![]() ![]() First, a combinatorial diversity in which recombination brings one of the 40-50 ‘V’ gene segments with a ‘D’ and ‘J’ gene segments at the germline followed by splicing of the C gene at the RNA-level. Figure 2A shows the assembly of a full-length BCR while Figure 2B shows the mechanism that generates a functional αβ TCR following V(D)J recombination of the V, D, J and C genes. The gene segments, referred to as the variable (V) gene, the joining (J) gene and an additional diversity (D) gene (for heavy-chain and β-chain) followed by a constant (C) gene is added to all receptors. Both the receptors are created by recombining multiple gene segments residing at multiple genomic loci in the germline DNA that are brought within a coding sequence during B and T cell development. More than 90% of TCRs are αβ TCR (Figure 2B), while the rest are γδ TCRs. TCRs are heterodimers of α and β polypeptide chains (αβ TCR), or γ and δ chains (γδ TCR). BCRs resemble the structure of an antibody with heavy and light chains and are membrane-bound (Figure 2A). Immune receptors expressed by the B cells (B cell receptors, BCRs) and T cells (T cell receptors, TCRs) are formed during B cell development in the bone marrow and T cell development in the thymus. Immune repertoire diversity – how is it generated? In this essay, I will give an overview of the immune receptors and discuss how MedGenome is leveraging the NGS data of immune receptor repertoire and developing tools that will not only enhance the fundamental knowledge of how our immune system works but also how the diversity can be interrogated to discover biomarkers of productive immune response eliminating pathogens, versus adverse response targeting body’s own cells leading to autoimmunity. Further, the receptor repertoire undergoes significant expansion and contraction during diseases and these changes have led to the development of novel diagnostics in the area of autoimmune diseases. Through these sequencing efforts, we know that two individuals, including monozygotic twins, do not share identical immune receptor repertoire, although each of us is capable of mounting an immune response against common pathogens indicating that there are enormous redundancy and plasticity in the recognition process. Figure 1: The figure shows the interaction between a T cell receptor and antigen in the context of MHC presented by an antigen presenting cell (APC) 1.ĭeeper insight into the immune-receptor diversity became possible with the advent of NGS and powerful bioinformatics and computational tools. It is estimated that there are 10 9 – 10 11 unique B cell receptors and 10 6 – 10 8 T cell receptors and about 301 known human leukocyte antigen (HLA) proteins expressed by the APCs in healthy humans. This diversity enables the immune system to identify and mount an attack against any foreign element invading from outside the body (bacteria, virus), or generated inside (tumor cells) protecting us from deadly diseases. The puzzle of how our immune system recognize new organisms/biomolecules that may not have existed when we were born was revealed by the work of Susumu Tonegawa and others who discovered that the recognition mechanism is mediated by a family of highly diverse immune receptors expressed by the cells of the adaptive immune system – B, T and antigen-presenting cells (APCs) (Figure 1). The miracle that makes this happen is our adaptive immune system, comprising of B and T cells, and a host of other regulatory cell-types that function as a central command to activate, mobilize and eventually suppress the army of rogue killers, once the threat is eliminated. It is a miracle of billion-years evolution that vertebrates, including us – the humans, are constantly thwarting attacks from an ever-expanding universe of foreign invaders such as bacteria, viruses and other pathogenic organisms throughout our lifetime. By Savita Jayaram Ph.D., Bioinformatics Scientist Keshav Bhojak, Bioinformatics Analyst, MedGenome Inc Introduction ![]()
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