Clinical Research

DnaJ Homolog Subfamily B Member 9 Is a Putative Autoantigen in Fibrillary GN

Nicole K. Andeen, Han-Yin Yang, Dao-Fu Dai, Michael J. MacCoss and Kelly D. Smith
JASN January 2018, 29 (1) 231-239; DOI: https://doi.org/10.1681/ASN.2017050566

Abstract

Fibrillary GN is a rare form of GN of uncertain pathogenesis that is characterized by the glomerular accumulation of randomly arranged, nonbranching fibrils (12–24 nm) composed of Ig and complement proteins. In this study, we used mass spectrometry to comprehensively define the glomerular proteome in fibrillary GN compared with that in controls and nonfibrillary GN renal diseases. We isolated glomeruli from formalin-fixed and paraffin-embedded biopsy specimens using laser capture microdissection and analyzed them with liquid chromatography and data-dependent tandem mass spectrometry. These studies identified DnaJ homolog subfamily B member 9 (DNAJB9) as a highly sampled protein detected only in fibrillary GN cases. The glomerular proteome of fibrillary GN cases also contained IgG1 as the dominant Ig and proteins of the classic complement pathway. In fibrillary GN specimens only, immunofluorescence and immunohistochemistry with an anti-DNAJB9 antibody showed strong and specific staining of the glomerular tufts in a distribution that mimicked that of the immune deposits. Our results identify DNAJB9 as a putative autoantigen in fibrillary GN and suggest IgG1 and classic complement effector pathways as likely mediators of the destructive glomerular injury in this disease.

Fibrillary GN (FGN) is characterized by glomerular accumulations of randomly arranged, nonbranching fibrils that resemble amyloid but differ by their Congo red negativity, larger diameter (12- to 24-nm versus 8- to 12-nm diameter for amyloid), positive immunostaining for Ig IgG and light chains, and complement fixation.1,2 FGN is diagnosed in 0.5%–1% of native kidney biopsies and usually presents in middle-aged to older adults with proteinuria, hematuria, and hypertension.1 The outcome is usually poor, with progression to ESRD occurring in 50% of patients within several years of diagnosis; the disease may also recur in the transplant.1 There are no established therapeutic regimens,1 although treatment with rituximab was reported to stabilize disease progression in some patients.3–5

The pathogenesis of FGN is uncertain, and it has been debated whether FGN represents a unique entity or should be considered as part of the spectrum of glomerular immune complex–mediated diseases that manifest as fibrillar deposits: the immunotactoid glomerulopathies.6–8 Prior gold immunoelectron microscopy studies suggest that the fibrillary deposits of FGN consist of IgG, complement component C3, and amyloid P but do not consist of matrix components, such as collagen type 4, heparan sulfate proteoglycan, fibronectin, or fibrillin.1,9 Characterization of amyloid fibrils by laser capture microdissection (LCM) and mass spectrometry is now common in clinical practice for subtyping amyloidosis, and mass spectrometry–based proteomics has been used in research to define other glomerulopathies.10 These studies confirmed the presence of IgG and C3 but not amyloid P in FGN, and also suggested that the abundance of apo E in the deposits may determine the fibril diameter.10

We hypothesized that specific proteins, such as novel autoantigens, contribute to the distinct morphology of the immune deposits and the pathogenesis of FGN. To test this hypothesis, we used LCM and liquid chromatography and tandem mass spectrometry (LC-MS/MS) to comprehensively define the glomerular proteome in FGN and identify candidate autoantigens for this elusive disease.

