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Activities, and Body Mass Index and Polygenic Variations, Hemolytic Diversity in Intrinsic Strengths of the Human Complement System: Serum C4 Protein Concentrations Correlate with C4 Gene Size and Polygenic Variations, Hemolytic This information is current as Activities, and Body Mass Index of September 23, 2021. Yan Yang, Erwin K. Chung, Bi Zhou, Carol A. Blanchong, C. Yung Yu, George Füst, Margit Kovács, Ágnes Vatay, Csaba Szalai, István Karádi and Lilian Varga J Immunol 2003; 171:2734-2745; ; Downloaded from doi: 10.4049/jimmunol.171.5.2734 http://www.jimmunol.org/content/171/5/2734 http://www.jimmunol.org/ References This article cites 65 articles, 14 of which you can access for free at: http://www.jimmunol.org/content/171/5/2734.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 23, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2003 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Diversity in Intrinsic Strengths of the Human Complement System: Serum C4 Protein Concentrations Correlate with C4 Gene Size and Polygenic Variations, Hemolytic Activities, and Body Mass Index1 Yan Yang,*†‡ Erwin K. Chung,*†‡ Bi Zhou,* Carol A. Blanchong,*‡ C. Yung Yu,2*†‡ George Fu¨st,2§ Margit Kova´cs,§ A´ gnes Vatay,§ Csaba Szalai,¶ Istva´n Kara´di,§ and Lilian Varga§ Among the genes and proteins of the human immune system, complement component C4 is extraordinary in its frequent germline variation in the size and number of genes. Definitive genotypic and phenotypic analyses were performed on a central European Downloaded from population to determine the C4 polygenic and gene size variations and their relationships with serum C4A and C4B protein concentrations and hemolytic activities. In a study population of 128 healthy subjects, the number of C4 genes present in a diploid genome varied between two to five, and 77.4% of the C4 genes belonged to the long form that contains the endogenous retrovirus HERV-K(C4). Intriguingly, higher C4 serum protein levels and higher C4 hemolytic activities were often detected in subjects with short C4 genes than those with long genes only, suggesting a negative epistatic effect of HERV-K(C4) on the expression of C4 proteins. Also, the body mass index appeared to affect the C4 serum levels, particularly in the individuals with medium or high http://www.jimmunol.org/ C4 gene dosages, a phenomenon that was dissimilar in several aspects from the established correlation between body mass index and serum C3. As expected, there were strong, positive correlations between total C4 gene dosage and serum C4 protein con- centrations, and between serum C4 protein concentrations and C4 hemolytic activities. There were also good correlations between the number of long genes with serum levels of C4A, and the number of short genes with serum levels of C4B. Thus, the polygenic and gene size variations of C4A and C4B contribute to the quantitative traits of C4 with a wide range of serum protein levels and hemolytic activities, and consequently the power of the innate defense system. The Journal of Immunology, 2003, 171: 2734–2745. iversities in immune functions are mainly achieved by nomenon has been observed over a decade ago (5–14), the molec- by guest on September 23, 2021 nucleotide polymorphisms/mutations and somatic re- ular genetic basis for the qualitative and quantitative variations of D combinations of gene segments (1, 2). Human comple- human complement C4 was often accounted for inaccurately. Until ment component C4 represents a new paradigm of complex, inborn recently, the sophistication of human C4 genetics has not been immune diversity (3). Phenotypically, there are acidic C4A and fully appreciated. A two-locus, C4A-C4B model with null alleles basic C4B proteins with multiple polymorphic variants in each of either locus was used to explain the great variation in the levels class (4). The plasma or serum protein levels of total C4 vary of C4A and C4B proteins in a population (15, 16). There are ac- between 100 and 1000 mg/L among different individuals, as do the tually a frequent, dichotomous gene size variation and polygenic relative quantities of C4A and C4B proteins. Although this phe- and modular duplications of C4A and C4B together with their flanking genes RP1 or RP2, CYP21A or CYP21B, and TNXA or TNXB in the MHC (Fig. 1A). Existing at the germline levels and *Center for Molecular and Human Genetics, Columbus Children’s Research Institute, †Department of Molecular Virology, Immunology, and Medical Genetics, and ‡De- inherent to different individuals, there are monomodular, bimodu- partment