Fc-gamma receptor polymorphisms differentially influence susceptibility to systemic lupus erythematosus and lupus nephritis

Tsang-A-Sjoe, M.; Nagelkerke, Sietse Q.; Bultink, Irene E. M.; Geissler, Judy; Tanck, Michael W.T.; Tacke, Carline E.; Ellis, Justine A.; Zenz, Werner; Bijl, Marc; Berden, J.H.M.; Leeuw, Karina de; Derksen, R. H. W. M.; Kuijpers, Taco W.; Voskuyl, Alexandre E.

doi:10.1093/rheumatology/kev433

Cited by 62 publications

(57 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the present study, the FcγRIIa R131H and FcγRIIIb NA1/NA2 polymorphisms, which decrease the affinity of IgG binding and alter IC clearance [48], were not associated to either SLE susceptibility or lupus nephritis occurrence. The influence of these polymorphisms on both SLE susceptibility and outcome was diversely estimated.…”

Section: Discussioncontrasting

confidence: 54%

“…However, in a study performed in a Brazilian population, Grecco et al [46] did not found any association between the FcγRIIIa F158V SNP and the SLE susceptibility. Besides, if the present study did not show any influence of the FcγRIIIa rs396991 SNP on SLE profile and outcome, the *G allele has been associated to lupus nephritis [45,47,48]. Indeed, the FcγRIIIa*V variant has a higher affinity towards IgG1 and IgG3, compared to the FcγRIIIa*F allele [44], which most likely results in a higher and more lasting activation of macrophages, via IC recognition.…”

Section: Discussionmentioning

confidence: 46%

See 1 more Smart Citation

PTPN22, CTLA4, FcγRIIa, FcγRIIIa and FcγRIIIb polymorphisms in Tunisian patients with systemic lupus erythematosus

Dhaouadi¹,

Sfar²,

Hassine³

et al. 2019

Int. J. Clin. Rheumatol

View full text Add to dashboard Cite

Background: Pathogenesis of systemic lupus erythematosus (SLE) involves both T cell tolerance breakdown and pathogenic autoantibodies. Polymorphisms in T cell regulatory proteins (PTPN22 and CTLA-4) and IgG receptors (FcγR) genes could impact their functions. Consequently, we aimed to study the role of PTPN22, CTLA-4, FcγRII and FcγRIII polymorphisms on either SLE susceptibility or its severity. Methods: Consequently, PTPN22 rs2476601 (R620W), CTLA-4 rs231775 (+49 A/G), FcγRIIa rs1801274 (R131H), FcγRIIIa rs396991 (F158V) and FcγRIIIb Na1/Na2 polymorphisms were examined in 137 SLE patients and 100 healthy blood donors matched in age, gender and ethnic origin. Results: The PTPN22-620*W mutant allele was significantly more prevalent in SLE patients comparatively to controls; p=0.001, OR [95% CI] = 7.8 [1.73-48.85]. Inversely, the frequency of the CTLA-4*G/G homozygous genotype was significantly lower in patients (35%) than in controls; p=0.02, OR [95% CI] = 0.54 [0.31-0.94]. Regarding to FcγR polymorphisms, while the FcγRIIIa*V allele was more prevalent in case of SLE (0.562 vs 0.35); p=0.001, OR [95% CI] = 2.77 [1.38-5.68], FcγRIIa and FcγRIIIb did not show any association with SLE. Analytic results showed that the prevalence of anti-dsDNA autoantibody was significantly higher in patients carrying PTPN22*W allele p=0.038. Otherwise, no correlation was found between the five studied polymorphisms and either clinical or biological patients characteristics. Conclusion: PTPN22 R620W, CTLA-A +49 A/G and FcγRIIIa F158V polymorphisms seem to be related to SLE susceptibility in Tunisian.

show abstract

Section: Discussioncontrasting

confidence: 54%

Section: Discussionmentioning

confidence: 46%

PTPN22, CTLA4, FcγRIIa, FcγRIIIa and FcγRIIIb polymorphisms in Tunisian patients with systemic lupus erythematosus

Dhaouadi¹,

Sfar²,

Hassine³

et al. 2019

Int. J. Clin. Rheumatol

View full text Add to dashboard Cite

show abstract

“…For NK cell isolation we only used PBMCs from FCGR-genotyped donors that have two copies of FCGR3-158F and do not have a FCGR2C-ORF allele to exclude FcgRIIc as a confounding factor (33). Genotyping was performed as described before (34,35).…”

Section: Human Samplesmentioning

confidence: 99%

Enhanced Effector Functions Due to Antibody Defucosylation Depend on the Effector Cell Fcγ Receptor Profile

