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Foster, Mary Helen

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:

Associate Professor of Medicine

Medicine, Nephrology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1982

M.D. — University of North Carolina at Chapel Hill

Medical Resident, Medicine

University of Virginia

Fellow In Nephrology, Medicine

Tufts University

Grants:

Dual humanization to model gene-environment interactions in ANCA vasculitis

Administered By
Medicine, Nephrology
AwardedBy
Vasculitis Foundation
Role
Principal Investigator
Start Date
February 01, 2017
End Date
January 31, 2018

Training Program in Inflammatory and Immunological Diseases

Administered By
Medicine, Rheumatology and Immunology
AwardedBy
National Institutes of Health
Role
Preceptor
Start Date
September 30, 1980
End Date
August 31, 2017

Mechanism of Silica-induced Autoimmunity

Administered By
Medicine, Nephrology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
August 01, 2014
End Date
July 31, 2017

Novel Receptor-Ligand Interactions in Glomerulonephritis

Administered By
Medicine, Nephrology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
August 01, 2011
End Date
July 31, 2017

Duke O'Brien Center for Kidney Research

Administered By
Medicine, Nephrology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
August 15, 2012
End Date
June 30, 2017

Proximal Determinants of Nephritogenic Autoimmunity

Administered By
Medicine, Nephrology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
January 01, 1995
End Date
September 24, 2012

IPA - Ting Yu

Administered By
Medicine, Nephrology
AwardedBy
Veterans Administration Medical Center
Role
Principal Investigator
Start Date
April 26, 2010
End Date
June 09, 2010

IPA - Melissa Weston

Administered By
Medicine, Nephrology
AwardedBy
Veterans Administration Medical Center
Role
Principal Investigator
Start Date
August 03, 2009
End Date
October 11, 2009
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Publications:

Optimizing the translational value of animal models of glomerulonephritis: insights from recent murine prototypes.

Animal models are indispensable for the study of glomerulonephritis, a group of diseases that destroy kidneys but for which specific therapies do not yet exist. Novel interventions are urgently needed, but their rational design requires suitable in vivo platforms to identify and test new candidates. Animal models can recreate the complex immunologic microenvironments that foster human autoimmunity and nephritis and provide access to tissue compartments not readily examined in patients. Study of rat Heymann nephritis identified fundamental disease mechanisms that ultimately revolutionized our understanding of human membranous nephropathy. Significant species differences in expression of a major target antigen, however, and lack of spontaneous autoimmunity in animals remain roadblocks to full exploitation of preclinical models in this disease. For several glomerulonephritides, humanized models have been developed to circumvent cross-species barriers and to study the effects of human genetic risk variants. Herein we review humanized mouse prototypes that provide fresh insight into mediators of IgA nephropathy and origins of antiglomerular basement membrane nephritis and Goodpasture's disease, as well as a means to test novel therapies for ANCA vasculitis. Additional and refined model systems are needed to mirror the full spectrum of human disease in a genetically diverse population, to facilitate development of patient-specific interventions, to determine the origin of nephritogenic autoimmunity, and to define the role of environmental exposures in disease initiation and relapse.

Authors
Foster, MH
MLA Citation
Foster, MH. "Optimizing the translational value of animal models of glomerulonephritis: insights from recent murine prototypes." American journal of physiology. Renal physiology 311.3 (September 2016): F487-F495. (Review)
PMID
27335377
Source
epmc
Published In
American Journal of Physiology: Renal Physiology
Volume
311
Issue
3
Publish Date
2016
Start Page
F487
End Page
F495
DOI
10.1152/ajprenal.00275.2016

Basement membranes and autoimmune diseases.

Basement membrane components are targets of autoimmune attack in diverse diseases that destroy kidneys, lungs, skin, mucous membranes, joints, and other organs in man. Epitopes on collagen and laminin, in particular, are targeted by autoantibodies and T cells in anti-glomerular basement membrane glomerulonephritis, Goodpasture's disease, rheumatoid arthritis, post-lung transplant bronchiolitis obliterans syndrome, and multiple autoimmune dermatoses. This review examines major diseases linked to basement membrane autoreactivity, with a focus on investigations in patients and animal models that advance our understanding of disease pathogenesis. Autoimmunity to glomerular basement membrane type IV is discussed in depth as a prototypic organ-specific autoimmune disease yielding novel insights into the complexity of anti-basement membrane immunity and the roles of genetic and environmental susceptibility.

Authors
Foster, MH
MLA Citation
Foster, MH. "Basement membranes and autoimmune diseases." Matrix biology : journal of the International Society for Matrix Biology (August 2, 2016). (Review)
PMID
27496347
Source
epmc
Published In
Matrix Biology
Publish Date
2016
DOI
10.1016/j.matbio.2016.07.008

Uncommon structural motifs dominate the antigen binding site in human autoantibodies reactive with basement membrane collagen.

Autoantibodies mediate organ destruction in multiple autoimmune diseases, yet their origins in patients remain poorly understood. To probe the genetic origins and structure of disease-associated autoantibodies, we engrafted immunodeficient mice with human CD34+ hematopoietic stem cells and immunized with the non-collagenous-1 (NC1) domain of the alpha3 chain of type IV collagen. This antigen is expressed in lungs and kidneys and is targeted by autoantibodies in anti-glomerular basement membrane (GBM) nephritis and Goodpasture syndrome (GPS), prototypic human organ-specific autoimmune diseases. Using Epstein Barr virus transformation and cell fusion, six human anti-alpha3(IV)NC1 collagen monoclonal autoantibodies (mAb) were recovered, including subsets reactive with human kidney and with epitopes recognized by patients' IgG. Sequence analysis reveals a long to exceptionally long heavy chain complementarity determining region3 (HCDR3), the major site of antigen binding, in all six mAb. Mean HCDR3 length is 25.5 amino acids (range 20-36), generated from inherently long DH and JH genes and extended regions of non-templated N-nucleotides. Long HCDR3 are suited to forming noncontiguous antigen contacts and to binding recessed, immunologically silent epitopes hidden from conventional antibodies, as seen with self-antigen crossreactive broadly neutralizing anti-HIV Ig (bnAb). The anti-alpha3(IV)NC1 collagen mAb also show preferential use of unmutated variable region genes that are enriched among human chronic lymphocytic leukemia antibodies that share features with natural polyreactive Ig. Our findings suggest unexpected relationships between pathogenic anti-collagen Ig, bnAb, and autoreactive Ig associated with malignancy, all of which arise from B cells expressing unconventional structural elements that may require transient escape from tolerance for successful expansion.

Authors
Foster, MH; Buckley, ES; Chen, BJ; Hwang, K-K; Clark, AG
MLA Citation
Foster, MH, Buckley, ES, Chen, BJ, Hwang, K-K, and Clark, AG. "Uncommon structural motifs dominate the antigen binding site in human autoantibodies reactive with basement membrane collagen." Molecular immunology 76 (August 2016): 123-133.
PMID
27450516
Source
epmc
Published In
Molecular Immunology
Volume
76
Publish Date
2016
Start Page
123
End Page
133
DOI
10.1016/j.molimm.2016.07.004

Recovery of a human natural antibody against the noncollagenous-1 domain of type IV collagen using humanized models.

Anti-glomerular basement membrane nephritis and Goodpasture syndrome result from autoantibody (Ab)-mediated destruction of kidney and lung. Ab target the noncollagenous 1 (NC1) domain of alpha3(IV) collagen, but little is known about Ab origins or structure. This ignorance is due in part to the inability to recover monoclonal Ab by transformation of patients' blood cells. The aim of this study was to assess the suitability of two humanized models for this purpose.NOD-scid-gamma immunodeficient mice were engrafted either with human CD34+ hematopoietic stem cells (HSC) (Hu-HSC mice) and immunized with alpha3(IV)NC1 collagen containing the Goodpasture epitopes or with nephritis patients' peripheral blood leukocytes (PBL) (Hu-PBL mice). After in vivo immune cell development and/or expansion, recovered human B cells were Epstein Barr virus (EBV)-transformed, screened for antigen (Ag) binding, electrofused with a mouse-human heterohybridoma, subcloned, and human Ab RNA sequenced by PCR after reverse transcription to cDNA. Flow cytometry was used to assess human B cell markers and differentiation in Hu-PBL mice.Sequence analysis of a human Ab derived from an immunized Hu-HSC mouse and reactive with alpha3(IV)NC1 collagen reveals that it is encoded by unmutated heavy and light chain genes. The heavy chain complementarity determining region 3, a major determinant of Ag binding, contains uncommon motifs, including an N-region somatically-introduced highly hydrophobic tetrapeptide and dual cysteines encoded by a uniquely human IGHD2-2 Ab gene segment that lacks a murine counterpart. Comparison of human and mouse autoantibodies suggests that structurally similar murine Ab may arise by convergent selection. In contrast to the Hu-HSC model, transformed human B cells are rarely recovered from Hu-PBL mice, in which human B cells terminally differentiate and lose expression of EBV receptor CD21, thus precluding their transformation and recovery.Hu-HSC mice reveal that potentially pathogenic B cells bearing unmutated Ig receptors reactive with the NC1 domain on alpha3(IV) collagen can be generated in, and not purged from, the human preimmune repertoire. Uniquely human gene elements are recruited to generate the antigen binding site in at least a subset of these autoantibodies, indicating that humanized models may provide insights inaccessible using conventional mouse models.

