Decreased Frequency of Rearrangement due to the Synergistic Effect of Nucleotide Changes in the Heptamer and Nonamer of the Recombination Signal Sequence of the Vκ Gene A2b, Which Is Associated with Increased Susceptibility of Navajos to Haemophilus influenzae Type b Disease

Abstract

Navajos and genetically related populations have a 10-fold increased incidence of Haemophilus influenzae type b (Hib) disease compared with control populations. The Vκ gene A2 is used to encode the majority of anti-Hib Abs, and these are the highest affinity anti-Hib Abs. Navajos carry a different allele of the A2 gene segment (A2b) that is defective in its ability to undergo V-J recombination. The A2b allele has only three nucleotide changes from the commonly occurring A2a allele, two of which could potentially affect its ability to recombine. In this study we used two independent in vitro assays to test whether the nucleotide change found in the A2b promoter and/or in the A2b recombination signal sequence (RSS) might be responsible for the decrease in recombination frequency observed in vivo. Using a luciferase reporter gene assay, we found no significant difference between A2a and A2b promoter activities. However, the competition recombination substrate assay showed a 4.5-fold reduction in the relative frequency of recombination of the A2b RSS compared with A2a. We show that this decreased frequency is due to a synergistic effect of the unique nucleotide change present in the heptamer of the A2b RSS and the shared nucleotide change present in the nonamer of both A2b and A2a. This in vitro relative frequency of rearrangement is not significantly different from that observed in vivo; therefore, the A2b RSS is probably the factor associated with the increased susceptibility to Hib disease among individuals carrying the A2b allele.

Disparities in Outcomes During Lower Respiratory Tract Infection in American Indian Children

“…11 In addition, genetic variation in carnitine palmitoyl transferase type 1A and Vk gene A2b have also been implicated in increased severity of infectious diseases among Indigenous populations. 14,15 Similar to other publications, our study shows increased rates of secondhand smoke exposure, decreased rates of complete vaccination including Influenza virus vaccine, and decreased rates of breast-feeding in AI children. However, our multivariate analysis showed that AI ethnicity alone was an independent predictor for PICU admission, longer length of hospitalization, and oxygen supplementation.…”

“…8,9 This difference in morbidity and mortality between AI and non-AI children is poorly understood. Factors including remote access to healthcare facilities, 10 household crowding, 11 secondhand smoke exposure, 12 breast-feeding history, 13 and genetic predisposition 14,15 have been identified as factors increasing the risk for LRTI infection among AI children.…”

Analysis of IGH allele content in a sample group of rheumatoid arthritis patients demonstrates unrevealed population heterogeneity

“…A similar observation to the IGHV4-34*01_S0742 allele, where an RSS polymorphism affected the V gene usage, was reported for a variant kappa V gene, IGKV2-29D, enriched in a Native American population. In that study the variant was associated with Haemophilus influenzae type b susceptibility ( 39 , 40 ). Of critical importance to this study was the observation that the frequency of the heterozygous IGHV4-34 variant in the patient group was identical to that found in the matched control group.…”

Determinants ofde novoB cell responses to drifted epitopes in post-vaccination SARS-CoV-2 infections

“…Finally, V gene usage during V(D)J recombination that gives rise to B cell receptors is uneven, as some segments are more heavily utilized than others 64,65 . In turn, this can create ‘holes’ in the repertoire, rendering some epitopes poorly immunogenic 66 . As SARS-CoV-2 variants of concern accumulate mutations in antigenic regions, immunodominance might change in ways that limit responses to drifted epitopes, with or without prior immunity.…”