A Functional Variant of Fcy Receptor IIIA in RA
A Functional Variant of Fcy Receptor IIIA in RA
Anti-glucose-6-phosphate isomerase (GPI) antibodies are known to be arthritogenic autoantibodies in K/B×N mice, although some groups have reported that few healthy humans retain these antibodies. The expression of Fcγ receptors (FcγRs) is genetically regulated and has strong implications for the development of experimental arthritis. The interaction between immune complexes and FcγRs might therefore be involved in the pathogenesis of some arthritic conditions. To explore the relationship between functional polymorphisms in FcγRs (FCGR3A-158V/F and FCGR2A-131H/R) and arthritis in individuals positive for anti-GPI antibodies, we evaluated these individuals with respect to FCGR genotype. Genotyping for FCGR3A-158V/F and FCGR2A-131H/R was performed by PCR amplification of the polymorphic site, followed by site specific restriction digestion using the genome of 187 Japanese patients with rheumatoid arthritis (including 23 who were anti-GPI antibody positive) and 158 Japanese healthy individuals (including nine who were anti-GPI antibody positive). We report here on the association of FCGR3A-158V/F functional polymorphism with anti-GPI antibody positive status. Eight out of nine healthy individuals who were positive for anti-GPI antibodies possessed the homozygous, low affinity genotype FCGR3A-158F (odds ratio = 0.09, 95% confidence interval 0.01–0.89; P = 0.0199), and probably were 'protected' from arthritogenic antibodies. Moreover, among those who were homozygous for the high affinity genotype FCGR3A-158V/V, there were clear differences in anti-human and anti-rabbit GPI titres between patients with rheumatoid arthritis and healthy subjects (P = 0.0027 and P = 0.0015, respectively). Our findings provide a molecular model of the genetic regulation of autoantibody-induced arthritis by allele-specific affinity of the FcγRs.
Rheumatoid arthritis (RA) is a heterogeneous autoimmune disease that is characterized by chronic inflammatory polyarthritis. One of the characteristic features of RA is the expression of several autoantibodies. The presence of such autoantibodies (e.g. rheumatoid factor [RF]), identified by screening, is commonly used as a diagnostic marker, although the pathogenic role played by autoantibodies in RA remains a mystery.
Fcγ receptors (FcγRs) play a pivotal role in the reaction between immune complex and myeloid cells. Three FcγR types have been identified in mice and humans (FcγRI, FcγRII and FcγRIII). In mouse arthritis models, FcγRIII deficient hosts exhibit resistance to collagen type II induced arthritis and anti-glucose-6-phosphate isomerase (GPI) antibody induced arthritis,, suggesting that FcγRIII is indispensible in autoantibody dependent arthritis. In humans FcγRs are encoded by eight genes, and the genes encoding the low affinity FcγRs (FCGR2A, FCGR3A, FCGR2C, FCGR3B and FCGR2B) are located within a gene cluster on chromosome 1q22-23. Of these FcγRs, FcγRIIIa and FcγRIIa are known to be stimulatory receptors. Various genetic polymorphisms of these receptors were reported to be associated with several autoimmune diseases,, one of which is a polymorphism in FCGR3A, with either a phenylalanine (F) or a valine (V) at amino acid position 158. Moreover, based on findings from a co-crystalization study with IgG1 and FcγRIIIa,, this residue directly interacts with the lower hinge region of IgG1, suggesting strong binding between IgG1 and FcγRIIIa-158V on both natural killer cells and macrophages. For FCGR2A genes, a polymorphism at position 131 (with either histidine [H] or arginine [R]) alters the ability of the receptor to bind to certain IgG subclasses.
In RA patients, FCGR3B-158V/F polymorphisms were reported to be frequent in UK Caucasian, North Indian and Pakistani individuals, but not in Japanese, Spanish and French individuals. The reason for these differences between populations is unknown, although it is possible that they might depend on the prevalence in these populations of patients with autoantibody related forms of RA, in particular the prevalence of those who have pathogenic autoantibodies that directly interact with FcγRs (especially FcγRIIIa).
Anti-GPI antibodies are candidate arthritogenic antibodies. In K/B×N mice, polyclonal or two monoclonal anti-GPI antibodies induced arthritis in several strains of mice. Moreover, FcγRIII deficient mice were resistant to anti-GPI antibody induced arthritis. Another recent report also confirmed that immune complex and FcγRIII are essential initiators of arthritis through sequential activation of effector cells, thus giving antibodies access into the joint. In human RA, anti-GPI antibodies have frequently been detected in patients with aggressive forms of arthritis, and their levels correlated significantly with extra-articular manifestations such as rheumatoid nodules, rheumatoid vasculitis and Felty's syndrome. Moreover, a modest association of homozygosity for the FCGR3A-158V allele with RA in the nodular phenotype was suggested by Morgan and coworkers, suggesting the presence of a link between anti-GPI antibodies and FCGR3A allele. However, whether anti-GPI antibody positive status correlates with RA is a matter of controversy. In our assay few healthy individuals retained anti-GPI antibodies; however, we do not know whether these protective phenotypes are associated with certain human gene polymorphisms.
In order to determine the relationship between functional polymorphisms of FCGR and possible arthritogenic anti-GPI antibodies in human conditions, we examined the correlation of these polymorphisms with anti-GPI positivity.
