The Experts below are selected from a list of 309 Experts worldwide ranked by ideXlab platform
Billy G. Hudson - One of the best experts on this subject based on the ideXlab platform.
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Molecular characteristics of the Goodpasture autoantigen
Kidney International, 2015Co-Authors: Billy G. Hudson, Raghuram Kalluri, Sripad Gunwar, Mariko Mariyama, M E Noelken, Stephen T ReedersAbstract:Molecular characteristics of the Goodpasture autoantigen. Goodpasture Syndrome is an autoimmune disease causing rapidly progressive glomerulonephritis and pulmonary hemorrhage. The clinical manifestations are caused by autoantibodies that bind to a constituent, termed the Goodpasture autoantigen, of alveolar and glomerular basement membranes. Searches for the identity of this constituent have recently culminated in the discovery of two new chains (α3 and α4) of type IV collagen and the identification of the α3 chain as the Goodpasture autoantigen. The gene, COL4A3, encoding this autoantigen was recently cloned and localized to the q35-37 region of chromosome 2. The major protomeric form of the α3 chain is a homotrimer. The ah-protomers associate through NC1-to-NC1 interactions mainly with each other to form a suprastructure, although some associate with protomers containing the α2(IV) and α2(IV) chains. The α3-protomers also form suprastructures involving triple helical interactions of three or more protomers. The Goodpasture epitope is localized to the carboxyl-terminal region of the α3(IV) chain, encompassing the last 36 residues of the chain, as the primary interaction site, and its structure is discontinuous.
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pathogenesis of Goodpasture Syndrome a molecular perspective
Seminars in Nephrology, 2003Co-Authors: Dorin-bogdan Borza, Eric G. Neilson, Billy G. HudsonAbstract:Goodpasture (GP) Syndrome is a form of anti-glomerular basement membrane (GBM) disease, in which autoantibodies bind to alpha3(IV) collagen in GBM causing rapidly progressive glomerulonephritis and pulmonary hemorrhage. The conformational GP epitopes have been mapped to 2 regions within the noncollagenous (NC1) domain of the alpha3(IV) chain. Recently, we described the molecular organization of the autoantigen in the native alpha3alpha4alpha5(IV) collagen network of the GBM. The crystal structure of the NC1 domain has revealed how the GP epitopes are sequestered in the native GBM. Further insight into the pathogenesis of disease has been obtained from better animal models. These advances provide a foundation for the development of new specific therapies.
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Goodpasture Syndrome selective removal of anti α3 iv collagen autoantibodies a potential therapeutic alternative to plasmapheresis
Experimental Nephrology, 1996Co-Authors: Ariel Boutaud, Raghu Kalluri, Tesfamichael Z Kahsai, Milton E Noelken, Billy G. HudsonAbstract:Anti-alpha 3(IV) collagen autoantibodies have been implicated in the pathogenesis of Goodpasture Syndrome, an autoimmune disorder causing glomerulonephritis and pulmonary hemorrhage. Currently treatment involves removal of the entire IgG fraction of plasma by plasmapheresis or adsorption to protein A. The present study shows that the anti-alpha 3(IV)NC1 autoantibodies can be removed from plasma specifically and quantitatively by affinity chromatography utilizing either alpha 3 NC1 domain of bovine type IV collagen or recombinant alpha 3 NC1 domain of human type IV collagen immobilized to agarose beads. This study shows the feasibility of using affinity chromatography, as an alternative to plasmapheresis, to exclusively remove the pathogenic autoantibodies from the plasma of patients with Goodpasture Syndrome.