Bruggeman

Dekkers

Bentlage

et al. 2017

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Abs of the IgG isotype are glycosylated in their Fc domain at a conserved asparagine at position 297. Removal of the core fucose of this glycan greatly increases the affinity for FcγRIII, resulting in enhanced FcγRIII-mediated effector functions. Normal plasma IgG contains ∼94% fucosylated Abs, but alloantibodies against, for example, Rhesus D (RhD) and platelet Ags frequently have reduced fucosylation that enhances their pathogenicity. The increased FcγRIII-mediated effector functions have been put to use in various afucosylated therapeutic Abs in anticancer treatment. To test the functional consequences of Ab fucosylation, we produced V-gene-matched recombinant anti-RhD IgG Abs of the four different subclasses (IgG1-4) with and without core fucose (i.e., 20% fucose remaining). Binding to all human FcγR types and their functional isoforms was assessed with surface plasmon resonance. All hypofucosylated anti-RhD IgGs of all IgG subclasses indeed showed enhanced binding affinity for isolated FcγRIII isoforms, without affecting binding affinity to other FcγRs. In contrast, when testing hypofucosylated anti-RhD Abs with FcγRIIIa-expressing NK cells, a 12- and 7-fold increased erythrocyte lysis was observed with the IgG1 and IgG3, respectively, but no increase with IgG2 and IgG4 anti-RhD Abs. Notably, none of the hypofucosylated IgGs enhanced effector function of macrophages, which, in contrast to NK cells, express a complex set of FcγRs, including FcγRIIIa. Our data suggest that the beneficial effects of afucosylated biologicals for clinical use can be particularly anticipated when there is a substantial involvement of FcγRIIIa-expressing cells, such as NK cells.

show abstract

“…However, the higher concordance rate in monozygotic twins and increased risk of SLE in relatives highlight the genetic factors in SLE pathogenesis (Kuo et al, ). Various genes have been suggested as SLE predisposing factors which are commonly known as “ SLE susceptibility genes” such as human leucocyte antigen (HLA) (Armstrong et al, ), mannose‐binding lectin (MBL) (Tanha et al, ), Fc gamma receptor (FcγR) (Tsang‐A‐Sjoe et al, ) and programmed cell death‐1 (PD‐1) (Gianchecchi, Delfino, & Fierabracci, ). Moreover, the cytokine production by immune cells is aberrantly imbalanced in SLE which may be associated with exacerbated immune response and increased disease severity (Jacob & Stohl, ).…”

Section: Introductionmentioning

confidence: 99%

Interleukin10 gene promoter polymorphisms (rs1800896, rs1800871 and rs1800872) and haplotypes are associated with the activity of systemic lupus erythematosus and IL10 levels in an Iranian population

Mohammadi

Jazi

Ebrahimabad

et al. 2018

Int J Immunogenetics

View full text Add to dashboard Cite

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with unknown aetiology. According to the role of interleukin 10 (IL10) in SLE pathogenesis, the genetic alterations in its promoter region could be associated with elevated IL10 levels and exacerbated disease. Here, we investigated the association of genotype and haplotype frequencies of three IL10 gene promoter polymorphisms with susceptibility to SLE, IL10 plasma levels and disease activity of patients in an Iranian population. A total of 116 SLE patients and 131 healthy subjects were enrolled. The PCR-RFLP technique was used to detect IL10 promoter genotypes at the positions of −1082 (G/A), −819 (C/T) and −592 (C/A) in association with IL10 plasma levels and SLEDAI scores. The GG genotype of −1082 polymorphism was associated with the increased risk of SLE [OR = 2.65, 95% CI (1.21-5.82), p-value = 0.046]. The CC genotype in −819 region was associated with SLE susceptibility [OR = 3.38, 95% CI (1.26-9.07), p-value = 0.034] and C allele was introduced as risk allele [OR = 1.86, 95% CI (1.15-3.01), p-value = 0.009] in this region. IL10 plasma levels were overexpressed in CC genotype carriers of −592 SNP and decreased in AA genotype carriers of −1082. IL10 was also increased in SLE patients with CGT (−592/−1082/−819) haplotype. The SLEDAI score was higher among CC genotype carriers at the position of −592 and TT genotype carriers at the region of −819. SLEDAI was also elevated among patients with CGC (−592/−1082/−819) and CAC (p = 0.011) haplotypes. The present study suggests that the IL10 -819(C/T), −1082(G/A) and −592(C/A) polymorphisms and the haplotypes are associated with SLE susceptibility, increased disease activity and elevated IL10 levels. While this is the first time to report such an association in an Iranian population, further studies are needed to confirm these findings. K E Y W O R D S haplotype, interleukin 10, polymorphism, promoter, systemic lupus erythematosus | 21 MOHAMMADI et Al.

show abstract

Fc-gamma receptor polymorphisms differentially influence susceptibility to systemic lupus erythematosus and lupus nephritis

Cited by 62 publications

References 41 publications

PTPN22, CTLA4, FcγRIIa, FcγRIIIa and FcγRIIIb polymorphisms in Tunisian patients with systemic lupus erythematosus

PTPN22, CTLA4, FcγRIIa, FcγRIIIa and FcγRIIIb polymorphisms in Tunisian patients with systemic lupus erythematosus

Enhanced Effector Functions Due to Antibody Defucosylation Depend on the Effector Cell Fcγ Receptor Profile

Interleukin10 gene promoter polymorphisms (rs1800896, rs1800871 and rs1800872) and haplotypes are associated with the activity of systemic lupus erythematosus and IL10 levels in an Iranian population

Contact Info

Product

Resources

About