Histocompatibility & transplantation immunology Flashcards
What is meant by the term ‘MHC restriction’?
MHC restriction, or major histocompatibility complex (MHC) restriction, refers to the phenomenon in immunology where T cells recognize and interact with antigens presented by MHC molecules on the surface of cells. The MHC is a set of cell surface proteins that play a crucial role in the immune system by presenting antigens to T cells.
There are two main classes of MHC molecules: MHC class I and MHC class II. MHC class I molecules are found on the surface of nearly all nucleated cells and present endogenous antigens (typically derived from intracellular pathogens or self-proteins) to CD8+ cytotoxic T cells. MHC class II molecules are primarily found on the surface of antigen-presenting cells (APCs) such as dendritic cells, macrophages, and B cells. They present exogenous antigens (derived from extracellular pathogens) to CD4+ helper T cells.
The specificity of T cell recognition is highly dependent on the interaction between the T cell receptor (TCR) on the surface of T cells and the peptide-MHC complex presented on the surface of antigen-presenting cells. MHC restriction ensures that T cells can recognize and respond to antigens only when presented in the context of the appropriate MHC molecules. In other words, CD8+ T cells are restricted to recognizing antigens presented by MHC class I molecules, while CD4+ T cells are restricted to recognizing antigens presented by MHC class II molecules.
MHC restriction is a crucial mechanism that helps ensure that T cells respond appropriately to foreign antigens while avoiding inappropriate responses against self-antigens. The concept is fundamental to the understanding of how the immune system distinguishes between self and non-self and plays a critical role in immune responses against infections, tumors, and other challenges to the immune system.
explain MHC Molecules in Humans (HLA - Human Leukocyte Antigens)
MHC Molecules in Humans (HLA - Human Leukocyte Antigens):
Name: In humans, MHC molecules are referred to as Human Leukocyte Antigens (HLA).
Nomenclature: The nomenclature committee established by the World Health Organization (WHO) in 1968 standardized the naming of these molecules.
Two Types of MHC Molecules:
MHC Class I:
Distribution: Found on the surface of all nucleated cells in the body.
Function: Presents antigens to cytotoxic CD8+ T cells (also known as cytotoxic T lymphocytes or CTLs).
Main Types: Three main types are HLA-A, HLA-B, and HLA-C.
MHC Class II:
Distribution: Found exclusively on antigen-presenting cells (APCs) such as macrophages, dendritic cells, and B cells.
Function: Presents antigens to helper CD4+ T cells, which play a central role in coordinating immune responses.
Main Types: Three main types are HLA-DP, HLA-DQ, and HLA-DR.
These MHC molecules, both class I and class II, are critical for the immune system’s ability to recognize and respond to a wide range of pathogens. MHC class I molecules present endogenous antigens derived from within the cell, while MHC class II molecules present exogenous antigens taken up by the cell from the external environment.
explain MHC antigens and their functions
MHC Antigens:
Definition: MHC (Major Histocompatibility Complex) antigens are a group of glycoproteins found on the surface of most cells in vertebrates.
Genetic Polymorphism: MHC antigens are encoded by a family of highly polymorphic genes, meaning that there is a high degree of genetic variation within the population. This polymorphism contributes to the diversity of MHC molecules among individuals.
Cellular Distribution: MHC antigens are present on the cell surface of virtually all nucleated cells in the body.
Functions of MHC Antigens:
Antigen Presentation: MHC molecules play a crucial role in the immune system by presenting antigenic peptides to T lymphocytes (T cells). This process is essential for the activation of T cell responses.
Immune Response Regulation: MHC molecules are central to the regulation of both humoral (antibody-mediated) and cell-mediated immune responses. They contribute to the activation, differentiation, and proliferation of T cells.
Tissue Compatibility in Transplantation: MHC antigens play a vital role in determining the compatibility of tissues for successful graft transplantation. Matching MHC profiles between the donor and recipient is crucial to minimize the risk of graft rejection.
Self-Nonself Discrimination: MHC molecules contribute to the discrimination between self and non-self. T cells are educated to recognize and respond to antigens presented in the context of self-MHC molecules, helping to prevent autoimmune responses.
