Activity of human IgG and IgA subclasses in immune defense against Neisseria meningitidis serogroup B.

Both IgG and IgA Abs have been implicated in host defense against bacterial infections, although their relative contributions remain unclear. We generated a unique panel of human chimeric Abs of all human IgG and IgA subclasses with identical V genes against porin A, a major subcapsular protein Ag of Neisseria meningitidis and a vaccine candidate. Chimeric Abs were produced in baby hamster kidney cells, and IgA-producing clones were cotransfected with human J chain and/or human secretory component. Although IgG (isotypes IgG1-3) mediated efficient complement-dependent lysis, IgA was unable to. However, IgA proved equally active to IgG in stimulating polymorphonuclear leukocyte respiratory burst. Remarkably, although porin-specific monomeric, dimeric, and polymeric IgA triggered efficient phagocytosis, secretory IgA did not. These studies reveal unique and nonoverlapping roles for IgG and IgA Abs in defense against meningococcal infections.

Pneumococcal capsular polysaccharide-specific IgA triggers efficient neutrophil effector functions via FcalphaRI (CD89).

Specific anti-capsular polysaccharide IgG is believed to be important for protection against infection by Streptococcus pneumoniae. Significant IgA responses have been observed after vaccination with pneumococcal vaccines, but the role of this isotype in anti-pneumococcal host defense is unclear. Here, it is shown that purified serum IgA specific for pneumococcal capsular polysaccharides can initiate efficient cellular effector functions, such as phagocytosis, via interaction with the myeloid IgA receptor, FcalphaRI (CD89). The efficiency of FcalphaR-triggered granulocyte effector functions was comparable to that of FcgammaRIIa (CD32), as shown in experiments with bispecific antibodies. These results support a role for polysaccharide-specific IgA in antipneumococcal cellular effector function and suggest that FcalphaRI represents an important leukocyte receptor for immunity against S. pneumoniae.

Effective phagocytosis and killing of Candida albicans via targeting FcgammaRI (CD64) or FcalphaRI (CD89) on neutrophils.

Invasive fungal infections are an increasing problem for immunocompromised patients. As an approach to improve targeting of polymorphonuclear leukocytes (PMNL) toward Candida albicans, the effect of bispecific antibodies (BsAbs) directed against C. albicans and either FcalphaRI or FcgammaRI was evaluated. Control PMNL and in vivo granulocyte colony-stimulating factor (G-CSF)-primed PMNL served as effector cells. A new radiometric killing assay for measuring candidacidal activity was developed to facilitate quantification of PMNL-mediated killing of C. albicans. BsAbs directed to either FcgammaRI (CD64) or FcalphaRI (CD89) on human PMNL effectively enhanced both phagocytosis and killing of C. albicans in vitro. Fungicidal activity triggered via FcgammaRI required in vivo priming with G-CSF, whereas FcalphaRI-mediated activity was not dependent on this growth factor. Furthermore, PMNL from human FcgammaRI-transgenic mice effectively phagocytosed and eliminated C. albicans in the presence of BsAbs. These results document the capacity of FcR-directed BsAbs and G-CSF to trigger antifungal immune responses.

Factor V Leiden, antiphospholipid antibodies and thrombosis in systemic lupus erythematosus.

Thromboembolic complications are frequently observed in patients with systemic lupus erythematosus (SLE). Significant associations have been reported between these complications and the presence of antiphospholipid antibodies, notably the lupus anticoagulant and anticardiolipin antibodies. Factor V Leiden is a genetic disorder associated with an increased risk of venous thrombosis. We studied these factors in 173 patients with SLE in relation to both arterial and venous thrombosis. The frequency of factor V Leiden in SLE patients in comparable to that in the Dutch population (5%) and a risk factor for venous thrombosis (odds ratio 4.9; CI 1.2-19.6), but not for arterial thrombosis. The lupus anticoagulant is a risk factor for both arterial thrombosis (odds ratio 7.1: CI 2.9-17.4) and venous thrombosis (odds ratio 6.4; CI 2.7-15.4). From multivariate analysis, both the lupus anticoagulant and factor V Leiden appeared independent risk factors for venous thrombosis.

The plasma concentration of soluble Fc-gamma RIII is related to production of neutrophils.

Fc gamma RIII (the CD16-antigen), a low-affinity receptor for IgG, is expressed by neutrophils, natural killer lymphocytes and macrophages. A soluble form of Fc gamma RIII has been identified in human plasma. This soluble form of Fc gamma RIII (sFc gamma RIII) originates from release by neutrophils. In the present study we show by transfusions of plasma that contains sFc gamma RIII of one allotype (NA1-Fc gamma RIII) in recipients homozygous for the other allotype (NA2-Fc gamma RIII) that the clearance of sFc gamma RIII is about 0.7 ml/min. Because the concentration of sFc gamma RIII was found to be constant in a small cohort of donors followed for about 1.5 years, the half-life of NA1-sFc gamma RIII is about 1.8 d, assuming a one-compartment model. The plasma concentration of sFc gamma RIII depended mainly on the production of neutrophils in the bone marrow, and was not influenced by shifts of neutrophils from one pool to another (storage, marginating or circulating pool). Because Fc gamma RIII is only expressed on mature neutrophils, this implies that the concentration of sFc gamma RIII depends on production of mature neutrophils.