Impaired intestinal tolerance in the absence of a functional complement system - 30/03/13
, Kirsi Vaali, PhD a, b, c, Hanna Jarva, MD, PhD a, d, Eliisa Kekäläinen, MD, PhD a, Iivo Hetemäki, MB a, Sami Junnikkala, PhD a, e, Merja Helminen, MD, PhD f, Outi Vaarala, MD, PhD b, Seppo Meri, MD, PhD a, d, T. Petteri Arstila, MD, PhD a
Corresponding author: Pirkka T. Pekkarinen, MD, Haartman Institute, Department of Bacteriology and Immunology, PB 21, 00014 University of Helsinki, Finland.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.
Le texte complet de cet article est disponible en PDF.Key words : Mucosal immunity, peripheral tolerance, complement C3, T lymphocytes, humoral immunity
Abbreviations used : C3ctrl, C3OVA, FOXP3, HRP, KO, OVA, PE, TCR, WT, WTctrl, WTOVA
Plan
| Supported by the Academy of Finland, Sigrid Jusélius Foundation, Finnish Cultural Foundation, Finnish Medical Foundation, Helsinki Biomedical Graduate School, Helsinki University Central Hospital funds (EVO), and HUSLAB funds. |
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| Disclosure of potential conflict of interest: P. T. Pekkarinen has received research support from the Finnish Cultural Foundation. O. Vaarala is on the Board of the Hero Institute for Infant Nutrition. S. Meri is employed by the University and University Hospital of Helsinki, has received research support from the Sigrid Jusélius Foundation and the Helsinki University Hospital Funds, has received lecture fees from Alexion, has received payment for developing educational presentations from the Academy for Complement Inhibition, and has received travel expenses from the International Congress. T. P. Arstila has received lecture fees from Schering-Plough, Bristol-Myers Squibb, and Roche. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 131 - N° 4
P. 1167-1175 - avril 2013 Retour au numéro
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