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Interactive Evect of MHC Class II and KM Genes on Anticentromere Antibody Production

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Interactive Evect of MHC Class II and KM Genes on Anticentromere Antibody Production 366 Ann Rheum Dis 1998;57:366–370 Immunoglobulin allotype gene polymorphisms in Ann Rheum Dis: first published as 10.1136/ard.57.6.366 on 1 June 1998. Downloaded from systemic sclerosis: interactive eVect of MHC class II and KM genes on anticentromere antibody production Hideto Kameda, Janardan P Pandey, Junichi Kaburaki, Hidetoshi Inoko, Masataka Kuwana Abstract were instead associated with the expression of Objective—To examine potential interac- SSc related ANAs.3 We have found MHC class tions between immunoglobulin (Ig)- II gene associations with serum SSc related allotype gene polymorphisms and ANAs in Japanese, including anti-topo I susceptibility to systemic sclerosis (SSc) antibody with DRB1*15024 and anticentro- as well as serological expression in SSc mere antibody (ACA) with DQB1*0501.5 patients. Moreover, anti-U1 small nuclear ribonucleo- Methods—IgG heavy chain allotypes protein (U1snRNP) antibodies, primarily de- G1M(f, z), G2M(n+, n-), G3M(b, g) and Ig tected in SSc patients with overlap features of light chain allotype KM(1, (1, 2), 3) were lupus and/or myositis, were associated with genotyped in 105 Japanese SSc patients DQB1*0302 in Japanese patients with connec- and 47 race matched normal controls tive tissue disease.6 using polymerase chain reaction (PCR) The immune response genes, which control based methods. Associations of each Ig immune responses to specific antigens, include allotype with SSc related antinuclear anti- MHC genes and genes coding for the immu- bodies were examined in combination noglobulin (Ig) allotypic markers, the latter are with or without MHC class II alleles. located in the constant regions of Ig heavy and 7 Results—GM/KM genotypic and allelic light chains. Previous studies have shown asso- frequencies were similar in SSc patients ciations between Ig allotypic phenotypes and and in normal controls. Frequencies of susceptibility to several autoimmune diseases 8 G1M(f) and G2M(n+) were significantly including systemic lupus erythematosus, 9 10 11 decreased in anticentromere antibody myasthenia gravis, and Graves’ disease. The (ACA) positive SSc patients compared presence of specific ANAs in patients with http://ard.bmj.com/ with ACA negative SSc patients (p = 0.04 autoimmune diseases was also shown to be 12 13 Division of and 0.02, respectively). Conversely, the associated with Ig allotypes. Interactive Rheumatology, presence of DQB1*0501 and KM(1, 2) sig- eVects of MHC antigens and Ig allotypes on Department of the production of antibodies directed against Medicine, Keio nificantly increased the risk of ACA posi- tivity. foreign and self antigens have been University School of 14 15 Medicine, Tokyo, Japan Conclusion—Ig allotype gene polymor- demonstrated. However, influences of Ig H Kameda phisms were not associated with suscepti- allotypes on serological expression in SSc J Kaburaki bility to SSc. Instead, the results suggested patients are largely undefined. on September 29, 2021 by guest. Protected copyright. M Kuwana that MHC class II and KM genes are asso- Recently, gene organisation of the Ig loci has ciated with autoimmune responses by been extensively analysed and polymerase Department of chain reaction (PCR) based molecular typing Microbiology and interactively promoting the production of methods for Ig allotypic markers have been Immunology, Medical ACA. 16–19 University of South (Ann Rheum Dis 1998;57:366–370) established. In this study, therefore, we Carolina, Charleston, identified Ig allotype gene polymorphisms in USA Japanese patients with SSc and examined for J P Pandey Systemic sclerosis (SSc) is a disease character- associations of these markers with ANA status ised by fibrosis of the dermis and internal in SSc patients. Interactive eVects of the two Division of Molecular Life Science, organs, microvascular injury, and the presence independent immune response genes, MHC Department of Genetic of circulating antinuclear antibodies (ANAs) to class II and Ig allotypes, on SSc related ANA Information, Tokai various nuclear proteins such as DNA topo- responses were also investigated. University School of isomerase I (topo I) and centromere/ Medicine, Isehara, kinetochore.1 The aetiology of SSc remains Methods Japan H Inoko unclear, but genetic factors are believed to PATIENTS AND CONTROLS influence its development, based on epidemio- We studied 105 unrelated Japanese SSc Correspondence to: logical studies showing familial clustering of patients, all of whom satisfied the American Dr M Kuwana, Division of SSc and SSc related disorders including College of Rheumatology (ACR; formerly the Rheumatology, Department 2 of Medicine, Keio University Raynaud’s phenomenon. Genes located American Rheumatism Association) prelimi- 20 School of Medicine, 35 within the major histocompatibility complex nary classification criteria of SSc. Ninety five