HLA

Consideration of HLA broadens our scope beyond the red cell membrane itself. While not traditional “blood group” antigens located on mature red blood cells, Human Leukocyte Antigens (HLA) are critically important surface proteins found on leukocytes, platelets, and almost all other nucleated cells. Encoded by the highly polymorphic Major Histocompatibility Complex (MHC) genes on chromosome 6, HLA molecules are essential for the immune system’s ability to distinguish ‘self’ from ‘non-self’. Their extreme diversity and presence on transfused platelets and contaminating white cells in other components make them highly relevant in transfusion medicine, particularly concerning platelet refractoriness, febrile reactions, and transfusion-related acute lung injury (TRALI)

HLA: The Immune System’s ID Card

• What are they?: HLA antigens are proteins found on the surface of almost all nucleated cells in the body. This includes white blood cells (leukocytes) and platelets. Critically, mature red blood cells generally lack HLA antigens, although platelets and contaminating leukocytes in RBC units do have them
• What’s their job?: Their main biological role is to present peptide fragments (from inside the cell, like viral proteins, or from outside, like bacterial proteins) to T-lymphocytes, initiating adaptive immune responses

Biochemistry and Genetics: Why HLA is SO Complex

• Major Histocompatibility Complex (MHC): HLA genes are located within a region on Chromosome 6 called the Major Histocompatibility Complex (MHC). This is one of the most gene-dense regions in the human genome
• Two Main Classes
  • HLA Class I (HLA-A, HLA-B, HLA-C): Found on virtually all nucleated cells and platelets. They primarily present peptides from within the cell (e.g., viral proteins, tumor antigens) to CD8+ cytotoxic T-lymphocytes
  • HLA Class II (HLA-DR, HLA-DQ, HLA-DP): Found primarily on antigen-presenting cells (APCs) like B-lymphocytes, monocytes, macrophages, and dendritic cells. They present peptides derived from outside the cell (e.g., bacterial proteins) to CD4+ helper T-lymphocytes
• Inheritance: HLA genes are inherited together as a block from each parent, called a haplotype. You get one haplotype from your mother and one from your father
• EXTREME Polymorphism: This is the absolute key feature! The HLA system is the most polymorphic genetic system known in humans. There are thousands of different known alleles (versions) for the major HLA genes (especially HLA-A, -B, and -DR). This incredible diversity means it’s very rare for two unrelated individuals to have identical HLA types. This diversity is great for the species’ ability to fight off diverse pathogens but makes finding compatible donors (for transfusion or transplantation) challenging

HLA vs. Red Cell Antigens: Key Differences

Feature	Red Cell Antigens (e.g., ABO, Rh)	HLA Antigens
Location	Primarily RBC membrane	Nucleated cells, Platelets
Primary Role	Structural, Transport, Enzymatic	Immune Recognition (Self/Non-self)
Polymorphism	Variable (some high, some low)	EXTREMELY High
Primary Impact	RBC Transfusion (Hemolysis), HDFN	Platelet Transfusion, TRALI, FNHTR, Transplantation

Clinical Relevance in Transfusion Medicine

Even though mature RBCs lack HLA, the presence of HLA antigens on platelets and contaminating leukocytes in blood components leads to several critical issues:

