ChApter 5 Immunoglobulin A ( IgA ) and Fc a rI peptide mimetics block IgA-induced neutrophil migration

ABStrACt Immunoglobulin A (IgA) represents the most prominent antibody class at mucosal surfaces and plays an important role in mucosal immunity. However, we recently demonstrated that cross-linking of the IgA Fc receptor (FcaRI; CD89) by IgA autoantibodies of patients with autoimmune skin blistering diseases induced massive recruitment of neutrophils, which resulted in severe tissue damage. Currently, there is no specific therapy for IgA-induced blistering diseases. Therefore, we developed specific peptides, which were based on either IgA or FcaRI sequences, and investigated whether these peptides could inhibit neutrophil migration. One linear IgA peptide and one FcaRI peptide effectively reduced neutrophil migration, and were further developed with CLIPS technology, which stabilizes the three-dimensional structure and increases peptides' half-life by introduction of covalently linked scaffolds. CLIPS peptides and linear peptides with the best blocking capacity were tested in ex vivo skin migration experiments. IgA-induced neutrophil migration was completely blocked in the presence of these peptides. Furthermore, Cetomacrogol cream, containing an IgA CLIPS peptide was developed, and penetration of the peptide in an ex vivo skin model was investigated after topical administration. Moreover, minimal penetration of peptides into the skin was observed in the absence of dodecyl-2-N, N-dimethylaminopropionate (DDAIP), which is a permeation enhancer. However, peptide penetration was increased in a dose dependent manner in the presence of DDAIP. Minimal levels of peptides were observed in the receptor fluid, which is a measure of systemic delivery. Thus, topical application of a cream containing peptides may safely block IgA-induced neutrophil migration in the skin, without systemic exposure. This may decrease severe morbidity and improve quality of life of patients with IgA-mediated blistering diseases.