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

University of Gothenburg, Goeteborg, Västra Götaland, Sweden
The Journal of Immunology (Impact Factor: 4.92). 08/1999; 163(2):913-9.
Source: PubMed


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.

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    • "The production of antigen-specific secretory immunoglobulin A (IgA) dominates the humoral mucosal immune response and provides an important, highaffinity , first line of defence in the intestine by preventing specific pathogens such as Salmonella typhimurium, Shigella flexneri, reovirus and pathogenderived toxins from crossing the intestinal epithelium (Michetti et al. 1992; Lycke et al. 1999; Silvey et al. 2001; Macpherson et al. 2008; Boullier et al. 2009; Mantis et al. 2011). In addition to effects on pathogenic microorganisms, secretory IgA also helps regulate the composition of the commensal gut microbiota (Mantis et al. 2011). "
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    • "Perhaps more informative, therefore , is the J-chain deletion, which abrogates the assembly of polymeric Ig's and thereby prevents the transport and formation of SIgA. Such animals display defective mucosal immunity (Lycke et al., 1999; Schwartz-Cornil et al., 2002). Mice with a deletion in the pIgR gene also lack SIgA (and SIgM) and have impaired epithelial barrier functions (Johansen et al., 1999), which have been shown to result in defects in immune defense (Asahi et al., 2002; Balu et al., 2011; Blutt et al., 2012; Uren et al., 2005) and immune deregulation in allergy (Karlsson et al., 2010). "
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    • "Perhaps more informative, therefore, is the J chain deletion that abrogates the assembly of polymeric Igs and thereby prevents the transport and formation of S-IgA. Such animals display defective mucosal immunity (Lycke et al., 1999; Schwartz-Cornil et al., 2002). Mice with a deletion in the pIgR gene also lack S-IgA (and S-IgM) and have impaired epithelial barrier functions (Johansen et al., 1999), but otherwise these animals have not been examined for defects in immune defense. "
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    ABSTRACT: Immunoglobulin (Ig) A is by far the most abundantly produced Ig in the human body, yet its physiological functions and pathological impact are incompletely understood. In part this is because IgA is the most structurally heterogeneous form of Ig, occurring in multiple molecular forms and subclasses, which are differentially distributed between two largely separate physiological compartments: the systemic circulation and tissues and the mucosal surfaces and their associated secretions. Secretory (S) IgA has evolved as the predominant mucosal Ig in mammals and birds. SIgA possesses a variety of functional properties capable of protecting the body against all types of pathogens and serving also to maintain mutualism with the commensal microbiota. Its mechanisms of protection are distinct from those of other Ig isotypes and are largely noninflammatory in nature. However, derangements in its production or arising from exploitation by microbes can lead to pathological consequences.
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