• Platelet Refractoriness (Immune-Mediated)
  • What it is: The patient doesn’t achieve the expected increase in platelet count after a platelet transfusion
  • HLA Role: The most common immune cause is the presence of recipient antibodies against donor HLA Class I antigens on the transfused platelets. These antibodies destroy the transfused platelets rapidly. (Antibodies to Platelet-Specific Antigens, HPA, are the other main immune cause)
  • Management: Requires providing HLA-matched or compatible platelets, where the donor platelets lack the HLA antigens the patient has antibodies against. Platelet crossmatching can also help select compatible units
• Febrile Non-Hemolytic Transfusion Reactions (FNHTR)
  • What it is: Fever and chills during or shortly after transfusion, without red cell destruction
  • HLA Role: Often caused by recipient antibodies reacting with HLA antigens on donor leukocytes (WBCs) present in the component. This interaction, or the presence of cytokines released from WBCs during storage, triggers the fever
  • Management: Largely prevented by Leukoreduction (filtering out most WBCs) of blood components
• Transfusion-Related Acute Lung Injury (TRALI)
  • What it is: A serious, potentially fatal complication characterized by acute respiratory distress and non-cardiogenic pulmonary edema occurring during or within 6 hours of transfusion
  • HLA Role: The most common mechanism involves donor antibodies (usually HLA Class I or Class II, or HNA - Human Neutrophil Antigens) directed against recipient leukocytes. These antibodies activate neutrophils in the recipient’s lungs, leading to capillary leakage and lung injury
  • Management: Primarily involves risk mitigation strategies, such as using plasma predominantly from male donors or female donors who have never been pregnant or have been tested and are negative for HLA antibodies (as pregnancy is a major route of HLA sensitization). Leukoreduction is not effective in preventing antibody-mediated TRALI
• Transfusion-Associated Graft-versus-Host Disease (TA-GVHD)
  • What it is: A rare but usually fatal complication where viable donor T-lymphocytes in a transfused component engraft in the recipient and attack the recipient’s tissues
  • HLA Role: Risk is highest when the recipient is immunocompromised or when the donor is homozygous for an HLA haplotype that the recipient is heterozygous for (making the recipient appear “foreign” to the donor lymphocytes, but the donor lymphocytes aren’t seen as foreign by the recipient initially)
  • Management: Prevented by Gamma Irradiation of cellular blood components for at-risk patients, which inactivates donor T-lymphocytes

HLA Antibodies

• Formation: Individuals become sensitized (form antibodies) to HLA antigens primarily through:
  • Pregnancy: Exposure to paternal HLA antigens on fetal cells
  • Transfusion: Exposure to HLA antigens on donor platelets and WBCs
  • Transplantation: Exposure to donor organ/tissue HLA antigens
• Type: Usually IgG

HLA Testing

• Performed in specialized HLA or Histocompatibility laboratories, not typically in the routine blood bank
• Methods: Include serological methods (complement-dependent cytotoxicity - CDC) and, more commonly now, molecular (DNA-based) methods which provide higher resolution typing. Antibody screening and identification are also performed
• Purpose: Primarily for transplantation matching (donor-recipient), identifying antibodies causing platelet refractoriness or TRALI, and selecting HLA-compatible donors

Mitigation Strategies in Blood Banking

• Universal Leukoreduction: Removing WBCs from RBC and platelet components significantly reduces FNHTR risk and may reduce HLA alloimmunization
• HLA-Selected Platelets: Providing HLA-matched or antigen-negative platelets for refractory patients
• TRALI Risk Mitigation Strategies: Managing plasma inventory based on donor history (sex, pregnancy)
• Irradiation: Preventing TA-GVHD in susceptible patients

Key Terms

• HLA (Human Leukocyte Antigen): Proteins found on the surface of most nucleated cells and platelets, encoded by genes in the Major Histocompatibility Complex (MHC), crucial for immune recognition and distinguishing self from non-self
• MHC (Major Histocompatibility Complex): A large genetic region on chromosome 6 containing the genes that code for HLA proteins
• Polymorphism: The existence of many different forms (alleles) of a gene within a population. The HLA system is extremely polymorphic
• Haplotype: A set of closely linked genes (like HLA genes) on a chromosome that are typically inherited together as a single unit
• Leukoreduction: The process of filtering blood components (RBCs, platelets) to remove the vast majority of white blood cells (leukocytes). Primarily used to reduce the risk of FNHTR, CMV transmission, and possibly HLA alloimmunization
• Platelet Refractoriness: The failure to achieve the expected rise in platelet count after platelet transfusion, often due to immune destruction of transfused platelets by recipient HLA or HPA antibodies
• FNHTR (Febrile Non-Hemolytic Transfusion Reaction): A common transfusion reaction characterized by fever and chills without red cell hemolysis, often caused by recipient antibodies to donor leukocyte HLA antigens or by cytokines released from leukocytes during storage
• TRALI (Transfusion-Related Acute Lung Injury): A serious transfusion reaction characterized by acute respiratory distress, often caused by donor antibodies (HLA or HNA) reacting with recipient leukocytes, leading to pulmonary edema
• Alloimmunization: The development of antibodies in response to foreign antigens (from a different individual of the same species) encountered through transfusion, transplantation, or pregnancy
• HPA (Human Platelet Antigen): Antigens specific to platelets, distinct from HLA antigens. Antibodies to HPAs are another cause of immune-mediated platelet refractoriness and neonatal alloimmune thrombocytopenia (NAIT)