Hypersensitivity and oral tolerance in the absence of a secretory immune system.
BACKGROUND
Mucosal immunity protects the epithelial barrier by immune exclusion of foreign antigens and by anti-inflammatory tolerance mechanisms, but there is a continuing debate about the role of secretory immunoglobulins (SIgs), particularly SIgA, in the protection against allergy and other inflammatory diseases. Lack of secretory antibodies may cause immune dysfunction and affect mucosally induced (oral) tolerance against food antigens.


METHODS
We used polymeric Ig receptor (pIgR) knockout (KO) mice, which cannot export SIgA or SIgM, to study oral tolerance induction by ovalbumin (OVA) feeding and for parenteral antigen sensitization in the same animal.


RESULTS
Remarkable systemic hyperreactivity was observed in pIgR KO mice, as 50% died after intradermal OVA challenge, which was not seen in similarly sensitized and challenged wild-type (WT) mice. Oral tolerance induced by OVA completely protected the sensitized pIgR KO mice against anaphylaxis and suppressed antibody levels (particularly IgG1) as well as delayed-type hypersensitivity (DTH) to OVA. Delayed-type hypersensitivity to a bystander antigen, human serum albumin, was also suppressed and T-cell proliferation against OVA in vitro was reduced in tolerized compared with non-tolerized pIgR KO mice. This effect was largely mediated by CD25+ T cells. Adoptive transfer of splenic putative regulatory T cells (CD4+ CD25+) obtained from OVA-fed pIgR KO mice to naïve WT mice mediated suppression of DTH against OVA after sensitization of the recipients.


CONCLUSIONS
Compensatory regulatory T-cell function becomes critical in pIgR-deficient mice to avoid the potentially catastrophic effects of systemic immune hyperreactivity, presumably resulting from defective secretory antibody-mediated immune exclusion of microbial components.
Karlsson
M R
MR
Centre for Immune Regulation, Oslo University Hospital, University of Oslo, Rikshospitalet, Norway.
Johansen
F-E
FE
Kahu
H
H
Macpherson
A
A
Brandtzaeg
P
P
D019264:Adoptive Transfer; D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005512:Food Hypersensitivity / Q000276:immunology; D006968:Hypersensitivity, Delayed / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology*; D018928:Immunity, Mucosal / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology; D019056:Receptors, Polymeric Immunoglobulin / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
D019056:Receptors, Polymeric Immunoglobulin; D010047:Ovalbumin