Erythrocytes don’t express MHC class I.
How do they protect themselves from the Immune Surveillance function of NK cells?
Erythrocytes, or red blood cells, do not express MHC class I molecules on their surface. This lack of MHC class I expression is thought to be a mechanism by which erythrocytes avoid recognition and destruction by cytotoxic T cells. However, this absence of MHC class I could potentially make them susceptible to natural killer (NK) cells, which are a type of immune cell that can recognize and eliminate cells lacking MHC class I molecules. NK cells play a crucial role in immune surveillance by targeting cells that may be infected or otherwise abnormal.
To protect themselves from NK cell recognition, erythrocytes have evolved additional mechanisms to avoid being targeted:
Lack of Surface Proteins: Erythrocytes have a relatively simple cell membrane with few surface proteins. The absence of these surface proteins makes it difficult for NK cells to recognize and engage with erythrocytes.
Presence of Inhibitory Signals: Erythrocytes may express inhibitory signals that dampen the activation of NK cells. These signals can prevent NK cells from initiating their cytotoxic functions against the erythrocytes.
It’s important to note that while erythrocytes lack MHC class I molecules and are generally resistant to NK cell recognition, they are not completely immune to destruction. In certain pathological conditions, such as autoimmune hemolytic anemia, erythrocytes can become targets for immune attack. Additionally, other immune mechanisms, such as phagocytosis by macrophages in the spleen and liver, play a role in the removal of aged or damaged erythrocytes from circulation.
explain the concept of MHC restriction
Concept of MHC Restriction:
Recognition of Self Antigens:
T cells are designed to recognize self-antigens, but this recognition is context-dependent.
T cells recognize self antigens when presented in the context of MHC molecules.
Antigen Presentation Requirement:
For T cells to become activated and responsive, antigens must be presented to them in association with MHC molecules.
If T cells do not encounter antigens presented by MHC molecules, they may become non-responsive or tolerant.
Thymic Education and Selection:
T cell education and selection occur in the thymus during T cell development.
T cells that strongly react to self-antigens presented by MHC molecules are usually eliminated or rendered tolerant through negative selection in the thymus.
Alertness to Non-Self Antigens:
MHC restriction ensures that T cells are most responsive to non-self antigens presented by MHC molecules.
T cells are primed to recognize and respond to foreign antigens while avoiding overreactivity to self-antigens.
Critical for Self/Non-Self Discrimination:
MHC restriction is a vital aspect of the adaptive immune system’s ability to discriminate between self and non-self.
T cells must be capable of distinguishing between normal, healthy cells presenting self-antigens and cells presenting foreign antigens.
MHC expression is fundamental to adaptive immunity. But can it also be harmful in any way?
While MHC expression is fundamental to adaptive immunity and plays a crucial role in defending the body against infections, there are situations in which MHC molecules can contribute to harmful immune responses or diseases. Here are a few scenarios where MHC expression can have potentially detrimental effects:
Autoimmune Diseases:
In autoimmune diseases, the immune system mistakenly targets and attacks the body’s own tissues. MHC molecules are involved in the presentation of self-antigens to T cells during their development and education in the thymus. If this process is dysregulated, it can lead to the production of autoreactive T cells that recognize and attack self-antigens, contributing to autoimmune diseases.
Graft Rejection:
MHC molecules are critical for determining tissue compatibility in transplantation. Mismatched MHC between the donor and recipient can lead to graft rejection, where the recipient’s immune system recognizes the transplanted tissue as foreign and mounts an immune response against it.
Hypersensitivity Reactions:
In certain immune hypersensitivity reactions (allergies), MHC molecules can play a role in presenting allergens to T cells, triggering an immune response that leads to inflammation and tissue damage.
Infectious Diseases:
Some pathogens have evolved mechanisms to interfere with MHC expression or antigen presentation to escape immune recognition. This can compromise the effectiveness of the adaptive immune response against the pathogen.
Role in Chronic Inflammation:
Dysregulation of MHC expression and antigen presentation can contribute to chronic inflammation, which is associated with various diseases, including autoimmune conditions and chronic infections.
