4.1 Major Histocompatibility Complex (MHC) molecules
3 min read•july 25, 2024
Major Histocompatibility Complex (MHC) molecules are crucial for . They present peptides from inside and outside cells to T cells, enabling the immune system to detect threats. MHC's structure and genetics are key to its function.
MHC genes are highly diverse, with multiple variants in the population. This diversity helps protect against a wide range of pathogens. MHC molecules come in two main classes, each with specific roles in immune responses.
MHC Structure and Genetics
Structure and function of MHC molecules
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- structure
- Heavy chain with three domains (α1, α2, α3) forms peptide-binding groove and CD8 binding site
- Non-covalently associated β2-microglobulin stabilizes structure and aids in
- Peptide-binding groove formed by α1 and α2 domains accommodates 8-10 amino acid peptides
- MHC class I function
- Present peptides from intracellular proteins enables immune surveillance of infected or transformed cells
- Interact with triggers cytotoxic responses against abnormal cells (virally infected, cancerous)
- structure
- Two chains: α and β, each with two domains create more open peptide-binding groove
- Peptide-binding groove formed by α1 and β1 domains allows binding of longer peptides (13-25 amino acids)
- MHC class II function
- Present peptides from extracellular proteins facilitates immune responses against extracellular pathogens
- Interact with initiates helper T cell responses and antibody production
Genetic organization of MHC loci
- MHC gene location
- Human chromosome 6 spans approximately 4 Mbp region
- Mouse chromosome 17 shows synteny with human MHC
- Classical MHC genes
- Class I: HLA-A, HLA-B, HLA-C (humans) encode cell surface glycoproteins
- Class II: HLA-DP, HLA-DQ, HLA-DR (humans) encode α and β chains of class II molecules
- Polygenic nature
- Multiple genes for each MHC class increases diversity of presented peptides
- Codominant expression
- Both alleles expressed in heterozygous individuals enhances capabilities
- Extreme polymorphism
- Numerous alleles for each gene in the population provides population-level resistance to pathogens
- Mechanisms of MHC diversity
- Point mutations introduce single nucleotide changes
- Gene conversion transfers genetic material between similar sequences
- Recombination shuffles alleles during meiosis
MHC Function and Expression
MHC in antigen presentation
- Antigen processing
- Intracellular antigens for MHC class I degraded by proteasome (cytosolic proteins, viral peptides)
- Extracellular antigens for MHC class II processed in endosomes and lysosomes (bacterial proteins, allergens)
- Peptide loading
- Endoplasmic reticulum for MHC class I involves TAP transporter and tapasin
- Endosomal compartments for MHC class II facilitated by HLA-DM and HLA-DO molecules
- T cell recognition
- MHC-peptide complex interacts with forms immunological synapse
- Co-receptor binding (CD8 or CD4) stabilizes interaction and enhances signaling
- Immune response initiation
- T cell activation and proliferation leads to clonal expansion
- Cytokine production shapes immune response (Th1, Th2, Th17)
- Effector function development includes cytotoxicity, B cell help, and macrophage activation
Expression patterns of MHC classes
- MHC class I expression
- Nearly all nucleated cells allows for constant immune surveillance
- High levels on lymphocytes and macrophages facilitates rapid immune responses
- MHC class II expression
- Professional antigen-presenting cells (APCs) specialize in antigen presentation
- Dendritic cells most potent APCs, initiate primary immune responses
- Macrophages present antigens from phagocytosed pathogens
- B cells present antigens captured by surface immunoglobulins
- Thymic epithelial cells crucial for T cell selection during development
- Activated T cells (in humans) can present antigens to other T cells
- Professional antigen-presenting cells (APCs) specialize in antigen presentation
- Regulation of MHC expression
- Constitutive vs inducible expression allows for dynamic immune responses
- Cytokine-mediated upregulation enhances antigen presentation during infections (IFN-γ)
- Tissue-specific variations in expression levels adapt immune responses to different environments
- Altered expression in disease states
- Viral infections often downregulate MHC class I to evade detection
- Tumors may lose MHC expression to escape immune recognition
Key Terms to Review (16)
Antigen Presentation: Antigen presentation is the process by which immune cells display antigens on their surface to enable T cells to recognize and respond to pathogens or infected cells. This crucial mechanism bridges innate and adaptive immunity, allowing for a targeted immune response against specific threats.
Autoimmune diseases: Autoimmune diseases are conditions where the immune system mistakenly attacks the body's own cells and tissues, treating them as foreign invaders. This misdirected immune response can lead to inflammation and damage in various organs, highlighting the complex interplay between immune regulation, self-tolerance, and disease pathogenesis.
CD4+ T cells: CD4+ T cells, also known as helper T cells, are a subtype of T lymphocytes characterized by the expression of the CD4 glycoprotein on their surface. These cells play a vital role in the immune system by orchestrating immune responses, particularly through their interaction with antigen-presenting cells and other immune cells.