Anti-glucose-6-phosphate isomerase (GPI) antibodies are known to be arthritogenic autoantibodies in K/B×N mice, although some groups have reported that few healthy humans retain these antibodies. The expression of Fcγ receptors (FcγRs) is genetically regulated and has strong implications for the development of experimental arthritis. The interaction between immune complexes and FcγRs might therefore be involved in the pathogenesis of some arthritic conditions. To explore the relationship between functional polymorphisms in FcγRs (FCGR3A-158V/F and FCGR2A-131H/R) and arthritis in individuals positive for anti-GPI antibodies, we evaluated these individuals with respect to FCGR genotype. Genotyping for FCGR3A-158V/F and FCGR2A-131H/R was performed by PCR amplification of the polymorphic site, followed by site specific restriction digestion using the genome of 187 Japanese patients with rheumatoid arthritis (including 23 who were anti-GPI antibody positive) and 158 Japanese healthy individuals (including nine who were anti-GPI antibody positive). We report here on the association of FCGR3A-158V/F functional polymorphism with anti-GPI antibody positive status. Eight out of nine healthy individuals who were positive for anti-GPI antibodies possessed the homozygous, low affinity genotype FCGR3A-158F (odds ratio = 0.09, 95% confidence interval 0.01–0.89; P = 0.0199), and probably were 'protected' from arthritogenic antibodies. Moreover, among those who were homozygous for the high affinity genotype FCGR3A-158V/V, there were clear differences in anti-human and anti-rabbit GPI titres between patients with rheumatoid arthritis and healthy subjects (P = 0.0027 and P = 0.0015, respectively). Our findings provide a molecular model of the genetic regulation of autoantibody-induced arthritis by allele-specific affinity of the FcγRs.
Rheumatoid arthritis (RA) is a heterogeneous autoimmune disease that is characterized by chronic inflammatory polyarthritis. One of the characteristic features of RA is the expression of several autoantibodies. The presence of such autoantibodies (e.g. rheumatoid factor [RF]), identified by screening, is commonly used as a diagnostic marker, although the pathogenic role played by autoantibodies in RA remains a mystery.
Fcγ receptors (FcγRs) play a pivotal role in the reaction between immune complex and myeloid cells. Three FcγR types have been identified in mice and humans (FcγRI, FcγRII and FcγRIII). In mouse arthritis models, FcγRIII deficient hosts exhibit resistance to collagen type II induced arthritis and anti-glucose-6-phosphate isomerase (GPI) antibody induced arthritis,, suggesting that FcγRIII is indispensible in autoantibody dependent arthritis. In humans FcγRs are encoded by eight genes, and the genes encoding the low affinity FcγRs (FCGR2A, FCGR3A, FCGR2C, FCGR3B and FCGR2B) are located within a gene cluster on chromosome 1q22-23. Of these FcγRs, FcγRIIIa and FcγRIIa are known to be stimulatory receptors. Various genetic polymorphisms of these receptors were reported to be associated with several autoimmune diseases,, one of which is a polymorphism in FCGR3A, with either a phenylalanine (F) or a valine (V) at amino acid position 158. Moreover, based on findings from a co-crystalization study with IgG1 and FcγRIIIa,, this residue directly interacts with the lower hinge region of IgG1, suggesting strong binding between IgG1 and FcγRIIIa-158V on both natural killer cells and macrophages. For FCGR2A genes, a polymorphism at position 131 (with either histidine [H] or arginine [R]) alters the ability of the receptor to bind to certain IgG subclasses.
In RA patients, FCGR3B-158V/F polymorphisms were reported to be frequent in UK Caucasian, North Indian and Pakistani individuals, but not in Japanese, Spanish and French individuals. The reason for these differences between populations is unknown, although it is possible that they might depend on the prevalence in these populations of patients with autoantibody related forms of RA, in particular the prevalence of those who have pathogenic autoantibodies that directly interact with FcγRs (especially FcγRIIIa).
Anti-GPI antibodies are candidate arthritogenic antibodies. In K/B×N mice, polyclonal or two monoclonal anti-GPI antibodies induced arthritis in several strains of mice. Moreover, FcγRIII deficient mice were resistant to anti-GPI antibody induced arthritis. Another recent report also confirmed that immune complex and FcγRIII are essential initiators of arthritis through sequential activation of effector cells, thus giving antibodies access into the joint. In human RA, anti-GPI antibodies have frequently been detected in patients with aggressive forms of arthritis, and their levels correlated significantly with extra-articular manifestations such as rheumatoid nodules, rheumatoid vasculitis and Felty's syndrome. Moreover, a modest association of homozygosity for the FCGR3A-158V allele with RA in the nodular phenotype was suggested by Morgan and coworkers, suggesting the presence of a link between anti-GPI antibodies and FCGR3A allele. However, whether anti-GPI antibody positive status correlates with RA is a matter of controversy. In our assay few healthy individuals retained anti-GPI antibodies; however, we do not know whether these protective phenotypes are associated with certain human gene polymorphisms.
In order to determine the relationship between functional polymorphisms of FCGR and possible arthritogenic anti-GPI antibodies in human conditions, we examined the correlation of these polymorphisms with anti-GPI positivity.
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