Pulmonary inflammation induced by a recombinant Brugia malayi γ-glutamyl transpeptidase homolog:: Involvement of humoral autoimmune responses

Background: A major allergen from the lymphatic filarial parasite Brugia malayi implicated in the pathogenesis of tropical pulmonary eosinophilia (TPE) has recently been cloned and identified as the homolog of the membrane-bound mammalian enzyme gamma -glutamyl transpeptidase (gamma -GT). Patients with acute TPE show autoreactive antibodies against endogenous gamma -GT from the pulmonary epithelium. Materials and Methods: Recombinant B. malayi gamma -GT, alone or adsorbed to aluminium hydroxide (AL), was used in a BALB/c mouse model to analyze its antigenic/allergenic potential, its potential to induce pulmonary inflammation, and its capacity to induce autoreacting antibodies. Results: Mice immunized with B. malayi gamma -GT showed significant levels of gamma -GT-specific IgG1, IgG2a, IgG3, IgA, IgE antibodies, and mild blood eosinophilia, even in the absence of adjuvant. Intranasal challenge with B. malayi gamma -GT induced peribronchial and characterized by a mixed infiltrate of lymphocytes, neutrophils, eosinophils, and macrophages. Both IL-4 and IFN-gamma were detected in the peripheral blood and in the bronchoalveolar lavage fluid of immunized and intranasally challenged mice. Histological analysis of murine lungs using affinity-purified antibodies from mice immunized with the parasite's gamma -GT revealed the presence of autoimmune antibodies against pulmonary epithelium. Western blot analysis identified the 55 kDa heavy chain subunit of the murine gamma -GT as the target of autorective / crossreacting antibodies. Conclusion: Our data from the bt vivo mouse model demonstrate the potent allergenicity/antigenicity of B. malayi gamma -GT, and its capacity to induce pulmonary inflammation upon intranasal challenge. This leads to breakdown of tolerance against endogenous murine gamma -GT. Thus, humoral autoimmunity against the airways epithelium may contribute to the pathogenesis of TPE.