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Immunoglobulin Allotype and Human Antibody Response and Susceptibility to Polysaccharide Encapsulated Bacteria

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Immunoglobulin Allotype and Human Antibody Response and Susceptibility to Polysaccharide Encapsulated Bacteria Correlation between G2m(n) immunoglobulin allotype and human antibody response and susceptibility to polysaccharide encapsulated bacteria. D M Ambrosino, … , E van Loghem, G R Siber J Clin Invest. 1985;75(6):1935-1942. https://doi.org/10.1172/JCI111909. Research Article To determine whether genetic factors influence the human antibody response to polysaccharides, we correlated Ig allotypes with the concentrations of antibody to 14 bacterial capsular antigens in 130 actively immunized Caucasian adults. The 88 individuals possessing G2m(n), an allotype antigen of IgG2 subclass heavy chains, had significantly higher postimmunization antibody levels to Haemophilus influenzae type b (Hib) and 8 of 11 pneumococcal types (P less than 0.05) than the 42 lacking this antigen. For Hib, pneumococcus type 14, and meningococcus group C, an increased response was observed in IgG class but not in IgM or IgA classes of antibody. The G2m(n) positive individuals also had higher preimmunization antibody levels to most polysaccharide antigens. Total IgG2 concentrations were correlated with the mean postimmunization antibody concentrations to pneumococci (P = 0.005), but this correlation was independent of G2m(n) by multiple regression analysis. To determine if the lack of G2m(n) was associated with increased susceptibility to infection, we compared the frequencies of various Ig allotypes in 98 children infected with Hib and 98 matched controls. Caucasian children with Hib infections other than epiglottitis were significantly more likely to lack the G2m(n) allotype than controls (P less than 0.05). G2m(n) negative Caucasian children less than or equal to 18 mo old have a 5.1-fold higher risk of nonepiglottitic Hib infections than G2m(n) positive children […] Find the latest version: https://jci.me/111909/pdf Correlation between G2m(n) Immunoglobulin Allotype and Human Antibody Response and Susceptibility to Polysaccharide Encapsulated Bacteria Donna M. Ambrosino, Gerald Schiffman, Emil C. Gotschlich, Peter H. Schur, Gail A. Rosenberg, Gerda G. DeLange, Ema van Loghem, and George R. Siber Laboratory ofInfectious Diseases, Dana-Farber Cancer Institute; Department ofInfectious Diseases, Children's Hospital Medical Center; and Department ofMedicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115; Massachusetts Public Health Biologic Laboratories, Jamaica Plain, Massachusetts 02130; Department ofMicrobiology and Immunology, State University ofNew York, Downstate Medical Center, Brooklyn, New York; Laboratory of Bacteriology and Immunology, The Rockefeller University, New York, New York; and Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, Amsterdam, Holland Abstract surface structures of these bacteria, particularly to the capsular To determine whether genetic factors influence the human polysaccharides, are important in protection against infection antibody response to polysaccharides, we correlated Ig allotypes (1-4). Several lines of evidence suggest that the antibody with the concentrations of antibody to 14 bacterial capsular response to polysaccharide antigens and susceptibility to these antigens in 130 actively immunized Caucasian adults. The 88 bacterial infections may be under genetic control. Children individuals possessing G2m(n), an allotype antigen of IgG2 who have recovered from meningitis have lower anti-Hib subclass heavy chains, had significantly higher postimmuniza- antibodies than age matched siblings (5) and do not respond tion antibody levels to Haemophilus influenzae type b (Hib) to immunization as well as controls (6). Siblings of patients and 8 of 11 pneumococcal types (P < 0.05) than the 42 lacking with meningitis have lower antibody responses to a Hib- this antigen. For Hib, pneumococcus type 14, and meningococcus pertussis complex vaccine than control children (7). Certain group C, an increased response was observed in IgG class but ethnic populations such as native Americans (8) and Alaskan not in IgM or IgA classes of antibody. The G2m(n) positive Eskimos (9) have an extremely high incidence of infection by individuals also had higher preimmunization antibody levels to Hib and pneumococci. Hib disease expression also differs in most polysaccharide antigens. Total IgG2 concentrations were various races. For example, epiglottitis is common in Caucasian correlated with the mean postimmunization antibody concen- and rare in Black, Eskimo, and native American children. trations to pneumococci (P = 0.005), but this correlation was There are differences between children with epiglottitis and independent of G2m(n) by multiple regression analysis. healthy