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11 ASHI Quarterly First Quarter 2015 S C I E N T I F I C C O M M U N I C A T I O N S S C I E N T I F I C C O M M U N I C A T I O N S HLA and its Applications in Anthropological Sciences Siva Kanangat, PhD, D(ABHI) The Familiar Face of HLA The first thing that comes to mind when we think of HLA is its application in histocompatibility testing for solid organ and stem cell transplantation Historically, even with the limited capacity of the serological methods used in the infant and toddler ages of HLA, one thing was conspicuous: the polymorphic nature of HLA antigens The next innovations were molecular HLA typing powered by the polymerase chain reaction and modified Sanger sequencing technology with thin capillaries (with more read length in short periods of time) coupled with innovative software that further elucidated the extent of HLA polymorphisms at the molecular level Hence, in that major area of clinical histocompatibility testing, the explosion of knowledge on HLA polymorphisms and the ability to detect specific HLA antibodies has allowed us to make giant leaps from the knowledge base of the early 70s and 80s to the new millennium of improved histocompatibility matching and more successful long- term allograft survival; the contributions of improved surgical techniques and innovative immunosuppressive regimens are also acknowledged However, there is another side of HLA that is totally independent of histocompatibility and transplantation: immunogenetics This topic received a great deal of attention at the 40 th ASHI annual meeting in Denver, Colorado There is an anecdote saying, "HLA is the transplant surgeon's nightmare and the geneticist's dream " The Other Side of HLA The most intriguing feature of HLA genes is the extensive polymorphism, which leads us to the role of HLA in anthropology The 40 th annual meeting in Denver gave an extensive exposure to this aspect of HLA by incorporating several talks related to HLA polymorphisms and the distribution of alleles and haplotypes in various parts of the world Topics included the search of descendants using HLA, disease association, vaccine studies, and drug sensitivity 1 Before delving into the exciting role of HLA in anthropological studies, let us briefly examine how and why this particular group of genes exhibits such extreme polymorphisms, which will help us better understand the role of HLA in anthropology Why Such Extensive Polymorphism in HLA? The fundamental role of HLA is thymic education of T cells to distinguish self from non-self, and in the induction of adaptive immune responses to endogenously and exogenously derived antigens that are foreign or unknown to the host's specific defense system This process is mostly driven by infectious organisms Since the adaptive immune response is specific to the antigen or antigenic peptide in question, the machinery that presents these specific antigenic peptides to the T cells, namely the HLA molecule, needs to be as versatile as the ever-emerging and ever-evolving antigenic configurations of the microbes This is because the structure of each HLA allele predetermines its ability to present a specifically structured antigenic peptide to the limited T cell receptor repertoire So it is reasonable to postulate the emergence of new HLA alleles on a continuous basis HLA-A, B, and C are subject to strong multi-allelic balancing selection, which, with recombination, imbues human populations with diverse HLA alleles and haplotypes of distinctive structures and frequencies that provide selective advantages for survival 2 Figure 1. HLA and Immune Response Figure 1. The normal role of HLA molecules is to educate the T cells to recognize self from non-self and present the non-self-antigenic peptides to T cells so that T cells, and B cells with the help of T cells, can mount selective adaptive immune responses toward non-self-antigenic peptides derived from infectious agents, tumor cells. and any foreign antigenic material. By extending this fundamental role of HLA molecules to the field of allogenic transplantation, the HLA antigens/alleles act as markers that determine compatibility of tissues/organs for transplantation by the very basic education given by the HLA molecules to the T cells in recognizing self vs non-self. And as our improved HLA allele-level resolution becomes more widespread with the anticipated use of the next generation sequencing (NGS) technology, we will see more alleles being documented Unique structural features in the peptide binding groove of certain HLA alleles could be responsible for HLA and diseases associations and drug sensitivities B-CELLS HLA with a Peptide in the Groove Cells with foreign (non-self- antigens), Bacteria/Viruses Cytotoxicity, antibody, cytokines etc.