This week marks two important science holidays: DNA Day (April 25) and Day of Immunology (April 29). DNA Day marks the anniversary of the 1953 publication of the double-helix structure of DNA and the 2003 completion of the Human Genome Project. Day of Immunology celebrates the understanding of this crucial field. In celebration, let’s look back at a bit of science that combines both genetics and immunology: antibody recombination!
Antibodies, or immunoglobulins, are components of the adaptive immune system, made by B cells in response to activation with an antigen. The DNA sequences encoding for antibody molecules allow for the production of different classes of antibodies with various heavy and light chain combinations. This is the promised link between immunology and DNA, as the process of generating the repertoire of antibodies present in any individual is based on permanent changes in the DNA of the B cell.
From the individual loci coding for heavy chains and light chains, there are, in theory, the possibility of producing tens of billions of unique antibodies. For B cells to actually produce any of these possible antibodies requires multiple steps of recombination, leading to the deletion of intermediate regions of DNA that are ultimately not translated into the immunoglobulin protein. V(D)J recombination is the process by which the gene segments encoding heavy and light chains are spliced together in each B cell. These chains then join to become a complete antibody molecule.
Five classes of antibodies can be made, as determined by the number of possible heavy chains encoded in the genome. The class of antibody produced by a B cell changes over the course of the immune response to a pathogen. The first type of antibody to be produced by B cells is IgM, which can be made by developing B cells even before they enter circulation. IgM can either be found in the membrane and function as an antigen receptor, or secreted as a pentamer, which upon binding of antigen can activate the complement system. IgD antibodies, which function almost exclusively as cell-surface antigen receptors, are also produced early in an immune response by B cells that have begun to circulate throughout the body. Later on, IgM-producing B cells can switch to producing other classes of antibody, such as IgG, IgA, and IgE, based on antigen stimulation and cytokine signaling in the immune microenvironment.
IgG, IgA, and IgE antibodies each have specific functional advantages over IgM and IgD antibodies. IgG is a key component in the mediation of antibody-dependent cellular cytotoxicity (ADCC). IgA is present in secretions from mucosal sites along the respiratory and digestive tracts. IgE is critical in allergic responses by mediating the immune response from basophils and mast cells that leads to the secretion of histamine.
The specificity and affinity of the antigen-binding region of an antibody is also based on DNA mutations. In this case, a small region of each the heavy and light chain, known as the hypervariable loops, can undergo point mutations that may lead to enhanced affinity for the target antigen. This process, known as somatic hypermutation, occurs towards the end of an immune response. The rapid proliferation of antigen-stimulated B cells naturally leads to mutations in the regions of the heavy and light chain loci corresponding to the antigen-binding domains of the antibody. In the case that a new, mutated antibody has a higher affinity for its antigen than its parent cell antibody, it is more likely to be stimulated—because stimulation of B cells induces their proliferation, the cycle of somatic hypermutation and proliferation ultimately leads to a repertoire of memory B cells that are highly specific for their target pathogen and help protect against repeat infections.
Altogether, a series of DNA splicing and mutations leads to the formation of a diverse and highly specific antibody repertoire. In the spirit of DNA Day and Day of Immunology, our understanding of this process clearly highlights the importance of cross-disciplinary collaborations, such as between genetics and immunology, for delving deep into complex questions in a particular field.
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