Results

DnaJ Homolog Subfamily B Member 9 Detection in FGN by Mass Spectrometry

Using LC-MS/MS with data-dependent acquisition, we detected DnaJ homolog subfamily B member 9 (DNAJB9; also known as MDG1 and ERDJ4; http://www.uniprot.org/uniprot/Q9UBS3) as a highly sampled protein in LCM glomeruli in seven of eight samples from five of five patients with FGN, but none of the samples from 114 patients without FGN or control samples [16 time zero allograft, 14 diabetic nephropathy, five idiopathic nodular glomerulosclerosis, six light-chain deposition disease, and 73 amyloid: 12 AA, 2 AH(IgG1), 29 AL(κ), 28 AL(λ), and two indeterminate type] (Figure 1). The sole FGN sample that had no detectable DNAJB9 was from a patient with very active crescentic disease (54%–65% of the glomeruli involved by crescents), and the marked inflammation may have interfered with detection of DNAJB9 in one of the samples from this patient. DNAJB9 is a member of the DNAJ family of chaperones, and the mature protein is secreted into the endoplasmic reticulum, where it has been implicated in ER stress and the unfolded protein responses (UPRs).11–14 No specific enrichment was seen for other components of the ER stress/UPR in the glomerular samples from FGN and control samples (Figure 1). Amyloid P serum component and apo E were detected in the majority of samples from amyloid, light-chain deposition disease, idiopathic nodular glomerulosclerosis, and diabetic nephropathy cases and at least one half of the FGN cases but only a small minority of the time zero allograft samples (Figure 1). The DNAJB9 protein normalized spectra abundance factor values in the FGN samples were significantly greater than the values for all other samples (Figure 2A), whereas type 4 collagen proteins, major components of the glomerular basement membrane (GBM), were detected at similar levels in FGN and non-FGN cases (Figure 2, B–D). DNAJB9 is a 223-amino acid protein with a predicted 23-amino acid signal peptide; mass spectrometry detected DNAJB9 peptides between amino acids 68 and 185 in the FGN samples (Figure 3), consistent with the mature form of the protein being associated with FGN. The majority of the samples had IgG1 followed by IgG4. All FGN cases had complement components C3 and C4-B and additional components of the complement cascade up through the membrane attack complex (Table 1).

Figure 1.
Figure 1.

DNAJB9 is present in glomeruli of FGN cases but not in controls. Mass spectrometry–based quantification of a DNAJB9 peptide in FGN and control samples. The DNAJB9 protein normalized spectra abundance factor (NSAF) is significantly increased in FGN cases (seven of eight samples) compared with controls (114 samples). UPR, a conserved response related to endoplasmic reticulum stress, is highlighted by proteins that are induced (red) or repressed (green).26 Amyloid P serum component and apo E (APOE) were detected in some but not all FGN samples and are present in the majority of amyloid samples. COL4A3, COL4A4, and COL4A5 NSAFs were similarly distributed among all samples. The gray background indicates that the protein was not detected in the sample.

Figure 2.
Figure 2.

Mass spectrometry–based quantification shows significantly increased DNAJB9 protein in FGN cases, which was not detected in controls. The DNAJB9 protein normalized spectra abundance factor (NSAF) is significantly increased in FGN cases (A) (eight samples) compared with controls (114 samples). COL4A3 (B), COL4A4 (C), and COL4A5 (D) NSAF values did not differ significantly between FGN and control cases (Mann–Whitney U test).

Figure 3.
Figure 3.

Mass spectrometry detected DNAJB9 peptides between amino acids 68 and 195 in seven of eight FGN samples from five of five patients. The predicted signal peptide is amino acids 1–23, and the predicted mature protein is amino acids 24–223. The findings are consistent with the mature form of the protein being associated with FGN. Peptides detected in each of the FGN samples are underlined.

View this table:
Table 1.

Detection of Ig and complement proteins in eight samples from five patients with FGN

DNAJB9 Detection in FGN by Immunohistochemistry and Immunofluorescence Microscopy

All 11 cases of FGN had strong, discrete staining for anti-DNAJB9 in GBMs and/or mesangial regions (Figures 4 and 5) by immunohistochemistry (IHC; n=8) or immunofluorescence microscopy (IF; n=3). Neither mesangial nor discrete GBM staining were seen in any of the non-FGN cases or controls (Figure 5 and Table 2), which consisted of those with PLA2R-negative membranous nephropathy (MN; 9), PLA2R-positive MN (8), time zero controls or explanted kidneys (8), immunotactoid glomerulopathy (2), MN with spherules (2), and diabetes (1). The extent of glomerular staining varied by glomerulus and matched the underlying morphologic changes, IgG staining, and fibril deposition by electron microscopy. Some showed strong and discrete but only segmental GBM staining; those that had less mesangial expansion generally had less mesangial staining. Dual immunofluorescence staining for anti-DNAJB9 and anti-IgG showed colocalization of DNAJB9 and IgG in both glomerular and extraglomerular immune deposits (Figure 6). In FGN and non-FGN, IHC had nonspecific staining, including variable podocyte cytoplasmic reactivity and staining of tubular epithelial cells and arterial vessel myocytes. IF studies showed lower background staining, with no significant reactivity in podocytes, tubulointerstitium, or extraglomerular vasculature.