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identification of the alpha 3 chain of type iv collagen as the common autoantigen in antibasement membrane disease and Goodpasture Syndrome
Journal of The American Society of Nephrology, 1995Co-Authors: Raghu Kalluri, Curtis B Wilson, M Weber, Sripad Gunwar, Arnold M Chonko, E G Neilson, Billy G. HudsonAbstract:Antiglomerular basement membrane (GBM) antibodies can cause glomerulonephritis or pulmonary hemorrhage by themselves or Goodpasture Syndrome when they occur together. It is unknown if variations in antibody reactivity contribute to the different patterns of organ involvement seen in this disease. This study examines the reactivity of the alpha 1-alpha 6 NC1 domains of Type IV collagen, the putative autoantigen, in sera from patients with anti-GBM antibodies after various clinical presentations of lung hemorrhage and renal injury. Serum or plasma containing anti-GBM antibodies from 35 patients with combined glomerulonephritis and pulmonary hemorrhage, 19 with glomerulonephritis alone, and 4 with pulmonary hemorrhage alone were compared with samples from 19 normal controls and 32 patients with other kidney diseases. Four different immunologic assays were performed with bovine alpha 1-alpha 6(IV) and recombinant human type alpha 1-alpha 5(IV) collagen NC1 domains. The study found that the anti-GBM antibodies from all patients reacted with the alpha 3(IV) NC1 (85% exclusively). Additional limited reactivity with the alpha 1(IV) NC1 and alpha 4(IV) NC1 was found in 15 and 3%, respectively. This non-alpha 3(IV) NC1 reactivity was most frequent in the patients with anti-GBM antibodies and glomerulonephritis alone. None of the patients had reactivity to other basement membrane components like laminin, fibronectin, heparan sulfate proteoglycan, entactin, or the 7S and triple helical fragments of Type IV collagen. The observed alpha-chain NC1 reactivity was confined to patients with anti-GBM antibodies with no additional reactivities detected among a large number of other kidney diseases controls. The correlation of alpha 1-alpha 6(IV) NC1 reactivity in a large number of patients with anti-GBM antibodies defined by classic assays definitively establishes that reactivity to alpha 3(IV) NC1 domains is both sufficient and necessary for the expression of autoimmune disease directed to the NC1 domain of Type IV collagen. On the basis of the evidence, the classification of antibasement membrane disease and Goodpasture Syndrome as anti-Type IV collagen disease is proposed.
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the alpha 3 chain of type iv collagen induces autoimmune Goodpasture Syndrome
Proceedings of the National Academy of Sciences of the United States of America, 1994Co-Authors: Raghuram Kalluri, Milton E Noelken, Vincent H Gattone, Billy G. HudsonAbstract:Abstract Human Goodpasture Syndrome is a lethal form of autoimmune disease that is characterized by pulmonary hemorrhage and glomerulonephritis. The tissue injury is mediated by autoantibodies that bind to glomerular and alveolar basement membrane. The target autoantigen is alpha 3(IV) collagen, one of six genetically distinct chains that comprise type IV collagen, and the epitope is sublocalized to the noncollagenous domain (NC1) of the alpha 3 chain. The present study reports the unique capacity of alpha 3(IV)NC1 dimer from bovine kidney to aberrantly engage the immune system of rabbits to respond to self, mimicking the organ-specific form of the human disease, whereas the other chains of type IV collagen are nonpathogenic. However, alpha 3(IV)NC1 hexamer was nonpathogenic, suggesting the exposure of a pathogenic epitope upon dissociation of hexamer into dimers. Exposure of the pathogenic epitope by infection or organic solvents, events which are thought to precede Goodpasture Syndrome, may be the principal factor in the etiology of the disease. The pathogenicity of alpha 3(IV) collagen brings full circle a decade of research that has identified four novel chains (alpha 3-alpha 6) of type IV collagen.
Mahin D Maines - One of the best experts on this subject based on the ideXlab platform.