Authors
Worni-Schudel, IM; Clark, AG; Chien, T; Hwang, K-K; Chen, BJ; Foster, MH
MLA Citation
Worni-Schudel, IM, Clark, AG, Chien, T, Hwang, K-K, Chen, BJ, and Foster, MH. "Recovery of a human natural antibody against the noncollagenous-1 domain of type IV collagen using humanized models." Journal of translational medicine 13 (January 2015): 185-.
PMID
26048777
Source
epmc
Published In
Journal of Translational Medicine
Volume
13
Publish Date
2015
Start Page
185
DOI
10.1186/s12967-015-0539-4

Lack of galectin-1 or galectin-3 alters B cell deletion and anergy in an autoantibody transgene model.

Members of the galectin family of proteins have been shown to regulate the development and the function of immune cells. We previously identified the increased expression of galectin-1 and galectin-3 mRNA and protein in anergic B cells relative to their naïve counterparts. To investigate the role of these galectins in maintaining B cell tolerance, we crossed mice deficient in galectin-1 or galectin-3 with mice bearing a lupus autoantigen-binding transgenic (Tg) B cell receptor, using a model with a well-characterized B cell tolerance phenotype of deletion, receptor editing and anergy. Here, we present data showing that the global knockout of galectin-1 or galectin-3 yields subtle alterations in B cell fate in autoantibody Tg mice. The absence of galectin-3 leads to a significant increase in the number of Tg spleen B cells, with the recovery of anti-laminin antibodies from a subset of mice. The B cell number increases further in antibody Tg mice with the dual deficiency of both galectin-1 and galectin-3. Isolated galectin-1 deficiency significantly enhances the proliferation of Tg B cells in response to lipopolysaccharide stimulation. These findings add to the growing body of evidence indicating a role for the various galectin family members, and for galectins 1 and 3 in particular, in the regulation of autoimmunity.

Authors
Clark, AG; Weston, ML; Foster, MH
MLA Citation
Clark, AG, Weston, ML, and Foster, MH. "Lack of galectin-1 or galectin-3 alters B cell deletion and anergy in an autoantibody transgene model." Glycobiology 23.7 (July 2013): 893-903.
PMID
23550149
Source
pubmed
Published In
Glycobiology
Volume
23
Issue
7
Publish Date
2013
Start Page
893
End Page
903
DOI
10.1093/glycob/cwt026

Regulation of basement membrane-reactive B cells in BXSB, (NZBxNZW)F1, NZB, and MRL/lpr lupus mice.

Autoantibodies to diverse antigens escape regulation in systemic lupus erythematosus under the influence of a multitude of predisposing genes. To gain insight into the differential impact of diverse genetic backgrounds on tolerance mechanisms controlling autoantibody production in lupus, we established a single lupus-derived nephritis associated anti-basement membrane Ig transgene on each of four inbred murine lupus strains, including BXSB, (NZBxNZW)F1, NZB, and MRL/lpr, as approved by the Duke University and the Durham Veterans Affairs Medical Centers' Animal Care and Use Committees. In nonautoimmune C57BL/6 mice, B cells bearing this anti-laminin Ig transgene are stringently regulated by central deletion, editing, and anergy. Here, we show that tolerance is generally intact in unmanipulated Ig transgenic BXSB, (NZBxNZW)F1, and NZB mice, based on absence of serum transgenic anti-laminin autoantibodies and failure to recover spontaneous anti-laminin monoclonal antibodies. Four- to six-fold depletion of splenic B cells in transgenic mice of these strains, as well as in MRL/lpr transgenic mice, and reduced frequency of IgM+ bone marrow B cells suggest that central deletion is grossly intact. Nonetheless the 4 strains demonstrate distinct transgenic B cell phenotypes, including endotoxin-stimulated production of anti-laminin antibodies by B cells from transgenic NZB mice, and in vitro hyperproliferation of both endotoxin- and BCR-stimulated B cells from transgenic BXSB mice, which are shown to have an enrichment of CD21-high marginal zone cells. Rare anti-laminin transgenic B cells spontaneously escape tolerance in MRL/lpr mice. Further study of the mechanisms underlying these strain-specific B cell fates will provide insight into genetic modification of humoral autoimmunity in lupus.

Authors
Clark, AG; Fan, Q; Brady, GF; Mackin, KM; Coffman, ED; Weston, ML; Foster, MH
MLA Citation
Clark, AG, Fan, Q, Brady, GF, Mackin, KM, Coffman, ED, Weston, ML, and Foster, MH. "Regulation of basement membrane-reactive B cells in BXSB, (NZBxNZW)F1, NZB, and MRL/lpr lupus mice." Autoimmunity 46.3 (May 2013): 188-204.
PMID
23157336
Source
pubmed
Published In
Autoimmunity (Informa)
Volume
46
Issue
3
Publish Date
2013
Start Page
188
End Page
204
DOI
10.3109/08916934.2012.746671

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, AG, Mackin, KM, and Foster, MH. "Genetic elimination of α3(IV) collagen fails to rescue anti-collagen B cells." Immunol Lett 141.1 (December 30, 2011): 134-139.
PMID
21963654
Source
pubmed
Published In
Immunology Letters
Volume
141
Issue
1
Publish Date
2011
Start Page
134
End Page
139
DOI
10.1016/j.imlet.2011.09.004

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, 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, and Coffman, TM. "Glomerular type 1 angiotensin receptors augment kidney injury and inflammation in murine autoimmune nephritis." J Clin Invest 119.4 (April 2009): 943-953.
PMID
19287096
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
119
Issue
4
Publish Date
2009
Start Page
943
End Page
953
DOI
10.1172/JCI34862

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, Y, Su, SC, Hecox, DB, Brady, GF, Mackin, KM, Clark, AG, and Foster, MH. "Central tolerance regulates B cells reactive with Goodpasture antigen alpha3(IV)NC1 collagen." J Immunol 181.9 (November 1, 2008): 6092-6100.
PMID
18941198
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
181
Issue
9
Publish Date
2008
Start Page
6092
End Page
6100

Novel targets for immunotherapy in glomerulonephritis.

Glomerulonephritis is a common cause of chronic kidney disease and end stage renal failure. Current therapy relies on variably effective, nonspecific and toxic immunosuppression. Recent insights into underlying biology and disease pathogenesis in human glomerulonephritis combined with advances in the fields of inflammation and autoimmunity promise a cadre of novel targeted interventions. This review highlights the therapeutic potential of two antigens, alpha3 (IV)NC1 collagen and podocyte neutral endopeptidase, and two cell signaling and effector molecules, IgG Fc receptors and complement, judged to be particularly amenable to therapeutic manipulation in man. It is anticipated that continued dissection of pathogenesis in the diverse disorders that comprise the glomerulonephritides will provide the basis for individualized disease-specific therapy.

Authors
Foster, MH
MLA Citation
Foster, MH. "Novel targets for immunotherapy in glomerulonephritis." Biologics 2.3 (September 2008): 531-545.
PMID
19707383
Source
pubmed
Published In
Biologics: Targets and Therapy
Volume
2
Issue
3
Publish Date
2008
Start Page
531
End Page
545

Tracking Differential Gene Expression in MRL/MpJ Versus C57BL/6 Anergic B Cells: Molecular Markers of Autoimmunity.

