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

Genetic elimination of α3(IV) collagen fails to rescue anti-collagen B cells.

Organ deposition of autoantibodies against the noncollagenous-1 domain of the α3 chain of type IV collagen leads to severe kidney and lung injury in anti-glomerular basement membrane disease. The origin and regulation of these highly pathogenic autoantibodies remains unknown. Anti-α3(IV) collagen B lymphocytes are predicted to mature in vivo ignorant of target antigen because α3(IV) collagen expression is highly tissue restricted and pathogenic epitopes are cryptic. However, a recent analysis of an anti-α3(IV)NC1 collagen autoantibody transgenic mouse model revealed that developing B cells are rapidly silenced by deletion and editing in the bone marrow. To dissect the role of collagen as central tolerogen in this model, we determined B cell fate in autoantibody transgenic mice genetically lacking α3(IV) collagen. We found that absence of the tissue target autoantigen has little impact on the fate of anti-α3(IV)NC1 B cells. This implies a more complex regulatory mechanism for preventing anti-glomerular basement membrane disease than has been previously considered, including the possibility that a second antigen present in bone marrow engages and tolerizes anti-α3(IV)NC1 collagen B cells.
Authors
Clark, AG; Mackin, KM; Foster, MH
MLA Citation
Clark, Amy G., et al. “Genetic elimination of α3(IV) collagen fails to rescue anti-collagen B cells.Immunol Lett, vol. 141, no. 1, Dec. 2011, pp. 134–39. Pubmed, doi:10.1016/j.imlet.2011.09.004.
URI
https://scholars.duke.edu/individual/pub771557
PMID
21963654
Source
pubmed
Published In
Immunol Lett
Volume
141
Published Date
Start Page
134
End Page
139
DOI
10.1016/j.imlet.2011.09.004

Complex tolerance phenotypes induced by lupus autoantigens.

Authors
Congdon, KC; Brady, GF; Foster, MH
MLA Citation
Congdon, K. C., et al. “Complex tolerance phenotypes induced by lupus autoantigens.Journal of the American Society of Nephrology, vol. 13, LIPPINCOTT WILLIAMS & WILKINS, Sept. 2002, pp. 171A-171A.
URI
https://scholars.duke.edu/individual/pub877882
Source
wos
Published In
Journal of the American Society of Nephrology
Volume
13
Published Date
Start Page
171A
End Page
171A

A subgroup of murine monoclonal anti-deoxyribonucleic acid antibodies traverse the cytoplasm and enter the nucleus in a time-and temperature- dependent manner.

BACKGROUND: The capacity of lupus autoantibodies to enter living cells and bind to molecules for which they have intrinsic affinity is not well appreciated. In previous studies, we identified a subgroup of three murine monoclonal IgG anti-DNA antibodies, derived from lupus-prone MRL-lpr/lpr mice, that localized within nuclei of cells in multiple organs and induced functional perturbations, in vivo, after passive transfer to normal mice. To examine the mechanisms of this phenomenon, we now extend these observations, using the same monoclonal anti-DNA antibodies and cultured cell lines. EXPERIMENTAL DESIGN: Multiple experimental approaches were utilized to track nuclear localization of anti-DNA antibodies, including direct immunofluorescence, confocal microscopy and immunoelectron microscopy. The requirements for nuclear localization were further evaluated quantitatively, in nuclei isolated from co-cultures of cells and 125I-Ig, under varying experimental conditions. RESULTS: Nuclear localization was observed with the same subset of anti-DNA antibodies that localized within nuclei in vivo; it was dependent on the antigen-binding region of the molecule; and it was not found with other anti-DNA antibodies. At progressive intervals, the Ig were observed: at the cell surface, within the cytoplasm, clustered at the nuclear pore, and within the nucleus. Nuclear localization of Ig was found to be a time- and temperature- dependent process, specific for a subset of anti-DNA antibodies and dependent on the antigen binding region of the Ig. CONCLUSIONS: This is the first demonstration that monoclonal autoantibodies can traverse both the cell and nuclear membranes to localize within the nuclei of cultured cells. Furthermore, nuclear localization of Ig was regulated in a manner analogous to that of other large cytoplasmic proteins that enter the nucleus. This confirms and extends our results using the same antibodies in whole animals, and it provides the basis to further examine the underlying mechanisms and consequences of this phenomenon.
Authors
Yanase, K; Smith, RM; Cĭzman, B; Foster, MH; Peachey, LD; Jarett, L; Madaio, MP
URI
https://scholars.duke.edu/individual/pub771575
PMID
8041118
Source
pubmed
Published In
Laboratory Investigation
Volume
71
Published Date
Start Page
52
End Page
60

Glomerular type 1 angiotensin receptors augment kidney injury and inflammation in murine autoimmune nephritis.

Studies in humans and animal models indicate a key contribution of angiotensin II to the pathogenesis of glomerular diseases. To examine the role of type 1 angiotensin (AT1) receptors in glomerular inflammation associated with autoimmune disease, we generated MRL-Faslpr/lpr (lpr) mice lacking the major murine type 1 angiotensin receptor (AT1A); lpr mice develop a generalized autoimmune disease with glomerulonephritis that resembles SLE. Surprisingly, AT1A deficiency was not protective against disease but instead substantially accelerated mortality, proteinuria, and kidney pathology. Increased disease severity was not a direct effect of immune cells, since transplantation of AT1A-deficient bone marrow did not affect survival. Moreover, autoimmune injury in extrarenal tissues, including skin, heart, and joints, was unaffected by AT1A deficiency. In murine systems, there is a second type 1 angiotensin receptor isoform, AT1B, and its expression is especially prominent in the renal glomerulus within podocytes. Further, expression of renin was enhanced in kidneys of AT1A-deficient lpr mice, and they showed evidence of exaggerated AT1B receptor activation, including substantially increased podocyte injury and expression of inflammatory mediators. Administration of losartan, which blocks all type 1 angiotensin receptors, reduced markers of kidney disease, including proteinuria, glomerular pathology, and cytokine mRNA expression. Since AT1A-deficient lpr mice had low blood pressure, these findings suggest that activation of type 1 angiotensin receptors in the glomerulus is sufficient to accelerate renal injury and inflammation in the absence of hypertension.
Authors
Crowley, SD; Vasievich, MP; Ruiz, P; Gould, SK; Parsons, KK; Pazmino, AK; Facemire, C; Chen, BJ; Kim, H-S; Tran, TT; Pisetsky, DS; Barisoni, L; Prieto-Carrasquero, MC; Jeansson, M; Foster, MH; Coffman, TM
MLA Citation
Crowley, Steven D., et al. “Glomerular type 1 angiotensin receptors augment kidney injury and inflammation in murine autoimmune nephritis.J Clin Invest, vol. 119, no. 4, Apr. 2009, pp. 943–53. Pubmed, doi:10.1172/JCI34862.
URI
https://scholars.duke.edu/individual/pub728066
PMID
19287096
Source
pubmed
Published In
J Clin Invest
Volume
119
Published Date
Start Page
943
End Page
953
DOI
10.1172/JCI34862