children in MNS erythrocyte antigen phenotypes (5). To determine if the lack of G2m(n) was associated with Although socioeconomic and epidemiologic factors may explain increased susceptibility to infection, we compared the frequen- some of these observations, genetic factors are also likely to cies of various Ig allotypes in 98 children infected with Hib be important. and 98 matched controls. Caucasian children with Hib infections We have previously shown that the human antibody re- other than epiglottitis were significantly more likely to lack sponse to bacterial polysaccharide antigens is correlated with the G2m(n) allotype than controls (P < 0.05). G2m(n) negative the individual's total IgG2 subclass concentration (10). The Caucasian children . 18 mo old have a 5.1-fold higher risk of majority of human IgG antibody to certain polysaccharide nonepiglottitic Hib infections than G2m(n) positive children (P antigens is of this subclass (11, 12). The concentrations of < 0.01). We conclude that allotypic variants of the gamma-2 IgG2 as well as IgG3 and IgG4 are higher in individuals with heavy chain genes, or genes in linkage equilibrium with them, particular Ig heavy chain antigens called allotypes (13-15). exert a regulatory influence on the caucasian antibody response Allotypes are genetically determined variants of Igs that provide to a variety of immunologically distinct bacterial polysaccharide a tool for examining the influence of genes located in or near antigens. Young Caucasian children of the low responder the heavy or light chain loci on the antibody response. In mice phenotype, i.e., those lacking the G2m(n) allotype, are geneti- (16, 17) and in humans (18-20), Ig allotype antigens have cally predisposed to Hib and perhaps other bacterial infections. been associated with increased or decreased antibody responses to a variety of antigens. Introduction In this study we examined the relationship between human of b and Ig allotype antigens and the antibody concentrations healthy Haemophilus influenzae type (Hib),' pneumococci, Caucasian adults before and after immunization with 14 meningococci are bacterial pathogens. Antibodies to the major polysaccharide antigens. We were particularly interested in the because of its location on the chain of Address reprint requests to Dr. Siber, Dana-Farber Cancer Institute, G2m(n) allotype heavy 44 Binney St., Boston, MA 02115. IgG2 subclass Igs. In the second phase of the study we Received for publication 2 August 1984 and in revised form 29 compared the Ig allotypes of children with Hib infections and January 1985. matched controls to determine whether Ig allotypes were correlated with the risk of infection. 1. Abbreviations used in this paper: CSF, cerebrospinal fluid; ELISA, enzyme-linked immunosorbent assay; Hib, Haemophilus influenza Methods type b. Study population (active immunization). 58 male and 72 female J. Clin. Invest. Caucasian plasma donors with a mean age of 33 yr were immunized © The American Society for Clinical Investigation, Inc. with 0.5 cc 14-valent pneumococcal vaccine (Pneumovax, Lot 1912B, 0021-9738/85/06/1935/08 $ 1.00 Merck, Sharp and Dohme, West Point, PA) and concurrently with 0.5 Volume 75, June 1985, 1935-1942 cc Hib vaccine (Lot 764-CF320; Merck, Sharp and Dohme) and 0.5 G2m(n) Allotype and Polysaccharide Encapsulated Pathogens 1935 cc bivalent meningococcal vaccine (Menomune A/C, Connaught Lab- 10.2 with 0.1 N NaOH. After 6 min, 0.4 mg tyramine in 1 ml 0.1 M oratories, Swiftwater, PA), combined in the same syringe. Serum for NaHCO3, 0.5 M NaCl, pH 8.5, was added. The mixture was incubated Ig allotyping, Ig concentrations, and polysaccharide antibodies was at room temperature for I h and at 40C for 24 h and dialyzed against obtained before and 4 wk after immunization and stored at -20'C phosphate-buffered saline. Wells of polystyrene microtiter plates (Flow until assay. Laboratories, Inc., McLean, VA) were coated with 100 Ml of tyraminated Study population (disease susceptibility). 98 children with Hib capsular polysaccharide at 1 Ag/ml for 90 min at 370C and were disease seen at Children's Hospital Medical Center, Boston, MA from washed with wash buffer (phosphate-buffered saline, 0.05% Tween). 1977 to 1982 were studied. Their clinical features are summarized in 100 Ml of serum diluted in wash buffer was added per well, incubated Table I. The case definition of Hib infection was the isolation of Hib at room temperature for 24 h, and washed. 100 Al of appropriately from the blood, cerebrospinal fluid (CSF), or other sterile body fluid diluted alkaline phosphatase conjugated IgG fractions of goat anti- (n = 79), or the detection of Hib capsular antigen in blood and/or CSF human IgG, IgM, or IgA (Atlantic Antibodies, Scarborough, ME) were in the presence of a clinical syndrome of meningitis, epiglottitis, added, incubated at 370C for 3 h, and
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