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Using HLA DRB1*1501 transgenic mice to study the HLA‐linked autoimmune Goodpasture's disease
Author(s) -
Ooi Joshua Daniel,
Fugger Lars,
Holdsworth Stephen R.,
Kitching A. Richard
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.667.20
Subject(s) - autoantibody , immunology , epitope , autoimmune disease , type iv collagen , human leukocyte antigen , autoimmunity , elispot , medicine , biology , t cell , antigen , immune system , antibody , cell , laminin , genetics
Goodpasture's disease is characterised by destruction of glomerular and alveolar basement membranes due to an autoimmune response against the non‐collagenous domain of the alpha 3 chain of type IV collagen [α3(IV)NC1]. It is strongly associated with HLA DRB1*1501 (OR: 8.5) and negatively associated with HLA DRB1*0101 and *0701. This study sought to determine if MHCII−/− HLA DRB1*1501 transgenic (*1501 tg) mice can be used to model human Goodpasture's disease and if the T‐cell autoepitopes are similar to that found in human disease. *1501 tg mice immunized with human α3(IV)NC1 developed autoantibodies specific for mouse α3(IV)NC1 (ELISA) and developed linear intraglomerular IgG binding (immunohistochemistry). Autoantibody binding was stronger when compared to C57BL/6J wildtype mice. *1501 tg mice also developed elevated urinary protein levels and significant structural abnormalities. T‐cell autoepitope studies performed by immunization with overlapping peptides of the α3(IV)NC1 reveal that immunogenic peptides (IFNγ‐ELISPOT) correlate with autoepitope studies with PBMCs from HLA DRB1*150x positive Goodpasture's patients; in particular a key candidate epitope which was not immunogenic in wildtype C57BL/6J or COL4A3 KO mice. The data suggest that *1501 tg mice are a promising tool in understanding the HLA‐linked susceptibility in Goodpasture's disease. This work supported by the Australian NHMRC.