| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
3(IV)NC1 Collagen1Department of Medicine and Durham Veterans Affairs Medical Center Research Service, Duke University Medical Center, Durham, NC 27710
Patients and rodents with Goodpasture’s syndrome (GPS) develop severe autoimmune crescentic glomerulonephritis, kidney failure, and lung hemorrhage due to binding of pathogenic autoantibodies to the NC1 domain of the 
3 chain of type IV collagen. Target epitopes are cryptic, normally hidden from circulating Abs by protein-protein interactions and the highly tissue-restricted expression of the 3(IV) collagen chain. Based on this limited Ag exposure, it has been suggested that target epitopes are not available as B cell tolerogens. To determine how pathogenic anti-GPS autoantibody responses are regulated, we generated an Ig transgenic (Tg) mouse model that expresses an Ig that binds 3(IV)NC1 collagen epitopes recognized by serum IgG of patients with GPS. Phenotypic analysis reveals B cell depletion and L chain editing in Tg mice. To determine the default tolerance phenotype in the absence of receptor editing and endogenous lymphocyte populations, we crossed Tg mice two generations with mice deficient in Rag. Resulting Tg Rag-deficient mice have central B cell deletion. Thus, development of Tg anti-3(IV)NC1 collagen B cells is halted in the bone marrow, at which point the cells are deleted unless rescued by a Rag enzyme-dependent process, such as editing. The central tolerance phenotype implies that tolerizing self-Ag is expressed in bone marrow.
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 in part by the National Institutes of Health (T32AI07217 to D.B.H.; R01DK47424 to M.H.F.), a Veterans Affairs Medical Center Merit Award (to M.H.F.), the Durham Veterans Affairs Medical Center Research Service and Institute for Medical Research, Duke University Undergraduate Research Support Grants (to S.C.S.), and a grant from the American Society of Nephrology (to M.H.F.).
2 Address correspondence and reprint requests to Dr. Mary H. Foster, Nephrology Research, Duke University Medical Center, Box 103015, Durham, NC 27710. E-mail address: mhfoster{at}duke.edu
3 Abbreviations used in this paper: GPS, Goodpasture syndrome; GBM, glomerular basement membrane; Tg, transgenic; B6, C57BL/6.
Related articles in The JI:
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