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human biliverdin reductase suppresses Goodpasture antigen binding protein gpbp kinase activity the reductase regulates tumor necrosis factor α nf κb dependent gpbp expression
Journal of Biological Chemistry, 2010Co-Authors: Tihomir Miralem, Juan Saus, Peter E M Gibbs, Fernando Revert, Mahin D MainesAbstract:The Ser/Thr/Tyr kinase activity of human biliverdin reductase (hBVR) and the expression of Goodpasture antigen-binding protein (GPBP), a nonconventional Ser/Thr kinase for the type IV collagen of basement membrane, are regulated by tumor necrosis factor (TNF-α). The pro-inflammatory cytokine stimulates kinase activity of hBVR and activates NF-κB, a transcriptional regulator of GPBP mRNA. Increased GPBP activity is associated with several autoimmune conditions, including Goodpasture Syndrome. Here we show that in HEK293A cells hBVR binds to GPBP and down-regulates its TNF-α-stimulated kinase activity; this was not due to a decrease in GPBP expression. Findings with small interfering RNA to hBVR and to the p65 regulatory subunit of NF-κB show the hBVR role in the initial stimulation of GPBP expression by TNF-α-activated NF-κB; hBVR was not a factor in mediating GPBP mRNA stability. The interacting domain was mapped to the 281CX10C motif in the C-terminal 24 residues of hBVR. A 7-residue peptide, KKRILHC281, corresponding to the core of the consensus D(δ)-Box motif in the interacting domain, was as effective as the intact 296-residue hBVR polypeptide in inhibiting GPBP kinase activity. GPBP neither regulated hBVR expression nor TNF-α dependent NF-κB expression. Collectively, our data reveal that hBVR is a regulator of the TNF-α-GPBP-collagen type IV signaling cascade and uncover a novel biological interaction that may be of relevance in autoimmune pathogenesis.
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human biliverdin reductase suppresses Goodpasture antigen binding protein gpbp kinase activity the reductase regulates tnf α nf κb dependent gpbp expression
Journal of Biological Chemistry, 2010Co-Authors: Tihomir Miralem, Juan Saus, Peter E M Gibbs, Fernando Revert, Mahin D MainesAbstract:Abstract The S/T/Y kinase activity of human biliverdin reductase (hBVR) and the expression of Goodpasture antigen-binding protein (GPBP), a nonconventional S/T kinase for the type IV collagen of basement membrane, are regulated by tumor necrosis factor (TNF-α). The pro-inflammatory cytokine stimulates kinase activity of hBVR and activates NF-κB, a transcriptional regulator of GPBP mRNA. Increased GPBP activity is associated with several autoimmune conditions, including Goodpasture Syndrome. Here we show that, in HEK293A cells, hBVR binds to GPBP and down-regulates its TNF-α-stimulated kinase activity; this was not due to a decrease in GPBP expression. Findings with si-hBVR and siRNA to the P65 regulatory subunit of NF-κB show hBVR's role in the initial stimulation of GPBP expression by TNF-α-activated NF-κB; hBVR was not a factor in mediating GPBP mRNA stability. The interacting domain was mapped to the C281X10C motif in the C-terminal 24 residues of hBVR. A 7-residue peptide, KKRILHC281, corresponding to the core of the consensus D(δ)-Box motif in the interacting domain, was as effective as the intact 296 residue hBVR polypeptide in inhibiting GPBP kinase activity. GPBP neither regulated hBVR expression nor TNF-α dependent NF-κB expression. Collectively, our data reveal that hBVR is a regulator of the TNF-α-GPBP-collagen type IV signaling cascade and uncover a novel biological interaction that may be of relevance in autoimmune pathogenesis.
Juan Saus - One of the best experts on this subject based on the ideXlab platform.
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human biliverdin reductase suppresses Goodpasture antigen binding protein gpbp kinase activity the reductase regulates tumor necrosis factor α nf κb dependent gpbp expression
Journal of Biological Chemistry, 2010Co-Authors: Tihomir Miralem, Juan Saus, Peter E M Gibbs, Fernando Revert, Mahin D MainesAbstract:The Ser/Thr/Tyr kinase activity of human biliverdin reductase (hBVR) and the expression of Goodpasture antigen-binding protein (GPBP), a nonconventional Ser/Thr kinase for the type IV collagen of basement membrane, are regulated by tumor necrosis factor (TNF-α). The pro-inflammatory cytokine stimulates kinase activity of hBVR and activates NF-κB, a transcriptional regulator of GPBP mRNA. Increased GPBP activity is associated with several autoimmune conditions, including Goodpasture Syndrome. Here we show that in HEK293A cells hBVR binds to GPBP and down-regulates its TNF-α-stimulated kinase activity; this was not due to a decrease in GPBP expression. Findings with small interfering RNA to hBVR and to the p65 regulatory subunit of NF-κB show the hBVR role in the initial stimulation of GPBP expression by TNF-α-activated NF-κB; hBVR was not a factor in mediating GPBP mRNA stability. The interacting domain was mapped to the 281CX10C motif in the C-terminal 24 residues of hBVR. A 7-residue peptide, KKRILHC281, corresponding to the core of the consensus D(δ)-Box motif in the interacting domain, was as effective as the intact 296-residue hBVR polypeptide in inhibiting GPBP kinase activity. GPBP neither regulated hBVR expression nor TNF-α dependent NF-κB expression. Collectively, our data reveal that hBVR is a regulator of the TNF-α-GPBP-collagen type IV signaling cascade and uncover a novel biological interaction that may be of relevance in autoimmune pathogenesis.