BACKGROUND: Anergy is a key mechanism controlling expression of autoreactive B cells and a major site for failed regulation in autoimmune diseases. Yet the molecular basis for this differentiated cell state remains poorly understood. The current lack of well-characterized surface or molecular markers hinders the isolation of anergic cells for further study. Global gene profiling recently identified transcripts whose expression differentiates anergic from naïve B cells in model mouse systems. The objective of the current study was to evaluate the molecular and cellular processes that differentiate anergic cells that develop in the healthy C57BL/6 (B6) milieu from those that develop in the autoimmune-prone MRL/MpJ (MRL) background. This approach takes advantage of B6 and MRL mice bearing an anti-laminin Ig transgene with a well characterized anergic B cell phenotype. RESULTS: Global gene expression was evaluated in purified transgenic B cells using Operon version 3.0 oligonucleotide microarray assaying >31,000 oligoprobes. Genes with a 2-fold expression difference in B6 as compared to MRL anergic B cells were identified. Expression of selected genes was confirmed using quantitative RT-PCR. This approach identified 43 probes corresponding to 37 characterized genes, including Ptpn22, CD74, Birc1f/Naip, and Ctla4, as differentially expressed in anergic B cells in the two strains. Gene Ontology classification identified differentiation, cell cycle, proliferation, development, apoptosis, and cell death as prominently represented ontology groups. Ingenuity Pathway Analysis identified two major networks incorporating 27 qualifying genes. Network 1 centers on beta-estradiol and TP53, and Network 2 encompasses RB1, p38 MAPK, and NFkB cell growth, proliferation, and cell cycle signaling pathways. CONCLUSION: Using microarray analysis we identified 37 characterized genes and two functional pathways engaged in maintenance of B cell anergy for which expression is distorted by underlying autoimmune genetic susceptibility. This approach identifes a new biological role for multiple genes and potential new therapeutic targets in autoimmunity.

Authors
Clark, AG; Mackin, KM; Foster, MH
MLA Citation
Clark, AG, Mackin, KM, and Foster, MH. "Tracking Differential Gene Expression in MRL/MpJ Versus C57BL/6 Anergic B Cells: Molecular Markers of Autoimmunity. (Published online)" Biomark Insights 3 (June 10, 2008): 335-350.
PMID
19578517
Source
pubmed
Published In
Biomark Insights
Volume
3
Publish Date
2008
Start Page
335
End Page
350

Systemic lupus erythematosus and the kidney

Authors
Kelley, VR; Morel, L; Foster, MH
MLA Citation
Kelley, VR, Morel, L, and Foster, MH. "Systemic lupus erythematosus and the kidney." Molecular and Genetic Basis of Renal Disease (2008): 509-530.
Source
scival
Published In
Molecular and Genetic Basis of Renal Disease
Publish Date
2008
Start Page
509
End Page
530
DOI
10.1016/B978-1-4160-0252-9.50033-1

Multifunctional regulators of cell growth are differentially expressed in anergic murine B cells.

Defective anergy is a major cause of failed tolerance and is amenable to therapeutic manipulation. To better define the molecular basis of anergy in B cells tolerized by matrix self-antigen, we used complementary approaches of representational difference analysis (RDA) and microarray to identify genes differentially transcribed in anergic as compared to non-tolerant B cells isolated from a well-characterized murine autoantibody transgenic model. Forty RDA clones representing 16 genes were isolated from receptor-stimulated B cells and independently confirmed as differentially expressed in tolerant cells using custom microarray, dot blotting and/or quantitative PCR. Differential expression was conserved in tolerant cells from two different transgenic founder lineages and from two genetically disparate backgrounds. Prominent among recovered gene fragments were genes encoding multifunctional proteins not previously implicated in B cell biology, but with roles in biologic processes fundamental to the tolerance phenotype, including cell growth, proliferation and differentiation. RDA also identified a novel transcript not previously reported in nucleic acid databases. To further explore dependence on receptor stimulation and to identify additional genes, commercial oligonucleotide arrays were probed with labeled B cell transcripts and analyzed for genes differentially expressed in resting as well as stimulated cells and in both B6 and MRL mouse strains. Arrays identified differential expression of a subset of RDA genes as well as 46 additional genes, including subsets engaged in signal transduction, transcriptional regulation, cell growth and apoptosis. Immunoblotting confirmed differential protein expression for galectin-3 and galectin-1, two interactive members of the galectin family, suggesting a novel role for galectins as regulators of immune tolerance.

Authors
Clark, AG; Chen, S; Zhang, H; Brady, GF; Ungewitter, EK; Bradley, JK; Sackey, FN; Foster, MH
MLA Citation
Clark, AG, Chen, S, Zhang, H, Brady, GF, Ungewitter, EK, Bradley, JK, Sackey, FN, and Foster, MH. "Multifunctional regulators of cell growth are differentially expressed in anergic murine B cells." Mol Immunol 44.6 (February 2007): 1274-1285.
PMID
16890292
Source
pubmed
Published In
Molecular Immunology
Volume
44
Issue
6
Publish Date
2007
Start Page
1274
End Page
1285
DOI
10.1016/j.molimm.2006.06.001

T cells and B cells in lupus nephritis.

T and B lymphocytes play diverse roles at multiple stages in the development and progression of lupus nephritis. Disruption of T- and B-cell regulatory functions by environmental and genetic influences permits pathogenic effectors to emerge in disease. New insights into the biology of these multifunctional cells offer novel targets for intervention in lupus nephritis and systemic autoimmunity.

Authors
Foster, MH
MLA Citation
Foster, MH. "T cells and B cells in lupus nephritis." Semin Nephrol 27.1 (January 2007): 47-58. (Review)
PMID
17336688
Source
pubmed
Published In
Seminars in Nephrology
Volume
27
Issue
1
Publish Date
2007
Start Page
47
End Page
58
DOI
10.1016/j.semnephrol.2006.09.007

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, MH, Zhang, Y, and Clark, AG. "Deconstructing B cell tolerance to basement membranes." Arch Immunol Ther Exp (Warsz) 54.4 (July 2006): 227-237. (Review)
PMID
16830221
Source
pubmed
Published In
Archivum Immunologiae et Therapiae Experimentalis
Volume
54
Issue
4
Publish Date
2006
Start Page
227
End Page
237
DOI
10.1007/s00005-006-0027-x

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 component. 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 α-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. Copyright © 2005 by The American Association of Immunologists, Inc.

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, H, Heilweil, M, Ulmansky, R, Szafer, F, Bar-Tana, R, Morel, L, Foster, MH, Mostoslavsky, G, Eilat, D, Pizov, G, and Naparstek, Y. "Treatment with a laminin-derived peptide suppresses lupus nephritis." Journal of Immunology 175.8 (2005): 5516-5523.
PMID
16210660
Source
scival
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
175
Issue
8
Publish Date
2005
Start Page
5516
End Page
5523

Kappa editing rescues autoreactive B cells destined for deletion in mice transgenic for a dual specific anti-laminin Ig.

We explored mechanisms involved in B cell self-tolerance in a double- and triple-transgenic mouse model bearing the LamH-C mu Ig H chain conventional transgene and a gene-targeted replacement for a functional V kappa 8J kappa 5 L chain gene. Whereas the H chain is known to generate anti-laminin Ig in combination with multiple L chains, the H + L Ig binds ssDNA in addition to laminin. Immune phenotyping indicates that H + L transgenic B cells are regulated by clonal deletion, receptor editing via secondary rearrangements at the nontargeted kappa allele, and anergy. Collectively, the data suggest that multiple receptor-tolerogen interactions regulate autoreactive cells in the H + L double-transgenic mice. Generation of H + LL triple-transgenic mice homozygous for the targeted L chain to exclude secondary kappa rearrangements resulted in profound B cell depletion with absence of mature B cells in the bone marrow. We propose that the primary tolerogen of dual reactive B cells in this model is not ssDNA, but a strongly cross-linking tolerogen, presumably basement membrane laminin, that triggers recombination-activating gene activity, L chain editing, and deletion.

Authors
Brady, GF; Congdon, KL; Clark, AG; Sackey, FNA; Rudolph, EH; Radic, MZ; Foster, MH
MLA Citation
Brady, GF, Congdon, KL, Clark, AG, Sackey, FNA, Rudolph, EH, Radic, MZ, and Foster, MH. "Kappa editing rescues autoreactive B cells destined for deletion in mice transgenic for a dual specific anti-laminin Ig." J Immunol 172.9 (May 1, 2004): 5313-5321.
PMID
15100270
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
172
Issue
9
Publish Date
2004
Start Page
5313
End Page
5321

κ Editing Rescues Autoreactive B Cells Destined for Deletion in Mice Transgenic for a Dual Specific Anti-Laminin Ig

We explored mechanisms involved in B cell self-tolerance in a double- and triple-transgenic mouse model bearing the LamH-Cμ Ig H chain conventional transgene and a gene-targeted replacement for a functional Vκ8Jκ5 L chain gene. Whereas the H chain is known to generate anti-laminin Ig in combination with multiple L chains, the H + L Ig binds ssDNA in addition to laminin. Immune phenotyping indicates that H + L transgenic B cells are regulated by clonal deletion, receptor editing via secondary rearrangements at the nontargeted κ allele, and anergy. Collectively, the data suggest that multiple receptor-tolerogen interactions regulate autoreactive cells in the H + L double-transgenic mice. Generation of H + LL triple-transgenic mice homozygous for the targeted L chain to exclude secondary κ rearrangements resulted in profound B cell depletion with absence of mature B cells in the bone marrow. We propose that the primary tolerogen of dual reactive B cells in this model is not ssDNA, but a strongly cross-linking tolerogen, presumably basement membrane laminin, that triggers recombination-activating gene activity, L chain editing, and deletion.

