RESUMEN
BACKGROUND: Anti-platelet factor 4 (PF4)/heparin immune complexes that cause heparin-induced thrombocytopenia (HIT) activate complement via the classical pathway. Previous studies have shown that the alternative pathway of complement substantially amplifies the classical pathway of complement activation through the C3b feedback cycle. OBJECTIVES: These studies sought to examine the contributions of the alternative pathway to complement activation by HIT antibodies. METHODS: Using IgG monoclonal (KKO) and/or patient-derived HIT antibodies, we compared the effects of classical pathway (BBK32 and C1-esterase inhibitor [C1-INH]), alternative pathway (anti-factor B [fB] or factor D [fD] inhibitor) or combined classical and alternative pathway inhibition (soluble complement receptor 1 [sCR1]) in whole blood or plasma. RESULTS: Classical pathway inhibitors BBK32 and C1-INH and the combined classical/alternative pathway inhibitor sCR1 prevented KKO/HIT immune complex-induced complement activation, including release of C3 and C5 activation products, binding of immune complexes to B cells, and neutrophil activation. The alternative pathway inhibitors fB and fD, however, did not affect complement activation by KKO/HIT immune complexes. Similarly, alternative pathway inhibition had no effect on complement activation by unrelated immune complexes consisting of anti-dinitrophenyl (DNP) antibody and the multivalent DNP--keyhole limpet hemocyanin antigen. CONCLUSIONS: Collectively, these findings suggest the alternative pathway contributes little in support of complement activation by HIT immune complexes. Additional in vitro and in vivo studies are required to examine if this property is shared by most IgG-containing immune complexes or if predominance of the classic pathway is limited to immune complexes composed of multivalent antigens.
Asunto(s)
Complejo Antígeno-Anticuerpo , Trombocitopenia , Humanos , Factor D del Complemento , Heparina/efectos adversos , Activación de Complemento , Proteínas del Sistema Complemento , Inmunoglobulina G , Receptores de Complemento , Esterasas/efectos adversosAsunto(s)
Enfermedades de los Trabajadores Agrícolas/inducido químicamente , Discapacidades del Desarrollo/inducido químicamente , Esterasas/efectos adversos , Insecticidas/efectos adversos , Compuestos Organofosforados , Crianza de Animales Domésticos , Arildialquilfosfatasa , Preescolar , Exposición a Riesgos Ambientales/efectos adversos , Humanos , LactanteRESUMEN
Complex genomic activity and environmental factors regulate neuronal plasticity, which operates during pre- and postnatal development, can be reactivated after injury, and is impaired during aging. In these contexts, the effects of chemicals are often unpredictable because the developing and aging nervous system may or may not be equally susceptible as that of the adult. Thus, the developing central nervous system may be more susceptible to the acute toxicity of certain organophosphorus esters, whereas the developing peripheral nervous system is resistant to organophosphate-induced delayed polyneuropathy. Reasons for age-related susceptibility are manifold, including both differences in toxicokinetics and toxicodynamics and in intrinsic susceptibility of the nervous system, which is related to given physiological conditions. Therefore, the identification of genetic and environmental factors regulating neuronal plasticity becomes critical to the understanding of age-related sensitivity to chemicals. The example of age-related sensitivity to organophosphate-induced delayed polyneuropathy is illustrated together with that of the promotion of axonopathies by certain esterase inhibitors, which also seem modulated according to age. The identification of the molecular targets of both organophosphate neuropathy and promotion of neuropathy might allow the understanding of processes involved in the expression of peripheral neurotoxicities according to age.