Lack of J chain inhibits the transport of gut IgA and abrogates the development of intestinal antitoxic protection.

Department of Medical Microbiology and Immunology, University of Göteborg, Sweden.
The Journal of Immunology (Impact Factor: 5.52). 08/1999; 163(2):913-9.
Source: PubMed

ABSTRACT 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.

1 Bookmark
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cholera, a diarrheal disease, is known for explosive epidemics that can quickly kill thousands. Endemic cholera is a seasonal torment that also has a significant mortality. Not all nations with extensive rural communities can achieve the required infrastructure or behavioral changes to prevent epidemic or endemic cholera. For some communities, a single-dose cholera vaccine that protects those at risk is the most efficacious means to reduce morbidity and mortality. It is clear that our understanding of what a protective cholera immune response is has not progressed at the rate our understanding of the pathogenesis and molecular biology of cholera infection has. This review addresses V. cholerae lipopolysaccharide (LPS)-based immunogens because LPS is the only immunogen proven to induce protective antibody in humans. We discuss the role of anti-LPS antibodies in protection from cholera, the importance and the potential role of B cell subsets in protection that is based on their anatomical location and the intrinsic antigen-receptor specificity of various subsets is introduced.
    Microbiology and Immunology 02/2006; 50(12):899-927. · 1.55 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Vaccination represents one of the most efficacious and cost-effective medical interventions. It is the only medical intervention proven to eliminate disease at a global level. Many of the pathogens against which we most require adequate vaccines infect via the highly exposed mucosal surfaces. For this reason the mucosa is often considered the first, and sometimes only, line of defense. Therefore, responses that protect the local mucosa are vital. In this review, we first explore the immunological mechanisms that protect the mucosa. We then review the literature of mucosal vaccines within the principles of antigenic composition, dose, and danger, highlighting the need and niche for the next generation of mucosal vaccines.
    Immunologic Research 02/2004; 30(1):35-71. · 2.96 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: To elucidate the specific role of somatic hypermutation (SHM) in mucosal immunity, we generated mice carrying a knock-in point mutation in Aicda, which encodes activation-induced cytidine deaminase (AID), an enzyme essential to SHM and class-switch recombination (CSR). These mutant AID(G23S) mice had much less SHM but had normal amounts of immunoglobulin in both serum and intestinal secretions. AID(G23S) mice developed hyperplasia of germinal center B cells in gut-associated lymphoid tissues, accompanied by expansion of microflora in the small intestine. Moreover, AID(G23S) mice had more translocation of Yersinia enterocolitica into mesenteric lymph nodes and were more susceptible than wild-type mice to oral challenge with cholera toxin. Together our results indicate that SHM is critical in maintaining intestinal homeostasis and efficient mucosal defense.
    Nature Immunology 03/2011; 12(3):264-70. · 26.20 Impact Factor


Available from