CD8+ T cells: CD8+ T cells, also known as cytotoxic T lymphocytes, are a subset of T cells that play a crucial role in the immune response by directly killing infected or cancerous cells. They recognize antigens presented by Major Histocompatibility Complex (MHC) class I molecules and are essential for the adaptive immune response, helping to maintain the body's defenses against intracellular pathogens and tumors.
Cytokine signaling: Cytokine signaling refers to the process by which cells communicate with each other through the release and reception of cytokines, which are small proteins that play crucial roles in cell signaling in the immune system. This signaling is essential for regulating various immune responses, including inflammation, cell differentiation, and the activation of immune cells. Understanding cytokine signaling is vital as it connects cellular communication to the actions of Major Histocompatibility Complex (MHC) molecules in presenting antigens and facilitating immune responses.
ELISA: ELISA, or Enzyme-Linked Immunosorbent Assay, is a widely used laboratory technique that detects and quantifies proteins, antibodies, and hormones. This method relies on antigen-antibody interactions to provide precise measurements, making it crucial in areas like diagnostics, vaccine development, and research on immune responses.
Flow cytometry: Flow cytometry is a powerful analytical technique used to measure the physical and chemical characteristics of cells or particles as they flow in a fluid stream through a laser beam. This method enables the identification and quantification of various cell types, allowing researchers to gain insights into cellular functions and interactions, which are crucial for understanding immune responses, differentiation processes, and tumor behavior.
Gene expression: Gene expression is the process by which information from a gene is used to synthesize functional gene products, typically proteins, that play critical roles in cellular functions. This process involves transcription of DNA into messenger RNA (mRNA) and subsequent translation of that mRNA into a specific protein. The regulation of gene expression is vital for maintaining cellular function and responding to environmental changes.
HLA genes: HLA genes, or human leukocyte antigen genes, are a group of genes located on chromosome 6 that play a crucial role in the immune system by encoding proteins responsible for presenting antigens to T cells. These genes are essential for the recognition of self versus non-self and are central to the functioning of Major Histocompatibility Complex (MHC) molecules, which help the immune system distinguish between healthy cells and pathogens or infected cells.
Immune Recognition: Immune recognition refers to the process by which the immune system identifies and distinguishes between self and non-self entities, such as pathogens and foreign substances. This crucial function relies on specialized receptors that detect unique molecular patterns, allowing immune cells to respond appropriately to threats while avoiding attacks on the body's own cells. Proper immune recognition is essential for maintaining health and preventing diseases like infections and autoimmune disorders.
MHC Class I: MHC Class I molecules are cell surface proteins that present endogenous antigens to CD8+ T cells, playing a crucial role in the immune system by enabling the recognition of infected or cancerous cells. These molecules are essential for distinguishing self from non-self, and their interactions with T cells are fundamental in the activation and differentiation of adaptive immune responses.
MHC Class II: MHC Class II molecules are proteins found on the surface of certain immune cells that play a crucial role in the adaptive immune response by presenting antigens to CD4+ T helper cells. These molecules specifically present processed extracellular antigens, enabling T cells to recognize and respond to pathogens such as bacteria and parasites, thus connecting them to the immune system's ability to differentiate between self and non-self.
MHC Polymorphism: MHC polymorphism refers to the extensive genetic variation observed in Major Histocompatibility Complex (MHC) molecules among individuals within a species. This variation is crucial for the immune system's ability to recognize and present a diverse range of antigens, enhancing the effectiveness of immune responses against pathogens. The high degree of polymorphism in MHC genes ensures that different individuals can respond uniquely to various infections, providing a selective advantage for the population as a whole.
Peptide binding: Peptide binding refers to the process where short chains of amino acids, known as peptides, attach to major histocompatibility complex (MHC) molecules, facilitating the presentation of these peptides to T cells. This interaction is crucial for the immune response, as it allows T cells to recognize and respond to pathogens or infected cells by detecting specific peptide-MHC complexes on their surfaces.
T cell receptor: The T cell receptor (TCR) is a molecule found on the surface of T cells that is essential for recognizing specific antigens presented by other cells. It plays a crucial role in the adaptive immune response by enabling T cells to identify and respond to pathogens, infected cells, and cancerous cells. TCRs work closely with Major Histocompatibility Complex (MHC) molecules to discern foreign invaders from self-cells and are critical for immune surveillance against tumors.
Transplant rejection: Transplant rejection is the immune system's response to foreign tissues that have been introduced into the body through organ or tissue transplantation. This reaction occurs because the immune system recognizes the transplanted tissue as non-self, leading to an attack on the foreign cells. The degree of rejection can vary, ranging from acute to chronic, and is influenced by factors such as the compatibility of Major Histocompatibility Complex (MHC) molecules between the donor and recipient.