Population-specific diversity of the immunoglobulin constant heavy G chain (IGHG) genes

Bashirova, Arman; Zheng, Wanjing; Akdag, Marjan; Augusto, Danillo G.; Vince, Nicolas; Dong, Krista; Ó'hUigín, Colm; Carrington, Mary

doi:10.1038/s41435-021-00156-2

Cited by 23 publications

(16 citation statements)

References 33 publications

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“…For example, the G1m-1,3 haplotype is dominant in individuals of European descent, while the G1m1,17 haplotype is more prevalent, reaching frequencies over 80%, within African and Asian populations as well as American and Australian First Nations peoples. 3,15,16 Here, we demonstrate that certain commercial anti-IgG1 antibodies display variable binding to G1m-1,3 and G1m1,17 IgG1 variants. We show that a detection antibody targeting the IgG1 hinge region preferentially binds G1m1,17 over G1m-1,3 variants, while IgG1 and pan-IgG clones raised against the Fc portion bind G1m-1,3 and G1m1,17 IgG1 equivalently.…”

Section: Introductionmentioning

confidence: 58%

“…As immunoglobulin allotypes are inherited in a Mendelian fashion, IgG1 haplotypes tend to cluster ethnically and geographically. For example, the G1m‐1,3 haplotype is dominant in individuals of European descent, while the G1m1,17 haplotype is more prevalent, reaching frequencies over 80%, within African and Asian populations as well as American and Australian First Nations peoples 3,15,16 …”

Section: Introductionmentioning

confidence: 99%

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Immunoglobulin G genetic variation can confound assessment of antibody levels via altered binding to detection reagents

Purcell,

Aurelia,

Esterbauer

et al. 2024

Clin & Trans Imm

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ObjectivesAmino acid variations across more than 30 immunoglobulin (Ig) allotypes may introduce structural changes that influence recognition by anti‐Ig detection reagents, consequently confounding interpretation of antibody responses, particularly in genetically diverse cohorts. Here, we assessed a panel of commercial monoclonal anti‐IgG1 clones for capacity to universally recognise two dominant IgG1 haplotypes (G1m‐1,3 and G1m1,17).MethodsFour commercial monoclonal anti‐human IgG1 clones were assessed via ELISAs and multiplex bead‐based assays for their ability to bind G1m‐1,3 and G1m1,17 IgG1 variants. Detection antibodies were validated against monoclonal IgG1 allotype standards and tested for capacity to recognise antigen‐specific plasma IgG1 from G1m‐1,3 and G1m1,17 homozygous and heterozygous SARS‐CoV‐2 BNT162b2 vaccinated (n = 28) and COVID‐19 convalescent (n = 44) individuals. An Fc‐specific pan‐IgG detection antibody corroborated differences between hinge‐ and Fc‐specific anti‐IgG1 responses.ResultsHinge‐specific anti‐IgG1 clone 4E3 preferentially bound G1m1,17 compared to G1m‐1,3 IgG1. Consequently, SARS‐CoV‐2 Spike‐specific IgG1 levels detected in G1m1,17/G1m1,17 BNT162b2 vaccinees appeared 9‐ to 17‐fold higher than in G1m‐1,3/G1m‐1,3 vaccinees. Fc‐specific IgG1 and pan‐IgG detection antibodies equivalently bound G1m‐1,3 and G1m1,17 IgG1 variants, and detected comparable Spike‐specific IgG1 levels between haplotypes. IgG1 responses against other human coronaviruses and influenza were similarly poorly detected by 4E3 anti‐IgG1 in G1m‐1,3/G1m‐1,3 subjects.ConclusionAnti‐IgG1 clone 4E3 confounds assessment of antibody responses in clinical cohorts owing to bias towards detection of G1m1,17 IgG1 variants. Validation of anti‐Ig clones should include evaluation of binding to relevant antibody variants, particularly as the role of immunogenetics upon humoral immunity is increasingly explored in diverse populations.

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Section: Introductionmentioning

confidence: 58%

Section: Introductionmentioning

confidence: 99%

Immunoglobulin G genetic variation can confound assessment of antibody levels via altered binding to detection reagents

Purcell,

Aurelia,

Esterbauer

et al. 2024

Clin & Trans Imm

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“…The constant region of the IgGs is encoded by the IGHG1-4 genes, which are highly homologous and polymorphic. IGHG polymorphisms have been associated with differences in the IgG half-life and effector functions [3]. Subsequently, they might be associated with heterogeneous neutralization-capacity and increased risk for infection and viral disease outcome.…”

