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Immunoglobulin Allotypes and Igg Subclass Antibody Response to Pseudomonas Aeruginosa Antigens in Chronically Infected Cystic Fibrosis Patients

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Immunoglobulin Allotypes and Igg Subclass Antibody Response to Pseudomonas Aeruginosa Antigens in Chronically Infected Cystic Fibrosis Patients Clin. exp. Immunol. (1992) 90, 209-214 Immunoglobulin allotypes and IgG subclass antibody response to Pseudomonas aeruginosa antigens in chronically infected cystic fibrosis patients T. PRESSLER*, J. P. PANDEYT, F. ESPERSENt, S. S. PEDERSENt, A. FOMSGAARDt, C. KOCH* & N. H0IBYt *Danish CF Centre, Department of Pediatrics, tDepartment of Clinical Microbiology, Rigshospitalet, University of Copenhagen, Denmark and tDepartment of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA (Acceptedfor publication 6 August 1992) SUMMARY Chronic Pseudomonas aeruginosa lung infection is the leading cause of death in patients with cystic fibrosis (CF). Poor prognosis correlates with a high number of anti-pseudomonas precipitins and with high levels ofIgG2 and IgG3 anti-pseudomonas antibodies. Reports ofseveral highly significant associations between certain Gm (genetic markers of IgG on human chromosome 14) and Km (k- type light chain determinants on chromosome 2) phenotypes and immune responsiveness to various antigens suggest that allotype-linked immune response genes do exist in man. Furthermore correlation between Gm types and IgG subclass levels has been reported. A group of 143 CF patients were investigated (31 non-infected and 112 chronic infected). The IgG subclass antibodies to three different P. aeruginosa antigens (P. aeruginosa standard antigen (St-Ag), alginate and LPS) were determinated. Immunoglobulin allotypes were determined by haemagglutination inhibition. Sam- ples were typed for Glm(1,2,3, and 17), G2m(23), G3m(5,21), and Km(1,3). Statistical analysis of our data demonstrate that IgG3 anti-pseudomonas antibody levels and Gm markers are related. IgG3 antibody levels to all investigated P. aeruginosa antigens are significantly higher in sera homozygous for Gm(3;5), somewhat lower in heterozygous sera, and significantly lower in sera homozygous for Gm(1,2,17;21). We suggest that genetic differences between the patients may explain the present differences in subclass patterns. Keywords Gm types IgG subclasses cystic fibrosis P. aeruginosa antigens INTRODUCTION aggressive infection, accounting for the correlation between Chronic Pseudomonas aeruginosa lung infection is the leading high IgG2 and IgG3 antibodies and poor pulmonary function. cause of death in patients with cystic fibrosis (CF). In the first On the other hand the IgG subclass antibodies have different decade oflife many patients with CF acquire a chronic broncho- biological properties and the differences in the clinical course of pulmonary infection with P. aeruginosa and despite intensive disease may be a result of the particular biological properties of antimicrobial treatment this infection cannot be eradicated. these subclasses. Specific antibodies against P. aeruginosa antigens increase when Considerable evidence from studies ofinbred strains ofmice the infection becomes chronic, and a poor prognosis has been indicates that the immune responsiveness to certain antigens is demonstrated to correlate with a high number of anti-pseudo- controlled by allotype-linked immune response (Ir) genes [8,9]. monas precipitins [1]. Studies on total IgG subclass distribution Reports of several highly significant associations between and specific IgG subclass pattern of antibodies to different P. certain Gm (genetic markers of IgG on human chromosome 14) aeruginosa antigens have revealed a correlation of high IgG2 and Km (k-type light chain determinants on chromosome 2) and IgG3 antibodies with poor lung function and poor clinical phenotypes and immune responsiveness to various antigens condition [2-7]. The interpretation of these findings may be suggest that such allotype-linked Ir genes do exist in man [10]. dual. The antibody pattern may be the result of a particular Furthermore, correlation between Gm types and IgG sub- class levels has been reported [11-13]. The four IgG subgroups Correspondence: Tacjana Pressler, Department of Clinical Micro- are encoded by different cistrons. Although each Gm marker is biology, Rigshospitalet, afsnit 8223, Juliane Maries Vej 28,2, 2100 restricted to only one heavy chain subgroup, it is found in some Copenhagen 0, Denmark. and not in all chains of the subgroup. The IgG heavy chain 209 210 T. Pressler et al. cistrons are very closely linked so that various Gm determinants The patient population was divided into four groups, stay together as gene complexes and studies on the inheritance according to the most probable genotypes; homozygotes for ofGm factors have shown that each ofseveral gene complexes is both Glm and G3m markers-one positive for Gm(3) and very stable. In Caucasians IgG1 chains have either Gm(l) and Gm(5), and another positive for Glm(l,17) or Glm(1,2,17) and Gm(17), or Gm(3), but not both markers; and IgG2 chains are G3m(21); heterozygotes