Mary Foster

Overview:

Research in the Foster Lab focuses on autoimmune glomerulonephritis, a major cause of acute and chronic kidney disease worldwide.

Our experiments explore the origins and regulation of the pathogenic immune  responses that underlie glomerulonephritis, and are designed to: identify tolerance mechanisms that regulate nephritogenic lymphocytes, with an emphasis on B cells and autoantibodies; determine the molecular basis of tolerance; identify defects in immune regulation and the contributions of genetic autoimmune predisposition; and identify environmental disease triggers. These experiments use novel models relevant to immune nephritis in both kidney-restricted and systemic autoimmunity (Goodpasture syndrome and systemic lupus erythematosus, respectively), that are amenable to mechanistic dissection using basic immunological, molecular biological, and proteomics approaches. An ultimate goal is to advance novel diagnostic and therapeutic approaches to improve the lives of patients.

Positions:

Professor of Medicine

Medicine, Nephrology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1982

University of North Carolina - Chapel Hill

Medical Resident, Medicine

University of Virginia

Fellow in Nephrology, Medicine

Tufts University

Grants:

Gene-Environment Collaboration in Autoimmune Disease

Administered By
Medicine, Nephrology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Dual humanization to model gene-environment interactions in ANCA vasculitis

Administered By
Medicine, Nephrology
Awarded By
Vasculitis Foundation
Role
Principal Investigator
Start Date
End Date

George M. O'Brien Kidney Research Core Centers

Administered By
Medicine, Nephrology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Mechanism of Silica-induced Autoimmunity

Administered By
Medicine, Nephrology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Novel Receptor-Ligand Interactions in Glomerulonephritis

Administered By
Medicine, Nephrology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Publications:

Silica Exposure Differentially Modulates Autoimmunity in Lupus Strains and Autoantibody Transgenic Mice.

Inhalational exposure to crystalline silica is linked to several debilitating systemic autoimmune diseases characterized by a prominent humoral immune component, but the mechanisms by which silica induces autoantibodies is poorly understood. To better understand how silica lung exposure breaks B cell tolerance and unleashes autoreactive B cells, we exposed both wildtype mice of healthy C57BL/6 and lupus-prone BXSB, MRL, and NZB strains and mice carrying an autoantibody transgene on each of these backgrounds to instilled silica or vehicle and monitored lung injury, autoimmunity, and B cell fate. Silica exposure induced lung damage and pulmonary lymphoid aggregates in all strains, including in genetically diverse backgrounds and in autoantibody transgenic models. In wildtype mice strain differences were observed in specificity of autoantibodies and site of enhanced autoantibody production, consistent with genetic modulation of the autoimmune response to silica. The unique autoantibody transgene reporter system permitted the in vivo fate of autoreactive B cells and tolerance mechanisms to be tracked directly, and demonstrated the presence of transgenic B cells and antibody in pulmonary lymphoid aggregates and bronchoalveolar lavage fluid, respectively, as well as in spleen and serum. Nonetheless, B cell enumeration and transgenic antibody quantitation indicated that B cell deletion and anergy were intact in the different genetic backgrounds. Thus, silica exposure sufficient to induce substantial lung immunopathology did not overtly disrupt central B cell tolerance, even when superimposed on autoimmune genetic susceptibility. This suggests that silica exposure subverts tolerance at alternative checkpoints, such as regulatory cells or follicle entry, or requires additional interactions or co-exposures to induce loss of tolerance. This possibility is supported by results of differentiation assays that demonstrated transgenic autoantibodies in supernatants of Toll-like receptor (TLR)7/TLR9-stimulated splenocytes harvested from silica-exposed, but not vehicle-exposed, C57BL/6 mice. This suggests that lung injury induced by silica exposure has systemic effects that subtly alter autoreactive B cell regulation, possibly modulating B cell anergy, and that can be unmasked by superimposed exposure to TLR ligands or other immunostimulants.
Authors
Foster, MH; Ord, JR; Zhao, EJ; Birukova, A; Fee, L; Korte, FM; Asfaw, YG; Roggli, VL; Ghio, AJ; Tighe, RM; Clark, AG
MLA Citation
Foster, Mary H., et al. “Silica Exposure Differentially Modulates Autoimmunity in Lupus Strains and Autoantibody Transgenic Mice.Front Immunol, vol. 10, 2019, p. 2336. Pubmed, doi:10.3389/fimmu.2019.02336.
URI
https://scholars.duke.edu/individual/pub1416455
PMID
31632407
Source
pubmed
Published In
Frontiers in Immunology
Volume
10
Published Date
Start Page
2336
DOI
10.3389/fimmu.2019.02336

A murine Ig light chain transgene reveals IGKV3 gene contributions to anti-collagen types IV and II specificities.