Figure 4.
Figure 4.

Diagnostic characteristics of FGN. (A) Diffuse mesangial expansion predominantly due to deposition of eosinophilic, silver negative material with extension into the capillary walls. Original magnification, ×400. (B) Electron microscopy reveals deposition of abundant haphazardly arranged fibrils with an average diameter of 13 nm. Glomerulus with confluent, pseudolinear staining in the peripheral capillary loops and mesangium by IF (C) anti-DNAJB9 and (D) anti-IgG. Original magnification, ×400.

Figure 5.
Figure 5.

Detection of DNAJB9 in glomeruli from FGN cases. Anti-DNAJB9 shows strong, discrete peripheral capillary wall and mesangial staining in (A and B) FGN but not in (C) MN, (D) immunotactoid glomerulopathy, (E) diabetic glomerulopathy, or (F) normal controls (IHC). Most cases show weak podocyte cytoplasmic staining by IHC and background staining in the tubulointerstitium. By IF, anti-DNAJB9 shows (G) bright peripheral capillary wall and mesangial staining in FGN but is (H) negative in normal controls. Original magnification, ×400.

View this table:
Table 2.

Immunohistochemical findings for anti-DNAJB9 in glomeruli in FGN and non-FGN cases

Figure 6.
Figure 6.

Dual staining reveals colocalization of IgG and DNAJB9 in immune deposits in FGN. IgG highlights (A) glomerular and (D) extraglomerular vascular deposits in FGN. DNAJB9 shows similar staining in (B) glomeruli and (E) rare vascular deposits. Merged images show substantial colocalization of these molecules in (C) glomerular and (F) extraglomerular deposits in FGN.

In total, we analyzed 16 cases of FGN by either mass spectrometry or immunostaining. At a cutoff of greater than trace staining intensity (scale 0–4+), 12 (75%) cases had associated glomerular deposition of C3, and four (25%) were positive for C1q, which was of modest (trace to 1+) staining intensity. Of the five FGN cases studied by mass spectrometry, two cases had polytypic IgG staining, and three cases had strong κ–light-chain bias by IF. Of the 11 FGN cases studied by IHC or IF, nine had polytypic IgG staining by IF, and two cases had light-chain bias. There was no appreciable difference in DNAJB9 staining between cases with polytypic IgG and cases with an Ig light-chain staining bias.

Discussion

In this study, we used mass spectrometry and IHC to investigate the glomerular proteome in FGN and correlate the findings with glomerular localization. The novel findings are the identification of a protein, DNAJB9, as a highly sampled protein that was detected only by mass spectrometry in cases of FGN. IHC and IF confirmed the increased abundance of DNAJB9 in FGN glomeruli and localized the protein to GBMs and mesangial regions as seen for the immune deposits in FGN. By IHC, DNAJB9 has been detected in most cells in normal tissue and displays cytoplasmic immunoreactivity (http://www.proteinatlas.org/ENSG00000128590-DNAJB9/tissue). In kidney biopsies, we showed DNAJB9 immunoreactivity in tubular epithelial cells, vascular myocytes, and podocytes by IHC. Notably, IF staining for DNAJB9 showed very low background and no appreciable staining of these same structures, but discrete extraglomerular immune deposits positive for DNAJB9 were identifiable by IF. Prominent GBM and mesangial DNAJB9 staining was only detected in cases of FGN (Figure 4), and DNAJB9 colocalized with IgG in the glomerular deposits of FGN cases(Figure 6). On the basis of these findings, we postulate that FGN is an autoimmune disease due to autoantibodies that target the putative autoantigen, DNAJB9.

