Genetics

Think of your genes as the ultimate instruction manual for your immune system. They dictate how your body builds its defense forces, from the incredible variety of B and T cell receptors that recognize invaders, to the critical HLA molecules that help distinguish your own cells from foreign ones (like those on transfused blood cells or transplanted organs). This genetic blueprint is why we inherit our blood types, why some people readily make antibodies after a transfusion while others don’t, and why finding compatible donors can be challenging

Genetics of the Immune Response: The Blueprint for Defense

Our genes control several key aspects of the immune response:

• Generating Receptor Diversity: How can our immune system recognize potentially billions of different antigens it has never seen before?
• Self vs. Non-Self Recognition: How does the immune system know what belongs to the body and what is foreign?
• Controlling the Response: How is the type and strength of an immune response regulated?
• Individual Variation: Why are some individuals more prone to making certain antibodies or rejecting grafts than others?

Let’s break these down:

Generating Receptor Diversity: The V(D)J Shuffle

The adaptive immune system relies on B cells (with their B cell receptors/antibodies) and T cells (with their T cell receptors or TCRs) to recognize specific antigens. The incredible diversity of these receptors doesn’t come from having billions of separate genes. Instead, it comes from a clever genetic process called gene rearrangement or V(D)J recombination

• The Problem: We need potentially billions of different antibody and TCR specificities to handle diverse threats
• The Genetic Toolkit: Within the DNA regions that code for the variable parts of antibodies (heavy and light chains) and TCRs (alpha, beta, gamma, delta chains), there are multiple different gene segments:
  • V (Variable): segments
  • D (Diversity): segments (only in heavy chains and some TCR chains)
  • J (Joining): segments
• The Process: As each individual B cell or T cell develops (in the bone marrow or thymus, respectively), it performs a “cut and paste” operation on its DNA:
  1. It randomly selects one V segment, one D segment (if applicable), and one J segment
  2. It cuts out the DNA in between these chosen segments
  3. It pastes the selected V, (D), and J segments together
  4. This newly assembled V(D)J sequence forms the variable region gene for that specific lymphocyte’s receptor
• Combinatorial Diversity: Since there are many different V, D, and J segments to choose from, the number of possible combinations is huge (thousands x dozens x several = millions!)
• Junctional Diversity: The “pasting” process is often imprecise, adding or deleting a few nucleotides at the junctions between segments. This creates even more variation right in the most critical antigen-binding part of the receptor
• Somatic Hypermutation (B cells only): After a B cell is activated by antigen and T cell help, its rearranged antibody genes undergo accelerated point mutations, especially in the variable region. B cells whose mutated receptors bind antigen better are preferentially selected to survive and proliferate. This affinity maturation leads to higher-affinity antibodies during the immune response (especially the secondary response)

Blood Bank Relevance

• This genetic shuffling is why you can make an antibody to virtually any foreign blood group antigen (like Kell, Duffy, Kidd, etc.) you might encounter through transfusion or pregnancy, even if you’ve never seen it before. Your body has B cells with pre-existing BCRs capable of recognizing that antigen, thanks to V(D)J recombination

Self vs. Non-Self Recognition: The MHC/HLA System

A critical part of immune function is distinguishing the body’s own cells from foreign invaders or altered self-cells (like infected or tumor cells). The Major Histocompatibility Complex (MHC) plays a central role here. In humans, the MHC is called the Human Leukocyte Antigen (HLA) system

• MHC/HLA Genes: Located in a dense cluster on Chromosome 6, these genes code for cell surface proteins that present antigen fragments to T cells
  • MHC Class I (HLA-A, HLA-B, HLA-C): Found on almost all nucleated cells. They present endogenous antigens (peptides from within the cell, like viral proteins or self-proteins) to CD8+ Cytotoxic T cells. Think of it as the cell showing the T cell what’s going on inside
  • MHC Class II (HLA-DP, HLA-DQ, HLA-DR): Found primarily on Antigen Presenting Cells (APCs) like macrophages, dendritic cells, and B cells. They present exogenous antigens (peptides from outside the cell that have been engulfed, like bacterial fragments or foreign proteins) to CD4+ T helper cells. Think of it as APCs showing T helper cells what they’ve found outside
• Extreme Polymorphism: The HLA genes are the most polymorphic genes known in humans – meaning there are hundreds or even thousands of different versions (alleles) of these genes in the human population. Each individual inherits a set of alleles from each parent. This vast diversity is great for the survival of the species (ensuring some individuals can always mount a response to new pathogens), but it makes finding compatible donors for transplantation very difficult
• Inheritance: HLA genes are inherited together as a block or set called a haplotype from each parent. You get one haplotype from your mother and one from your father. This is why siblings have a 25% chance of being HLA-identical
• T cell Education: During T cell development in the thymus, T cells learn to recognize self-MHC molecules presenting self-peptides. T cells that react too strongly (potential autoimmunity) or too weakly (useless) are eliminated. This ensures T cells are self-MHC restricted (only recognize antigen presented by your own MHC type) and self-tolerant (don’t usually attack your own tissues)

