The Arrangement of the Genes - Essay Example

?Evaluate how the arrangement of the genes which for T-cell receptors can account for the degree of variability observed in these receptors within an individual The human body is constantly bombarded with pathogens. Whenever we go outside, whenever we touch something, whenever we breathe, we take millions of possibly harmful microorganisms into the body. The only thing keeping us safe from them is our immune system. Our innate immune system (e.g. skin, mucous membranes, sneezing, blinking, excretion of waste, etc.) is the first responder and is responsible for most of the pathogens we encounter everyday. For the uncommon pathogens, we rely on our adaptive immune system to quickly develop and combat new and rare pathogens that the innate immune system cannot handle. That aside, it also changes itself to be prepared for a repeated attack by the same organism. It is amazing to think about how many harmful organisms are repelled again and again by this system that continuously changes to keep us safe. Some of the key players in our adaptive immune system are our T cell antigen receptors (TCR). They are ‘highly variable antigen-recognition structures’1 whose job is to recognize antigens and activate the appropriate lymphocytes to combat them. Since the TCRs are antigen-MHC compound specific and insoluble at the same time, isolating them was very difficult until scientists started using clonotypic monoclonal antibodies.2 With this method, they were able to determine that the TCRs were heterodimers of 2 sets of chain genes: the ?:? and the ?:? chains. The two have similar structures, but they detect different antigens. The ?:? is the most common (90-99%) while the ?:? is the minority (1-10%).3 The former detects antigens presented with Major Histocompatibility Complex (MHC) while the latter doesn’t need MHC to detect certain antigens. The genetic structure of the TCR is similar to that of the immunoglobulins (Ig) in B cells. It is composed of Variable (V) and Constant (C) regions. The variable region contains Variable (V), Joining (J) and Diversity (D) segments depending on whether the chain is a light or heavy immunoglobulin (or an ? or ?, or a ? or ? chain for a TCR). In heavy immunoglobulin chains, VDJ gene segments join together randomly, while in the light chains (Lambda and Kappa), they only have V and J segments to join. Combinatorial association in B cells further increases variability by giving the ability to create ‘any one possible heavy chain and any one possible light chain’ in all individual B cells.4 Because of the large number of possible gene rearrangements, the structure of Ig or TCR genes is virtually unique for each B or T lymphocyte.5 Figure 1 T-cell receptor ?- and ?-chain gene rearrangement and expression6 Since T cells also have antigen receptors like the immunoglobulin, they also have a similar process of gene rearrangement and expression. In Figure 1, we can see an ?- and ?-chain rearranging and coming together to form a TCR. The ?-chain gene rearrangement is similar to the light chain because they do not have a D? to combine. The ?-chain is also similar to the heavy chain because it combines V?, D? and J? gene segments. The less common ?- and ?-chains are structurally similar to the TCR?- and ?-chains, but with a few changes. The ? chain is found inside the TCR? chain, between the V? and the J? gene segments. This arrangement causes a loss of ? chain whenever the TCR?-chain rearranges, since any segments in between V? and J? will be deleted. The ?-chain is similar to the TCR?-chain in that it has V, D, and J segments. The ?:? receptors are largely a mystery to scientists as of the moment.7 One of the few things determined to be true is the fact that they can detect non-classical major histocompatibility complex class I molecules T10 and T22.8 Combinatorial association further increases the variability, making it possible to have a unique genetic arrangement for every T cell receptor. Figure 2 The numbers of human T-cell receptor gene segments and the sources of T-cell receptor diversity compared with those of immunoglobulins9 With all those factors contributing to the variability of the antigen receptors, it would not be hard to imagine the uniqueness of each receptor. The arrangement of genes in the receptors alone accounts for the total diversity seen on Figure 2. If you take that into account with the somatic hypermutation of immunoglobulins (generation of variant immunoglobulins in the V region of the DNA10), combinatorial association, multispecificity (cross reactions between antigenic determinants of similar structure allowing an antibody to react with more than one antigenic determinant11), and N region insertion (catalyzation of random polymerizations of nucleotides into DNA by terminal transferase at the junction of the J and D segments12) mechanisms, then we are looking at a truly wide variety of antigen receptors ready to combat any harmful microorganisms that may endanger the human body. Bibliography CHIEN, Y. H. and KONIGSHOFER, Y., ‘Antigen recognition by gammadelta T cells’, Immunology Review, 215 (Feb 2007), 46-58 , accessed 19 June 2012. GOLDSBY, R. A., KINDT, T. J., and OSBORNE, B. A., Kuby Immunology (5th edn.; New York: W.H. Freeman, 2006). JANEWAY, C. A. Jr., et al., Immunobiology: The Immune System in Health and Disease [online text] (5th edn.; New York; Garland Science, 2001), in NCBI Bookshelf, accessed 19 June 2012. MAYER, GENE, ‘Chapter Six: Genetics Of Immunoglobulins’, in David Male et al. (eds.), Immunology [online text] (South Carolina: The Board of Trustees of the University of South Carolina, 2011), in Microbiology and Immunology On-line, accessed 19 June 2012. WILLIAMS, M.E., et al., ‘Immunoglobulin and T cell receptor gene rearrangements in human lymphoma and leukemia’, Blood, 1987/69 (2011), 79-86, , accessed 19 June 2012. Read More