It’s important to note that while MHC molecules can contribute to harmful immune responses in certain contexts, they are generally essential for the normal functioning of the immune system.
explain the structure of MHC Class I molecules
Structure of MHC Class I:
Composition:
MHC Class I molecules are composed of two polypeptide subunits: an α chain (heavy chain) and a β2-microglobulin chain.
Variation and Organization:
The α chain exhibits the most variation among Class I molecules.
The α chain is organized into three extracellular domains: α1, α2, and α3, along with a transmembrane region and a cytoplasmic tail.
Peptide-Binding Groove:
The α1 and α2 domains fold together to form a peptide-binding groove, also known as a peptide-binding cleft.
Function of α Chain:
The α chain is crucial for presenting antigens to cytotoxic CD8+ T cells.
It plays a central role in determining the specificity of antigen recognition.
β2-Microglobulin Chain:
The β2-microglobulin chain is a smaller, non-polymorphic protein made up of β-pleated sheets.
It interacts with the α chain and provides molecular stability to the MHC Class I molecule.
Affinity of Peptide Binding:
β2-microglobulin increases the affinity of peptide binding by the groove, contributing to the stability of the peptide-MHC complex.
Lack of Transmembrane Domain:
Unlike the α chain, β2-microglobulin does not have a transmembrane domain. It is associated with the membrane indirectly through its interaction with the α chain.
What are the main structural differences between MHC Class I and class II molecules?
MHC Class I:
Cellular Distribution:
Where Found: Found on the surface of all nucleated cells in the body.
Subunit Composition:
Chain Composition: Composed of two polypeptide subunits: an α chain (heavy chain) and a non-polymorphic β2-microglobulin chain.
α Chain Variation: The α chain exhibits the most variation among Class I molecules.
Peptide-Binding Groove:
Structure: The α1 and α2 domains of the α chain fold together to form a peptide-binding groove or cleft.
Function: Presents endogenous antigens (derived from within the cell) to cytotoxic CD8+ T cells.
Interaction with β2-Microglobulin:
Role: β2-microglobulin interacts with the α chain, providing stability to the MHC Class I molecule.
Transmembrane Domain: β2-microglobulin lacks a transmembrane domain.
MHC Class II:
Cellular Distribution:
Where Found: Found primarily on antigen-presenting cells (APCs) such as macrophages, dendritic cells, and B cells.
Subunit Composition:
Chain Composition: Composed of two chains: α and β chains, each with polymorphic regions.
Variation in Both Chains: Both α and β chains contribute to the overall polymorphism of Class II molecules.
Peptide-Binding Groove:
Structure: The α1 and β1 domains of the α and β chains, respectively, form a peptide-binding groove.
Function: Presents exogenous antigens (derived from outside the cell) to helper CD4+ T cells.
Interaction Between α and β Chains:
Association: The α and β chains are associated non-covalently.
Transmembrane Domain: Both α and β chains have transmembrane domains.
Summary:
MHC Class I molecules present endogenous antigens to cytotoxic T cells on the surface of all nucleated cells.
MHC Class II molecules present exogenous antigens to helper T cells and are primarily found on antigen-presenting cells.
The differences in structure reflect the distinct roles and antigen presentation functions of Class I and Class II molecules in the adaptive immune response.
explain the structure of MHC Class II molecules
Structure of MHC Class II:
Composition:
MHC Class II molecules are composed of two homologous polypeptide chains: α and β.
Peptide-Binding Groove:
The α1 and β1 domains of the α and β chains fold together to form the peptide-binding groove.
The groove is highly polymorphic, reflecting variations in antigen presentation.
Conserved Region (Ig-like Region):
A conserved region, known as the Ig-like region, consists of the α2 and β2 domains.
Interaction with CD4 Receptor:
The β2 domain of MHC Class II interacts with the CD4 receptor on helper T cells (Th cells).
Transmembrane Regions and Cytoplasmic Tails:
Both the α and β chains of MHC Class II molecules have transmembrane regions and cytoplasmic tails.