Authors
Brady, GF; Congdon, KL; Clark, AG; Sackey, FNA; Rudolph, EH; Radic, MZ; Foster, MH
MLA Citation
Brady, GF, Congdon, KL, Clark, AG, Sackey, FNA, Rudolph, EH, Radic, MZ, and Foster, MH. "κ Editing Rescues Autoreactive B Cells Destined for Deletion in Mice Transgenic for a Dual Specific Anti-Laminin Ig." Journal of Immunology 172.9 (2004): 5313-5321.
Source
scival
Published In
Journal of Immunology
Volume
172
Issue
9
Publish Date
2004
Start Page
5313
End Page
5321

Taking HAART in HIVAN: Will protease inhibitor sparing regimens alter renal outcome?

Authors
Foster, MH
MLA Citation
Foster, MH. "Taking HAART in HIVAN: Will protease inhibitor sparing regimens alter renal outcome?." Kidney International 65.3 (2004): 1105-1106.
PMID
14871432
Source
scival
Published In
Kidney International
Volume
65
Issue
3
Publish Date
2004
Start Page
1105
End Page
1106
DOI
10.1111/j.1523-1755.2004.00527.x

Tracking immune tolerance in autoimmune susceptible mice.

Authors
Brady, GF; Mixon, GT; Clark, AG; Foster, MH
MLA Citation
Brady, GF, Mixon, GT, Clark, AG, and Foster, MH. "Tracking immune tolerance in autoimmune susceptible mice." November 2003.
Source
wos-lite
Published In
Journal of the American Society of Nephrology : JASN
Volume
14
Publish Date
2003
Start Page
383A
End Page
383A

Unique gene expression patterns in MRL and B6 tolerant B cells revealed by microarray

Authors
Foster, MH; Brady, GF; Lobenhofer, EK; Clark, AG
MLA Citation
Foster, MH, Brady, GF, Lobenhofer, EK, and Clark, AG. "Unique gene expression patterns in MRL and B6 tolerant B cells revealed by microarray." April 14, 2003.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
17
Issue
7
Publish Date
2003
Start Page
C180
End Page
C180

Dissecting the biochemical basis of tolerance: Role for differential activation of MAPKs, NF-kB and NFAT.

Authors
Sackey, FN; Foster, MH
MLA Citation
Sackey, FN, and Foster, MH. "Dissecting the biochemical basis of tolerance: Role for differential activation of MAPKs, NF-kB and NFAT." JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 13 (September 2002): 346A-346A.
Source
wos-lite
Published In
Journal of the American Society of Nephrology : JASN
Volume
13
Publish Date
2002
Start Page
346A
End Page
346A

Defining immune tolerance through gene expression profiling.

Authors
Clark, AG; Brady, GF; Sackey, FN; Foster, MH
MLA Citation
Clark, AG, Brady, GF, Sackey, FN, and Foster, MH. "Defining immune tolerance through gene expression profiling." JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 13 (September 2002): 348A-348A.
Source
wos-lite
Published In
Journal of the American Society of Nephrology : JASN
Volume
13
Publish Date
2002
Start Page
348A
End Page
348A

Complex tolerance phenotypes induced by lupus autoantigens.

Authors
Congdon, KC; Brady, GF; Foster, MH
MLA Citation
Congdon, KC, Brady, GF, and Foster, MH. "Complex tolerance phenotypes induced by lupus autoantigens." JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 13 (September 2002): 171A-171A.
Source
wos-lite
Published In
Journal of the American Society of Nephrology : JASN
Volume
13
Publish Date
2002
Start Page
171A
End Page
171A

Humoral autoimmunity to basement membrane antigens is regulated in C57BL/6 and MRL/MpJ mice transgenic for anti-laminin Ig receptors.

Basement membrane proteins are targeted in organ-limited and systemic autoimmune nephritis, yet little is known about the origin or regulation of immunity to these complex extracellular matrices. We used mice transgenic for a nephrotropic systemic lupus erythematosus (SLE) Ig H chain to test the hypothesis that humoral immunity to basement membrane is actively regulated. The LamH-Cmu Ig H chain transgene combines with diverse L chains to produce nephrotropic Ig reactive with murine laminin alpha1. To determine the fate of transgene-bearing B cells in vivo, transgenic mice were outcrossed onto nonautoimmune B6 and SLE-prone MRL backgrounds and exposed to potent mitogen or Ag in adjuvant. In this work we demonstrate that transgenic autoantibodies are absent in serum from M6 and M29 lineage transgenic mice and transgenic B cells hypoproliferate and fail to increase Ig production upon exposure to endotoxin or when subjected to B cell receptor cross-linking. Administration of LPS or immunization with autologous or heterologous laminin, maneuvers that induce nonoverlapping endogenous anti-laminin IgG responses, fails to induce a transgenic anti-laminin response. The marked reduction in splenic B cell number suggests that selected LamH-Cmu H chain and endogenous L chain combinations generate autospecificities that lead to B cell deletion. It thus appears that SLE-like anti-laminin B cells have access to and engage a tolerizing self-Ag in vivo. Failure to induce autoimmunity by global perturbations in immune regulation introduced by the MRL autoimmune background and exposure to potent environmental challenge suggests that humoral immunity to nephritogenic basement membrane epitopes targeted in systemic autoimmunity is tightly regulated.

Authors
Rudolph, EH; Congdon, KL; Sackey, FNA; Fitzsimons, MM; Foster, MH
MLA Citation
Rudolph, EH, Congdon, KL, Sackey, FNA, Fitzsimons, MM, and Foster, MH. "Humoral autoimmunity to basement membrane antigens is regulated in C57BL/6 and MRL/MpJ mice transgenic for anti-laminin Ig receptors." J Immunol 168.11 (June 1, 2002): 5943-5953.
PMID
12023401
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
168
Issue
11
Publish Date
2002
Start Page
5943
End Page
5953

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-Cμ, resulted in secretion of intact Ig pairing 238H-Cμ with a lambda L chain; however, transfectant Ig lacked autoreactivity and pathogenicity. Introduction of the 238H-Cμ H chain as a transgene onto the non-autoimmune C57BL/6 background resulted in abundant B cell surface expression of 238H-Cμ, however, four transgenic Ig recovered by fusion of LPS-stimulated splenocytes and formed by combination of 238H-Cμ 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-Cμ transgenic model should prove useful in dissecting the in vivo fate of 238H-Cμ-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, BG, Rahman, MM, Rudolph, EH, and Foster, MH. "In vitro and in vivo expression of a nephritogenic Ig heavy chain determinant: Pathogenic autoreactivity requires permissive light chains." Immunology and Cell Biology 79.3 (2001): 222-230.
PMID
11380674
Source
scival
Published In
Immunology and cell biology
Volume
79
Issue
3
Publish Date
2001
Start Page
222
End Page
230
DOI
10.1046/j.1440-1711.2001.01001.x

Diverse endogenous light chains contribute to basement membrane reactivity in nonautoimmune mice transgenic for an anti-laminin Ig heavy chain

Basement membrane proteins are targeted in a variety of pathologic autoimmune responses, yet little is known regarding the origins and regulation of this subset of pathogenic lymphocytes. To examine the generation and fate of B cells reactive with a matrix autoantigen, nonautoimmune C57BL/6 mice were rendered transgenic for a nephrotropic lupus anti-laminin immunoglobulin (Ig) H chain, termed LamH-Cμ. We previously reported recovery of two distinct phenotypes among LamH-Cμ-transgenic mice: progeny of founders M6 and M29 contained abundant transgene-expressing B cells but little anti-laminin Ig, whereas spontaneous autoreactivity was readily recovered from the M7 lineage that expressed minimal B-cell mIgM. To explore the spectrum of autoreactivity generated in vivo by different LamH-Cμ-endogenous L-chain combinations, we determined in vitro and in vivo antigen reactivity and L-chain V-region sequences of 17 LamH-Cμ-transgenic anti-laminin Igs. The results reveal a heterogeneous population of anti-laminin Igs with different fine specificities encoded by diverse endogenous L chains, encompassing nine different Vk gene families, 11 Vk genes, and three Jk genes. Many of the L chains are identical to known or putative unmutated germline Vk genes used to encode Igs reactive with self and foreign antigens in nonautoimmune and genetically autoimmune-prone mouse strains. These observations confirm that the LamH-Cμ H chain plays a dominant role in determining anti-laminin reactivity, and indicate that nonautoimmune B6 mice are fully capable of generating a diverse pool of basement-membrane-reactive B cells using unmutated Ig genes. When interpreted in the context of the divergent M61M29 and M7 transgenic mouse phenotypes, our findings further suggest that these matrix-reactive lymphocytes are not spontaneously activated in vivo under normal circumstances.

