Untitled Quiz

Major Histocompatibility Complex (MHC)

• MHC is a cluster of genes located on chromosome 6, band 2
• These genes code for proteins that play a role in immune recognition
• MHC encodes the human leukocyte antigens (HLA)
• HLAs are the molecular basis for T-cell discrimination of self from non-self
• Transplanted tissue can trigger rejection if recipient's cells recognize MHC proteins as foreign

Histocompatibility Antigens

• Nucleated cells (like leukocytes and tissues) possess many cell surface protein antigens
• These antigens readily provoke an immune response if transferred to a different individual of the same species (allogenic)
• Some antigens form the major histocompatibility complex (MHC), also called HLA in humans
• MHC protein antigens were initially identified on white blood cells (leukocytes)
• MHC antigens are potent immunogens
• They play a significant role in organ transplant rejection

MHC Classes

• MHC occurs in three classes
• Two functional classes are involved in antigen presentation
  • MHC class I is found on virtually all tissue cells
  • MHC class II is found only on some immune system cells (e.g., macrophages, dendritic cells, and B cells)
• MHC class I interacts with CD8+ (cytotoxic) T cells
• MHC class II interacts with CD4+ (helper) T cells
• MHC Class III genes code for secreted products that have immune functions (e.g., complement components, inflammatory cytokines)

Cell-Mediated MHC Display Properties

• MHC I is found on virtually all tissue cells
• Displays only proteins produced inside the cell (endogenous antigens), such as viral or cancer proteins
• Stimulates CD8+ (cytotoxic) T-cell population
  • Forms cytotoxic T cells (Killer T cells, TC), formerly T8 cells
• MHC II is found on B cells, some T cells, and antigen-presenting cells (APCs)
• Displays proteins derived from phagocytosed target cells
• Presents exogenous antigens (foreign proteins from outside the cell) to PM surface
• Stimulates CD4+ (helper) T-cells, formerly T4 cells

HLA Genotypes and Risk of Disease

• HLA testing is used for diagnosis and genetic counseling
• HLA antigens are linked to several immune-mediated reactions, autoimmune diseases, some neoplasms, and other disorders
• Risk of certain diseases increases with association to specific HLA antigens (e.g., 100x+ increased risk of ankylosing spondylitis with HLA-B27)

HLA and Organ Transplant

• MHC gene products play a crucial role in clinical immunology of transplants
• Transplants are rejected if performed against MHC barriers - requiring immunosuppressive therapy
• HLA antigens are vital for organ survival; second in importance only to ABO antigens

Immunological Tolerance

• Immunological tolerance is the state of unresponsiveness of T- and B-lymphocytes to a particular antigen
• Clonal antigen receptors of lymphocytes are generated by random recombination, requiring a system to sort out dangerous receptors that can recognize and destroy self tissues
• Breakdown of this tolerance to self-antigens causes autoimmune diseases
• The immune system needs to balance broad recognition of diverse pathogens against preventing attack on the host's own cells

T-cell Tolerance

• T-cell tolerance is established at two levels: Central and Peripheral tolerance
• Central tolerance: immature thymocytes undergo harsh selection processes in the thymus, deleting most T cells with high affinity for self-antigens
• Peripheral tolerance: mechanisms outside the thymus that enforce and maintain T-cell tolerance

Central Tolerance

• Central tolerance refers to the selection processes of T-cell precursors in the thymus
• Thymic epithelial cells and dendritic cells present self-antigens to immature T-cell precursors
• Self-reactive T cells undergo apoptosis (negative selection)
• T cells that do not react strongly to self-antigens but recognize peptide/MHC complexes receive a survival signal (positive selection)

Peripheral T-cell Tolerance

• Despite central tolerance, some autoreactive T cells may escape
• Peripheral tolerance mechanisms regulate and enforce T-cell tolerance outside the thymus
• These include immunological ignorance, anergy, peripheral deletion, and regulatory T cell suppression

B-cell Tolerance

• Established by mechanisms including clonal deletion of autoreactive B cells, receptor editing, and B-cell anergy
• B-cell tolerance is maintained by tolerant T cells; if T-cells are tolerant, B cells will typically follow suit