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 at 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
Role
Principal Investigator
Start Date
End Date

Duke O'Brien Center for Kidney Research

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. 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

Altered toll-like receptor responsiveness underlies a dominant heritable defect in B cell tolerance in autoimmune New Zealand Black mice.

Systemic lupus erythematosus is a debilitating autoimmune disease in which autoantibodies and autoreactive T cells destroy kidneys and other organs. Disease is clinically and genetically heterogeneous, suggesting that underlying mechanisms vary between patients. We previously used an autoantibody transgenic mouse reporter system to examine the effect of different autoimmune backgrounds on B-cell tolerance, failure of which is a fundamental defect in lupus. We identified a defect consistent with reversible anergy induced by endotoxin stimulation of B cells from Ig transgenic New Zealand Black (NZB) mice. Herein we report that the tolerance defect is revealed by TLR7 and TLR9 as well as TLR4 ligands, with additive effect, and is partially reversed by Mek inhibition. Gene expression analysis reveals significant differences in transcription of multiple TLR pathway genes and ptpn22 in stimulated NZB compared to B6 B cells. Additionally, the defect is detected in Ig transgenic NZB F1 hybrid strains (NZBxNZW)F1 and (B6xNZB)F1. These results implicate an inherited defect wherein NZB anergic B cells maintain coordinated TLR/BCR signaling that permits autoantibody production. Agents targeting these pathways may have therapeutic benefit in the subset of lupus patients that manifest similar defects in B-cell regulation.
Authors
MLA Citation
Clark, Amy G., et al. “Altered toll-like receptor responsiveness underlies a dominant heritable defect in B cell tolerance in autoimmune New Zealand Black mice..” Eur J Immunol, vol. 48, no. 3, Mar. 2018, pp. 492–97. Pubmed, doi:10.1002/eji.201747287.
URI
https://scholars.duke.edu/individual/pub1293682
PMID
29251774
Source
pubmed
Published In
Eur J Immunol
Volume
48
Published Date
Start Page
492
End Page
497
DOI
10.1002/eji.201747287

Deconstructing B cell tolerance to basement membranes.

Basement membrane antigens are frequent targets of autoantibody attack in systemic and organ-restricted autoimmunity. These specialized and highly organized matrices are composed of multiple components with restricted tissue distributions and limited epitope exposure. To dissect mechanisms controlling humoral autoimmunity to nephritogenic basement membrane antigens, we developed autoantibody transgenic models. In mice bearing the LamH Ig transgene encoding B cell receptors specific for laminin, autoreactive B cells are readily generated but actively regulated in vivo. In this model, anti-laminin B cells are immunologically censored by mechanisms that include central deletion, kappa light-chain editing, and anergy. Tolerance is maintained when the transgene is established in MRL and BXSB genetic backgrounds with inherited autoimmune susceptibility, and despite provocation with potent environmental stimulants. Collectively, these studies indicate that the pathogenic anti-laminin reactivity characteristic of systemic lupus is tightly regulated. A novel anti-collagen transgenic model is used to assess the tolerogenesis of a structurally distinct pathogenic basement membrane epitope and to determine if reactivity to putative cryptic epitopes targeted in organ-restricted disease is regulated. These studies should provide insight into the molecular mechanisms controlling basement membrane autoreactivity and ultimately facilitate the development of novel strategies to inactivate autoreactive cells and treat autoimmune disease.
Authors
Foster, MH; Zhang, Y; Clark, AG
MLA Citation
Foster, Mary H., et al. “Deconstructing B cell tolerance to basement membranes..” Arch Immunol Ther Exp (Warsz), vol. 54, no. 4, July 2006, pp. 227–37. Pubmed, doi:10.1007/s00005-006-0027-x.
URI
https://scholars.duke.edu/individual/pub719171
PMID
16830221
Source
pubmed
Published In
Archivum Immunologiae Et Therapiae Experimentalis
Volume
54
Published Date
Start Page
227
End Page
237
DOI
10.1007/s00005-006-0027-x

Relevance of systemic lupus erythematosus nephritis animal models to human disease.