Section: Introductionmentioning

confidence: 99%

“…IgG3 (encoded by the IGHG3 gene) is the unique subclass that varies in its hinge length by different copies of a 15 amino acid exonrepeat. The most common IGHG3 has 4 repeats, and a less common 3-repeats and rare 5-repeats have been reported [3]. Some studies have demonstrated that increased hinge length drives better phagocytosis and neutralization capacities, what is likely a consequence of greater flexibility that facilitates the binding to multiple epitopes [4,5].…”

Section: Introductionmentioning

confidence: 99%

IGHG3 hinge length variation was associated with the risk of critical disease and death in a Spanish COVID-19 cohort

et al. 2022

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IgG3 would play an important role in the immune adaptive response against SARS-CoV-2, and low plasma levels might increase the risk of COVID-19 severity and mortality. The IgG3 hinge sequence has a variable repeat of a 15 amino acid exon with common 4-repeats (M) and 3-repeats (S). This length IGHG3 polymorphism might affect the IgG3 effector functions. The short hinge length would reduce the IgG3 flexibility and impairs the neutralization and phagocytosis compared to larger length-isoforms. We genotyped the IGHG3 length polymorphism in patients with critical COVID-19 (N = 516; 107 death) and 152 moderate-severe but no-critical cases. Carriers of the S allele had an increased risk of critical ICU and mortality (p < 0.001, OR = 2.79, 95% CI = 1.66-4.65). This adverse effect might be explained by a less flexibility and reduced ability to induce phagocytosis or viral neutralization for the short length allele. We concluded that the IgG3 hinge length polymorphism could be a predictor of critical COVID-19 and the risk of death. This study was based on a limited number of patients from a single population, and requires validation in larger cohorts.

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“…As a result, no current AIRR-seq strategy resolves the complete heavy chain transcript, including all IGHC exons alongside the recombined IGHV, IGHD, and IGHJ genes. Our team has recently shown that population-based polymorphisms within the IGHV, IGHD, IGHJ and IGL loci are far more extensive than previously known; the IGHC region has also been shown to contain genomic diversity, although the extent of this diversity has likely not been fully explored (20)(21)(22)(23)(24)(25)(26)(27). Although it is understood that the Fc domain mediates Ab effector functions, there is limited knowledge as to how genetic variation in this region may impact functional capabilities or posttranslational modification (5,28,29).…”

Section: Introductionmentioning

confidence: 99%

FLAIRR-seq: A novel method for single molecule resolution of near full-length immunoglobulin heavy chain repertoires

Ford¹,

Tieri²,

Rodriguez³

et al. 2022

Preprint

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Current Adaptive Immune Receptor Repertoire Sequencing (AIRR-seq) strategies resolve immunoglobulin (IG) variable region transcripts with limited resolution of the constant region. Here we present a novel near full-length AIRR-seq (FLAIRR-Seq) method that utilizes targeted heavy chain amplification by rapid amplification of cDNA ends (RACE), combined with single molecule, real-time (SMRT) sequencing to generate highly accurate (>Q40, 99.99%), immunoglobulin heavy chain transcripts. FLAIRR-seq was benchmarked by comparing V, D, and J gene usage, complementarity-determining region 3 (CDR3) length, and the extent of total variable gene somatic hypermutation to matched datasets generated with standard RACE AIRR-seq and full-length isoform sequencing methods. Together these data demonstrate robust, unbiased FLAIRR-seq performance using RNA samples derived from peripheral blood mononuclear cells, purified B cells, and whole blood, which recapitulated results generated by commonly used methods, while resolving novel constant region features. FLAIRR-seq data provides, for the first time, simultaneous, single-molecule characterization of variable and constant region genes and alleles, allele-resolved subisotype definition, and identification of class-switch recombination within a clonal lineage. FLAIRR-seq, in conjunction with IGHC genotyping, of the IgM- and IgG repertoires from 10 individuals resulted in the identification of 32 unique IGHC alleles; 28/32 (87%) that were not represented by sequences curated in the IMmunoGeneTics Information System (IMGT) database. Together, these data demonstrate the capabilities of FLAIRR-seq to characterize IGHV, D, J and C gene diversity for the most comprehensive view of B cell repertoires to date.

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Population-specific diversity of the immunoglobulin constant heavy G chain (IGHG) genes

Cited by 23 publications

References 33 publications

Immunoglobulin G genetic variation can confound assessment of antibody levels via altered binding to detection reagents

Immunoglobulin G genetic variation can confound assessment of antibody levels via altered binding to detection reagents

IGHG3 hinge length variation was associated with the risk of critical disease and death in a Spanish COVID-19 cohort

FLAIRR-seq: A novel method for single molecule resolution of near full-length immunoglobulin heavy chain repertoires

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