of Pediatrics, Ohio State University, Columbus, OH 43205; §Third Depart- lar, trimodular, or quadrimodular structures of discrete segments in ment of Internal Medicine, Semmelweis Medical University, Budapest, Hungary; and ¶Section of Molecular Immunology, Hungarian Academy of Sciences, and the MHC containing one, two, three, or four RP-C4-CYP21-TNX Heim Pa´l Pediatric Hospital, Budapest, Hungary (RCCX)3 modules (17–19). Each C4 gene may code for C4A or Received for publication February 25, 2003. Accepted for publication July 2, 2003. C4B. Each C4A or C4B gene may be 21 kb (long) or 14.6 kb The costs of publication of this article were defrayed in part by the payment of page (short) in size (20). The long C4 gene contains a 6.36-kb endog- charges. This article must therefore be hereby marked advertisement in accordance enous retrovirus HERV-K(C4) in its intron 9 (21, 22). Recently, with 18 U.S.C. Section 1734 solely to indicate this fact. we showed that the bimodular RCCX haplotypes constitute 1 This work in the United States was supported by the National Institute of Arthritis slightly more than two-thirds of the Caucasian population in the and Musculoskeletal and Skin Diseases Grants R01 43969 and 1R01 AR050078, the National Institute of Diabetes and Digestive and Kidney Diseases Grant P01 midwestern United States, while the frequencies of monomodular DK55546, an institutional grant from the Columbus Children’s Research Institute and trimodular RCCX haplotypes were 0.17 and 0.14, respectively (297401), and Pittsburgh Supercomputing Center through National Institutes of (18). Quadrimodular RCCX haplotypes with four C4 genes in a Health Center for Research Resources Cooperative Agreement Grant 1P41 RR06009 (to C.Y.Y.); and in Hungary this work was supported by research grants from the Hungarian Academy of Sciences (2000-107 3,2) and Hungarian National Research Fund (T032661) (to G.F.). 3 Abbreviations used in this paper: RCCX, four-gene module in human MHC with 2 Address correspondence and reprint requests to Dr. C. Yung Yu, Children’s Re- serine/threonine nuclear protein kinase RP, complement C4, steroid 21-hydroxylase search Institute, Department of Pediatrics, The Ohio State University, 700 Children’s CYP21, and extracellular matrix protein tenascin TNX; BMI, body mass index; C4HA, Drive, Columbus, OH 43205. E-mail address: [email protected]; or Dr. George Fu¨st, C4 hemolytic activity; HERV-K(C4), human endogenous retrovirus in long C4 gene; Third Department of Medicine, Semmelweis Medical University, Budapest, HVAGE, high voltage agarose gel electrophoresis; L, RCCX module with long C4 Ku´tvo¨lgyi u´t 4, H-1125, Hungary. E-mail address: [email protected]. gene; S, RCCX module with short C4 gene. Copyright © 2003 by The American Association of Immunologists, Inc. 0022-1767/03/$02.00 The Journal of Immunology 2735 row are rare in Caucasians, but relatively common in Asians (19, Preparation of genomic DNA, Southern blot analysis, and 23). The impacts of the C4 polygenic and gene size variations on DNA probes C4 protein levels and functional activities have not been accurately Genomic DNAs were prepared from PBMC (40). Southern blot analyses of studied in a population. TaqI-digested or PshAI-digested genomic DNAs were performed, as de- Complement component C4 is important in immunity, toler- scribed in previous publications (18, 41). The TaqI genomic blots were ance, and autoimmunity (24–27). It plays essential roles in linking hybridized with three specific probes corresponding to RP, CYP21, and the recognition pathways of the complement system initiated by TNX. The results revealed the presence and dosage of RP1-C4L (7.0 kb), RP1-C4S (6.4 kb), RP2-C4L (6.0 kb), and RP2-C4S (5.4 kb); the presence Ag-Ab or Ag-mannan-binding lectin complexes to the effectors of and relative dosage of CYP21B (3.7 kb) and CYP21A (3.2 kb); and the the humoral immune response. Complete deficiency of comple- presence and relative dosage of TNXB (2.5 kb) and TNXA (2.4 kb). The ment C4 (i.e., both C4A and C4B) is one of the most penetrant number of RCCX modules was independently confirmed by PshAI-RFLP genetic risk factors in autoimmune disease such as systemic lupus using a RP 3Ј probe to determine the relative dosage of RP1 (7.2-kb) and RP2 (8.3-kb) fragments. The relative dosages of C4A and C4B genes were erythematosus (28, 29). Complete or partial deficiencies of C4B determined by PshAI RFLP using a C4d-specific probe corresponding to are related to vulnerability and severity of microbial infections (30, C4 gene exons 28–31 (Fig.
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