Pulmonary inflammation induced by a recombinant Brugia malayi gamma-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.


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 perivascular inflammation 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 autoreactive/crossreacting antibodies.


CONCLUSIONS
Our data from the in 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.
Gounni
A S
AS
Meakins Christie Laboratories, McGill University, Montreal, Canada.
Spanel-Borowski
K
K
Palacios
M
M
Heusser
C
C
Moncada
S
S
Lobos
E
E
D000818:Animals; D000953:Antigens, Protozoan / Q000276:immunology; D001323:Autoantibodies / Q000096:biosynthesis*; D015153:Blotting, Western; D001985:Bronchial Provocation Tests; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002009:Brugia / Q000201:enzymology*; D004591:Electrophoresis, Polyacrylamide Gel; D004802:Eosinophilia / Q000276:immunology; D005260:Female; D007114:Immunization; D007070:Immunoglobulin A / Q000276:immunology; D007073:Immunoglobulin E / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D007371:Interferon-gamma / Q000097:blood / Q000276:immunology; D015847:Interleukin-4 / Q000097:blood / Q000276:immunology; D008168:Lung / Q000166:cytology / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D011014:Pneumonia / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D011994:Recombinant Proteins; D012680:Sensitivity and Specificity; D005723:gamma-Glutamyltransferase / Q000235:genetics / Q000276:immunology*
D000953:Antigens, Protozoan; D001323:Autoantibodies; D007070:Immunoglobulin A; D007074:Immunoglobulin G; C063362:QF116 antigen, Plasmodium falciparum; D011994:Recombinant Proteins; D015847:Interleukin-4; D007073:Immunoglobulin E; D007371:Interferon-gamma; D005723:gamma-Glutamyltransferase