A subset of autoimmune diseases result from autoantibodies targeting epitopes on matrix collagen. The most extensively studied are anti-glomerular basement membrane glomerulonephritis (or its systemic counterpart Goodpasture's disease) that destroys kidneys and lungs, and rheumatoid arthritis that leads to disabling arthritis. Autoantibodies in these disorders bind evolutionarily conserved conformational epitopes on the noncollagenous domain 1 (NC1) of the alpha3 chain of type IV [alpha3(IV)NC1] collagen in glomerular and alveolar basement membranes, and on native or citrullinated type II collagen (CII) in joint cartilage, respectively. The genetic origins of pathogenic anti-collagen B cells in these diseases is unknown, but observations from murine models raise the possibility that they overlap despite distinct in vivo immunopathologies. Monoclonal autoantibodies isolated from mice immunized with alpha3(IV)NC1 collagen or CII show a biased use of Ig light chains (LC) encoded by genes of the IGKV3 subgroup (previously Vk21 family), paired with diverse Ig heavy chains. To further explore this relationship and determine if a single murine IGKV3 LC independently predisposes to both anti-collagen responses, we generated a novel transgenic (Tg) C57BL/6 mouse that expresses a productively rearranged IGKV3-encoded LC, termed mLCV3-Tg, in conjunction with endogenously rearranged Ig heavy chains. Tg mice are also genetically deficient in endogenous kappa chains to permit tracking of the mLCV3 transgene. We show that mLCV3-Tg mice are susceptible to humoral autoimmunity against both collagen chains. Anti-alpha3(IV)NC1 collagen, but not anti-CII, mLCV3-encoded Ig are detected in serum of unmanipulated Tg mice, while Toll-like receptor ligands induce secretion of mLCV3-Tg autoantibodies of both collagen specificities from splenocytes ex vivo. This indicates developmental survival of mLCV3-Tg B cells reactive with each antigen, and is consistent with production of the two anti-collagen autoIg from distinct B cell populations. Reduced B cell numbers, low serum Ig kappa levels, low cell surface Ig kappa density, and abundant endogenous lambda chain expression suggest that subsets of IGKV3-encoded B cells are regulated in vivo by mechanisms that include deletion, anergy, and LC editing. These results support the notion that murine IGKV3 LCs contribute structural fitness to antigen binding sites that support diverse anti-collagen autoimmune responses, that these responses are regulated in vivo, and that these cells can nonetheless readily escape immune regulation.
Authors
Clark, AG; Worni-Schudel, IM; Korte, FM; Foster, MH
MLA Citation
Clark, Amy G., et al. “A murine Ig light chain transgene reveals IGKV3 gene contributions to anti-collagen types IV and II specificities.Mol Immunol, vol. 91, Nov. 2017, pp. 49–56. Pubmed, doi:10.1016/j.molimm.2017.08.015.
URI
https://scholars.duke.edu/individual/pub1276368
PMID
28886586
Source
pubmed
Published In
Mol Immunol
Volume
91
Published Date
Start Page
49
End Page
56
DOI
10.1016/j.molimm.2017.08.015

Treatment with a laminin-derived peptide suppresses lupus nephritis.

