Naive antibody gene-segment frequencies are heritable and unaltered by chronic lymphocyte ablation

Abstract

A diverse antibody repertoire is essential for an effective adaptive immune response to novel molecular surfaces. Although past studies have observed common patterns of V-segment use, as well as variation in V-segment use between individuals, the relative contributions to variance from genetics, disease, age, and environment have remained unclear. Using high-throughput sequence analysis of monozygotic twins, we show that variation in naive V H and D H segment use is strongly determined by an individual's germ-line genetic background. The inherited segment-use profiles are resilient to differential environmental exposure, disease processes, and chronic lymphocyte depletion therapy. Signatures of the inherited profiles were observed in class switched germ-line use of each individual. However, despite heritable segment use, the rearranged complementarity-determining region-H3 repertoires remained highly specific to the individual. As it has been previously demonstrated that certain V-segments exhibit biased representation in autoimmunity, lymphoma, and viral infection, we anticipate our findings may provide a unique mechanism for stratifying individual risk profiles in specific diseases.heritable variation | next generation sequencing | V-gene S pecific biases in the antibody repertoire have been found in many diseases, from viral infections to cancers to autoimmune disorders (1-15). Although it is possible that heritable variation in the composition of the antibody repertoire could alter inherent risk to specific diseases, the diversity of the antibody repertoire has hindered direct characterization of heritable influences.Early twin studies provided some evidence of genetic variation affecting reactive titers from the antibody repertoire. Multiple studies observed both total Ig and antigen-specific titers to be more correlated in monozygotic twins than dizygotic twins or unrelated individuals (16)(17)(18). In some cases of monozygotic twins discordant for autoimmune diseases, the healthy twin often shared high autoantibody reactive titers with their affected twin (16,19,20).Early sequencing studies were able to identify some systematic biases in the antibody repertoire with limited sampling depth. The first sequencing studies to characterize V(D)J diversification mechanisms identified the gene segment recombination process, but also implied a repertoire too diverse to exhaustively interrogate by traditional sequencing technologies (21). Complete characterization of V-segment loci established ∼50 V H , 40 V κ , and 30 V λ segments in an individual, with a number of allelic variants for the majority of segments (22)(23)(24). Evaluation of use across individuals revealed biased V-gene representation that preceded selection (25)(26)(27). Quantitative PCR of V-gene families showed family use largely stable over time, with fluctuations in use correlated to antigen-specific responses (28). In the T-cell receptor (TCR) repertoire, TCRB-V use was more highly correlated in healthy monozygotic twins than unrelated individua...

CNS Aquaporin‐4‐specific B cells connect with multiple B‐cell compartments in neuromyelitis optica spectrum disorder

“…The VH family distribution of the naive B cells approximated the expected germline frequency with a slight overrepresentation of the VH5 family across the different populations (average distribution of VH1 19%, VH2 5%, VH3 34%, VH4: 23%, VH5: 12%). VH family distributions were similar to those reported by Glanville et al14, 15 and demonstrated no significant differences between peripheral blood B‐cell populations (Fig. S1).…”

The immunoglobulin heavy chain locus: genetic variation, missing data, and implications for human disease

“…Such descriptions will allow for more complete characterization of duplicated and deleted IGHV gene haplotypes, which likely make important contributions to an individual's expressed B-cell repertoire. 6,7 The pairing of genomic data to expressed repertoire deep sequencing will also be important for understanding direct connections between germline variation in the IGHV cluster and expressed repertoire variability between individuals. Currently, it is not fully known how well genetic variation in the IGHV gene cluster is represented by highthroughput genomic methods; however, analyses conducted in this review suggest that a portion of known variants have likely not been captured by GWAS.…”

“…IGHV gene usage frequencies were also correlated in antigen-experienced repertoires between monozygotic twin pairs, and despite minor differences for particular IGHV genes, gene usage in antigen-experienced repertoires reflected observed usage in the naive repertoires for many IGHV genes. 7 As discussed by Glanville et al, 7 this finding is critically important to our understanding of the role of expressed repertoires in disease, as there are many instances in which biased gene usage in antibody repertoires has been associated with particular infectious or autoimmune diseases. It is also interesting to note that a recent investigation of expressed repertoires in fetal cord blood samples from two infants suggests that IGHV gene usage biases differ between cord blood repertoires and adult repertoires.…”

“…Indeed, IG loci are among the most dynamic regions of the human genome, known to exhibit high allelic and copy number variation (CNV). Importantly, germline variation contributes to differences in antibody function, 5 and is also reflected in interindividual variation of expressed naive antibody repertoires, 6,7 which are now known to be heritable. 7 Despite the primary role of antibodies in the adaptive immune system, few connections between specific IG polymorphisms and disease have been unequivocally established.…”

“…Importantly, germline variation contributes to differences in antibody function, 5 and is also reflected in interindividual variation of expressed naive antibody repertoires, 6,7 which are now known to be heritable. 7 Despite the primary role of antibodies in the adaptive immune system, few connections between specific IG polymorphisms and disease have been unequivocally established. Most known associations were discovered using candidate gene approaches, and have not been confirmed by subsequent candidate gene studies or in more recent genome-wide association studies (GWAS).…”