Authors
Fitzsimons, MM; Chen, H; Foster, MH
MLA Citation
Fitzsimons, MM, Chen, H, and Foster, MH. "Diverse endogenous light chains contribute to basement membrane reactivity in nonautoimmune mice transgenic for an anti-laminin Ig heavy chain." Immunogenetics 51.1 (2000): 20-29.
PMID
10663558
Source
scival
Published In
Immunogenetics
Volume
51
Issue
1
Publish Date
2000
Start Page
20
End Page
29

Chronic salicylism resulting in noncardiogenic pulmonary edema requiring hemodialysis.

Salicylate intoxication is frequently overlooked as a cause of noncardiogenic pulmonary edema and altered mental status in adult patients. We describe a 42-year-old woman who presented with two episodes of recurrent noncardiogenic pulmonary edema requiring intubation. The first admission to hospital triggered an extensive initial workup that did not indicate a cause for the pulmonary edema. At the second presentation, recognition of the clinical syndrome in the emergency department led to the correct diagnosis of salicylate intoxication. The patient was successfully treated with hemodialysis and urinary alkalinization, leading to rapid resolution of pulmonary edema and extubation. Several aspects of the clinical presentation suggest that the patient suffers from chronic salicylism, probably complicated by episodic superimposed acute intoxication, a condition often misdiagnosed or diagnosed late in the course of disease, contributing to substantial morbidity and mortality in these patients. Maintenance of a high index of suspicion and rapid institution of appropriate therapy including hemodialysis once the diagnosis is established is an important determinant of outcome in this serious but underdiagnosed disorder.

Authors
Cohen, DL; Post, J; Ferroggiaro, AA; Perrone, J; Foster, MH
MLA Citation
Cohen, DL, Post, J, Ferroggiaro, AA, Perrone, J, and Foster, MH. "Chronic salicylism resulting in noncardiogenic pulmonary edema requiring hemodialysis." American journal of kidney diseases : the official journal of the National Kidney Foundation 36.3 (2000): E20-.
PMID
10977813
Source
scival
Published In
American journal of kidney diseases : the official journal of the National Kidney Foundation
Volume
36
Issue
3
Publish Date
2000
Start Page
E20

Lupus nephritis: update on pathogenesis and disease mechanisms.

Immune-mediated nephritis is a common complication of systemic lupus erythematosus (SLE). It is now clear that multiple and independent mechanisms contribute to disease onset and pathogenesis, which may explain the remarkable phenotypic and histopathological heterogeneity observed in human SLE. Identification and characterization of disease-relevant autoantibodies, cellular effectors, and soluble immune elements have provided crucial insight into the immunologic interactions that promote renal immune injury. It is now clear that nephritogenic autoantibodies of diverse specificity localize to the kidney by a variety of mechanisms. They are accompanied by activated macrophages and T cells recruited in part through enhanced and abnormal production of macrophage growth factors and cytokines. These pathways provide novel targets for therapeutic intervention to prevent or ameliorate the aggressive autoimmune nephritis that characterizes SLE.

Authors
Foster, MH; Kelley, VR
MLA Citation
Foster, MH, and Kelley, VR. "Lupus nephritis: update on pathogenesis and disease mechanisms." Semin Nephrol 19.2 (March 1999): 173-181. (Review)
PMID
10192250
Source
pubmed
Published In
Seminars in Nephrology
Volume
19
Issue
2
Publish Date
1999
Start Page
173
End Page
181

Membranoproliferative glomerulonephritis type I, mixed cryoglobulinemia and lymphoma in the absence of hepatitis C infection

Chronic hepatitis C virus infection has been linked to cryoglobulinemia, membranoproliferative glomerulonephritis, and malignant B-cell lymphoproliferation, suggesting a possible pathogenetic link between these disorders. We report a patient with the latter clinical triad in the absence of hepatitis C infection. We postulate that the persistent and dysregulated immunologic activity associated with chronic antigen stimulation, inflammation and/or B-cell malignancy induces nephritogenic autoantibodies, including cryoglobulins, that produce a similar clinical syndrome in genetically susceptible individuals.

Authors
Rosas, SE; Tomaszewski, JE; Feldman, HI; Foster, MH
MLA Citation
Rosas, SE, Tomaszewski, JE, Feldman, HI, and Foster, MH. "Membranoproliferative glomerulonephritis type I, mixed cryoglobulinemia and lymphoma in the absence of hepatitis C infection." American Journal of Nephrology 19.5 (1999): 599-604.
PMID
10575191
Source
scival
Published In
American journal of nephrology
Volume
19
Issue
5
Publish Date
1999
Start Page
599
End Page
604

Antiidiotypic antibody recognizes an amiloride binding domain within the α subunit of the epithelial Na+ channel

We previously raised an antibody (RA6.3) by an antiidiotypic approach which was designed to be directed against an amiloride binding domain on the epithelial Na+ channel (ENaC). This antibody mimicked amiloride in that it inhibited transepithelial Na+ transport across A6 cell monolayers. RA6.3 recognized a 72-kDa polypeptide in A6 epithelia treated with tunicamycin, consistent with the size of nonglycosylated Xenopus laevis αENaC. RA6.3 specifically recognized an amiloride binding domain within the α-subunit of mouse and bovine ENaC. The deduced amino acid sequence of RA6.3 was used to generate a three-dimensional model structure of the antibody. The combining site of RA6.3 was epitope mapped using a novel computer-based strategy. Organic residues that potentially interact with the RA6.3 combining site were identified by data base screening using the program LUDI. Selected residues docked to the antibody in a manner corresponding to the ordered linear array of amino acid residues within an amiloride binding domain on the α-subunit of ENaC. A synthetic peptide spanning this domain inhibited the binding of RA6.3 to αENaC. This analysis provided a novel approach to develop models of antibody-antigen interaction as well as a molecular perspective of RA6.3 binding to an amiloride binding domain within αENaC.

Authors
Kieber-Emmons, T; Lin, C; Foster, MH; Kleyman, TR
MLA Citation
Kieber-Emmons, T, Lin, C, Foster, MH, and Kleyman, TR. "Antiidiotypic antibody recognizes an amiloride binding domain within the α subunit of the epithelial Na+ channel." Journal of Biological Chemistry 274.14 (1999): 9648-9655.
PMID
10092651
Source
scival
Published In
The Journal of biological chemistry
Volume
274
Issue
14
Publish Date
1999
Start Page
9648
End Page
9655
DOI
10.1074/jbc.274.14.9648

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
Foster, MH
MLA Citation
Foster, MH. "Relevance of systemic lupus erythematosus nephritis animal models to human disease." Seminars in Nephrology 19.1 (1999): 12-24.
PMID
9952277
Source
scival
Published In
Seminars in Nephrology
Volume
19
Issue
1
Publish Date
1999
Start Page
12
End Page
24

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, MH, Cooperstone, BG, and Chen, H. "Anti-idiotypic monoclonal Ig specific for an anti-laminin Ig heavy chain transgene variable region." Hybridoma 17.4 (1998): 323-329.
PMID
9790066
Source
scival
Published In
Hybridoma
Volume
17
Issue
4
Publish Date
1998
Start Page
323
End Page
329

Lupus-like nephrotropic autoantibodies in non-autoimmune mice harboring an anti-basement membrane/anti-DNA Ig heavy chain transgene

Autoantibodies target a diverse group of tissue antigens in human and experimental autoimmune nephritis. The proximal events that generate and regulate these various pathogenic Ab remain obscure. To examine the origins and fate in normal mice of autoantibodies reactive with renal basement membrane antigen, we established mice transgenic for an IgM H chain encoding an unmutated nephrotropic V region, termed LamH, derived from an MRL/lpr mouse and directed against basement membrane laminin. We previously demonstrated that in vitro transfectants combining LamH-Cμ with unmutated L chains generate distinct nephrotropic autoantibodies. Herein we report in vivo reconstruction of diverse pathogenic autoreactivity by association of LamH-Cμ with endogenous L chains. Progeny of one founder, termed M7, express a distinct phenotype characterized by minimal B cell mIgM and spontaneous production of LamH-Cμ autoreactivity. Similar Ab were not recovered from two phenotypically distinct transgenic lines expressing abundant transgene mIgM. The results suggest that lupus-like autoantibodies are readily generated in the normal genetic background by random recombinatorial events in the absence of mutation and that these Ab may contribute to disease if normal regulation is disturbed.

