MHC Class II and Non-MHC Class II Genes Differentially Influence Humoral Immunity to Bacillus anthracis Lethal Factor and Protective Antigen

Garman, Lori; Dumas, Eric K.; Kurella, Sridevi; Hunt, Jonathan J.; Crowe, Sherry R.; Nguyen, Melissa; Cox, Philip M.; James, Judith A.; Farris, A. Darise

doi:10.3390/toxins4121451

“…Similarly, markers in HLA-DRB5 were found to be associated with elevated antibody response. In our own previous study in this population [37], carriage of three haplotypes in this region ( DRB1*1501-DQA1*0102-DQB1*0602 , DRB1*0101-DQA1*0101-DQB1*0501 , and DRB1*0102-DQA1*0101-DQB1*0501) were all significantly associated with lower AbPA levels in the longitudinal analyses [18]. Recently in an animal study [37], MHC class II locus has been associated with high antibody titers to a component of anthrax toxin, lethal factor whereas non-MHC class loci were discovered to influence antibody titers to protective antigen.…”

Section: Discussionmentioning

confidence: 76%

Genomic Copy Number Variants: Evidence for Association with Antibody Response to Anthrax Vaccine Adsorbed

Falola

¹

,

Wiener

²

,

Cutter

³

et al. 2013

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BackgroundAnthrax and its etiologic agent remain a biological threat. Anthrax vaccine is highly effective, but vaccine-induced IgG antibody responses vary widely following required doses of vaccinations. Such variation can be related to genetic factors, especially genomic copy number variants (CNVs) that are known to be enriched among genes with immunologic function. We have tested this hypothesis in two study populations from a clinical trial of anthrax vaccination.MethodsWe performed CNV-based genome-wide association analyses separately on 794 European Americans and 200 African-Americans. Antibodies to protective antigen were measured at week 8 (early response) and week 30 (peak response) using an enzyme-linked immunosorbent assay. We used DNA microarray data (Affymetrix 6.0) and two CNV detection algorithms, hidden markov model (PennCNV) and circular binary segmentation (GeneSpring) to determine CNVs in all individuals. Multivariable regression analyses were used to identify CNV-specific associations after adjusting for relevant non-genetic covariates.ResultsWithin the 22 autosomal chromosomes, 2,943 non-overlapping CNV regions were detected by both algorithms. Genomic insertions containing HLA-DRB5, DRB1 and DQA1/DRA genes in the major histocompatibility complex (MHC) region (chromosome 6p21.3) were moderately associated with elevated early antibody response (β = 0.14, p = 1.78×10−3) among European Americans, and the strongest association was observed between peak antibody response and a segmental insertion on chromosome 1, containing NBPF4, NBPF5, STXMP3, CLCC1, and GPSM2 genes (β = 1.66, p = 6.06×10−5). For African-Americans, segmental deletions spanning PRR20, PCDH17 and PCH68 genes on chromosome 13 were associated with elevated early antibody production (β = 0.18, p = 4.47×10−5). Population-specific findings aside, one genomic insertion on chromosome 17 (containing NSF, ARL17 and LRRC37A genes) was associated with elevated peak antibody response in both populations.ConclusionMultiple CNV regions, including the one consisting of MHC genes that is consistent with earlier research, can be important to humoral immune responses to anthrax vaccine adsorbed.

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“…A key experiment in this regard was to compare the impact of STI challenge on survival and the control of bacterial load in mice, all on a C57BL/6 background and lacking expression of endogenous murine MHC class II heterodimers but differing in expression of specific HLA-DR or HLA-DQ alleles. The background C57BL/6 strain is considered one that mounts a low antibody response to anthrax PA and LF [37]. We found that HLA-DR15 transgenics (expressing the HLA-DRB1*1501 allele) were the most susceptible to challenge, echoing the results of human AVA HLA-DRB1*1501 + vaccinees [38].…”

Section: Discussionmentioning

confidence: 86%

“…In seeking an improved understanding of the interaction between B. anthracis and protection by the human immune system, a key question has been the impact of immunogenetic heterogeneity at the population level [36]; work in mouse models has suggested that, as expected, both MHC and non-MHC polymorphisms are influencing these factors [37]. With respect to human vaccination, there is evidence of reduced immune responsiveness to PA in individuals with the DRB1*1501/DQB1*0602 haplotype [38].…”

Section: Discussionmentioning

confidence: 99%

HLA class II polymorphism influences the immune response to protective antigen and susceptibility to Bacillus anthracis