These regions anchor the molecule to the cell membrane and play a role in intracellular signaling.
Peptide Presentation Capacity:
MHC Class II molecules can present larger peptides, typically 12-25 amino acids in length, compared to MHC Class I molecules, which present shorter peptides (up to 9 amino acids).
The structural differences between MHC Class I and Class II molecules reflect their distinct roles in presenting antigens to different types of T cells. MHC Class II is primarily involved in presenting exogenous antigens to helper CD4+ T cells, contributing to the coordination of immune responses.
Apart form the peptide size presented, can you name 2 other differences between MHC Class I & Class II antigen presentation?
Besides the difference in peptide size, here are two other key differences between MHC Class I and Class II antigen presentation:
Source of Antigens:
MHC Class I: Presents endogenous antigens derived from within the cell. These antigens are typically produced by the cell itself, such as viral or tumor antigens.
MHC Class II: Presents exogenous antigens derived from outside the cell. These antigens are typically taken up by antigen-presenting cells (APCs), processed, and presented to helper T cells.
Target T Cell Types:
MHC Class I: Presents antigens to cytotoxic CD8+ T cells. The activation of cytotoxic T cells is crucial for the elimination of infected or abnormal cells.
MHC Class II: Presents antigens to helper CD4+ T cells. The activation of helper T cells is essential for coordinating various immune responses, including the activation of B cells, cytotoxic T cells, and other immune cells.
These differences in antigen source and target T cell types highlight the specialized roles of MHC Class I and Class II molecules in immune surveillance and immune response coordination, respectively.
explain the MHC Class II antigen presentation pathway for extracellular antigens
MHC Class II Antigen Presentation (Extracellular):
Antigen Uptake by APCs:
MHC Class II molecules present peptides derived from antigens internalized by antigen-presenting cells (APCs) from outside the cell. This often involves the phagocytosis of pathogens such as bacteria.
Enzymatic Digestion in Phagolysosome:
Inside the cell, the internalized antigen is digested enzymatically within a phagolysosome, leading to the generation of peptides.
Synthesis of MHC Class II in Endoplasmic Reticulum (ER):
MHC Class II molecules are synthesized in the endoplasmic reticulum (ER).
Transport to Endosome:
MHC Class II molecules are transported from the ER to endosomes within the cell.
Fusion of Phagolysosome and Endosome:
The phagolysosome, containing the antigenic peptides, fuses with the endosome containing MHC Class II molecules.
Peptide Binding to MHC Class II:
The peptides and MHC Class II molecules join together via the binding groove of MHC Class II.
Transport to Cell Membrane:
The MHC Class II-peptide complex is transported to and inserted into the cell membrane, making it available for presentation on the cell surface.
Recognition by Helper T Cells (Th Cells):
The MHC Class II-peptide complex on the cell surface is recognized by helper CD4+ T cells (Th cells). This recognition is a key step in the activation of helper T cells and the initiation of immune responses.
This process ensures that extracellular antigens, internalized by APCs, are presented to helper T cells, which then coordinate immune responses against the specific pathogens.
Can class II molecules also present endogenous antigens?
Under normal circumstances, MHC Class II molecules primarily present exogenous antigens derived from extracellular sources, such as pathogens that have been engulfed by antigen-presenting cells (APCs) through processes like phagocytosis. However, there are situations where MHC Class II molecules can also present endogenous antigens.
This phenomenon is known as “cross-presentation” or “cross-priming.” In cross-presentation, extracellular antigens that enter the cell can be processed and presented by MHC Class II molecules. This process is not as efficient or common as the presentation of exogenous antigens, which is the primary function of MHC Class II.
Cross-presentation is particularly relevant in certain immune responses, such as during viral infections. Viral particles entering cells can lead to the presentation of viral peptides on MHC Class II molecules, allowing the activation of CD4+ helper T cells. This can contribute to the coordination of immune responses against intracellular pathogens.