DNAJB9 is a 223-amino acid protein that is a member of the DNAJ family of chaperones. DNAJ proteins influence many cellular processes by regulating the ATPase activity of 70-kD heat shock proteins. DNAJB9 is involved in ER stress and the UPR, and it is a cochaperone for BiP/Grp78, a master regulator of the UPR.11,15 DNAJB9 is upregulated by ER stress, nitric oxide, and other inflammatory mediators16; protects against cell death17,18; protects hematopoietic stems cells during stress13; and is required for normal B cell development and antibody production.11 DNAJB9 also specifically binds aggregation-prone regions in proteins.14 No specific enrichment was seen for other components of the ER stress/UPR in the glomerular proteome in FGN cases, suggesting that the enrichment for DNAJB9 in FGN glomeruli did not represent a localized induction of the ER stress/UPR. Given DNAJB9’s role in ER stress responses, it is intriguing to speculate that the UPR and DNAJB9 binding to aggregation-prone peptide sequences may be linked to the pathogenesis of FGN.

In classic clinical and pathologic presentations, FGN is characterized by polytypic IgG glomerular staining by IF, structured immune deposits with fibril diameter of 12–24 nm, and Congo red negativity. However, in some cases, a diagnosis of FGN is diagnostically challenging. Approximately 15% of cases have monoclonal (κ or λ restricted) rather than polytypic light-chain staining by IF.19 In addition, the fibril diameter in FGN (12–24 nm) can overlap with those seen in amyloidosis (8–12 nm) and immunotactoid glomerulopathy (generally >30 nm).1 Finally, recent reports of Congo red–positive FGN20 further complicate the pathologic diagnosis of FGN. The findings in our study suggest that mass spectrometry, IF, or IHC may be used identify DNAJB9 in glomeruli and confirm the diagnosis of FGN in diagnostically challenging cases.

FGN usually presents clinically as nephritic syndrome, and pathologically, biopsies typically exhibit GN, including endocapillary hypercellularity, segmental necrosis, crescents, and segmental scarring. The glomerular proteomic analysis revealed that the most frequently sampled Ig in the immune deposits of FGN is IgG1, which is a potent activator of the classic complement cascade and binds avidly to Fc receptors on myeloid and NK cells.21,22 Immune deposits in FGN were originally characterized as IgG4 dominant23; however, more recent studies indicate that both IgG1 and IgG4 are present in FGN.5,24,25 Similar to other techniques, quantifying proteins by mass spectrometry has inherent limitations, because differences in protein stability, digestibility, and ionization can affect detection. Thus, it may be difficult to assess the relative abundance for certain proteins, even with internal controls and specialized data acquisition methods. Further evaluation of IgG isotypes in FGN may help determine whether IgG isotype usage influences disease activity or outcome.

The glomerular proteome of FGN cases also revealed activation of the classic complement cascade. C1q was not detected in the samples, and in general, we have noted that C1q is infrequently sampled in our mass spectrometry studies, which may reflect low abundance or technical issues. The finding of only modest C1q staining by IF in only 25% of our FGN cases lends some support to the former possibility. Using the same technique, C4 is readily detected in all FGN samples, supporting activation of the classic complement pathway. Thus, our findings suggest that classic complement effector pathways are mediators of the destructive kidney injury in FGN.

Our findings raise multiple additional questions that are incompletely addressed in this study and fodder for future analyses. On the basis of the specific detection of DNAJB9 in FGN but not other glomerular diseases and the colocalization of IgG with DNAJB9 in the immune deposits of FGN, we hypothesize that DNAJB9 represents an autoantigen in FGN. Future studies are needed to determine whether patients with FGN harbor circulating antibodies against DNAJB9 and refine our understanding of the biologic mechanisms that affect the onset, duration, and severity of FGN.

In conclusion, we show that DNAJB9 is specifically enriched in the glomerular immune deposits of FGN. We hypothesize that DNAJB9 is a putative autoantigen in FGN and that DNAJB9 is the target of an IgG-mediated autoantibody response that is the cause for this progressive GN. Thus, anti-DNAJB9 autoantibodies and IgG and classic complement effector pathways represent potential diagnostic and therapeutic targets for FGN that warrant future investigation.

