An abnormality of the gene that encodes neutrophil Fc receptor III in a patient with systemic lupus erythematosus.

Clark, Marcus R.; Liu, L; Clarkson, S B; Ory, P A; Goldstein, Ira M.

doi:10.1172/jci114706

Cited by 80 publications

(45 citation statements)

References 34 publications

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“…Mice deficient in the g-chain and thus lacking all activating FcgRs have significant defects in IC-dependent effector cell responses (73,75) and are resistant to induction of various IC-induced autoimmune diseases (74,(76)(77)(78). Furthermore, FcR polymorphisms and/or disturbed FcgR expression have been described in patients with autoimmune diseases (74,(79)(80)(81). These data indicate that a wide range of inflammatory and autoimmune diseases are triggered by FcgR-mediated activation of inflammatory cells.…”

Section: Discussionmentioning

confidence: 94%

Immobilized Immune Complexes Induce Neutrophil Extracellular Trap Release by Human Neutrophil Granulocytes via FcγRIIIB and Mac-1

Behnen

Leschczyk

Möller

et al. 2014

The Journal of Immunology

214

191

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Canonical neutrophil antimicrobial effector mechanisms, such as degranulation, production of reactive oxygen species, and release of neutrophil extracellular traps (NETs), can result in severe pathology. Activation of neutrophils through immune complexes (ICs) plays a central role in the pathogenesis of many autoimmune inflammatory diseases. In this study, we report that immobilized ICs (iICs), which are hallmarks of several autoimmune diseases, induce the release of NETs from primary human neutrophils. The iIC-induced NET formation was found to require production of reactive oxygen species by NADPH oxidase and myeloperoxidase and to be mediated by FcγRIIIb. Blocking of the β2 integrin macrophage-1 Ag but not lymphocyte function–associated Ag-1 abolished iIC-induced NET formation. This suggests that FcγRIIIb signals in association with macrophage-1 Ag. As intracellular signaling pathways involved in iIC-induced NET formation we identified the tyrosine kinase Src/Syk pathway, which downstream regulates the PI3K/Akt, p38 MAPK, and ERK1/2 pathways. To our knowledge, the present study shows for the first time that iICs induce NET formation. Thus, we conclude that NETs contribute to pathology in autoimmune inflammatory disorders associated with surface-bound ICs.

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Section: Discussionmentioning

confidence: 94%

Immobilized Immune Complexes Induce Neutrophil Extracellular Trap Release by Human Neutrophil Granulocytes via FcγRIIIB and Mac-1

Behnen

Leschczyk

Möller

et al. 2014

The Journal of Immunology

214

191

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“…5,33,34 NA1 and NA2 alleles mediate quantitatively different capacity for phagocytosis despite equivalent ligand binding and density of receptor expression. 13 Of particular interest, there are two reports of patients with Fc␥RIIIB deficiency who developed SLE, 35,36 although development of SLE is observed in only a small proportion of individuals deficient in Fc␥RIIIB. To our knowledge, the present study is the first to demonstrate significant association of Fc␥RIIIB polymorphism and SLE in a population-based association study.…”

Section: Discussionmentioning

confidence: 99%

Association of Fcγ receptor IIIB, but not of Fcγ receptor IIA and IIIA, polymorphisms with systemic lupus erythematosus in Japanese

et al. 1999

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Human Fc␥ receptor (Fc␥R) genes form a clustered gene family on chromosome 1q21-24. Although the association of Fc␥R polymorphisms with systemic lupus erythematosus (SLE) has been extensively studied, the results are often contradictory. In this study, Fc␥RIIA-131H/R, Fc␥RIIIA-176F/V and Fc␥RIIIB-NA1/2 genotypes were determined in the Japanese patients with SLE (n = 81) or rheumatoid arthritis (RA, n = 115) as well as in healthy individuals (n = 217), and possible association with the disease was tested using case-control analysis. Unlike in other populations, significant difference was not observed in the frequencies of Fc␥RIIA and Fc␥RIIIA genotypes between patients with SLE and healthy individuals. However, significant difference was detected in the frequencies of Fc␥RIIIB genotypes between SLE and healthy individuals (P = 0.008). The odds ratio [OR] of the Fc␥RIIIB-NA2/NA2 homozygotes for the development of SLE was 2.52 (95% confidence interval [CI]: 1.33-4.79). Among the patients with SLE, individuals with NA2/2 were significantly more likely to have lupus nephritis (P = 0.007). No association was observed between any of the Fc␥R polymorphisms and RA. Significant linkage disequilibrium was detected between Fc␥RIIIA and IIIB, but neither between IIA and IIIA, nor between IIA and IIIB. These observations may underscore the relevance of defective immune complex handling in the pathogenesis of SLE, or may suggest the presence of primarily associated gene(s) in linkage disequilibrium with Fc␥R genes.

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“…88 Two studies have identified patients who express a rare NA-null allele, leading to a complete absence of the Fc␥RIIIB gene itself. 89,90 Because these null alleles are extremely rare in the general population, the null allele itself my represent a risk factor for the development of lupus. A study performed to assess the possible association between Fc␥RIIIB and SLE was evaluated in a Japanese collection of SLE patients.…”

Section: Fc␥ Receptorsmentioning

confidence: 99%

The genetics of systemic lupus erythematosus: putting the pieces together

2002

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An abnormality of the gene that encodes neutrophil Fc receptor III in a patient with systemic lupus erythematosus.

Abstract: In the course of examining the structure

Cited by 80 publications

References 34 publications

Immobilized Immune Complexes Induce Neutrophil Extracellular Trap Release by Human Neutrophil Granulocytes via FcγRIIIB and Mac-1

Immobilized Immune Complexes Induce Neutrophil Extracellular Trap Release by Human Neutrophil Granulocytes via FcγRIIIB and Mac-1

Association of Fcγ receptor IIIB, but not of Fcγ receptor IIA and IIIA, polymorphisms with systemic lupus erythematosus in Japanese

The genetics of systemic lupus erythematosus: putting the pieces together

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