Association of Human FcγRIIa (CD32) Polymorphism with Susceptibility to and Severity of Meningococcal Disease

Alexander E. Platonov 0 1 German A. Shipulin 0 1 Irina V. Vershinina 0 1 Jacob Dankert 0 1 Jan G. J. van de Winkel 0 1 Ed J. Kuijper 0 1 0 Received 24 November 1997; revised 13 May 1998. This work was presented in part at the 8th European Congress on Clinical Microbiology and Infectious Diseases held in Lausanne, Switzerland, 25 - 28 May 1997. A short form of the abstract was published in Clinical Microbiology and Infection 1997; 3:S196. Grant support: This study was supported by the International Association for the Promotion of Co-operation with Scientists from the Independent States of the Former Soviet Union (INTAS; 1010-CT93-0011). crobiology, Academic Medical Centre , Meibergdreef 9, 115 AZ, Amsterdam , the Netherlands 1 From the Central Institute of Epidemiology , Moscow , Russia; and the Department of Medical Microbiology, Reference Laboratory for Bacterial Meningitis, The University of Amsterdam and Academic Medical Centre , Amsterdam , and the Department of Immunology, University Hospital Utrecht , Utrecht , the Netherlands Phagocytosis of bacteria constitutes an important defense mechanism against invasive bacterial diseases. Efficacy of phagocytosis by polymorphonuclear neutrophils is known to vary between allotypes of FcgRIIa (a class of Fc receptors for immunoglobulins that is constitutively expressed on neutrophils). We compared the distribution of FcgRIIa-R131 and FcgRIIa-H131 allotypes in 98 Slavic complement-sufficient patients with meningococcal disease with that of the allotypes in 107 healthy controls. A strong association was found between the IIa-R/R131 allotype and the development of meningococcal disease after the age of 5 years, compared with IIa-R/H131 and IIaH/H131 allotypes (P .03; odds ratio [OR], 2.9). A severe course of meningococcal disease was observed in 21 (68%) of 31 episodes in patients with IIa-R/R131 genotype and in 22 (54%) of 41 episodes in patients with IIa-R/H131 genotype, in contrast to eight (31%) of 26 episodes in patients with IIa-H/H131 genotype (P .02; OR, 4.7). Our data show that individuals older than 5 years of age who have the IIa-H/H131 allotype are less susceptible to severe meningococcal disease than are individuals with the IIa-R/R131 or IIa-R/H131 genotype. - Meningococcal disease is an infectious disease associated with a high rate of mortality that affects otherwise healthy individuals and causes severe neurological sequelae. The annual incidence of meningococcal disease in western Europe and in Russia fluctuates around one to six cases per 100,000 individuals [1]. Most cases of meningococcal disease occur in the first 4 years of life, but the occurrence peaks again during the teenage years [1]. The rates of mortality (5% 20%) and of morbidity and sequelae (5% 30%) due to meningococcal disease depend on both bacterial virulence factors and host immune defense mechanisms, such as the complement system, antibody production, cytokine production, and phagocytic killing [2 7]. The effectiveness of phagocytosis depends significantly on the Fc receptors (FcRs) for immunoglobulins that are found on phagocytes [4, 8, 9, 10]. Three major classes of leukocyte FcRs for IgG exist in humans: FcgRI (CD64), FcgRII (CD32), and FcgRIII (CD16) [11]. The latter two classes are constitutively expressed on neutrophils as FcgRIIa and FcgRIIIb and exhibit structural and functional polymorphisms. Both receptors can bind to human IgG1 and IgG3 subclasses, but FcgRIIa represents the sole leukocyte FcR capable of binding to IgG2 [12]. Two allotypic forms of FcgRIIa are known (FcgRIIaR131 and FcgRIIa-H131) because of the presence of arginine or histidine at position 131 in the extracellular domain of the receptor, respectively [12]. The IgG2 isotype dominates in the immune response to encapsulated bacteria, such as meningococci [13, 14]. In vitro, neutrophils with the IIa-H/H131 allotype optimally phagocytose IgG2-opsonized Haemophilus influenzae type b, Staphylococcus aureus, Neisseria meningitidis group B, and group B streptococcus type III [4, 8, 9]. Neutrophils with the IIa-R/ R131 allotype are less effective than neutrophils with the IIaH/H131 allotype, and neutrophils with a heterozygous allotype exhibit intermediate levels of phagocytosis [4, 8, 9]. On the basis of these in vitro data, we hypothesized that individuals with IIa-R/R131 allotypes are more susceptible to meningococcal disease than are individuals with IIa-H/H131 and IIa-R/ H131 allotypes. A prospective study was designed to collect DNA samples from patients with meningococcal disease who were admitted to the Second Moscow Hospital of Infectious Diseases; the FcgRIIa allotypes were analyzed by using a recently developed molecular biological approach. Patients and Methods Patients. Ninety-eight patients admitted consecutively to the Second Moscow Hospital of Infectious Diseases because of a diagnosis of systemic meningococcal disease (see below) were enrolled in the study. Criteria for inclusion were Slavic origin, intact hemolytic activity of the classic and alternative complement pathways, and normal levels of complement components. All patients included in the study were Caucasian, had Slavic surnames, used Russian as their native language, and considered themselves as Russians. The age and sex distribution corresponded to that observed for patients admitted previously to the hospital because of meningococcal disease in Moscow; 62 patients (63%) were male, and the median age of the patients was 5 years (range, 1 month to 59 years). The controls consisted of 107 healthy Slavic adult (age range, 18 40 years) blood donors from Moscow. Diagnosis of meningococcal disease. Analyses of the patients clinical diagnoses and severity of disease were performed retrospectively; these analyses were based on information obtained by the treating physicians that was documented on standard case records and discharge letters. The diagnosis of meningococcal disease was made on the basis of the following: bacterial culture yielding N. meningitidis (group A, 13 organisms; group B, 9; group C, 3; group W135, 1; and nongroupable, 2), 28 cases; PCR analysis specific for meningococci [15, 16], 28 cases; positive CSF test for meningococcal antigen, 20 cases; direct microscopy revealing diplococci on a gramstained preparation of CSF or a methylene blue stained preparation of blood, 14 cases; and typical clinical picture only, 8 cases. Results of laboratory tests for other bacterial pathogens causing meningitis, including a modified PCR method based on the 16S rRNA of H. influenzae and Streptococcus pneumoniae, were negative for all patients [17]. Criteria for estimation of the severity of meningococcal disease. Two previously described grades of severity were used to classify episodes of meningococcal disease in the patients included in this study [7]: severe coma; shock, defined and graded according to Martin and Silverman [18] (including tachypnea, tachycardia, and inadequate (...truncated)