Authors
Foster, MH; Fitzsimons, MM
MLA Citation
Foster, MH, and Fitzsimons, MM. "Lupus-like nephrotropic autoantibodies in non-autoimmune mice harboring an anti-basement membrane/anti-DNA Ig heavy chain transgene." Molecular Immunology 35.2 (1998): 83-94.
PMID
9683254
Source
scival
Published In
Molecular Immunology
Volume
35
Issue
2
Publish Date
1998
Start Page
83
End Page
94
DOI
10.1016/S0161-5890(98)00018-2

The nephritogenic immune response.

Recent insights into the etiopathogenesis of nephritogenic immune responses are derived primarily from experimental models of systemic and organ-specific autoimmunity. Genetic analyses and immune-related gene ablation studies indicate that multiple independent mechanisms determine disease susceptibility. However, full characterization of proximal immunologic events in many diseases awaits identification of the renal antigens recognized by nephritogenic lymphocytes. Advances in characterization of effector mechanisms include epitope mapping of several putative pathogenic glomerular antigens and identification of novel pathways of immune-mediated tissue injury, including those involved in glomerular-tubulointerstitial communication and tubulointerstitial fibrosis. Finally, successful interruption of signal transduction pathways and transforming growth factor-beta 1 blockade by gene therapy suggest novel approaches to therapeutic intervention in immunologic renal injury.

Authors
Fitzsimons, MM; Foster, MH
MLA Citation
Fitzsimons, MM, and Foster, MH. "The nephritogenic immune response." Curr Opin Nephrol Hypertens 6.3 (May 1997): 267-275. (Review)
PMID
9263670
Source
pubmed
Published In
Current Opinion in Nephrology and Hypertension
Volume
6
Issue
3
Publish Date
1997
Start Page
267
End Page
275

Anti-laminin reactivity and glomerular immune deposition by in vitro recombinant antibodies

Growing evidence suggests that recombinatorial events prior to antigen contact can generate pathogenic autoantibodies in the nonautoimmune individual, thus providing potential disease mediators if conditions arise that permit bypass of tolerance and activation of autoreactive lymphocytes. To examine the disease potential of selected germline antibody genes, Ig were created de novo by in vitro recombination of Ig H and L chains. H chain loss variant (i.e., L-chain only) cell lines were transfected with a DNA construct encoding the variable region and regulatory sequences (LamH) of a nephrotropic murine lupus anti-laminin Ig, and the resultant Ig were examined for in vitro antigen reactivity and in vivo glomerular immune deposition. The results indicate that two light chains, LamL (Vk8, Jk5) and 238L (Vk4, Jk5), expressing unrelated germline V1 genes, combine with LamH to generate Ig that bind basement membrane laminin in vitro, diverge in their capacity to bind ssDNA, and produce two distinct patterns of glomerular immune deposits in vivo: dense mesangial matrix (LamH/LamL) and dramatic linear glomerular basement membrane (LamH/238L) deposits. The Ig genes used by both LamH and 238L are present in nonautoimmune mice as well as in lupus-prone strains. We conclude that certain unmutated Ig genes can contribute to multiple distinct disease associated specificities, including binding to intrinsic kidney antigens, and that mutation is not essential to generate these Ig. Collectively, these observations suggest that pathogenic autoantibodies can be generated in the normal preimmune repertoire by random recombinatorial and somatic events in the absence of mutation.

Authors
Foster, MH; Liu, Q; Chen, H; Nemazee, D; Cooperstone, BG
MLA Citation
Foster, MH, Liu, Q, Chen, H, Nemazee, D, and Cooperstone, BG. "Anti-laminin reactivity and glomerular immune deposition by in vitro recombinant antibodies." Autoimmunity 26.4 (1997): 231-243.
PMID
9543184
Source
scival
Published In
Autoimmunity (Informa)
Volume
26
Issue
4
Publish Date
1997
Start Page
231
End Page
243

Structural features of nephritogenic lupus autoantibodies

We have identified monoclonal antibodies derived from MRL-Ipr/Ipr lupus-prone mice that produced nephritis after passive transfer to normal mice. Our present goal was to elucidate the structural and immunochemical features of nephritogenic Ig that facilitate immune deposition. For this purpose the antigen binding properties, capacity to form immune deposits, and nucleotide sequence of a genetically related autoantibody subgroup were compared. The prototype, H147 (an IgG encoded by 7183/81X VH gene), produced glomerular and tubular basement membrane, mesangial immune deposits, and proliferative glomerulonephritis after passive transfer to normal mice. For comparison three other 7183/81X encoded anti-DNA IgG (H257, H171, and H8a) were evaluated (predicted heavy chain aa homology > 75%). H257 produced similar types of immune deposits as H147, and this was associated with nephritis; H8a produced predominantly mesangial deposits, whereas H171 did not produce significant deposits. Although their antigen binding profile to a panel of soluble autoantigens was variable, only H147 and H257 bound to both mesangial and aortic endothelial cell surfaces. V gene sequence analysis of the IgG suggests that individual residues, motifs, and conformations influence the autoantigen binding specificities that contributed to the observed differences in immune deposit formation.

Authors
Vargas, MT; Gustilo, K; D'Andrea, DM; Kalluri, R; Foster, MH; Madaio, MP
MLA Citation
Vargas, MT, Gustilo, K, D'Andrea, DM, Kalluri, R, Foster, MH, and Madaio, MP. "Structural features of nephritogenic lupus autoantibodies." Methods: A Companion to Methods in Enzymology 11.1 (1997): 62-69.
PMID
8990090
Source
scival
Published In
Methods
Volume
11
Issue
1
Publish Date
1997
Start Page
62
End Page
69
DOI
10.1006/meth.1996.0388

Nuclear localization of autoantibodies. Novel insights into protein translocation and cellular function

Authors
Madaio, MP; Yanase, K; Foster, MH; Smith, RM; Emmons, TK; Fabbi, M; Puccetti, A; Jarett, L
MLA Citation
Madaio, MP, Yanase, K, Foster, MH, Smith, RM, Emmons, TK, Fabbi, M, Puccetti, A, and Jarett, L. "Nuclear localization of autoantibodies. Novel insights into protein translocation and cellular function." Annals of the New York Academy of Sciences 815 (1997): 263-266.
PMID
9186663
Source
scival
Published In
Annals of the New York Academy of Sciences
Volume
815
Publish Date
1997
Start Page
263
End Page
266
DOI
10.1111/j.1749-6632.1997.tb52068.x

Lupus autoantibodies interact directly with distinct glomerular and vascular cell surface antigens

We have identified monoclonal anti-DNA antibodies derived from lupus prone MRL-lpr/lpr mice that produce glomerular immune deposits and nephritis after passive transfer to normal mice. Particularly noteworthy is that the location of immune deposition varied among nephritogenic Ig, and this was associated with distinctive histologies and clinical disease profiles. Although their autoantigen binding properties differed, they were highly cross-reactive, in a manner similar to Ig deposited in glomeruli of lupus mice. This antigen binding profile was also typical of other previously described nephritogenic autoantibodies that bound directly to glomerular antigens to initiate immune deposit formation. In this study, we questioned whether ligation of different glomerular antigens by individual autoantibodies could contribute to the observed differences in the location of immune deposits. To examine this possibility, monoclonal anti-DNA antibodies (IgG2a) that produced glomerular immune deposits in different locations were evaluated. H221 produced mesangial, intracapillary (that is, intraluminal or within the capillary lumen) and subendothelial deposits associated with heavy proteinuria, whereas H147 produced mesangial, subendothelial and linear basement membrane deposits associated with proliferative glomerulonephritis. Initially, the capacity of H221 and H147 to bind directly to glomerular and vascular cell surfaces was evaluated. As demonstrated by FACS, H221 bound preferentially to mesangial cells whereas H147 bound preferentially to endothelial cells. To identify possible target cell surface antigens, Western blots, immunoprecipitation of surface labeled cells, and 2D gel electrophoresis were employed. H221 reacted with a 108 kDa protein on mesangial cells not identified by H147, whereas H147 reacted with a 45 kDa protein on endothelial cells not identified by H221. These results support the hypothesis that some nephritogenic lupus autoantibodies initiate immune deposit formation through direct interaction with glomerular antigens. Furthermore, they suggest that the site of immune deposition is determined by both antigen binding properties of the relevant antibody and the location of its target ligand within the glomerulus. In a given individual, therefore, the predominant autoantibody glomerular antigen interaction may influence the morphologic and clinical phenotype expressed. Variation in the predominant interaction may also contribute to variations in disease expression among individuals with lupus nephritis.

