Mannose-binding lectin deficiency associated with neutrophil chemotactic unresponsiveness to C5a

Mannose-binding lectin (MBL) plays an important role in host defense by activating the complement cascade.

Three children with a history of recurrent infections since infancy were found to have MBL deficiency associated with a neutrophil chemotactic unresponsiveness specific to C5a. We have studied the genomic sequence of the C5a receptor (C5aR) in 2 of the subjects to determine whether this unresponsiveness was due to a genetic mutation or to aberrant complement activation associated with the MBL deficiency.

MBL genotype analysis was performed by PCR-based methods with use of specific primers and restriction enzymes to detect the 3 previously reported mutations. Expression of C5aR was analyzed by flow cytometry. The C5aR gene was amplified from the patient's genomic DNA by PCR and sequenced by standard procedures.

C5aR was found to be expressed normally on the neutrophils of one of the subjects. Sequence analysis of the C5aR gene revealed a point mutation that substituted threonine at position 261 for alanine in one patient but no abnormality in the other, suggesting gene polymorphism. Treatment of 2 patients with granulocyte-colony stimulating factor corrected the neutrophil chemotactic abnormality in vitro and induced a significant clinical improvement.

MBL deficiency can be associated with neutrophil chemotactic unresponsiveness to C5a and it is clinically manifested by recurrent and chronic infections. Treatment of these patients with granulocyte colony-stimulating factor results in normalization of neutrophil chemotaxis against C5a and significant clearing of infections.