Fcγriia polymorphism as a risk factor for invasive pneumococcal infections in systemic lupus erythematosus

Patients with systemic lupus erythematosus (SLE) may be at increased risk for severe Streptococcus pneumoniae infections. In a report of the National Institutes of Health cohort of 467 SLE patients, 9 individuals (1.9%) were identified as having had extrapulmonary or invasive pneumococcal infections. A variety of invasive pneumococcal infections in SLE patients has been previously reported, including bacteremia, spontaneous peritonitis, epiglottitis, cellulitis, and fasciitis. The native humoral immune response to pneumococcus is predominantly mediated by IgG2 subclass antibodies, which appear to play a special role in host defense against encapsulated organisms. Opsonization of bacteria by IgG2 enables efficient clearance of the contagion from the pulmonary air spaces by alveolar phagocytes. Pneumococci which are not phagocytosed and killed may escape into the interstitial tissue and the lymphatic drainage, resulting in bacteremic dissemination. This pivotal function of IgG2 in the defense against S. pneumoniae is intriguing in view of the observation that the only human Fc gamma receptor (Fc gamma R) which ligates IgG2 and clears IgG2 immune complexes is the H131 variant of Fc gamma RIIA (7,8). This allelic variant has a histidine residue in the 131 position of the second extracellular immunoglobulin-like domain, which is involved in ligand binding. By contrast, the codominant R131 allelic variant possesses an arginine residue in that position and has markedly lower affinity for IgG2. Other Fc gamma R (i.e., Fc gamma RI and Fc gamma RIII) also ligate IgG2 poorly. Consequently, in functional studies, phagocytes from individuals that are R131 homozygotes are less efficient than those from H131 homozygotes in internalizing IgG2-opsonized probes. R131/H131 heterozygote cells exhibit intermediate function. Since IgG2 is a poor activator of complement, optimal handling of IgG2-opsonized pneumococci is dependent upon Fc gamma RIIA genotype. We therefore hypothesize that this Fc gamma RIIA allelic polymorphism plays a role in the susceptibility of SLE patients to fulminant pneumococcal infections.