MHC Molecules and Peptide Presentation

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Questions and Answers

What role do MHC molecules play in antigen presentation?

MHC molecules are responsible for presenting processed peptide fragments to T cells, which is crucial for initiating immune responses.

How might the understanding of antigen presentation be exploited to enhance immunotherapy?

Insights into antigen presentation can help tailor immunotherapies to boost the immune response against specific antigens.

What is the significance of peptide motifs revealed by pool sequencing of HLA ligands?

Peptide motifs help identify common characteristics among peptides that influence their binding to MHC molecules.

Describe one method by which cell proteins are degraded before being presented by MHC class I molecules.

Proteasomes degrade cell proteins into peptides, which are then transported to the endoplasmic reticulum for MHC class I loading. Signup and view all the answers

What challenges does phosphorylation of peptides present in relation to MHC class I presentation?

Phosphorylated peptides can alter their interactions with MHC class I, potentially affecting T cell recognition. Signup and view all the answers

What is the role of HLA-DM in antigen presentation?

HLA-DM acts as a peptide exchange catalyst, facilitating the loading of peptides onto class II MHC molecules. Signup and view all the answers

How do inhibitors of the proteasome affect antigen presentation?

Proteasome inhibitors block the degradation of proteins, resulting in reduced peptide availability for MHC class I presentation. Signup and view all the answers

What are some potential consequences of impaired antigen catabolism in macrophages?

Impaired antigen catabolism can lead to decreased antigen presentation and diminished T cell activation. Signup and view all the answers

Explain the concept of cross-priming in the context of antigen presentation.

Cross-priming is the process where antigen-presenting cells capture extracellular antigens and present them on MHC class I molecules. Signup and view all the answers

What is the impact of glycosylation inhibition on HLA class I expression?

Inhibition of glycosylation can disrupt the association of HLA class I heavy chains with beta 2-microglobulin, affecting surface expression. Signup and view all the answers

Study Notes

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Major Histocompatibility Complex (MHC) Overview

MHC class I and II molecules are crucial for immune response, taking about 40 years to fully understand.
These molecules present peptides to T cells, shaping immune responses and affecting areas like organ transplantation and cancer therapy.

Antigen Presentation Mechanisms

T cells can identify infected or abnormal cells via antigen presentation but cannot directly sense the pathogens within.
MHC class I molecules present endogenous antigens to CD8+ T cells, enabling detection of viral infections or tumors.
MHC class II molecules present exogenous antigens to CD4+ T cells, primarily from professional antigen-presenting cells (APCs) like dendritic cells and macrophages.

T Cell Functionality

T cells require interaction with MHC molecules displaying antigens to perform their roles effectively.
TCRs specifically recognize antigenic peptides in the context of MHC molecules, which directs their activity.

MHC Polymorphism and Specificity

MHC molecules exhibit extreme polymorphism (>10,000 alleles for MHC I), allowing diverse peptide presentation.
Specificity of T cell receptors (TCRs) arises from interactions with polymorphic residues on MHC molecules.

Peptide Presentation Diversity

MHC I can display around 6 × 20^(6-7) different peptides, while MHC II can present about 12 × 20^(10) peptides.
Realistically, the number of different presented peptides per cell often does not exceed 10,000 due to expression limitations.

Evolutionary Significance of MHC Polymorphism

MHC polymorphism aids in population survival by limiting pathogen transmission between genetically similar individuals.
Females may preferentially mate with males having dissimilar MHC alleles, promoting diversity.

Implications of MHC in Disease and Transplantation

High MHC diversity can complicate organ transplantation and may lead to rejection.
Interestingly, MHC deficiency in species may increase susceptibility to diseases, demonstrated by cancer spread in Tasmanian Devils.

Mechanisms of Peptide Loading onto MHC Molecules

Proteins are degraded into peptides by the proteasome, with specific peptides loaded onto MHC molecules via specialized chaperones like tapasin.
Peptides that bind MHC I stabilizes the molecule for transport to the cell surface.

Immune Response and Antigen Mutations

Pathogen-induced mutations in antigenic epitopes can evade immune detection in individuals with certain MHC variations.
Cumulative polymorphism and neo-epitopes can promote immune recognition of abnormal cells.

