title: Impaired intestinal tolerance in the absence of a functional complement system.
abstract: BACKGROUND
  Cells of the innate immune system regulate both adaptive immune responses and the maintenance of tolerance, especially in the gut. However, relatively little is known about the effects of complement on lymphocyte homeostasis.
  
  
  OBJECTIVE
  This study explored complement C3 deficiency in mice and human subjects for its effect on intestinal tolerance.
  
  
  METHODS
  C3-deficient mice and control C57BL/6 mice were fed ovalbumin (OVA) by means of gavage, and subsequent response to immunization with OVA in Freund's adjuvant was monitored. Serum antibodies against commensal microbes were measured, and the activation status of peripheral blood lymphocytes bearing mucosal homing markers was determined from 2 rare cases of C3-deficient patients.
  
  
  RESULTS
  We show in C3-deficient mice and human patients that intestinal tolerance fails in the absence of functional complement. In contrast to wild-type control animals, in which oral tolerance was induced, intragastric administration of OVA did not result in a significantly decreased response to subsequent subcutaneous OVA challenge in C3-deficient mice. In the jejunum of C3-deficient mice the cytokine ratio between IL-10 and IFN-γ or IL-17 levels was decreased, indicating a shift in favor of proinflammatory cytokines. In 2 C3-deficient children the frequency of gut-homing T cells expressing activation markers was increased, and the patients had increased serum IgG levels against gut commensal microbes. The data also suggest that the impaired oral tolerance was at least partly caused by the absence of signaling through C3-binding complement regulators in T cells.
  
  
  CONCLUSIONS
  Taken together, our results identify complement as an important and nonredundant regulator of intestinal tolerance.
authors.affiliation: Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, and Helsinki University Central Hospital, Helsinki, Finland. pirkka.pekkarinen@helsinki.fi
authors.forename: Pirkka T
authors.initials: PT
authors.lastname: Pekkarinen
authors.forename: Kirsi
authors.initials: K
authors.lastname: Vaali
authors.forename: Hanna
authors.initials: H
authors.lastname: Jarva
authors.forename: Eliisa
authors.initials: E
authors.lastname: Kekäläinen
authors.forename: Iivo
authors.initials: I
authors.lastname: Hetemäki
authors.forename: Sami
authors.initials: S
authors.lastname: Junnikkala
authors.forename: Merja
authors.initials: M
authors.lastname: Helminen
authors.forename: Outi
authors.initials: O
authors.lastname: Vaarala
authors.forename: Seppo
authors.initials: S
authors.lastname: Meri
authors.forename: T Petteri
authors.initials: TP
authors.lastname: Arstila
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology*; D000946:Antigens, Fungal / Q000276:immunology*; D016022:Case-Control Studies; D002675:Child, Preschool; D003176:Complement C3 / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D005620:Freund's Adjuvant / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D018928:Immunity, Mucosal; D007074:Immunoglobulin G / Q000276:immunology; D007279:Injections, Subcutaneous; D007371:Interferon-gamma / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D007583:Jejunum / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D055815:Young Adult
chemical_list: D000942:Antigens, Bacterial; D000946:Antigens, Fungal; D003176:Complement C3; C556062:IL10 protein, mouse; D007074:Immunoglobulin G; D020381:Interleukin-17; D016753:Interleukin-10; D007371:Interferon-gamma; D010047:Ovalbumin; D005620:Freund's Adjuvant