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human biliverdin reductase suppresses Goodpasture antigen binding protein gpbp kinase activity the reductase regulates tnf α nf κb dependent gpbp expression
Journal of Biological Chemistry, 2010Co-Authors: Tihomir Miralem, Juan Saus, Peter E M Gibbs, Fernando Revert, Mahin D MainesAbstract:Abstract The S/T/Y kinase activity of human biliverdin reductase (hBVR) and the expression of Goodpasture antigen-binding protein (GPBP), a nonconventional S/T kinase for the type IV collagen of basement membrane, are regulated by tumor necrosis factor (TNF-α). The pro-inflammatory cytokine stimulates kinase activity of hBVR and activates NF-κB, a transcriptional regulator of GPBP mRNA. Increased GPBP activity is associated with several autoimmune conditions, including Goodpasture Syndrome. Here we show that, in HEK293A cells, hBVR binds to GPBP and down-regulates its TNF-α-stimulated kinase activity; this was not due to a decrease in GPBP expression. Findings with si-hBVR and siRNA to the P65 regulatory subunit of NF-κB show hBVR's role in the initial stimulation of GPBP expression by TNF-α-activated NF-κB; hBVR was not a factor in mediating GPBP mRNA stability. The interacting domain was mapped to the C281X10C motif in the C-terminal 24 residues of hBVR. A 7-residue peptide, KKRILHC281, corresponding to the core of the consensus D(δ)-Box motif in the interacting domain, was as effective as the intact 296 residue hBVR polypeptide in inhibiting GPBP kinase activity. GPBP neither regulated hBVR expression nor TNF-α dependent NF-κB expression. Collectively, our data reveal that hBVR is a regulator of the TNF-α-GPBP-collagen type IV signaling cascade and uncover a novel biological interaction that may be of relevance in autoimmune pathogenesis.
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Exon/intron structure of the human alpha 3(IV) gene encompassing the Goodpasture antigen (alpha 3(IV)NC1). Identification of a potentially antigenic region at the triple helix/NC1 domain junction.
The Journal of biological chemistry, 1992Co-Authors: S Quinones, Dolores Bernal, M García-sogo, Santiago F. Elena, Juan SausAbstract:The Goodpasture antigen has been identified as the non-collagenous (NC1) domain of alpha 3(IV), a novel collagen IV chain (Saus, J., Wieslander, J., Langeveld, J., Quinones, S., and Hudson, B.G. (1988) J. Biol. Chem. 263, 13374-13380). In the present study, the exon/intron structure and sequence for 285 amino acids of human alpha 3(IV), comprising 53 amino acids of the triple-helical domain and the complete NC1 domain (232 amino acids), were determined. Based on the comparison of the amino acid sequences of the alpha 1(IV), alpha 2(IV), alpha 3(IV), and alpha 5(IV) NC1 domains, a phylogenetic tree was constructed which indicates that alpha 2(IV) was the first chain to evolve, followed by alpha 3(IV), and then by alpha 1(IV) and alpha 5(IV). The exon/intron structure of these domains is consistent with this evolution model. In addition, it appears that alpha 3(IV) changed most after diverging from the parental gene. Analysis of its primary structure reveals that, at the junction between the triple-helical and NC1 domains, there exists a previously unrecognized, highly hydrophilic region (GLKGKRGDSGSPATWTTR) which is unique to the human alpha 3(IV) chain, containing a cell adhesion motif (RGD) as an integral part of a sequence (KRGDSGSP) conforming to a number of protein kinase recognition sites. Based on primary structure data, we outline new aspects to be explored concerning the molecular basis of collagen IV function and Goodpasture Syndrome.