Shinanomachi, Shinjuku-ku, (MHC) locus have been extensively analysed SSc patients in this study had been analysed in Tokyo 160–8582, Japan. as candidate genes for susceptibility to SSc, but our previous studies that examined for associa- Accepted for publication the findings have suggested that MHC class II tions between MHC class II alleles and SSc 18 May 1998 genes were associated less with SSc in itself but related ANAs.4–6 All SSc patients had been Immunoglobulin allotypes in SSc 367 Table 1 GM/KM allotype gene polymorphisms analysed in this study Ann Rheum Dis: first published as 10.1136/ard.57.6.366 on 1 June 1998. Downloaded from Chromosomal Typing Polymorphic System Subclass Domain Nomenclature location method position(s) Reference GM IgG1 CH1 G1M(f, z) 14q32.33 PCR-SSO codon 214 16 IgG2 CH2 G2M(n+, n−) 14q32.33 PCR-RFLP codon 282 17 IgG3 CH2 G3M(b, g) 14q32.33 PCR-RFLP codons 291, 296 18 CH3 codon 384 KM CL KM(1,(1, 2), 3) 2p12 PCR-RFLP codons 153, 191 19 PCR-SSO = polymerase chain reaction and sequence specific oligonucleotide probes, PCR-RFLP = polymerase chain reaction and restriction fragment length polymorphisms. observed regularly by clinical staV of the Divi- described previously.16–19 GM/KM allotype sion of Rheumatology, Keio University Hos- polymorphisms analysed in this study are sum- pital for more than three years or had died of marised in table 1. Briefly, the G1M, G2M, causes related to SSc within three years of G3M, and KM genes corresponding to the CH diagnosis. The mean time between their first domains including known polymorphisms visit and the latest follow up evaluation was 8.9 were amplified using subclass specific primers. years (range 0.8–24 years). Forty seven unre- Nucleic acid diVerences were discriminated by lated healthy Japanese volunteers living in restriction enzyme digestion of PCR amplified Tokyo metropolitan area were selected as race products (PCR-RFLP; G2M, G3M, and KM) matched normal controls. or hybridisation of PCR amplified products with sequence specific oligonucleotide probes ANA ASSAYS (PCR-SSO; G1M). Serum samples, obtained from SSc patients at ° first visit, were stored at −20 C. Three major STATISTICAL ANALYSIS SSc related ANAs were identified as described DiVerences in frequencies were analysed by previously; anti-topo I and anti-U1snRNP Fisher’s two tailed exact tests. Odds ratio (OR) antibodies by double immunodiVusion using with 95% confidence intervals (95%CI) were rabbit thymus extract as an antigen source and also calculated. 35 immunoprecipitation assays using S-labelled To analyse interactive eVects of MHC class HeLa cell extracts; and ACA by indirect II alleles and GM/KM allotypes on SSc related immunofluorescence on HeLa cell chromo- ANA responses, complex interactions for con- 21 somal spreads. tingency tables were investigated by fitting log- linear models according to the hierarchial MHC CLASS II ALLELE GENOTYPING principle.15 23 Interaction between a particular The DRB1, DQB1, and DPB1 genes were combination of the MHC class II allele and the typed using restriction fragment length poly- GM/KM allotype on the production of certain morphisms of PCR amplified genomic DNA as SSc related ANA was considered to be present described previously.22 The numbers of alleles when all of the following findings was satisfied: http://ard.bmj.com/ defined by this method are 52 (DRB1), 17 (a) risk for developing the SSc related ANA (DQB1), and 19 (DPB1). response aVected by non-additive eVects of two genetic markers (MHC class II alleles and IG ALLOTYPE GENOTYPING GM/KM allotypes) was significant by appro- Genotyping of Ig heavy chain (GM) and light priate G2 likelihood ratio statistic; (b) when chain (KM) allotypes was carried out as individuals with neither risk were taken as a Table 2 Genotypic and allelic frequencies of GM/KM allotypes in SSc patients and reference, frequency of individuals possessing normal controls both genetic markers in the ANA positive on September 29, 2021 by guest. Protected copyright. patients was significantly increased compared Normal SSc controls with those in the ANA negative patients and Ig allotypes (n=105) (n=47) p Value OR (95% CI) normal controls, using pairwise comparisons Genotypic frequency (%) by Fisher’s exact tests; and (c) frequency of G1M f 1 0 ns — individuals possessing a single genetic marker z 79 89 ns 0.44 (0.14 to 1.5) in the ANA positive patients was not signifi- f,z 21 11 ns 2.1 (0.61 to 7.2) G2M n+ 1 0 ns — cantly increased compared with those in the n− 78 87 ns 0.52 (0.16 to 1.7) ANA negative patients and normal controls. n+,n− 21 13 ns 1.8 (0.55 to 6.0) G3M b 7 0 ns — g 70 77 ns 0.73 (0.25 to 2.1) b,g 15 11 ns 1.5 (0.31 to 7.5) Results untypable* 8 13 ns 0.56 (0.12 to 2.7) GM/KM ALLOTYPES IN SSC AND NORMAL KM (1,2) 9 9 ns 1.0 (0.96 to 1.1) CONTROLS 3 45 49 ns 0.85 (0.29 to 2.5) Genotypic and allelic frequencies of GM/KM (1, 2),3 47 43 ns 1.2 (0.39 to 3.6) Allelic frequency (%) allotypes including G1M(f, z), G2M(n+, n-), G1M f 21 11 ns 2.2 (0.67 to 7.4) G3M(b, g), and KM(1, (1,2), 3) were com- z 99 100 ns — G2M n+ 22 13 ns 1.9 (0.60 to 6.
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