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Questions and Answers
Which of the following HLA classes are primarily involved in organ rejection during transplantation?
Which of the following HLA classes are primarily involved in organ rejection during transplantation?
What is the best possible match of HLA antigens in a transplantation scenario?
What is the best possible match of HLA antigens in a transplantation scenario?
What term describes the unresponsiveness of T- and B-lymphocytes to particular antigens?
What term describes the unresponsiveness of T- and B-lymphocytes to particular antigens?
Which process is described as the manipulation of the immune system to protect against certain allergens?
Which process is described as the manipulation of the immune system to protect against certain allergens?
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What is a consequence of the breakdown of immunological tolerance to self-antigens?
What is a consequence of the breakdown of immunological tolerance to self-antigens?
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In T-cell tolerance, what happens during central tolerance?
In T-cell tolerance, what happens during central tolerance?
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Which statement best describes the balance the immune system must maintain?
Which statement best describes the balance the immune system must maintain?
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How many different T-cell receptors could theoretically be generated due to random recombination?
How many different T-cell receptors could theoretically be generated due to random recombination?
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What is the primary outcome of negative selection during T cell development in the thymus?
What is the primary outcome of negative selection during T cell development in the thymus?
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Which mechanism contributes to the maintenance of peripheral T cell tolerance?
Which mechanism contributes to the maintenance of peripheral T cell tolerance?
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What is receptor editing in the context of B cell tolerance?
What is receptor editing in the context of B cell tolerance?
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What is the role of regulatory T cells in immune tolerance?
What is the role of regulatory T cells in immune tolerance?
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Which statement about central tolerance is true?
Which statement about central tolerance is true?
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What does peripheral deletion of autoreactive T cells primarily rely on?
What does peripheral deletion of autoreactive T cells primarily rely on?
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Which of the following is NOT a mechanism of B cell tolerance?
Which of the following is NOT a mechanism of B cell tolerance?
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What percentage of T cell precursors typically survives the selection process in the thymus?
What percentage of T cell precursors typically survives the selection process in the thymus?
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What is the principal role of the major histocompatibility complex (MHC) in organ transplantation?
What is the principal role of the major histocompatibility complex (MHC) in organ transplantation?
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Which classes of MHC proteins are primarily involved in antigen presentation?
Which classes of MHC proteins are primarily involved in antigen presentation?
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What is a consequence of the recipient's cells recognizing the MHC proteins on transplanted tissue as foreign?
What is a consequence of the recipient's cells recognizing the MHC proteins on transplanted tissue as foreign?
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Which T cell type interacts with MHC II proteins?
Which T cell type interacts with MHC II proteins?
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Autoimmunity can arise when the immune system fails to distinguish between self and nonself. What is a key mechanism that should normally prevent this?
Autoimmunity can arise when the immune system fails to distinguish between self and nonself. What is a key mechanism that should normally prevent this?
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Study Notes
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
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