Tihomir Miralem - One of the best experts on this subject based on the ideXlab platform.
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human biliverdin reductase suppresses Goodpasture antigen binding protein gpbp kinase activity the reductase regulates tumor necrosis factor α nf κb dependent gpbp expression
Journal of Biological Chemistry, 2010Co-Authors: Tihomir Miralem, Juan Saus, Peter E M Gibbs, Fernando Revert, Mahin D MainesAbstract:The Ser/Thr/Tyr kinase activity of human biliverdin reductase (hBVR) and the expression of Goodpasture antigen-binding protein (GPBP), a nonconventional Ser/Thr kinase for the type IV collagen of basement membrane, are regulated by tumor necrosis factor (TNF-α). The pro-inflammatory cytokine stimulates kinase activity of hBVR and activates NF-κB, a transcriptional regulator of GPBP mRNA. Increased GPBP activity is associated with several autoimmune conditions, including Goodpasture Syndrome. Here we show that in HEK293A cells hBVR binds to GPBP and down-regulates its TNF-α-stimulated kinase activity; this was not due to a decrease in GPBP expression. Findings with small interfering RNA to hBVR and to the p65 regulatory subunit of NF-κB show the hBVR role in the initial stimulation of GPBP expression by TNF-α-activated NF-κB; hBVR was not a factor in mediating GPBP mRNA stability. The interacting domain was mapped to the 281CX10C motif in the C-terminal 24 residues of hBVR. A 7-residue peptide, KKRILHC281, corresponding to the core of the consensus D(δ)-Box motif in the interacting domain, was as effective as the intact 296-residue hBVR polypeptide in inhibiting GPBP kinase activity. GPBP neither regulated hBVR expression nor TNF-α dependent NF-κB expression. Collectively, our data reveal that hBVR is a regulator of the TNF-α-GPBP-collagen type IV signaling cascade and uncover a novel biological interaction that may be of relevance in autoimmune pathogenesis.
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human biliverdin reductase suppresses Goodpasture antigen binding protein gpbp kinase activity the reductase regulates tnf α nf κb dependent gpbp expression
Journal of Biological Chemistry, 2010Co-Authors: Tihomir Miralem, Juan Saus, Peter E M Gibbs, Fernando Revert, Mahin D MainesAbstract:Abstract The S/T/Y kinase activity of human biliverdin reductase (hBVR) and the expression of Goodpasture antigen-binding protein (GPBP), a nonconventional S/T kinase for the type IV collagen of basement membrane, are regulated by tumor necrosis factor (TNF-α). The pro-inflammatory cytokine stimulates kinase activity of hBVR and activates NF-κB, a transcriptional regulator of GPBP mRNA. Increased GPBP activity is associated with several autoimmune conditions, including Goodpasture Syndrome. Here we show that, in HEK293A cells, hBVR binds to GPBP and down-regulates its TNF-α-stimulated kinase activity; this was not due to a decrease in GPBP expression. Findings with si-hBVR and siRNA to the P65 regulatory subunit of NF-κB show hBVR's role in the initial stimulation of GPBP expression by TNF-α-activated NF-κB; hBVR was not a factor in mediating GPBP mRNA stability. The interacting domain was mapped to the C281X10C motif in the C-terminal 24 residues of hBVR. A 7-residue peptide, KKRILHC281, corresponding to the core of the consensus D(δ)-Box motif in the interacting domain, was as effective as the intact 296 residue hBVR polypeptide in inhibiting GPBP kinase activity. GPBP neither regulated hBVR expression nor TNF-α dependent NF-κB expression. Collectively, our data reveal that hBVR is a regulator of the TNF-α-GPBP-collagen type IV signaling cascade and uncover a novel biological interaction that may be of relevance in autoimmune pathogenesis.