While cross-presentation can occur, it’s important to note that the main role of MHC Class II molecules is to present exogenous antigens. MHC Class I molecules are more specialized for presenting endogenous antigens, particularly those generated within the cell due to viral infection or other intracellular events.
explain the MHC Class I antigen presentation pathway for intracellular antigens
MHC Class I Antigen Presentation (Intracellular):
Source of Antigens:
MHC Class I molecules present peptides derived from antigens synthesized within the cell. This includes self-antigens and antigens from intracellular pathogens, such as viruses infecting the cell.
Proteasome-Mediated Degradation:
Antigens are digested into small peptides through a process that involves ubiquitination and proteasome-mediated degradation. The proteasome is a cellular structure responsible for breaking down proteins into smaller fragments.
Transport to Endoplasmic Reticulum (ER):
Peptides generated in the cytoplasm are transported into the endoplasmic reticulum (ER).
Peptide Binding to MHC Class I:
Peptides bind to the peptide-binding cleft of MHC Class I molecules in the lumen of the ER.
Vesicle Packaging by Golgi Body:
The MHC Class I-peptide complex is packaged into vesicles by the Golgi body.
Insertion into Cell Membrane:
The vesicles containing the MHC Class I-peptide complex are then inserted into the cell membrane for presentation.
Survey of Intracellular Proteins:
MHC Class I molecules constantly sample peptides from proteins synthesized within the cell, presenting fragments to cytotoxic CD8+ T cells. This allows T cells to monitor the internal state of cells.
T Cell Recognition:
The presentation of endogenous peptides on MHC Class I molecules enables cytotoxic T cells to recognize and respond to cells that are infected with intracellular pathogens or have abnormalities, such as tumor cells.
This process is fundamental to immune surveillance, as it allows the immune system to detect and eliminate cells that may be compromised by infections or other internal abnormalities.
Can class I molecules also present exogenous antigens?
MHC Class I molecules are primarily designed to present endogenous antigens, which are derived from proteins synthesized within the cell. The peptides presented by MHC Class I molecules are typically generated from intracellular sources such as viral proteins in virus-infected cells or abnormal proteins in cancer cells.
However, there are instances where MHC Class I molecules can, to some extent, present exogenous antigens. This phenomenon is known as “cross-presentation.” Cross-presentation is the ability of certain antigen-presenting cells, especially dendritic cells, to take up extracellular antigens, process them, and present the resulting peptides on MHC Class I molecules. This process allows the activation of cytotoxic CD8+ T cells against exogenous antigens.
Cross-presentation is particularly important in the context of immune responses to pathogens that infect non-phagocytic cells. Dendritic cells, known for their ability to cross-present, can capture antigens from infected cells, process them, and present the generated peptides on MHC Class I molecules to cytotoxic T cells.
While cross-presentation occurs, it is not as efficient or common as MHC Class II presentation of exogenous antigens. MHC Class II molecules are specialized for presenting peptides derived from extracellular sources, and they play a crucial role in activating helper CD4+ T cells.
explain the challenge of transplantation and the inherent conflict with the immune system’s response to foreign materials
Donor-Recipient Transplant Relationship:
Definition of Transplantation:
Transplantation involves the transfer of biological material, such as organs, tissues, or cells, from one organism (the donor) to another (the recipient).
Immune System’s Response to Foreign Material:
The immune system is responsible for identifying and removing anything it considers foreign or non-self. This response is a protective mechanism to defend the body against potential threats, such as infections.
Challenge in Transplantation:
In transplantation, the challenge arises because the immune system recognizes the transplanted material as foreign and mounts an immune response against it. This response, while appropriate from the immune system’s perspective, can lead to rejection of the transplanted organ.
Desired Outcome in Transplantation Medicine:
In transplantation medicine, the goal is to prevent or minimize the immune response to the transplanted material. The desired outcome is for the transplanted organ, tissue, or cells to survive and function in the recipient’s body without being rejected.
Immunosuppression:
To achieve successful transplantation, immunosuppressive medications are often used to dampen the recipient’s immune response. These medications help reduce the risk of rejection and allow the transplanted material to integrate and function in the recipient’s body.
Balancing Act:
Transplantation involves a delicate balance between preventing rejection and avoiding over-suppression of the immune system, which could lead to increased susceptibility to infections.