Systemic lupus erythematosus (SLE) is characterized by spontaneous B and T cell autoreactivity and multiorgan immune injury including severe glomerulonephritis. This autoimmune syndrome results from a global derangement in immune regulation dependent on the interaction of complex genetic and environmental susceptibility factors. Animal models have provided a powerful tool to study disease mechanisms and novel therapeutic interventions under well-defined conditions, and bypass the barriers inherent in the study of human lupus. Classical models of spontaneous and investigator-induced murine lupus, their mutant variants, and novel transgenic and gene-targeted mutant lineages have been particularly useful. Extensive genome typing in inbred and recombinant lupus-prone strains permits mapping and characterization of multiple lupus susceptibility loci and genes and their contribution to various disease phenotypes. Murine models provide important insight into the identity of targeted self-antigens, the molecules and pathways that maintain tolerance, immune cell and cytokine interactions that promote autoimmunity, and mechanisms of renal localization and injury by immune effectors. These models reveal that multiple and independent mechanisms contribute to disease pathogenesis and provide a better understanding of the remarkable phenotypic and histopathologic heterogeneity that characterizes human SLE.
Authors
MLA Citation
Foster, M. H. “Relevance of systemic lupus erythematosus nephritis animal models to human disease..” Semin Nephrol, vol. 19, no. 1, Jan. 1999, pp. 12–24.
URI
https://scholars.duke.edu/individual/pub771566
PMID
9952277
Source
pubmed
Published In
Seminars in Nephrology
Volume
19
Published Date
Start Page
12
End Page
24

Anti-DNA antibodies form immune deposits at distinct glomerular and vascular sites.

To investigate the capacity of lupus autoAb to produce glomerular immune deposits (ID) and nephritis, 24 murine monoclonal (m) anti-DNA antibodies (Ab), derived from either MRL-lpr/lpr, SNF1 or NZB lupus-prone mice and selected based on properties shared with nephritogenic Ig, were administered i.p. (as hybridomas) and i.v. (as purified Ig) to normal mice; at least four mice/mAb were evaluated. Three general patterns of immune deposit formation (IDF) were observed: extracellular ID within glomeruli (+/- blood vessels, N = 8); intranuclear ID (N = 5); or minimal or no ID (N = 11). The four MRL m anti-DNA Ab that produced significant extracellular ID demonstrated different disease profiles including: (a) mesangial and subendothelial ID with anti-basement membrane staining, associated with proliferative glomerulonephritis, PMN infiltration, and proteinuria; (b) diffuse fine granular mesangial and extraglomerular vascular ID, associated with proliferative glomerulonephritis and proteinuria; (c) dense intramembranous ID and intraluminal ID, associated with capillary wall thickening, mesangial interposition and expansion, aneurysmal dilatation and intraluminal occlusion of glomerular capillary loops, and heavy proteinuria; and (d) mesangial and extraglomerular vascular ID, associated with mild segmental mesangial expansion, without proteinuria. These MRL mAb were derived from four different mice, and they had variable pIs and isotypes. They all cross reacted with multiple autoantigens (autoAg), however, their autoAg binding profiles were distinguishable. Among the SNF1 derived mAb, four produced histologically and clinically indistinguishable disease characterized by diffuse mesangial and capillary wall ID, associated with cellular proliferation/infiltration and proteinuria. Three of the four mAb were derived from the same mouse and were clonally related; they were: IgG2b with SWR allotype, relatively cationic, highly cross reactive with similar Ag binding patterns, idiotypically related and encoded by identical VH and nearly identical VL sequences. We conclude that both the capacity of lupus autoAb to form ID and the location of IDF are dependent on properties unique to individual Ig. The results also indicate that the Ag binding region of the autoAb is influential in this process, and they suggest that multiple Ab-Ag interactions contribute to IDF in individuals with lupus nephritis. Furthermore, these observations raise the possibility that the pathologic and clinical abnormalities resulting from these interactions are influenced by the location of IDF, and that the dominant interaction, in a given individual, may be highly influential in the phenotypic expression of nephritis.
Authors
Vlahakos, DV; Foster, MH; Adams, S; Katz, M; Ucci, AA; Barrett, KJ; Datta, SK; Madaio, MP
MLA Citation
Vlahakos, D. V., et al. “Anti-DNA antibodies form immune deposits at distinct glomerular and vascular sites..” Kidney Int, vol. 41, no. 6, June 1992, pp. 1690–700. Pubmed, doi:10.1038/ki.1992.242.
URI
https://scholars.duke.edu/individual/pub771578
PMID
1501424
Source
pubmed
Published In
Kidney International
Volume
41
Published Date
Start Page
1690
End Page
1700
DOI
10.1038/ki.1992.242