Role of Immunoproteasomes and Alternative Proteolytic Pathways

Immunoproteasomes produce unique peptides during infection and stress, enhancing their presentation on MHC I.
Tumor cells may adapt by losing MHC expression or altering the antigen presentation pathway to evade immune detection.

Cross-Presentation and Immune Surveillance

Dendritic cells utilize cross-presentation to present antigens from other infected cells, activating naive CD8+ T cells and initiating immune responses.
Various mechanisms for cross-presentation exist, including cytosolic transfer of antigens from phagosomes to MHC I molecules.

Understanding Immune Evasion Mechanisms

Some viruses manipulate the antigen presentation system at multiple stages to prevent detection by immune cells.
Gaps in knowledge about how these mechanisms work underline the complexity of immune evasion strategies in cancer and viral infections.

Summary of MHC Class I Pathway

MHC class I exclusively presents endogenous antigens, but neighboring cells can share peptides through gap junctions, complicating immune targeting.
This system highlights the importance of peptide diversity and the need for immune system adaptability in detecting irregular cell states.### Mechanisms of Cross-Presentation
Priming of CD8+ T cells may involve different peptides than those encountered in infected cells due to the use of various proteases.
Cross-presentation mechanisms, including phagosome-to-cytosol, may also create inconsistencies in peptide presentation depending on inflammatory states.
Cross-presentation allows MHC I molecules to present antigens typically presented by MHC II molecules.

MHC Class I vs. MHC Class II

MHC II molecules are primarily expressed on immune cells (B cells, monocytes, macrophages, dendritic cells) and epithelial cells post-inflammation, while MHC I molecules have broader expression across all cell types.
MHC II molecules are crucial for activating naïve CD4+ T cells, leading to interactions with B cells and macrophages.
Patients lacking MHC class II face severe vulnerabilities to infections, highlighting its critical immune role.

Structure and Function of MHC Class II

MHC II molecules present larger peptide fragments; their binding grooves are open, allowing for outgoing extensions.
Associated with the invariant chain (Ii) during assembly, which directs MHC II towards the endosomal pathway and maintains groove occupancy until degradation.
Once degraded, CLIP fragments must be replaced with higher-affinity peptides facilitated by the HLA-DM chaperone.

Peptide Loading and Transport

MHC II movement to the plasma membrane is regulated and increases following dendritic cell activation, which enhances MHC II surface numbers.
Proteins like MARCH-1 and co-chaperones (e.g., HLA-DO) influence MHC II expression and peptide loading efficiency.
Variability in protease activity among immune cells affects antigen processing for MHC II presentation.

Polymorphism and Autoimmunity

MHC II molecules exhibit extensive polymorphism (over 3,000 alleles), which influences peptide binding and is associated with various autoimmune diseases.
Specific MHC II alleles like HLA-DQ2 correlate with conditions like Celiac disease due to their ability to present certain peptides to CD4+ T cells.
Autoimmune diseases may involve misconfigured peptides binding to MHC II in absence of DM, leading to erroneous self-recognition.

Genetic Variations Impacting Antigen Presentation

The invariant chain has splice variants impacting MHC II functionality; varying proteases and inhibitors also contribute to selective peptide degradation.
Activation of immune cells can enhance MHC II expression; pathogens may exploit this through various mechanisms to evade immune detection.

Future Directions in Immunology

Understanding antigen presentation mechanisms aids in developing better diagnostic and therapeutic approaches, particularly for cancer immunotherapy.
Identifying defects in antigen presentation may help predict patient responses to treatments and could lead to more effective immunotherapies.
Continuous research is revealing new components within antigen presentation pathways that may clarify remaining uncertainties.

Unanswered Questions

Challenges remain in accurately predicting peptides presented by MHC molecules and the roles of various proteases in peptide processing.
Variations in antigen presentation components across tissues may drive autoimmune responses by presenting self-antigens differently.
Understanding the mechanisms behind MHC polymorphisms and their link to diseases is an ongoing area of research, aiming to improve therapeutic strategies.

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Description

This quiz explores the role of MHC I and MHC II molecules in the immune system, focusing on their capabilities in presenting peptides. Learn about the diversity of peptide presentation and the theoretical limits of MHC-mediated interactions. Test your knowledge on the alleles inherited from parents and their implications for immune response.