The role of DNA as the target for pathogenic lupus autoantibodies in systemic lupus erythematosus is equivocal and renal damage may be due to cross-reactivity of lupus Abs with glomerular components. We have previously shown that lupus autoantibodies bind to the laminin component of the extracellular matrix. In the present work, we have analyzed the fine specificity of the interaction of pathogenic murine lupus autoantibodies with this molecule and the effect of inhibiting their binding to laminin during the course of the disease. We have found that pathogenic murine lupus autoantibodies react with a 21-mer peptide located in the globular part of the alpha-chain of laminin. Immunization of young lupus-prone mice with this peptide accelerated renal disease. Analysis of transgenic, congenic, and RAG-1(-/-) mice confirmed the importance of this epitope in the pathogenesis of lupus renal disease. We have synthesized a panel of peptides that cross-react with the anti-laminin Abs and have found that the binding of lupus autoantibodies to the extracellular matrix could be inhibited in vitro by some of these competitive peptides. Treatment of MRL/lpr/lpr mice with these peptides prevented Ab deposition in the kidneys, ameliorated renal disease, and prolonged survival of the peptide-treated mice. We suggest that laminin components can serve as the target for lupus Abs. The interaction with these Ags can explain both the tissue distribution and the immunopathological findings in lupus. Moreover, inhibition of autoantibody binding to the extracellular matrix can lead to suppression of disease.
Authors
Amital, H; Heilweil, M; Ulmansky, R; Szafer, F; Bar-Tana, R; Morel, L; Foster, MH; Mostoslavsky, G; Eilat, D; Pizov, G; Naparstek, Y
MLA Citation
Amital, Howard, et al. “Treatment with a laminin-derived peptide suppresses lupus nephritis.J Immunol, vol. 175, no. 8, Oct. 2005, pp. 5516–23. Pubmed, doi:10.4049/jimmunol.175.8.5516.
URI
https://scholars.duke.edu/individual/pub771558
PMID
16210660
Source
pubmed
Published In
The Journal of Immunology
Volume
175
Published Date
Start Page
5516
End Page
5523
DOI
10.4049/jimmunol.175.8.5516

Anti-idiotypic monoclonal Ig specific for an anti-laminin Ig heavy chain transgene variable region.

Techniques currently available to obtain anti-idiotypic reagents reactive with a single chain of a lymphocyte antigen receptor rely on immunization with intact soluble or cell-bound Ig or T-cell receptors. Ready recovery of single-chain-specific monoclonal antibodies (MAbs) depends on the presence of an immunodominant epitope on the desired chain and chance recovery of the responding clone. Here we present a method to maximize recovery of an Ig heavy-chain-specific anti-idiotypic Ig, using sequential immunization with MAbs expressing the H chain V region in combination with different H chain isotypes and with different light chains. The latter was produced by in vitro transfection of an H-chain-loss variant myeloma cell line with a transgene construct expressing the Ig H chain V region of interest. Sequential immunization may be a useful strategy to enhance selection of anti-Id reagents reactive with single chain-specific epitopes.
Authors
Foster, MH; Cooperstone, BG; Chen, H
MLA Citation
Foster, M. H., et al. “Anti-idiotypic monoclonal Ig specific for an anti-laminin Ig heavy chain transgene variable region.Hybridoma, vol. 17, no. 4, Aug. 1998, pp. 323–29. Pubmed, doi:10.1089/hyb.1998.17.323.
URI
https://scholars.duke.edu/individual/pub771567
PMID
9790066
Source
pubmed
Published In
Hybridoma
Volume
17
Published Date
Start Page
323
End Page
329
DOI
10.1089/hyb.1998.17.323

Murine monoclonal anti-DNA antibodies penetrate cells, bind to nuclei, and induce glomerular proliferation and proteinuria in vivo.

The production of relatively high quantities of autoantibodies (autoAb) that react with DNA and other intranuclear antigens is characteristic of individuals with systemic lupus erythematosus and other autoimmune diseases. However, the capacity of these Ab to penetrate cells and induce functional perturbations in vivo is not well appreciated. To address this issue, monoclonal (m) anti-DNA Ab (mAb), derived from MRL-lpr/lpr and (NZB x SWR)F1 mice, were administered to normal mice, and the animals were examined for morphologic and functional abnormalities. A subset of five mAb produced intranuclear immunoglobulin deposits in multiple organs. Intranuclear immunoglobulin deposits were also observed after cross-linking the tissue before direct immunofluorescence and after i.v. injection of F(ab')2 fragments of one anti-DNA Ab. This phenomenon was reproducible and was only associated with this subset of autoAb. Furthermore, intranuclear deposits of anti-DNA Ab within glomeruli were associated with morphologic and functional abnormalities including: hypercellularity, epithelial foot process fusion, new fiber bundle formation within the mesangium suggestive of new collagen synthesis, and proteinuria. These results indicate that a subset of autoAb may penetrate cells in vivo to influence normal cellular and nuclear function and to contribute to functional and pathologic abnormalities in individuals with systemic lupus.
Authors
Vlahakos, D; Foster, MH; Ucci, AA; Barrett, KJ; Datta, SK; Madaio, MP
MLA Citation
URI
https://scholars.duke.edu/individual/pub771577
PMID
1627759
Source
pubmed
Published In
Journal of the American Society of Nephrology
Volume
2
Published Date
Start Page
1345
End Page
1354