Evidence for non-random distribution of Fcγ receptor genotype combinations

Pol, W. Ludo van der; Jansen, Marc; Sluiter, Wim J.; Sluis, Bart van de; Straat, Fredriek G. J. Leppers-van de; Kobayashi, Tetsuo; Westendorp, Rudi G. J.; Huizinga, Tom W J; Winkel, Jan G. J. van de

doi:10.1007/s00251-003-0574-9

Cited by 57 publications

(56 citation statements)

References 52 publications

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“…However, there are no known associations between polymorphisms in Fc␥R genes and other genes. In contrast, there is a linkage between the Fc␥RIIa and Fc␥RIIIa genes, such that the higher affinity alleles of both genes are more commonly found together (29); this linkage may account for the fact that in a Cox model, including genotypes from both Fc␥RIIa and Fc␥RIIIa, only the Fc␥RIIa genotype significantly influenced the relationship between ADCVI and infection rate. It is unclear why vaccinees with lower affinity receptors would benefit most from higher ADCVI Ab.…”

Section: Discussionmentioning

confidence: 75%

“…Because of linkage disequilibrium between the Fc␥RIIa and IIIa genes, we used two interaction terms in a Cox model to determine whether each gene independently influenced the relationship between ADCVI activity and infection (29). In that analysis, with ADCVI as a continuous variable, Fc␥RIIa independently influenced the relationship ( p ϭ 0.002) whereas Fc␥RIIIa did not ( p ϭ 0.16).…”

Section: Fc␥riia and Fc␥riiia Gene Polymorphisms Influence The Adcvi mentioning

confidence: 99%

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Recombinant gp120 Vaccine-Induced Antibodies Inhibit Clinical Strains of HIV-1 in the Presence of Fc Receptor-Bearing Effector Cells and Correlate Inversely with HIV Infection Rate

Forthal

Gilbert

Landucci

et al. 2007

The Journal of Immunology

163

157

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Nonneutralizing Abs may play a role in protecting animals and humans from lentiviral infections. We explored the Ab-dependent, cell-mediated virus inhibition (ADCVI) Ab response to recombinant gp120 (rgp120) vaccination in sera from 530 participants in the Vax 004 trial. Serum ADCVI activity was measured against a clinical R5 strain of HIV-1 using peripheral blood mononuclear effector cells from healthy donors. The level of vaccine-induced ADCVI activity correlated inversely with the rate of acquiring HIV infection following vaccination, such that for every 10% increase in ADCVI activity, there was a 6.3% decrease in the hazard rate of infection (p = 0.019). Some vaccinated individuals also mounted an ADCVI response against two other clinical R5 strains of HIV-1. However, ADCVI activity correlated poorly with neutralizing or CD4-gp120-blocking Ab activity measured against laboratory strains. Finally, the degree to which the ADCVI Ab response predicted the rate of infection was influenced by polymorphisms at the FcγRIIa and FcγRIIIa gene loci. These data indicate that rgp120 vaccination can elicit Abs with antiviral activity against clinical strains of HIV-1. However, such activity requires the presence of FcR-bearing effector cells. Our results provide further evidence that ADCVI may play a role in preventing HIV infection.

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Section: Discussionmentioning

confidence: 75%

Section: Fc␥riia and Fc␥riiia Gene Polymorphisms Influence The Adcvi mentioning

confidence: 99%

Recombinant gp120 Vaccine-Induced Antibodies Inhibit Clinical Strains of HIV-1 in the Presence of Fc Receptor-Bearing Effector Cells and Correlate Inversely with HIV Infection Rate

Forthal

Gilbert

Landucci

et al. 2007

The Journal of Immunology

163

157

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“…5 In conclusion, our study demonstrates no association of FcγRIIIa and FcγRIIa polymorphisms and response to standard R-CHOP, suggesting that ADCC via FcγRIIIa and FcγRIIa receptors may not be the major mechanism of the elimination of lymphoma cells in patients treated with immunochemotherapy.…”

Section: 101314mentioning

confidence: 85%

FC RIIIA and FC RIIA polymorphisms are not associated with response to rituximab and CHOP in patients with diffuse large B-cell lymphoma

