Mannose-Binding Lectin (MBL) Substitution: Recovery of Opsonic Function In Vivo Lags behind MBL Serum Levels

Abstract

Mannose-binding lectin (MBL) deficiency is often associated with an increased risk of infection or worse prognosis in immunocompromised patients. MBL substitution in these patients might diminish these risks. We therefore performed an open, uncontrolled safety and pharmacokinetic MBL-substitution study in 12 pediatric oncology patients with chemotherapy-induced neutropenia. Twice weekly MBL infusions with plasma-derived MBL yielded MBL trough levels >1.0 μg/ml. We tested whether MBL substitution in vivo increased MBL-dependent complement activation and opsonophagocytosis of zymosan in vitro. Upon MBL substitution, opsonophagocytosis by control neutrophils increased significantly (p < 0.001) but remained suboptimal, although repeated MBL infusions resulted in improvement over time. The MBL-dependent MBL-associated serine protease (MASP)-mediated complement C3 and C4 activation also showed a suboptimal increase. To explain these results, complement activation was studied in detail. We found that in the presence of normal MASP-2 blood levels, MASP-2 activity (p < 0.0001) was reduced as well as the alternative pathway of complement activation (p < 0.05). This MBL-substitution study demonstrates that plasma-derived MBL infusions increase MBL/MASP-mediated C3 and C4 activation and opsonophagocytosis, but that higher circulating levels of plasma-derived MBL are required to achieve MBL-mediated complement activation comparable to healthy controls. Other patient cohorts should be considered to demonstrate clinical efficacy in phase II/III MBL-substitution studies, because we found a suboptimal recovery of (in vitro) biological activity upon MBL substitution in our neutropenic pediatric oncology cohort.

TFPI inhibits lectin pathway of complement activation by direct interaction with MASP‐2

“…MBL binding to mannan was measured by ELISA, as previously described by Brouwer et al [22] Briefly, mannan was coated to the solid phase and biotinylated mAb αMBL-1 was used for detection. After washing, plates were developed as described above.…”

Risk of infection and sepsis in severely injured patients related to single nucleotide polymorphisms in the lectin pathway

“…Substitution therapy would be one way to overcome deficiencies caused by genetic variation. MBL substitution therapy phase I trials have already shown interesting results.…”

Displasia ectodérmica anhidrótica asociada a déficit de lectina de unión a manosa

“…La MBL es una proteína sérica perteneciente a la familia de las colectinas, con una estructura similar al C1q 11 . Ambas, tanto MBL como C1q, son proteínas del sistema immunitario innato que pueden activar el complemento a través de las proteasas asociadas [12][13][14] . El C1q activa el complemento por la vía clásica y la MBL inicia la vía de las lectinas del complemento después de su unión a los azúcares de la estructura de múltiples microorganismo, incluidos El déficit de MBL se asocia a una amplia gama de fenotipos infecciosos, incluyendo enfermedad neumocócica invasiva, sepsis grave, sepsis meningocócica, infecciones graves tras quimioterapia y trasplante alogénico de células madre hematopoyéticas, duración prolongada de fiebre neutropénica en pacientes oncológicos e infecciones del tracto respiratorio 12,13,16 .…”