Authors
D'Andrea, DM; Coupaye-Gerard, B; Kleyman, TR; Foster, MH; Madaio, MP
MLA Citation
D'Andrea, DM, Coupaye-Gerard, B, Kleyman, TR, Foster, MH, and Madaio, MP. "Lupus autoantibodies interact directly with distinct glomerular and vascular cell surface antigens." Kidney International 49.5 (1996): 1214-1221.
PMID
8731084
Source
scival
Published In
Kidney international
Volume
49
Issue
5
Publish Date
1996
Start Page
1214
End Page
1221

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, MH, Kieber-Emmons, T, Ohliger, M, and Madaio, MP. "Molecular and structural analysis of nuclear localizing anti-DNA lupus antibodies." Immunol Res 13.2-3 (1994): 186-206.
PMID
7775809
Source
pubmed
Published In
Immunologic Research
Volume
13
Issue
2-3
Publish Date
1994
Start Page
186
End Page
206

Topology of an amiloride-binding protein

Amiloride and structurally related compounds inhibit many transport proteins, enzymes, and drug or hormone receptors, although the topology of amiloride binding sites on these proteins has not been defined. We have previously raised and characterized a monoclonal anti-amiloride antibody (mAb BA7.1) which is similar to epithelial Na+ channels in its specificity of binding of amiloride and amiloride analogs, suggesting that their amiloride binding sites may be similar in topology. mAb BA7.1 was used as a model system to analyze the three-dimensional conformation of an amiloride binding site. The photoactive amiloride analog 2'-methoxy-5'-nitrobenzamil specifically labeled the heavy chain of mAb BA7.1, suggesting that the heavy chain participates in amiloride binding. The nucleotide sequences of the variable regions of the heavy and light chains of mAb BA7.1 were determined and amino acid sequences deduced to analyze the structure of the amiloride binding site. A comparative modeling approach was used to construct a model of the amiloride binding domain of mAb BA7.1, and a docking procedure was used to place amiloride within this domain. The model indicated that planar aromatic amino acid residues form a pocket into which amiloride, a planar molecule, inserts. Constraints on amiloride binding predicted by this model correlated with the measured specificity of binding of amiloride analogs with mAb BA7.1. These results provide a potential guide for the identification of motifs or amino acid contact residues present within other amiloride- sensitive proteins.

Authors
Lin, C; Kieber-Emmons, T; Villalobos, AP; Foster, MH; Wahlgren, C; Kleyman, TR
MLA Citation
Lin, C, Kieber-Emmons, T, Villalobos, AP, Foster, MH, Wahlgren, C, and Kleyman, TR. "Topology of an amiloride-binding protein." Journal of Biological Chemistry 269.4 (1994): 2805-2813.
PMID
8300613
Source
scival
Published In
The Journal of biological chemistry
Volume
269
Issue
4
Publish Date
1994
Start Page
2805
End Page
2813

Structural properties of a subset of nephritogenic anti-DNA antibodies

Structural analysis of lupus autoantibodies is beginning to provide clues to the molecular basis for antigenic specificity and pathogenicity. The present analysis indicates that multiple light and heavy chains contain residues which can facilitate DNA binding, reaffirming the notion that there are multiple ways that different amino acids combine to form an antigen-binding pocket with affinity for dsDNA and ssDNA. Furthermore, this analysis suggests that these conformations and contact residues are intrinsic to germline sequences, although amino acid changes at critical locations (somatically introduced) modulate antigen binding, and appear to influence the capacity of individual immunoglobulin to form immune deposits. Analysis of additional individual immunoglobulins with closely related V-region sequences and differing pathogenic properties will be required to resolve the contribution of specific motifs to pathogenecity. © 1994 Humana Press Inc.

Authors
Kieber-Emmons, T; Foster, MH; Williams, WV; Madaio, MP
MLA Citation
Kieber-Emmons, T, Foster, MH, Williams, WV, and Madaio, MP. "Structural properties of a subset of nephritogenic anti-DNA antibodies." Immunologic Research 13.2-3 (1994): 172-185.
PMID
7775808
Source
scival
Published In
Immunologic Research
Volume
13
Issue
2-3
Publish Date
1994
Start Page
172
End Page
185
DOI
10.1007/BF02918278

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; Cizman, B; Foster, MH; Peachey, LD; Jarett, L; Madaio, MP
MLA Citation
Yanase, K, Smith, RM, Cizman, B, Foster, MH, Peachey, LD, Jarett, L, and Madaio, MP. "A subgroup of murine monoclonal anti-deoxyribonucleic acid antibodies traverse the cytoplasm and enter the nucleus in a time- and temperature- dependent manner." Laboratory Investigation 71.1 (1994): 52-60.
PMID
8041118
Source
scival
Published In
Laboratory Investigation
Volume
71
Issue
1
Publish Date
1994
Start Page
52
End Page
60

Molecular analysis of spontaneous nephrotropic anti-laminin antibodies in an autoimmune MRL-lpr/lpr mouse.

To explore the genetic relationship between anti-laminin and anti-DNA autoantibodies (autoAb), VH gene and gene family expression were determined among autoAb derived from an individual 6-mo-old MRL-lpr/lpr mouse. Whereas 85% of the anti-DNA Ig were identified by one of two VH family probes, 7183 and VHJ558, none of the anti-laminin antibodies (Ab) examined were recognized by these probes. Subsequent V region sequence analysis of three of the anti-laminin Ab revealed that they in fact utilized a J558 VH gene (VH50). Furthermore, FR2 and CDR2 oligonucleotide probes complementary to VH50 recognized multiple anti-laminin Ab by Northern blot analysis; the FR2 probe recognized two control anti-DNA Ab, but neither probe recognized anti-DNA Ab from the same mouse. Polymerase chain reaction amplification of MRL-lpr/lpr genomic liver DNA using primers generated from VH50 and Vk50 sequences indicated that all three anti-laminin Ig have a single replacement mutation in both their VH and Vk genes. Search of the nucleic acid databases revealed that both germline VH and Vk genes are expressed unmutated by murine lupus anti-dsDNA autoAb, previously sequenced in other laboratories. Sequence comparisons suggest that differences in anti-DNA and anti-laminin reactivity may be dependent upon somatically generated differences in the CDR3 regions of the H and L chains. The results indicate that lupus anti-laminin Ab can arise from distinct B cell populations but express the same unmutated germline V region genes as lupus anti-dsDNA autoAb. They further raise the possibility that these distinct B cell populations may be activated and expanded either: independently, by distinct Ig receptor ligands such as the Ag, laminin and DNA; or simultaneously, by a common ligand such as an anti-Id recognizing a common V region epitope.

Authors
Foster, MH; Sabbaga, J; Line, SR; Thompson, KS; Barrett, KJ; Madaio, MP
MLA Citation
Foster, MH, Sabbaga, J, Line, SR, Thompson, KS, Barrett, KJ, and Madaio, MP. "Molecular analysis of spontaneous nephrotropic anti-laminin antibodies in an autoimmune MRL-lpr/lpr mouse." J Immunol 151.2 (July 15, 1993): 814-824.
PMID
8335911
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
151
Issue
2
Publish Date
1993
Start Page
814
End Page
824

Independently derived murine glomerular immune deposit-forming anti-DNA antibodies are encoded by near-identical VH gene sequences.

To examine the influence of variable region sequences on the capacity of individual lupus autoantibodies (autoAb) to form glomerular immune deposits, the complete VH and VL region sequences of three anti-DNA mAb that produced morphologically similar immune deposits after administration to normal mice were determined. The Ig were independently derived from 1-mo-old (H238, IgM), 3-mo-old (H8, IgG2a), and 6-mo-old (H161, IgG3) MRL-lpr/lpr mice, and they all produced subendothelial and mesangial immune deposits after passive transfer to normal mice. In addition, H238 and H161 produced granular deposits in small extraglomerular vessels. The mAb had nearly identical VH gene sequences; H8 differed from H238 and H161 by a single nucleotide in FR1 that resulted in a histidine for glutamine substitution. This VH gene sequence was also > 99% homologous to another anti-DNA Ab (termed H241), that we previously reported to produce glomerular immune deposits in a similar morphologic pattern. H161 and H238 were encoded by DFL16 and JH2 genes, whereas H8 was encoded by a JH4 gene. Different Vk family genes were used to encode the three mAb, however H161 and H238 both used a Jk5 gene. The results indicate that an identical or highly related VH gene is used to encode a subgroup of murine lupus autoAb that share immune deposit forming properties. Furthermore, they raise the possibility that amino acid residues independent from those encoded by VH genes may be influential in immune deposit formation at extraglomerular sites.