Mitrović

Aurer²,

Radman³

et al. 2007

Haematologica

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FCγRIIIA and FCγRIIA polymorphisms are not associated with response to rituximab and CHOP in patients with diffuse large B-cell lymphomaWe investigated the association of Fcγ γRIIIa and Fcγ γRIIa polymorphisms and response to R-CHOP in 58 patients with diffuse large B-cell lymphoma (DLBCL). Fcγ γRIIIa and Fcγ γRIIa polymorphisms did not influence response, event-free or overall survival. These results suggest that ADCC via Fcγ γRIIIa and Fcγ γRIIa may not be the major mechanism of activity of the R-CHOP combination in DLBCL. Haematologica 2007; 92:998-999 Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid neoplasm accounting for approximately 30-40% of all non-Hodgkin lymphomas (NHLs). Recently, the combination of rituximab (R) and CHOP (cyclophosphamide, doxorubicin, vincristin, prednisone) led to significant improvement in the outcomes of patients with DLBCL, establishing R-CHOP as the new standard treatment.1,2 The proposed mechanisms of rituximab activity include: antibody dependent cellular cytotoxicity (ADCC), complement dependent cytotoxicity (CDC), direct induction of apoptosis and chemosensitization of tumor cells to the cytotoxic effects of chemotherapy.3,4 The clinical importance of each is still a matter of debate. ADCC is mediated by effector cells that engage the Fc portion of the antibody via receptors for immunoglobulin (FcγRs). Three FcγR classes (FcγRI, II, III) and eight subclasses have been described with significantly different haplotype distribution between various ethnic groups.5 FcγRIIIa receptor is expressed on natural killer (NK) cells, macrophages, while FcγRIIa is expressed on neutrophils and macrophages. Genomic polymorphism of the FcγRIIIa receptor corresponding to phenotypic expression of valine (V) or phenylalanine (F) at position 158 influences the binding of IgG1 to this receptor.6 It has been shown that NK cells with valine homozygous FcγRIIIa receptors (V/V) have a higher affinity to rituximab than those with phenylalanine homozygous receptors (F/F) resulting in more effective ADCC.7 Several studies investigated the influence of FcγRIIIa and FcγRIIa polymorphisms on response to rituximab-containing treatment in different types of lymphoma. In follicular lymphoma (FL), patients with FcγRIIIa 158 V/V phenotype respond better than F carriers to rituximab monotherapy, 8,9 but not to R-CHOP. 10,11FcγRIIIa 158 V/V phenotype is associated with improved response to rituximab monotherapy in Waldenstrom's macroglobulinemia, 12 in contrast to chronic lymphocytic leukemia (CLL).13 A recently published study found that Korean DLBCL patients with FcγRIIIa 158 V/V phenotype respond better to R-CHOP than F carriers, although there were no differences in event-free survival (EFS) and overall survival (OS).14 In one series, patients with FL homozygous for histidine (H) on position 131 of FcγRIIa responded better to rituximab monotherapy than heterozygous patients or patients homozygous for arginine (R).9 Others failed to confirm this association. 8,10,13,14 We examined the cor...

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“…Outside of Asia, the HH and RR genotypes each occur in ϳ25% of the population, and the RH genotype occurs in ϳ50% (23,24). There is marked skewing of this distribution in East Asia, where 50 -60% of individuals are H homozygotes and Ͻ10% carry the RR genotype (23,25,26).…”

Section: H Uman Immunodeficiency Virus (Hiv) Infection Is Char-mentioning

confidence: 99%

FcγRIIa Genotype Predicts Progression of HIV Infection

Forthal

Landucci

Bream

et al. 2007

The Journal of Immunology

118

127

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Polymorphisms in FcγR genes are associated with susceptibility to or severity of a number of autoimmune and infectious diseases. We found that HIV-infected men in the Multicenter AIDS Cohort Study with the FcγRIIa RR genotype progressed to a CD4+ cell count of <200/mm3 at a faster rate than individuals with the RH or HH genotypes (relative hazard = 1.6; p = 0.0001). However, progression to AIDS (using the broad definition of either a CD4+ cell count <200/mm3 or development of an AIDS-defining illness) was less impacted by FcγRIIa genotype, largely because HH homozygotes had an increased risk of Pneumocystis jiroveci pneumonia as an AIDS-defining illness. We also showed that chronically infected subjects develop a substantial anti-gp120-specific IgG2 response. Moreover, HIV-1 immune complexes are more efficiently internalized by monocytes from HH subjects compared with RR subjects, likely because of the presence of IgG2 in the complexes. Finally, the FcγRIIIa F/V gene polymorphism was not associated with progression of HIV infection, but, as demonstrated previously, did predict the risk of Kaposi’s sarcoma. These results demonstrate the importance of FcγRs in AIDS pathogenesis and point toward a critical role for interactions between FcγRs and immune complexes in disease progression.

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Evidence for non-random distribution of Fcγ receptor genotype combinations

Cited by 57 publications

References 52 publications

Recombinant gp120 Vaccine-Induced Antibodies Inhibit Clinical Strains of HIV-1 in the Presence of Fc Receptor-Bearing Effector Cells and Correlate Inversely with HIV Infection Rate

Recombinant gp120 Vaccine-Induced Antibodies Inhibit Clinical Strains of HIV-1 in the Presence of Fc Receptor-Bearing Effector Cells and Correlate Inversely with HIV Infection Rate

FC RIIIA and FC RIIA polymorphisms are not associated with response to rituximab and CHOP in patients with diffuse large B-cell lymphoma

FcγRIIa Genotype Predicts Progression of HIV Infection

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