Sharon A Chung - One of the best experts on this subject based on the ideXlab platform.
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kallikrein genes are associated with lupus and glomerular basement membrane specific antibody induced nephritis in mice and humans
Journal of Clinical Investigation, 2009Co-Authors: Quan Zhen Li, Angelica M Delgadovega, Annakarin Abelson, Jinchun Zhou, Qiu Ye, Xin J Zhou, Jennifer A Kelly, Li Li, Elena Sánchez, Sharon A ChungAbstract:Immune-mediated nephritis contributes to disease in systemic lupus erythematosus, Goodpasture Syndrome (caused by antibodies specific for glomerular basement membrane [anti-GBM antibodies]), and spontaneous lupus nephritis. Inbred mouse strains differ in susceptibility to anti-GBM antibody–induced and spontaneous lupus nephritis. This study sought to clarify the genetic and molecular factors that may be responsible for enhanced immune-mediated renal disease in these models. When the kidneys of 3 mouse strains sensitive to anti-GBM antibody–induced nephritis were compared with those of 2 control strains using microarray analysis, one-fifth of the underexpressed genes belonged to the kallikrein gene family, which encodes serine esterases. Mouse strains that upregulated renal and urinary kallikreins exhibited less evidence of disease. Antagonizing the kallikrein pathway augmented disease, while agonists dampened the severity of anti-GBM antibody–induced nephritis. In addition, nephritis-sensitive mouse strains had kallikrein haplotypes that were distinct from those of control strains, including several regulatory polymorphisms, some of which were associated with functional consequences. Indeed, increased susceptibility to anti-GBM antibody–induced nephritis and spontaneous lupus nephritis was achieved by breeding mice with a genetic interval harboring the kallikrein genes onto a disease-resistant background. Finally, both human SLE and spontaneous lupus nephritis were found to be associated with kallikrein genes, particularly KLK1 and the KLK3 promoter, when DNA SNPs from independent cohorts of SLE patients and controls were compared. Collectively, these studies suggest that kallikreins are protective disease-associated genes in anti-GBM antibody–induced nephritis and lupus.
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kallikrein genes are associated with lupus and glomerular basement membrane specific antibody induced nephritis in mice and humans
Journal of Clinical Investigation, 2009Co-Authors: Quan Zhen Li, Angelica M Delgadovega, Annakarin Abelson, Jinchun Zhou, Qiu Ye, Xin J Zhou, Jennifer A Kelly, Li Li, Elena Sánchez, Sharon A ChungAbstract:Immune-mediated nephritis contributes to disease in systemic lupus erythematosus, Goodpasture Syndrome (caused by antibodies specific for glomerular basement membrane [anti-GBM antibodies]), and spontaneous lupus nephritis. Inbred mouse strains differ in susceptibility to anti-GBM antibody–induced and spontaneous lupus nephritis. This study sought to clarify the genetic and molecular factors that may be responsible for enhanced immune-mediated renal disease in these models. When the kidneys of 3 mouse strains sensitive to anti-GBM antibody–induced nephritis were compared with those of 2 control strains using microarray analysis, one-fifth of the underexpressed genes belonged to the kallikrein gene family, which encodes serine esterases. Mouse strains that upregulated renal and urinary kallikreins exhibited less evidence of disease. Antagonizing the kallikrein pathway augmented disease, while agonists dampened the severity of anti-GBM antibody–induced nephritis. In addition, nephritis-sensitive mouse strains had kallikrein haplotypes that were distinct from those of control strains, including several regulatory polymorphisms, some of which were associated with functional consequences. Indeed, increased susceptibility to anti-GBM antibody–induced nephritis and spontaneous lupus nephritis was achieved by breeding mice with a genetic interval harboring the kallikrein genes onto a disease-resistant background. Finally, both human SLE and spontaneous lupus nephritis were found to be associated with kallikrein genes, particularly KLK1 and the KLK3 promoter, when DNA SNPs from independent cohorts of SLE patients and controls were compared. Collectively, these studies suggest that kallikreins are protective disease-associated genes in anti-GBM antibody–induced nephritis and lupus.