Authors
Katz, MS; Foster, MH; Madaio, MP
MLA Citation
Katz, MS, Foster, MH, and Madaio, MP. "Independently derived murine glomerular immune deposit-forming anti-DNA antibodies are encoded by near-identical VH gene sequences." J Clin Invest 91.2 (February 1993): 402-408.
PMID
8432848
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
91
Issue
2
Publish Date
1993
Start Page
402
End Page
408
DOI
10.1172/JCI116214

Nephritogenic autoantibodies in systemic lupus erythematosus: Immunochemical properties, mechanisms of immune deposition, and genetic origins

Authors
Foster, MH; Cizman, B; Madaio, MP
MLA Citation
Foster, MH, Cizman, B, and Madaio, MP. "Nephritogenic autoantibodies in systemic lupus erythematosus: Immunochemical properties, mechanisms of immune deposition, and genetic origins." Laboratory Investigation 69.5 (1993): 494-507.
PMID
8246442
Source
scival
Published In
Laboratory Investigation
Volume
69
Issue
5
Publish Date
1993
Start Page
494
End Page
507

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, DV, Foster, MH, Adams, S, Katz, M, Ucci, AA, Barrett, KJ, Datta, SK, and Madaio, MP. "Anti-DNA antibodies form immune deposits at distinct glomerular and vascular sites." Kidney Int 41.6 (June 1992): 1690-1700.
PMID
1501424
Source
pubmed
Published In
Kidney international
Volume
41
Issue
6
Publish Date
1992
Start Page
1690
End Page
1700

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
Vlahakos, D, Foster, MH, Ucci, AA, Barrett, KJ, Datta, SK, and Madaio, MP. "Murine monoclonal anti-DNA antibodies penetrate cells, bind to nuclei, and induce glomerular proliferation and proteinuria in vivo." J Am Soc Nephrol 2.8 (February 1992): 1345-1354.
PMID
1627759
Source
pubmed
Published In
Journal of the American Society of Nephrology : JASN
Volume
2
Issue
8
Publish Date
1992
Start Page
1345
End Page
1354

Variable region sequence analysis of anti-DNA antibodies: Evidence for a family of closely related germ-line V(H) genes encoding lupus autoantibodies

Cloning and sequencing of the V regions of the anti-DNA monoclonal antibodies (mAbs), H438 and H130, indicate that H438 is encoded by a J558 V(H) gene, a single D region nucleotide, and unmutated J(H)1, V(χ)-1C and J(χ)1 genes, and the H130 L chain is encoded by a V(χ)-21 subgroup gene and J(χ)1 gene. Identification of V(H)438, which shared V(H) hybridization pattern with 6% of a panel of 352 MRL/lpr hybridomas, suggests that the frequency of J558 use among spontaneously activated B cells in MRL/lpr mice is greater than previously reported. The V(H)H438 J558 family gene is identical to V(H)PAR, which encodes the independently derived MRL/lpr autoantibody, MRP-2, and is highly homologous to the previously reported V(H)H130, which is identical to a BALB/c germ-line V(H) gene. Comparison of consensus sequences of homologous autoantibodies and previously reported restriction mapping suggest that a minimum of three highly related J558 germ- line genes encode lupus autoantibodies.

Authors
Foster, MH; Madaio, MP; Barrett, KJ
MLA Citation
Foster, MH, Madaio, MP, and Barrett, KJ. "Variable region sequence analysis of anti-DNA antibodies: Evidence for a family of closely related germ-line V(H) genes encoding lupus autoantibodies." DNA and Cell Biology 11.3 (1992): 175-182.
PMID
1567551
Source
scival
Published In
DNA and Cell Biology
Volume
11
Issue
3
Publish Date
1992
Start Page
175
End Page
182

VH gene analysis of spontaneously activated B cells in adult MRL-lpr/lpr mice. J558 bias is not limited to classic lupus autoantibodies.

To determine the genetic origins of lupus auto-antibodies, we analyzed the relationship between VH gene usage and auto-Ag-binding properties of 352 B cell hybridomas derived from MRL-lpr/lpr mice. The hybridomas were derived from neonatal, 1-month-old, 3-month-old, and 6-month-old mice. The experimental strategy provided that the hybridomas were monoclonal at initial evaluation, so the Ag binding and V gene frequencies of the entire population could be determined. Initially, 1032 Ig-producing hybridomas were evaluated for binding to six Ag; VH gene family use was determined in 119 anti-DNA and anti-rabbit thymus extract (RTE) antibodies (autoantibodies) and in 233 age-matched Ig that did not bind to any of the six Ag (nonbinders). Neonatal B cells, including cross-reactive IgM autoantibodies and nonbinder IgM, used relatively 3' VH genes. The majority of B cells in adult mice used VH genes of the J558 family. Although J558 use was significantly higher among the autoantibodies (anti-DNA and anti-RTE) than among the nonbinder Ig, this difference was due to a higher frequency of J558 use by 1-month-old mice. At 3 months, J558 use by the nonbinder Ig increased to the same frequency of J558 use as in the autoantibody population. J558 use in both groups of antibodies exceeded a previously reported estimation of J558 expression in the functional B cell repertoire of young adult MRL-lpr/lpr mice. Several subgroups of antibodies that share properties with pathogenic Ig, including IgG, cross-reactive Ig, and anti-dsDNA autoantibodies, demonstrated a marked preferential expression of the J558 family. These results suggest that there is an age-related bias in the activation of B cells using J558 VH genes in MRL-lpr/lpr mice that is under the influence of a selective force distinct from, or in addition to, an ssDNA or RTE auto-Ag-driven response.

Authors
Foster, MH; MacDonald, M; Barrett, KJ; Madaio, MP
MLA Citation
Foster, MH, MacDonald, M, Barrett, KJ, and Madaio, MP. "VH gene analysis of spontaneously activated B cells in adult MRL-lpr/lpr mice. J558 bias is not limited to classic lupus autoantibodies." J Immunol 147.5 (September 1, 1991): 1504-1511.
PMID
1908876
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
147
Issue
5
Publish Date
1991
Start Page
1504
End Page
1511

Prolonged survival with a remnant kidney

Surgical ablation of five-sixths renal mass in Munich-Wistar rats fed a high protein diet leads to focal sclerosis in the remnant kidney and progressive renal failure. Experimental data suggest that this injury results from intraglomerular hypertension and/or chronic glomerular hyperfiltration. Data in humans largely are limited to patients with unilateral renal agenesis or uninephrectomy, either for unilateral renal disease or for kidney transplant donation. Isolated case reports have documented focal sclerosis and progressive renal failure in two patients with a remnant kidney. To obtain data in humans with a remnant kidney, we surveyed more than 800 urologists and nephrologists in the United States and abroad. Criteria for inclusion in the study were (1) surgical resection (in one or more operations) resulting in the presence of a remnant kidney; and (2) an adequate period of follow-up, defined as 5 years or greater. A total of 13 patients were identified (from 13 different centers). Twelve patients had renal cancer and one had tuberculosis. Six patients were observed for 10 or more years postoperatively and all have stable serum creatinine levels of less than 270 μmol/L (3.0 mg/dL); two of these six patients are now more than 25 and 30 years postoperation. The other seven patients, observed for 5 to 7 years, have serum creatinine levels less than 270 μmol/L (3 mg/dL), while one has an increasing serum creatinine level. The two longest surviving patients both have undergone successful pregnancy with no overall change in serum creatinine. These observations demonstrate that it is possible for humans to survive more than 30 years with a stable serum creatinine, despite the presence of only a remnant kidney.

Authors
Foster, MH; Sant, GR; Donohoe, JF; Harrington, JT
MLA Citation
Foster, MH, Sant, GR, Donohoe, JF, and Harrington, JT. "Prolonged survival with a remnant kidney." American Journal of Kidney Diseases 17.3 (1991): 261-265.
PMID
1996566
Source
scival
Published In
American Journal of Kidney Diseases
Volume
17
Issue
3
Publish Date
1991
Start Page
261
End Page
265
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