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:

Systemic lupus erythematosus and the kidney

Authors
MLA Citation
Kelley, V. R., et al. “Systemic lupus erythematosus and the kidney.” Molecular and Genetic Basis of Renal Disease: A Companion to Brenner and Rector’s The Kidney, 2007, pp. 509–30. Scopus, doi:10.1016/B978-1-4160-0252-9/50033-1.
URI
https://scholars.duke.edu/individual/pub1529052
Source
scopus
Published Date
Start Page
509
End Page
530
DOI
10.1016/B978-1-4160-0252-9/50033-1

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

Central tolerance regulates B cells reactive with Goodpasture antigen alpha3(IV)NC1 collagen.

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 alpha3 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 alpha3(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 alpha3(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-alpha3(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.
Authors
Zhang, Y; Su, SC; Hecox, DB; Brady, GF; Mackin, KM; Clark, AG; Foster, MH
MLA Citation
Zhang, Ying, et al. “Central tolerance regulates B cells reactive with Goodpasture antigen alpha3(IV)NC1 collagen.J Immunol, vol. 181, no. 9, Nov. 2008, pp. 6092–100. Pubmed, doi:10.4049/jimmunol.181.9.6092.
URI
https://scholars.duke.edu/individual/pub719181
PMID
18941198
Source
pubmed
Published In
J Immunol
Volume
181
Published Date
Start Page
6092
End Page
6100
DOI
10.4049/jimmunol.181.9.6092

In vitro and in vivo expression of a nephritogenic Ig heavy chain determinant: pathogenic autoreactivity requires permissive light chains.

Lymphocyte antigen receptors are promising targets for immune intervention strategies in disorders marked by repertoire skewing or expansion of lymphocyte subsets. Appropriate application of immune receptor modulation is predicated on understanding the role of a particular receptor in pathogenesis and disease regulation. The VHB/W16 gene, restricted to mice carrying the j haplotype for the J558 family, is overexpressed by murine lupus anti-DNA Ig. This gene is also expressed recurrently among nephritogenic anti-DNA Ig recovered from several autoimmune strains, suggesting that cells expressing this pathogenic receptor are positively selected during disease progression. To explore the extent and mechanisms by which Ig H chains expressing this gene contribute to autoimmunity, an Ig H chain gene was engineered for in vitro and in vivo recombination studies. Site-directed mutagenesis generated unique restriction sites to link PCR-amplified V region (VDJ) cDNA to previously isolated genomic fragments containing Ig regulatory and signal sequences. The new 3 kb VDJ gene was then ligated to a 9 kb fragment encoding the IgM constant region. Transfection of H chain loss variant myeloma with the complete 12 kb construct, termed 238H-Cmicro, resulted in secretion of intact Ig pairing 238H-Cmicro, with a lambda L chain; however, transfectant Ig lacked autoreactivity and pathogenicity. Introduction of the 238H-Cmicro H chain as a transgene onto the non-autoimmune C57BL/6 background resulted in abundant B cell surface expression of 238H-Cmicro, however, four transgenic Ig recovered by fusion of LPS-stimulated splenocytes and formed by combination of 238H-Cmicro, with endogenous kappa chains do not bind DNA or laminin. These results indicate that the antigen binding sites encoded by this disease-associated gene and/or H chain must associate with permissive L chains to specify autoimmunity. The 238H-Cmicro, transgenic model should prove useful in dissecting the in vivo fate of 238H-Cmicro, L combinations that produce pathogenic autoreactive receptors and in evaluating receptor-targeted interventions.
Authors
Cooperstone, BG; Rahman, MM; Rudolph, EH; Foster, MH
MLA Citation
Cooperstone, B. G., et al. “In vitro and in vivo expression of a nephritogenic Ig heavy chain determinant: pathogenic autoreactivity requires permissive light chains.Immunol Cell Biol, vol. 79, no. 3, June 2001, pp. 222–30. Pubmed, doi:10.1046/j.1440-1711.2001.01001.x.
URI
https://scholars.duke.edu/individual/pub771561
PMID
11380674
Source
pubmed
Published In
Immunology and Cell Biology
Volume
79
Published Date
Start Page
222
End Page
230
DOI
10.1046/j.1440-1711.2001.01001.x

Molecular and structural analysis of nuclear localizing anti-DNA lupus antibodies.

To determine the structure of three nuclear localizing lupus anti-DNA immunoglobulins (Igs) and to search for clues to mechanisms of cellular and/or nuclear access, their H- and L-chain variable region sequences were determined and subjected to three-dimensional modeling. Although the results indicate heterogeneity in their primary structures, the H chains are encoded by 3 members of the J558 VH gene family with a common tertiary conformation that is not shared by a J558-encoded nonnuclear localizing anti-DNA control Ig. Furthermore, at least two of the Igs share a conformational motif in the H-chain CDR3, and all three Igs contain multiple positively charged amino acids in their CDRs, resembling nuclear localization signals that direct protein nuclear import. Notably, each VH and VK gene is also found recurrently among previously described autoantibodies. Molecular analysis further indicates that both germline-encoded and significantly mutated V genes can generate nuclear localizing anti-DNA Ig.
Authors
Foster, MH; Kieber-Emmons, T; Ohliger, M; Madaio, MP
MLA Citation
Foster, M. H., et al. “Molecular and structural analysis of nuclear localizing anti-DNA lupus antibodies.Immunol Res, vol. 13, no. 2–3, 1994, pp. 186–206. Pubmed, doi:10.1007/BF02918279.
URI
https://scholars.duke.edu/individual/pub719179
PMID
7775809
Source
pubmed
Published In
Immunologic Research
Volume
13
Published Date
Start Page
186
End Page
206
DOI
10.1007/BF02918279

Research Areas:

Muser Mentor