Antigen presentation and MHC

Introduction

The process of antigen presentation and Major Histocompatibility Complex (MHC) molecules plays a fundamental role in the immune system, orchestrating adaptive immunity against invading pathogens. This intricate interplay between antigens, MHC molecules, and T cells forms the basis for specific immune responses, ensuring effective clearance of foreign entities while preserving self-tolerance.

Overview

This course provides an in-depth examination of the mechanisms involved in antigen presentation and the crucial role of Major Histocompatibility Complex (MHC) molecules. We will explore the structure and function of MHC proteins, the process of antigen internalization and processing, and the intricate interactions between MHC complexes and T cells. The course also delves into the significance of MHC polymorphism, its impact on immune responses, and the broader implications for transplantation and autoimmune diseases.

Chapter 1: Major Histocompatibility Complex (MHC) and Its Components

1.1 Historical Background and Discovery

The discovery of MHC proteins stems from observations made during organ transplantation, where it was evident that the compatibility between donor and recipient played a crucial role in graft survival. The subsequent identification of genes encoding these proteins marked a significant milestone in our understanding of the immune system.

1.2 Structure and Classification of MHC Molecules

MHC molecules are transmembrane proteins that exhibit a complex structure consisting of a heavy chain, a light chain, and a peptide-binding groove. These molecules can be classified into three main classes: I, II, and III. This classification is primarily based on their structural features, cellular expression, and the types of antigens they present.

1.2.1 Class I MHC Molecules

Class I MHC molecules are expressed ubiquitously on almost all nucleated cells. They consist of a heavy chain (α) and a light chain (β2-microglobulin), both encoded by genes located within the MHC region on chromosome 6. Their peptide-binding groove is formed by the heavy chain and can bind to short, hydrophilic peptides derived from intracellular proteins.

1.2.2 Class II MHC Molecules

Class II MHC molecules are predominantly expressed on antigen-presenting cells (APCs), such as dendritic cells and B cells. They consist of two heavy chains (α and β) that combine to form a heterodimer, along with associated invariant chain components. The peptide-binding groove in Class II MHC molecules is larger than in Class I and can accommodate longer, hydrophilic peptides derived from extracellular proteins.

1.2.3 Class III MHC Molecules

Class III MHC molecules primarily function as components of the complement system, playing a role in the innate immune response. They are structurally distinct from Class I and II MHC molecules and include proteins such as complement components C4 and C2, as well as tumor necrosis factor (TNF) receptor-1.

1.3 The Role of MHC Molecules in Antigen Presentation

MHC molecules serve as vital intermediaries between the innate and adaptive immune responses by presenting processed antigens to T cells. This process triggers a cascade of events leading to the activation, proliferation, and differentiation of T cells into effector cells capable of eliminating the invading pathogen.

Chapter 2: Antigen Internalization, Processing, and Loading onto MHC Molecules

2.1 Phagocytosis and Endocytosis

Antigens can enter cells through two main mechanisms: phagocytosis (for large particulate matter) and endocytosis (for smaller antigens). These processes lead to the internalization of antigen-containing vesicles, known as phagosomes or endosomes.

2.2 Proteolytic Degradation and Peptide Loading onto MHC Molecules

Within the phagosome/endosome, antigens undergo proteolytic degradation, resulting in the formation of peptides that can subsequently bind to the MHC molecules. The process by which these peptides are loaded onto MHC molecules is intricate and involves several enzymes and chaperones, ensuring the appropriate presentation of antigens for effective T cell activation.

2.3 Quality Control and Editing Processes

The immune system employs a series of quality control mechanisms to ensure that only the correct peptides are loaded onto MHC molecules. This is essential to maintain self-tolerance while allowing for the efficient presentation of foreign antigens.

Chapter 3: Interactions between MHC Complexes and T Cells

3.1 Recognition and Activation of CD4+ and CD8+ T Cells

Once peptides are loaded onto MHC molecules, they are displayed on the cell surface for recognition by CD4+ (helper) and CD8+ (cytotoxic) T cells. This recognition occurs through the interaction between the T-cell receptor (TCR) and the MHC-peptide complex, resulting in the activation of these T cells.

3.2 Co-stimulation and Signaling Pathways

Activation of T cells is not solely dependent on the interaction between the TCR and MHC-peptide complexes. Co-stimulatory molecules play an essential role in providing secondary signals that enhance T cell activation, proliferation, and differentiation. This dual signal requirement helps to prevent inappropriate activation of self-reactive T cells and maintain self-tolerance.

3.3 Regulation and Homeostasis

The immune system employs various mechanisms to regulate the balance between T cell activation, proliferation, and differentiation. These regulatory processes are crucial in maintaining homeostasis and preventing excessive or prolonged immune responses that could lead to tissue damage and autoimmune diseases.

Chapter 4: MHC Polymorphism, Implications for Immune Responses, Transplantation, and Autoimmunity

4.1 MHC Polymorphism and its Genetic Basis

MHC molecules exhibit a high degree of polymorphism, with numerous alleles encoding different peptide-binding grooves. This diversity provides the immune system with the ability to recognize a vast array of pathogens and allows for greater adaptability in responding to new threats.

4.2 Implications for Immune Responses and Transplantation

MHC polymorphism has profound implications for immune responses, as the compatibility between donor and recipient MHC alleles can determine the success or failure of a transplant. The challenge lies in finding suitable matches to minimize the risk of rejection while ensuring adequate immune protection against pathogens.

4.3 Role in Autoimmune Diseases

MHC polymorphism also plays a significant role in susceptibility to autoimmune diseases, as certain MHC alleles can predispose individuals to develop specific autoimmune disorders. The underlying mechanisms contributing to this association are complex and multifactorial, involving both genetic and environmental factors.

Conclusion

The intricate process of antigen presentation by MHC molecules represents a cornerstone of adaptive immunity. Understanding the structure, function, and regulation of MHC proteins provides valuable insights into the mechanisms underpinning effective immune responses against pathogens while maintaining self-tolerance. Furthermore, this knowledge can aid in the development of strategies for improving transplant outcomes and managing autoimmune diseases.