for both Glm and G3m markers- either Gm(23) or lack any known Gm factor; IgG3 chains have positive for both Glm(1,2,3,17)/Gm(1,3,17) and G3m(5,21); either Gm(5) or Gm(21) but not both markers [14]. Thus, an and a group heterozygous for GIm markers-Glm(l,2,3,17) or individual can be described as being homozygous or hetero- Glm(1,3,17) and homozygous for G3m-either G3m(5) or zygous for these factors. G3m(21). The purpose of this study was to determine if there is a relationship between subclass-specific antibody levels to differ- ent P. aeruginosa antigens and Gm and Km markers in a Antigens population of chronically infected patients with CF. P. aeruginosa standard antigen (St-Ag). Water-soluble antigens were produced from each of 17 serotypes of the MATERIALS AND METHODS International Antigenic Typing Scheme of P. aeruginosa [1]; equal volumes of each were mixed and designated standard CFpatients antigen. Diagnosis ofCF was established on the basis ofabnormal sweat P. aeruginosa alginate. Alginate is a linear heteropolysac- electrolytes and characteristic clinical features. After diagnosis, charide of the two uronic acids and is characteristic for the all CF patients were seen monthly at the Danish CF centre in mucoid capsule of CF strains. It was isolated and purified from Copenhagen. At each visit the clinical condition and sputum mucoid P. aeruginosa [17]. The alginate did not cross-react with bacteriology were examined and have thus been recorded antibodies against lipopolysaccharide or protein antigens of P. prospectively since 1970. The infection was regarded as chronic aeruginosa. A mixture of three serologically cross-reacting if P. aeruginosa had been cultured from sputum at monthly alginates was used [17]. intervals for 6 months. P. aeruginosa lipopolysaccharide (LPS). P. aeruginosa A group of 143 patients from our centre were investigated. strain 1118 0: 3 was isolated from a patient with CF. LPS was This group was a random sample of our entire patient extracted by the phenol-chloroform-petroleum ether method population and includes 31 non-infected and 112 chronically [18] and purified and characterized as reported elsewhere [19]. infected patients. The duration ofchronic infection ranged from This is the most common O-group of P. aeruginosa and it cross- I to 24 years (median 10-8). The age of the patients was evenly reacts serologically with polyagglutinable strains which are distributed in the range 4-40 years (median 18 9 years). All common in CF [20]. serum samples for antibody determinations and Gm and Km allotyping were collected during a period of 1 month. In order to avoid differences in management of chronic P. aeruginosa lung Enzyme-linked immunosorbent assays infection in different time periods we chose a group of CF IgG subclass antibody response was measured by 12 ELISAs patients (n = 77) with duration of a chronic P. aeruginosa that detected IgG subclass antibodies specific for the three infection between 6 and 15 years (median I1 years). This group different P. aeruginosa antigen preparations. Details of the of patients has been admitted every 3 months for a 2-week assays have been published [4,3,21]. course of intravenous anti-pseudomonal treatment since chro- Reagent volumes, blocking and dilution buffer, washing nic infection was established. This treatment regimen has been buffer and washing steps, and development of colour reaction used in our centre since 1976 [15]. were common in all assays. The procedures used are shown in The subclass antibody levels in this group of patients were Table 1. used to evaluate the correlation between Gm markers and anti- Reagent volumes were 01 ml, the dilution buffer was pseudomonas IgG subclass levels. phosphate-buffered saline (PBS, pH 7-2) with 0 1% Tween 20 (Polysorbate, Sigma, St Louis, MO) and 0-5 M NaCl. Between Immunoglobulin allotype each step, plates were washed three times in PBS-Tween. After Immunoglobulin allotypes were determined by haemagglutina- coating with either alginate or St-Ag residual binding sites tion inhibition [16]. Samples were typed for Glm(1,2,3, and 17), were blocked with dilution buffer. Dilutions of serum were G2m(23), G3m(5,21), and Km(1,3). incubated for 1 h in the anti-alginate and anti-LPS assays and Table 1. Experimental details of ELISAs used to determine antibodies to P. aeruginosa antigens in patients with cystic fibrosis MoAb dilution Serum dilution Coating anti-IgG conc. Time IgG horseradish peroxidase-conjugated Temp. 0C Antigen Solid phase (mg/ml) (h) 1 2 3 4 1 2 3 4 all steps Alginate MicroWell 30 1 1:500 1:500 1:500 1:250 1:6000 1:2000 1:2000 1:500 35 St-Ag Maxisorb 22 1 1:3000 1:3000 1:3000 1:3000 1:20000 1:3000 1:1000 1:8000 22 LPS Polysorb 10 18 1:2000 1:250 1:2000 1:250 1:5000 1:1000 1:1000 1:500 22shaking Gm types and IgG subclass antibodies in CF 211 overnight in the anti-St-Ag assays. Horseradish peroxidase- RESULTS labelled monoclonal anti-IgG subclass specific antibodies Gm phenotypes (Janssen Biochimica, Belgium, Catalogue number: 24.145.89, The frequencies of the Gm phenotypes observed in the popula- 24.144.88, 24.143.87 and 24.142.86) were added to each well.
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