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* Transplantation Research Center, Brigham and Women’s Hospital, Children’s Hospital Boston and Harvard Medical School, Boston, MA 02115;
Novartis Pharma, Infectious Diseases, Transplantation & Immunology, Basel, Switzerland; and
Massachusetts General Hospital, Center for Cancer Research, Charlestown, MA 02129
Natural Abs specific for the carbohydrate Ag Gal
1–3Galβ1–4GlcNAc-R (Gal) play an important role in providing protective host immunity to various pathogens; yet little is known about how production of these or other anti-carbohydrate natural Abs is regulated. In this study, we describe the generation of Ig knock-in mice carrying functionally rearranged H chain and L chain variable region genes isolated from a B cell hybridoma producing Gal-specific IgM Ab that make it possible to examine the development of B cells producing anti-carbohydrate natural Abs in the presence or absence of Gal as a self-Ag. Knock-in mice on a Gal-deficient background spontaneously developed Gal-specific IgM Abs of a sufficiently high titer to mediate rejection of Gal expressing cardiac transplants. In the spleen of these mice, B cells expressing Gal-specific IgM are located in the marginal zone. In knock-in mice that express Gal, B cells expressing the knocked in BCR undergo negative selection via receptor editing. Interestingly, production of low affinity Gal-specific Ab was observed in mice that express Gal that carry two copies of the knocked in H chain. We suggest that in these mice, receptor editing functioned to lower the affinity for self-Ag below a threshold that would result in overt pathology, while allowing development of low affinity anti-self Abs.
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 supported by Grants R01AI044268-09 and R01 AI050602-06 from the National Institutes of Health (to J.I.).
2 Address correspondence and reprint requests to Dr. John Iacomini, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital Boston, Harvard Medical School, 221 Longwood Avenue, Room LM303, Boston, MA 02115. E-mail address: jiacomini{at}rics.bwh.harvard.edu
3 Abbreviations used in this paper: sIgM, surface IgM; MZ, marginal zone.
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