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Involvement of the IgE‐basophil system and mild complement activation in haemophilia B with anti‐factor IX neutralizing antibodies and anaphylaxis
Author(s) -
Cugno M.,
Mancuso M. E.,
Tedeschi A.,
Santagostino E.,
Lorini M.,
Carbonelli V.,
Peyvandi F.,
Mannucci P. M.
Publication year - 2017
Publication title -
haemophilia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.213
H-Index - 92
eISSN - 1365-2516
pISSN - 1351-8216
DOI - 10.1111/hae.13282
Subject(s) - medicine , anaphylaxis , haemophilia b , immunology , factor ix , immunoglobulin e , neutralizing antibody , antibody , haemophilia , haemophilia a , complement system , basophil activation , c1 inhibitor , allergy , angioedema , basophil , surgery
Patients with haemophilia B who develop factor IX ( FIX ) neutralizing antibodies (inhibitors) after FIX infusion are at high risk of hypersensitivity reactions upon FIX re‐exposure, but the underlying mechanisms are incompletely understood. Aim To investigate biomechanisms of FIX hypersensitivity. Methods A cellular antigen stimulation test ( CAST ) was employed to evaluate leukotriene C4 ( LTC 4) release from basophils stimulated by FIX in three treated children with haemophilia B, one of whom developed FIX inhibitor and experienced anaphylaxis following FIX re‐exposure. Anti‐ FIX IgE and IgG antibodies and markers of complement activation (C5b9, C3d and iC 3b) were measured in plasma, the last also after FIX infusion. Ten healthy children served as controls. Results The patient who developed anti‐ FIX inhibitors and anaphylaxis had a nonsense mutation in FIX gene (p.Arg298Stop) and, compared to controls, had higher plasma levels of specific anti‐ FIX IgE (2.285 vs 0.084 OD 492 nm ), with marked LTC 4 release from his FIX ‐stimulated basophils (519.8 vs 39.9 pg/mL). Further, he had higher plasma levels of anti‐ FIX IgG of all the four subclasses (total IgG 1.180 vs 0.120 OD 492 nm ) with FIX neutralizing activity (1.5 BU); mild complement activation occurred during FIX ‐induced anaphylaxis (C5b9 increased from 258.5 to 351.1 ng/mL). The same parameters were normal in the two patients who tolerated FIX infusion. Conclusion In the patient with haemophilia B who experienced anaphylaxis after FIX , but not in the patients with haemophilia B who tolerated FIX , the CAST assay showed FIX ‐induced LTC 4 release, which was associated with high plasma levels of specific anti‐ FIX IgE and IgG antibodies.