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Immunology

Genetics

This is a fascinating and mind-bending topic. It gets to the very heart of the question: How does our body prepare for an almost infinite number of potential enemies (antigens) using a finite amount of genetic information? The answer is one of the most elegant and clever systems in all of biology

Think of your genome as a dictionary. For most body systems, the dictionary has a specific word (a gene) for every specific protein it needs to make. But the immune system can’t work that way; it would need a dictionary with billions of words to be ready for every possible pathogen. Instead, the immune system has a handful of letters and a set of rules for combining them into new, unique “words” on the fly

Let’s explore the three main genetic systems that make the adaptive immune response possible: Antibody diversity, T-cell receptor diversity, and the Major Histocompatibility Complex (MHC)

Part 1: Genetic Lottery - Generating Antibody and B-Cell Receptor Diversity

The central paradox of immunology is that each human can produce more than 10^11 (100 billion) different types of antibodies, yet we only have about 20,000 protein-coding genes in our entire genome. There is no one-gene-one-antibody system. The solution is a remarkable process of somatic recombination that occurs as B-cells mature in the bone marrow

Imagine you have a box of Lego blocks, with a few different shapes and colors. You could build hundreds of different unique structures by combining them in different ways. This is exactly what a developing B-cell does with its DNA

  • Gene Segments, Not Whole Genes: The genes that code for the variable regions of antibodies (the part that binds to the antigen) are not present as a single, complete gene. Instead, they exist in the DNA as scattered clusters of gene segments

    • For the antibody Heavy Chain, there are segments called V (Variable), D (Diversity), and J (Joining)
    • For the antibody Light Chain, there are only V and J segments

  • V(D)J Recombination: As a B-cell matures, special enzymes, most notably RAG-1 and RAG-2 (Recombination-Activating Genes), act like a pair of molecular scissors and glue. They randomly select and stitch together one V segment, one D segment, and one J segment for the heavy chain, and one V and one J for the light chain. All the DNA in between is permanently deleted from that cell’s genome. This random “cut and paste” job creates a brand new, unique gene that codes for the variable region of that B-cell’s antibody

  • This is a One-Time, Permanent Edit: Each B-cell performs this genetic gamble only once. The resulting antibody gene is then fixed for the life of that cell and all of its future clones. This ensures that a single B-cell is locked into producing only one specific type of antibody

  • Other Sources of Insane Diversity: V(D)J recombination is just the start. Two other mechanisms amplify this diversity to astronomical levels:

    • Combinatorial Diversity: After making a pool of unique heavy chains and a pool of unique light chains, any heavy chain can pair with any light chain. This exponentially increases the total number of possible antibody-binding sites
    • Junctional Diversity: The RAG enzymes are intentionally “sloppy.” When they cut and paste the DNA segments, another enzyme called TdT comes in and adds random extra nucleotides at the junctions. This creates even more variability right in the most critical part of the antigen-binding site

This entire process generates a massive, diverse army of naive B-cells before the body ever sees an antigen. It’s a proactive system that tries to create a receptor for anything it might possibly encounter in the future

Part 2: T-Cell Receptor (TCR) Diversity - A Familiar Story

The T-cell faces the same problem as the B-cell: how to create millions of unique T-cell receptors (TCRs). The good news is that nature found a great solution and decided to use it again

The generation of TCR diversity is almost identical to the process for antibodies * The genes for the TCR chains (alpha and beta chains) also exist as V, D, and J segments * The same RAG enzymes perform the random cutting and pasting * The same process of junctional diversity adds extra variability

The fundamental genetic mechanism is conserved, but the final product is different—a TCR that stays on the T-cell surface instead of a secreted antibody

Part 3: MHC System - A Different Kind of Diversity

While antibody and TCR diversity is all about creating variety within an individual, the Major Histocompatibility Complex (MHC) is about creating variety across the entire human population

MHC molecules are the “serving platters” that present peptide antigens to T-cells. The specific shape of the platter determines which peptides it can hold and present effectively. You want a population with many different kinds of platters to ensure that no single pathogen can evolve to be “invisible” to everyone. The MHC system achieves this through three key genetic principles:

  • Polygenic: The MHC system is encoded by a cluster of genes, not just one. For example, MHC Class I is encoded by the HLA-A, HLA-B, and HLA-C genes. MHC Class II by HLA-DP, HLA-DQ, and HLA-DR genes. (HLA stands for Human Leukocyte Antigen, the human version of MHC). You get a set of these from each parent

  • Polymorphic: This is the most important concept. For each of these HLA genes, there are hundreds or even thousands of different versions, or alleles, in the human population. This makes the HLA genes the most polymorphic genes in the human genome. This massive diversity at the population level ensures that it’s extremely rare for two unrelated individuals to have the exact same set of MHC molecules

  • Co-dominant Expression: You express the alleles you inherit from both your mother and your father simultaneously. This doubles the variety of MHC molecules you have on your cells, increasing the range of peptides you can present

Clinical Significance for the Lab

  • Transplantation (Histocompatibility): The extreme polymorphism of the HLA system is why finding a compatible organ or bone marrow donor is so difficult. The recipient’s T-cells will see the donor’s “foreign” HLA molecules as a threat and attack them, causing transplant rejection. A huge part of the clinical immunology lab is dedicated to HLA typing to find the closest possible match between donor and recipient

  • Autoimmune Disease Susceptibility: An individual’s specific set of HLA alleles is strongly associated with their risk of developing certain autoimmune diseases. For example, over 90% of people with Ankylosing Spondylitis have the HLA-B27 allele. The theory is that this specific “serving platter” is particularly good at presenting a self-antigen that triggers an autoimmune response

  • Immunodeficiency: Rare genetic defects in the RAG genes are catastrophic. A person born with non-functional RAG enzymes cannot perform V(D)J recombination. This means they cannot produce any functional B-cells or T-cells, a condition known as Severe Combined Immunodeficiency (SCID)