antibody repertoire dominated by few clones

The responsiveness of the peripheral repertoire to vaccination is also impaired during aging ( de Bourcy et al., 2017 Wang et al., 2014). In humans, antibody-repertoire sequencing has uncovered a number of important age-related changes, including reduced numbers of clones and unique sequences, increased baseline mutation, more frequent and larger clonal expansions, impaired B-cell selection, and a shift toward the memory compartment ( de Bourcy et al., 2017 Jiang et al., 2013 Wang et al., 2014). Sampling the resulting repertoire of antibody sequences in an individual using high-throughput sequencing can yield important insights into the diversity, clonal composition, and history of antibody-mediated immunity in that organism, as well as the effect of age, antigen exposure, and other factors on the diversity and functionality of the adaptive immune system ( Weinstein et al., 2009 de Bourcy et al., 2017 Miho et al., 2018). The efficacy of the humoral immune system rests on its ability to generate an enormous array of different antibody sequences, with a correspondingly vast range of antigen specificities, and to progressively adjust the composition of this antibody population in response to antigen exposure ( Schatz and Swanson, 2011 Di Noia and Neuberger, 2007 Magor, 2015 Elhanati et al., 2015). These changes are major contributors to a generalized immunosenescent phenotype that significantly impairs health and quality of life in the elderly. In the humoral immune system, aging is accompanied by a decline in naïve B-cell output from the primary lymphoid organs impaired production of specific antibodies in response to antigenic challenge and a decline in antibody quality ( Ademokun et al., 2010 Kogut et al., 2012 Sasaki et al., 2011 Aberle et al., 2013), as well as impairments in the establishment of novel immune memory ( Aberle et al., 2013). The adaptive immune system undergoes a severe and systemic decline in proper function with age, resulting in higher susceptibility to a wide range of infections and decreased efficacy of vaccination in elderly individuals ( Ademokun et al., 2010 Kogut et al., 2012 Dunn-Walters and Ademokun, 2010). organ-specific aging dynamics in the adaptive immune system. Our results highlight important differences in systemic vs. Lower intestinal repertoire diversity was also associated with transcriptomic signatures of reduced B-cell activity, supporting a functional role for diversity changes in killifish immunosenescence. The immune repertoires of isolated intestinal samples exhibit especially dramatic age-related diversity loss, related to an elevated prevalence of expanded clones.

Large, expanded B-cell clones exhibit far greater diversity loss with age than small clones, suggesting important differences in how age affects different B-cell populations. Whole-body killifish repertoires decline rapidly in within-individual diversity with age, while between-individual variability increases. Despite their extremely short lifespans, these killifish exhibit complex and individualized heavy-chain repertoires, with a generative process capable of producing millions of distinct productive sequences. Here, we perform the first study of immune-repertoire aging in an emerging model of vertebrate aging, the African turquoise killifish ( Nothobranchius furzeri). Previous studies have found a pervasive loss of immune-repertoire diversity in human peripheral blood during aging however, little is known about repertoire aging in other immune compartments, or in species other than humans. Aging individuals exhibit a pervasive decline in adaptive immune function, with important implications for health and lifespan.

Antibody repertoire dominated by few clones