The figure was generated from data inElhanati et al. models to BCR repertoires and discuss the issues we believe need be addressed for this interdisciplinary field to flourish. Keywords:molecular evolution, B-cell receptor, diversity, immunoglobulin, infection. == Introduction == The adaptive immune system ensures the survival of humans and other vertebrates in the face of rapidly evolving and genetically diverse infectious diseases. B lymphocytes are an essential component of this system and express receptors on their cell surface (B-cell receptors; BCRs) capable of specifically binding foreign antigens. BCRs are membrane-bound immunoglobulins composed of two large heavy chain molecules and two smaller light chain molecules, encoded in humans by the genesIGHandIGL(orIGK), respectively. The diversity of BCRs expressed by an individuals B cells is vast, and comprises both naive receptors that are randomly generated from the germline during development, as well as receptors that are retained after successfully binding antigen during previous infections. Populations of BCRs MK-2894 can rapidly improve antigen binding during infection through an evolutionary process of mutation and selection known as affinity maturation (Liu et al. 1991). Because BCR sequences are diverse and diverge rapidly, concepts from molecular evolution should be beneficial in understanding the dynamics of the adaptive immune system within individuals. T-cell receptors (TCRs) are a second class of immune receptors that can bind foreign antigen. Although diverse TCRs are also generated randomly from germline gene sequences, and their comparison with BCRs can be illuminating, TCRs do not undergo affinity maturation nor exhibit rapid evolution during infection. Therefore in this review, we focus solely on BCR biology. Apart from molecular assays that MK-2894 characterize sequence length polymorphisms (e.g., TCR immunoscope assays; seeBercovici et al. 2000) there was, until recently, a paucity of data on within-individual BCR sequence diversity for researchers to explore. That situation has now changed with the application of next-generation sequencing to BCRs (Boyd et al. 2009;Six et al. 2013). With this technique, researchers can directly observe the somatic genetic changes that generate the diversity of the BCR repertoire, providing an unprecedented picture of the adaptive immune system as an evolving population of cells. Analyses of these data from an evolutionary perspective have led to insights into the aging of the B-cell repertoire (Wang, Liu, Xu, et GP9 al. 2014) and into the process of affinity maturation (Elhanati et al. 2015;Yaari et al. 2015), and have many applications across a broad range of diseases (seetable 1). == Table 1. == .Applications of BCR Repertoire Sequencing. Potential for use as vaccine targets (Haynes et al. 2012) Provide model system MK-2894 for understanding affinity maturation, coevolution, and immune development (e.g.,Wu et al. 2015) Lineages are often large and diverse, often with high levels of MK-2894 hypermutation, long CDR3s, and poly reactivity (Haynes et al. 2012) A model system for immune response with a known stimulus (Galson et al. 2014) Identifying correlates of immune protection following vaccination Distinguishing vaccine-specific changes to the BCR repertoire from healthy repertoire diversity Variable immune responses among individuals to the same stimulus (Ademokun et al. 2011;Jiang et al. 2013) Identifies migration of B cells between tissue compartments (von Bdingen et al. 2012) Can identify the sites at which B cells mature (Stern et al. 2014) Accurate B-cell lineage assignment Modeling potentially complex migration patterns Differential sampling between tissues A direct and potentially cheap diagnosis tool Improved understanding of disease Provide clinical markers of disease progression (Robinson et al. 2013) Complex and multiple disease.