Altmann

¹

,

Ascough

²

,

Ingram

³

et al. 2019

Preprint

0

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The causative agent of anthrax, Bacillus anthracis, evades the host immune response and establishes infection through the production of binary exotoxins composed of Protective Antigen (PA) and one of two subunits, lethal factor (LF) or edema factor (EF). The majority of vaccination strategies have focused upon the antibody response to the PA subunit. We have used a panel of humanised HLA class II transgenic mouse strains to define HLA-DR-restricted and HLA-DQ-restricted CD4+ T cell responses to the immunodominant epitopes of PA. This was correlated with the binding affinities of epitopes to HLA class II molecules, as well as the responses of two human cohorts: individuals vaccinated with the Anthrax Vaccine Precipitated (AVP) vaccine (which contains PA and trace amounts of LF), and patients recovering from cutaneous anthrax infections. The infected and vaccinated cohorts expressing different HLA types were found to make CD4+ T cell responses to multiple and diverse epitopes of PA. The effects of HLA polymorphism were explored using transgenic mouse lines, which demonstrated differential susceptibility, indicating that HLA-DR1 and HLA-DQ8 alleles conferred protective immunity relative to HLA-DR15, HLA-DR4 and HLA-DQ6. The HLA transgenics enabled a reductionist approach, allowing us to better define CD4+ T cell epitopes. Appreciating the effects of HLA polymorphism on the variability of responses to natural infection and vaccination will be vital in planning protective strategies against anthrax.Author SummaryThe bacterium responsible for causing the disease anthrax, Bacillus anthracis, produces a binary toxin composed of Protective Antigen (PA) and either Lethal Factor (LF) or Edema Factor (EF). Previous vaccination strategies have focused upon the antibody response to the PA subunit. However, within the field of bacterial immunity, there is a growing appreciation of the importance of the adaptive immune response, specifically led by CD4+ T cells. We identified long-term CD4+ T cell responses to PA epitopes following cutaneous human anthrax infection and vaccination, indicating that this toxin component is a principle B. anthracis antigen. To characterise the impact of polymorphism in HLA class II alleles at DR and DQ loci, we used transgenic mice to map the immunodominant epitopes from PA. This was correlated with survival in the transgenic lines following live anthrax challenge. We were able to demonstrate the differential impact of HLA class II alleles upon the CD4+ T cell immunodominant epitopes which shaped the immune hierarchy and therefore susceptibility to anthrax infection.

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“…In seeking an improved understanding of the interaction between B. anthracis and protection by the human immune system, a key question has been the impact of immunogenetic heterogeneity at the population level [ 45 ]. Work in mouse models has suggested that, as expected, both MHC and non-MHC polymorphisms influence these factors [ 46 ]. With respect to human vaccination, there is evidence of reduced immune responsiveness to PA in individuals with the DRB1*1501/DQB1*0602 haplotype [ 47 ].…”

Section: Discussionmentioning

confidence: 88%

Impact of HLA Polymorphism on the Immune Response to Bacillus Anthracis Protective Antigen in Vaccination versus Natural Infection

Ascough

¹

,

Ingram

²

,

Chu

³

et al. 2022

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The causative agent of anthrax, Bacillus anthracis, evades the host immune response and establishes infection through the production of binary exotoxins composed of Protective Antigen (PA) and one of two subunits, lethal factor (LF) or edema factor (EF). The majority of vaccination strategies have focused upon the antibody response to the PA subunit. We have used a panel of humanised HLA class II transgenic mouse strains to define HLA-DR-restricted and HLA-DQ-restricted CD4+ T cell responses to the immunodominant epitopes of PA. This was correlated with the binding affinities of epitopes to HLA class II molecules, as well as the responses of two human cohorts: individuals vaccinated with the Anthrax Vaccine Precipitated (AVP) vaccine (which contains PA and trace amounts of LF), and patients recovering from cutaneous anthrax infections. The infected and vaccinated cohorts expressing different HLA types were found to make CD4+ T cell responses to multiple and diverse epitopes of PA. The effects of HLA polymorphism were explored using transgenic mouse lines, which demonstrated differential susceptibility, indicating that HLA-DR1 and HLA-DQ8 alleles conferred protective immunity relative to HLA-DR15, HLA-DR4 and HLA-DQ6. The HLA transgenics enabled a reductionist approach, allowing us to better define CD4+ T cell epitopes. Appreciating the effects of HLA polymorphism on the variability of responses to natural infection and vaccination is vital in planning protective strategies against anthrax.

show abstract

MHC Class II and Non-MHC Class II Genes Differentially Influence Humoral Immunity to Bacillus anthracis Lethal Factor and Protective Antigen

Cited by 9 publications

References 40 publications

Genomic Copy Number Variants: Evidence for Association with Antibody Response to Anthrax Vaccine Adsorbed

Genomic Copy Number Variants: Evidence for Association with Antibody Response to Anthrax Vaccine Adsorbed

HLA class II polymorphism influences the immune response to protective antigen and susceptibility to Bacillus anthracis

Impact of HLA Polymorphism on the Immune Response to Bacillus Anthracis Protective Antigen in Vaccination versus Natural Infection

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