Immunology Of Human Leukocyte Antigens

Introduction

This article aims to provide a comprehensive understanding of the immunology of human leukocyte antigens (HLA) for medical students preparing for the United States Medical Licensing Examination (USMLE). HLA molecules play a crucial role in immune recognition and response, making them essential for understanding transplantation, autoimmune diseases, and immune-related disorders.

Human Leukocyte Antigens (HLA)

Definition

HLA, also known as major histocompatibility complex (MHC) molecules, are cell surface proteins that regulate immune responses by presenting antigens to T lymphocytes. These antigens can be self or non-self, leading to activation or suppression of immune responses.

Classification

HLA molecules are categorized into two classes: Class I and Class II.

1. Class I HLA molecules: Expressed on almost all nucleated cells, Class I HLA molecules consist of three loci: HLA-A, HLA-B, and HLA-C. They present antigens derived from intracellular pathogens to cytotoxic CD8+ T cells.

2. Class II HLA molecules: Expressed primarily on antigen-presenting cells (APCs) such as macrophages, dendritic cells, and B cells, Class II HLA molecules consist of three loci: HLA-DP, HLA-DQ, and HLA-DR. They present antigens derived from extracellular pathogens to helper CD4+ T cells.

Polymorphism

HLA molecules exhibit a high degree of polymorphism, meaning there are numerous alleles for each HLA gene. This diversity enables individuals to recognize a wide range of antigens, enhancing immune responses against various pathogens.

HLA Typing

HLA typing is performed to determine an individual's specific HLA alleles. This process is crucial for organ and tissue transplantation, as well as identifying disease susceptibility and compatibility for blood transfusions.

HLA and Transplantation

Histocompatibility

Transplantation requires histocompatibility between the donor and recipient to minimize the risk of rejection. HLA matching is a critical factor in determining compatibility, especially for solid organ and bone marrow transplantation.

HLA Matching and Rejection

• Hyperacute rejection: Occurs immediately after transplantation due to pre-existing recipient antibodies against donor HLA antigens.

• Acute rejection: Results from a cellular immune response against mismatched HLA antigens, primarily mediated by CD8+ T cells.

• Chronic rejection: Develops over time due to a continuous immune response against minor HLA mismatches and non-HLA antigens.

HLA and Graft-Versus-Host Disease (GVHD)

GVHD occurs when transplanted immunocompetent T cells from the donor recognize the recipient's tissues as foreign. HLA mismatching between the donor and recipient increases the risk of GVHD.

HLA and Autoimmune Diseases

Genetic Susceptibility

Certain HLA alleles are associated with an increased risk of developing autoimmune diseases. For example:

• HLA-B27: Associated with ankylosing spondylitis, reactive arthritis, and other seronegative spondyloarthropathies.

• HLA-DR3 and HLA-DR4: Associated with increased susceptibility to type 1 diabetes, rheumatoid arthritis, and systemic lupus erythematosus.

Molecular Mimicry

Some HLA alleles can present self-antigens derived from infections, leading to molecular mimicry. This phenomenon may trigger autoimmune responses, potentially causing tissue damage.

HLA and Immune-Related Disorders

HLA and Drug Hypersensitivity

Certain drugs can bind to HLA molecules and form stable complexes, resulting in an immune response against the drug-HLA complex. This immune reaction can lead to severe hypersensitivity reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis.

HLA and Hypersensitivity Reactions

HLA molecules play a role in drug-induced hypersensitivity reactions, including type I (immediate) and type IV (delayed) hypersensitivity reactions. HLA-B*57:01 is strongly associated with hypersensitivity to the antiretroviral drug abacavir.

Conclusion

Understanding the immunology of HLA molecules is crucial for comprehending transplantation, autoimmune diseases, and immune-related disorders. This comprehensive guide provides medical students with the necessary knowledge to tackle related questions on the USMLE.