Lack of J chain inhibits the transport of gut IgA and abrogates the development of intestinal antitoxic protection.
Recent publications have provided confusing information on the importance of the J chain for secretion of dimeric IgA at mucosal surfaces. Using J chain-deficient (J chain-/-) mice, we addressed whether a lack of J chain had any functional consequence for the ability to resist challenge with cholera toxin (CT) in intestinal loops. J chain-/- mice had normal levels of IgA plasma cells in the gut mucosa, and the Peyer's patches exhibited normal IgA B cell differentiation and germinal center reactions. The total IgA levels in gut lavage were reduced by roughly 90% as compared with that in wild-type controls, while concomitantly serum IgA levels were significantly increased. Total serum IgM levels were depressed, whereas IgG concentrations were normal. Following oral immunizations with CT, J chain-/- mice developed 10-fold increased serum antitoxin IgA titers, but gut lavage anti-CT IgA levels were substantially reduced. However, anti-CT IgA spot-forming cell frequencies in the gut lamina propria were normal. Anti-CT IgM concentrations were low in serum and gut lavage, whereas anti-CT IgG titers were unaltered. Challenge of small intestinal ligated loops with CT caused dramatic fluid accumulation in immunized J chain-/- mice, and only 20% protection was detected compared with unimmunized controls. In contrast, wild-type mice demonstrated 80% protection against CT challenge. Mice heterozygous for the J chain deletion exhibited intermediate gut lavage anti-CT IgA and intestinal protection levels, arguing for a J chain gene-dosage effect on the transport of secretory IgA. This study unequivocally demonstrates a direct relationship between mucosal transport of secretory SIgA and intestinal immune protection.
Department of Medical Microbiology and Immunology, University of Göteborg, Sweden. nils.lycke@microbio.gu.se
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Lycke
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Erlandsson
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Ekman
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Schön
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Leanderson
D000284:Administration, Oral; D000818:Animals; D000992:Antitoxins / Q000097:blood / Q000378:metabolism; D001693:Biological Transport, Active / Q000235:genetics / Q000276:immunology; D002772:Cholera Toxin / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000276:immunology*; D007070:Immunoglobulin A / Q000097:blood / Q000378:metabolism*; D007144:Immunoglobulin J-Chains / Q000235:genetics*; D007075:Immunoglobulin M / Q000097:blood / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology* / Q000378:metabolism*; D008026:Ligation; D051379:Mice; D018345:Mice, Knockout; D007507:Therapeutic Irrigation; D014611:Vaccination
D000992:Antitoxins; D007070:Immunoglobulin A; D007144:Immunoglobulin J-Chains; D007075:Immunoglobulin M; D002772:Cholera Toxin