Blood Bank Relevance

• Transplantation: HLA matching between donor and recipient is CRITICAL for solid organ and hematopoietic stem cell transplantation. Mismatched HLA molecules are seen as foreign by the recipient’s T cells (or donor T cells in GVHD), leading to rejection or Graft-versus-Host Disease
• Platelet Refractoriness: Some patients become refractory (unresponsive) to platelet transfusions because they develop HLA antibodies (usually against Class I) from previous transfusions or pregnancies. These antibodies destroy the transfused platelets. HLA-matched platelets are often required
• Transfusion-Related Acute Lung Injury (TRALI): Often caused by antibodies in the donor’s plasma directed against the recipient’s HLA (or sometimes neutrophil) antigens, triggering neutrophil activation and lung injury
• Febrile Non-Hemolytic Transfusion Reactions (FNHTR): While often caused by cytokines, interactions between residual donor leukocytes and recipient antibodies (including HLA antibodies) can contribute
• Transfusion-Associated Graft-versus-Host Disease (TA-GVHD): Occurs when viable donor T lymphocytes engraft in a susceptible recipient and attack recipient tissues as foreign (recognizing different HLA). Irradiation prevents this by inactivating donor T cells

Blood Group Genetics: Inherited Antigens

Blood group antigens (like ABO, Rh, Kell, Duffy, Kidd, MNS, etc.) are molecules on the surface of red blood cells (and sometimes other cells). Their presence or absence is determined by specific genes inherited from our parents

• Genes Code for Antigens: Genes contain the instructions for making proteins or enzymes
  • Some blood group genes code directly for the antigen protein itself (e.g., the RHD and RHCE genes code for the RhD and RhCE proteins)
  • Other genes code for enzymes (often glycosyltransferases) that add specific sugar molecules onto a precursor substance on the cell surface, creating the antigen (e.g., the ABO genes code for transferases that create the A and B antigens from the H antigen precursor)
• Alleles Determine Phenotype: Different versions (alleles) of these genes result in different antigens being expressed (or no antigen being expressed, like the O allele in the ABO system or the d allele representing the absence of RHD)
• Mendelian Inheritance: Blood group genes are inherited according to standard Mendelian principles (dominant, recessive, co-dominant). This allows us to predict antigen types in families and populations

Blood Bank Relevance

• Compatibility Testing: The entire foundation of pre-transfusion testing relies on understanding the genetics of the ABO and Rh systems, and other clinically significant blood groups, to provide antigen-negative blood to patients with corresponding antibodies
• Alloimmunization: Genetic differences in blood group antigens between a blood donor/fetus and a recipient/mother are the reason alloimmunization occurs. If a recipient lacks an antigen (due to their genes) and receives blood positive for that antigen, their immune system may recognize it as foreign and produce an antibody
• Hemolytic Disease of the Fetus and Newborn (HDFN): Arises from genetic incompatibility (most famously RhD) between mother and fetus, leading to maternal antibody production against fetal antigens
• Predicting Antigen Frequency: Population genetics helps us know the frequency of various blood group antigens, which is useful for finding rare blood units

Genetic Control of Response Strength & Cytokines

Genes also influence the intensity and type of immune response

• Cytokine Genes: Genes control the production of cytokines (the chemical messengers of the immune system like interleukins, interferons, TNF). Polymorphisms (variations) in cytokine genes can lead to individuals producing higher or lower levels of certain cytokines, influencing inflammation and the direction of the immune response (e.g., favoring antibody production vs. cell-mediated immunity)
• Immune Regulatory Genes: Genes involved in controlling immune cell activation, proliferation, and apoptosis influence overall immune responsiveness

Blood Bank Relevance

• Explains some of the variability seen in patients – why some readily form antibodies after exposure while others exposed to the same antigens do not
• May influence susceptibility to certain transfusion reactions or the severity of HDFN

Summary

Genetics is intricately woven into every aspect of the immune response relevant to blood banking:

• V(D)J recombination: provides the genetic mechanism for the vast diversity of antibodies and T cell receptors needed to recognize foreign antigens, including blood group antigens
• The highly polymorphic HLA genes control antigen presentation and self/non-self discrimination, making them critical determinants in transplantation compatibility, platelet refractoriness, TRALI, and GVHD
• Blood group genes: dictate the presence or absence of red cell antigens, forming the basis for compatibility testing, alloimmunization risk, and HDFN
• Genetic variations in cytokine and regulatory genes contribute to the individual differences observed in immune responsiveness

Understanding these genetic underpinnings helps us appreciate why immune reactions occur in transfusion and transplantation medicine and guides the strategies we use to prevent them!

Key Terms

• Gene Rearrangement (V(D)J Recombination): The process by which developing B and T cells randomly select and combine V, D, and J gene segments to create the unique variable region gene for their specific antigen receptor (antibody or TCR). This is the primary mechanism for generating receptor diversity
• Somatic Hypermutation: A process occurring in activated B cells where point mutations are introduced into the variable region genes of antibodies. Coupled with selection, this leads to affinity maturation (higher binding strength antibodies)
• Major Histocompatibility Complex (MHC): A set of genes coding for cell surface proteins essential for antigen presentation to T cells and self/non-self recognition
• Human Leukocyte Antigen (HLA): The human MHC system, located on Chromosome 6. Includes Class I (HLA-A, -B, -C) and Class II (HLA-DP, -DQ, -DR) genes
• Polymorphism: The existence of multiple different forms (alleles) of a gene within a population. HLA genes are highly polymorphic
• Haplotype: A set of closely linked genes (like HLA genes) on a chromosome that are typically inherited together as a single unit
• Allele: A variant form of a specific gene. For example, A, B, and O are alleles of the ABO gene
• Blood Group System: A group of related blood group antigens controlled by a specific gene or set of closely linked genes (e.g., ABO system, Rh system, Kell system)
• Alloimmunization: The process of developing an immune response (specifically antibodies) against foreign antigens from the same species, typically encountered through transfusion or pregnancy. This is driven by genetic differences in antigen expression between individuals