatible and accepted by the recipient or is recognized as foreign and rejected. - MHC molecules are found on all nucleated cells in the body and play a significant role in humoral and cell-mediated immunity. - While initially identified by their antigenicity in organ transplantation, their main immune function is to serve as carriers of peptide antigens for recognition by T cells. ## Connections - **The Florida Panther**: Polymorphism of MHC genes in a species is thought to serve as a protection against infectious diseases. - **Genetic Diversity**: The Florida Panther is a good example for what happens when there is a lack of genetic diversity. In the early 1990s, only about 20 to 25 adult panthers remained in Florida due to habitat destruction and inbreeding, making them vulnerable to viral diseases. Conservationists successfully introduced eight females from the Texas population to Florida. By 2012, the Florida panther population had increased to at least 100 individuals, exhibiting improved health and fitness. ## Genes Coding for MHC Molecules (HLA Antigens) - MHC molecules are encoded by the most polymorphic gene system found in humans. - This high degree of polymorphism is thought to improve our chances of survival as a species because it allows for immune response to diverse pathogens. - MHC genes are found on the short arm of chromosome 6 and are divided into three categories or classes: - **Class I genes**: A, B, and C - **Class II genes**: DR, DQ, and DP - **Class III genes**: C4a, C4b, C2, and B, and cytokines such as tumor necrosis factor (TNF) ### Class I MHC molecules - They are expressed on all nucleated cells. - Each class I antigen is a glycoprotein dimer made up of two noncovalently linked polypeptide chains. - **a chain**: Mol. wt. 44,000 Da, folded into three domains - a1, a2, and a3 - **ß2-microglobulin**: Mol. wt 12,000 Da. Encoded by a single gene on chromosome 15. Not polymorphic - The a chain is inserted into the cell membrane via a hydrophobic transmembrane segment. - The three external domains consist of about 90 amino acids each. - The transmembrane domain has about 25 hydrophobic amino acids, along with a short stretch of about 5 hydrophilic amino acids, as well as an anchor of 30 amino acids. - The a1 and a2 domains of the molecule contain an alpha helix, forming the walls of a deep groove that functions as the peptide-binding site. - HLA-E, -F, and -G are considered nonclassical class I MHC molecules. - These are not expressed on the surfaces of cells and do usually not present peptide antigen to cytotoxic T cells. - HLA-G is primarily expressed on fetal trophoblast cells during the first trimester of pregnancy. - HLA-G molecules are thought to contribute to maternal immune tolerance of the fetus by protecting placental tissue from the action of NK cells, preventing an NK-cell-driven cytotoxic response. ### Class II MHC molecules - They are found on APCs, including: B lymphocytes, monocytes, macrophages, dendritic cells, and thymic epithelial cells. - They consist of two noncovalently bound polypeptide chains: a and ß. - **a chain**: Mol. wt. 34,000 Da. - **ß chain**: Mol. wt. 29,000 Da. - The a1 and B1 domains each contribute an alpha helix, forming the peptide-binding site, which is analogous to the groove found on class I molecules. - The a2 domains and the B2 domains are evolutionarily conserved. - **Nonclassical Class II MHC Genes**: HLA-DM, -DN, and -DO, playing a regulatory role in antigen processing. ## Role of Class I and II Molecules in the Immune Response - **Class I MHC**: Present antigen fragments derived from degraded proteins to CD8+ T lymphocytes. - **Class II MHC**: Present peptide fragments derived from exogenous proteins to CD4+ T lymphocytes. ## The Class I MHC–Peptide Presentation Pathway - Referred to as the endogenous pathway of antigen presentation. - The class I MHC presentation pathway begins with the proteasome, a macromolecular structure containing dozens of enzymatic subunits arranged cylindrically to form a proteolytic tunnel. It degrades proteins and generates peptide chains which are released into the cytosol. - Class I MHC molecules are synthesized by ribosomes associated with the rough endoplasmic reticulum. - TAP1 and TAP2 are important transporters for shuttling antigenic peptides into the lumen of the endoplasmic reticulum. - The TAP-driven translocation is dependent on adenosine triphosphate (ATP) and more efficient for peptides of 8 to 16 amino acids in length. - The MHC peptide complex is rapidly transported to the cell surface. ## The Class II MHC–Peptide Presentation Pathway - Referred to as the exogenous pathway of antigen presentation. - This pathway begins with phagocytosis or endocytosis, allowing cells to ingest materials by enclosing them in a small portion of the plasma membrane. - Proteins are digested by hydrolytic enzymes. - CLIP is removed from the peptide-binding cleft, allowing the binding groove to open to a more extended peptide. - The complex is then transported to the cell surface. ## Clinical Significance of MHC - MHC molecules are expressed in tissues throughout the body and are crucial for the immune response. - **MHC testing**: To ensure a successful tissue transplantation, to prevent graft rejection, and to identify MHC types of donor and recipient. - **HLA types**: Certain HLA types can predispose individuals to autoimmunity. ## Table: Association of HLA Alleles and Disease | **Disease** | **Symptoms** | **HLA Allele** | **Strength of Association** | |:---|:---|:---|:---| | Ankylosing Spondylitis | Inflammation of the vertebrae of the spine | B27 | +++ | | Celiac Disease | Diarrhea, weight loss, intolerance to gluten | DQ2 | +++ | | | | DQ8 | ++ | | Rheumatoid Arthritis | Inflammation of multiple joints | DR4 | + | | Type 1 Diabetes | Increase in blood glucose because of destruction of insulin-producing cells | DQ8 | ++ | | | | DQ2 | + | ## Summary - Immunogens are substances that are capable of stimulating an adaptive immune response, either in the form of antibody production by B cells or the activation of T cells. - Antigens are substances recognized by the adaptive immune system, but they may not necessarily elicit an adaptive response by itself (as in the case of haptens). - Most immunogens are high-molecular-weight proteins or polysaccharides that are foreign to the host. - Immunogenicity, or ability to induce an immune response, can be influenced by factors such as age, health, route of inoculation, and genetic capacity. - Immunogens are fairly large molecules, but the response of each B and T cell is directed against a small portion of the entire molecule, or epitope. - B cells recognize epitopes found on the exterior of a protein, those regions that antibodies can reach. - T cells only recognize linear epitopes bound to MHC molecules. - Haptens are substances that don’t provoke an adaptive immune response alone, but they stimulate such a response when combined with a carrier molecule. - Adjuvants are substances that can be mixed with antigen to enhance the immune response. - Once antibody response is generated, haptens can react with that antibody, but precipitation or aggluination reactions may not occur due to the small size of the complexes formed. - MHC molecules determine the types of peptide antigen to which an individual can mount an adaptive immune response and potentially define their ability to overcome an infection. - Vaccines can be developed to target certain groups of MHC molecules, potentially avoiding the use of live organisms. - Knowledge of an individual's MHC type can help predict the development or absence of drug sensitivities, allergies, and autoimmune diseases.