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Korponay-Szabo, I. R.1; Halttunen, T.1; Kovacs, J. B.2; Mäki, M.1
1Paediatric Research Centre, University of Tampere, Tampere, Finland, 2Dept.of Gastroenterology, Heim Pal Children’s Hospital, Budapest, Hungary
Submitted by: Ilma.Korponay-Szabo@uta.fi
Introduction: Coeliac disease is characterised by IgA class autoantibody production against a specific autoantigen, transglutaminase 2 (TG2) and these antibodies were found to exert biological effects in vitro. However, it is not yet clear to which extent they contribute to disease pathogenesis as coeliac disease occurs also in patients with humoral immunodeficiency. We have previously shown that coeliac IgA binds in vivo to extracellularly located TG2 in the jejunum and extraintestinal tissues of the patients. In this study we investigated whether coeliac patients with IgA deficiency (IgAD) have an autoantibody targeting of TG2.
Methods: Unfixed frozen small-intestinal biopsy sections from 18 untreated patients with IgAD and coeliac disease (total serum IgA<0.05g/l, age 2–37 years) were evaluated by multi-colour immunofluorescence for in situ IgA, IgG and IgM. Sections from 5 non-coeliac IgAD patients were used as controls. Jejunal TG2 was recognised by monoclonal antibodies and TG2 activity labelling by incorporation of Texas-red cadaverine. Further, the sections were incubated with IgA class serum anti-TG2 antibodies from IgA competent coeliac patients (n=3) and the binding sites were compared with in situ immunoglobulins. Serum IgA, IgG and IgM class anti-TG2 antibodies were measured by ELISA.
Results: IgA and IgA containing plasma cells were completely absent in the jejunum of 16/18 IgAD coeliac patients and of all controls. Two IgAD coeliac patients had some IgA plasma cells, but no extracellular IgA deposition or circulating IgA class anti-TG2. All 18 IgAD coeliac samples contained IgM both in plasma cells and also extracellularly along the surface and crypt basement membranes. These IgM deposits co-localised with TG2 and were absent in controls. Similar deposits of IgG class were clearly seen in 11 out of the 18 IgAD patients, but it was difficult to evaluate the samples due to the high background observed also in controls. External IgA anti-TG2 antibodies bound very poorly to the jejunum samples of IgAD coeliac patients, indicating that the target binding sites were already occupied by competing IgM or IgG immunoglobulins. All IgAD coeliac patients had high levels of circulating IgG class anti-TG2 antibodies. Circulating IgM class anti-TG2 antibodies were detectable only in two cases.
Conclusion: In vivo targeting of jejunal TG2 is mediated by IgM in IgAD coeliac patients instead of IgA. These IgM autoan-tibodies remain mainly sequestred in the gut. Our results further support the general importance of humoral immunity in the pathogenesis of coeliac disease.
© 2004 Lippincott Williams & Wilkins, Inc.
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