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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0901315v1 183/8/4871    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Yuvaraj, S. Articles by Bos, N. A. PubMed PubMed Citation Articles by Yuvaraj, S. Articles by Bos, N. A.

Evidence for Local Expansion of IgA Plasma Cell Precursors in Human Ileum^1,2

Saravanan Yuvaraj,^3* Gerard Dijkstra, Johannes G. M. Burgerhof, Peter M. Dammers,^* Maaike Stoel,¹ Annie Visser,^* Frans G. M. Kroese,^* and Nicolaas A. Bos^4*

^*Department of Cell Biology, Section Immunology, Department of Gastroenterology and Hepatology, Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

IgA plays a crucial role in establishment and maintenance of mucosal homeostasis between host cells and commensal bacteria. To this end, numerous IgA plasma cells are located in the intestinal lamina propria. Whether the (immediate) precursor cells for these plasma cells can expand locally is not completely known and was studied here. The total number of IgA plasma cells in human ileal biopsies was counted. Sequence analysis of IgA V_H genes from human ileal biopsies revealed the occurrence of many clonally related sequences within a biopsy, but not between different biopsies. This observation strongly argues for local expansion of IgA precursor cells. By comparing the number of unique sequences with the number of clonally related sequences within a biopsy, we estimated that 100–300 precursors were responsible for the 75,000 IgA-producing cells that were present per biopsy. These precursor cells must therefore have divided locally 9–10 times. Since all sequences contained mutations and most of the mutations present in clonally related sequences were shared, the IgA precursor cells must have arrived initially as mutated cells in the lamina propria. Our data show evidence for the existence of two waves of expansion for IgA-producing cells in human ileum. The first wave occurs during initial stimulation in germinal centers as evidenced by somatic hypermutations. A second wave of expansion of IgA-committed cells occurs locally within the lamina propria as evidenced by the high frequency of clonally related cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was financially supported by a Ubbo Emmius Fellowship (to S.Y.), by Valorisation Grant 6848 from the Dutch Technology Foundation, and by the Dutch Digestive Foundation.

² Sequences are available at the EMBL (http://www.ebi.ac.uk/) under accession numbers AM279466-AM279644.

³ Current address: Department of Food Science & Technology and the Food Processing Center, University of Nebraska-Lincoln, 143 Food Industry Complex, PO Box 830930, Lincoln, NE 68583-0930.

⁴ Address correspondence and reprint requests to Dr. Nicolaas A. Bos, Department of Cell Biology, Section Immunology, University Medical Center Groningen, University of Groningen, A. Deusinglaan 1, 9713AV Groningen, The Netherlands. E-mail address: n.a.bos{at}med.umcg.nl

⁵ Abbreviations used in this paper: SHM, somatic hypermutation; H-CDR3, H chain CDR3; CI, confidence interval; FR, framework; R:S, replacement:silent.

⁶ The online version of this article contains supplemental material.