Concise Methods

Case Selection

The study was approved by the University of Washington Institutional Review Board (IRB 48306) and adheres to the Declaration of Helsinki. The cases were entirely composed of renal biopsy specimens from 2003 to 2015, during which FGN was diagnosed in 73 native kidney biopsies at our institution. Cases were selected on the basis of the number of patent glomeruli in the sample submitted for light microscopy. For both FGN and controls, cases with many crescents or globally sclerosed glomeruli were avoided, because these would be expected to give a peptide signal related to these secondary lesions and nonspecific staining by IHC or IF. Cases of FGN and controls for which mass spectrometry was performed contained a median of 12 (range, 5–34) glomeruli. Cases stained with anti-DNAJB9 by IHC contained a median of six (range, 1–34) glomeruli for light microscopy. Six cases for IHC were excluded due to inadequate number of glomeruli.

LCM

Formalin-fixed, paraffin-embedded tissues were sectioned to 10-μm thick on DIRECTOR laser microdissection slides (Expression Pathology) and then stained with Congo red. For amyloid cases, glomeruli with Congo red–positive deposits were microdissected, and for all other cases, representative glomeruli were microdissected (Leica LMD650 Laser Microdissection System). Two replicates were microdissected for each case. A few cases did not have two replicates because of limited availability of glomeruli. At least two glomeruli containing an area of at least 50,000–60,000 μm2 were dissected for each replicate. The microdissected tissue was collected into 0.5-ml microcentrifuge tube caps, 25 μl 0.1% Rapigest buffer (Waters Corporation, Milford, MA) was added to the caps, and the samples were stored in –80°C until further processing.

Sample Preparation and LC-MS/MS Analyses

The samples were thawed at 4°C, and an additional 35 μl 0.1% RepiGest was added to a final volume of 60 μl. This microdissected tissue suspension was heated at 98°C for 90 minutes and sonicated in a water bath for 1 hour at room temperature. Samples were treated with 5 mM dithiothreitol at 60°C for 30 minutes to reduce disulfide bonds. Free sulfhydryls were alkylated with treatment of 15 mM iodoacetamide at room temperature for 30 minutes. Resulting proteins were digested by adding 5 μl 0.2 μg/μl Trypsin and incubating at 37°C for 18 hours. Trypsin activity was halted, and the Rapigest was hydrolyzed with the addition of 5 M HCl to a final concentration of 50 mM and incubation at 37°C for 60 minutes. Samples were centrifuged for 10 minutes at 14,000×g, and the supernatants were separated by liquid chromatography (Waters nanoACQUITY) and analyzed by Q-Exactive HF mass spectrometry (Thermo Fisher Scientific). The liquid chromatography mobile phase consisted of buffer A (water and 0.1% formic acid) and buffer B (acetonitrile and 0.1% formic acid). Peptides were loaded onto a 3-cm fused silica trapping column (150-μm inner diameter) at 2 μl/min for 5 minutes with 2% buffer B. The trap column was packed with Jupiter PROTEO C12 material (Phenomenex; 90 Å, 4 μm). Peptides were then separated at a flow rate of 250 nl/min over a homemade 15-cm-long, 75-μm-inner diameter fused silica capillary column packed with C18 resin (Maisch; Reprosil-Pur-C18-AQ, 3 μm). The gradient used was 2%–35% buffer B for 60 minutes, 35%–60% buffer B for 5 minutes, 60% buffer B for 5 minutes, 60%–95% buffer B for 1 minute, a 5-minute wash with 95% buffer B at 500 nl/min, and then re-equilibration with 2% buffer B at 500 nl/min for 13 minutes. Spectra were acquired using a data-dependent acquisition approach, in which one high-resolution mass spectrometry scan (400–1400 m/z; 120,000 resolution at 200 m/z) was followed by 20 tandem mass spectrometry scans (isolation window of 2 m/z; 15,000 resolution at 200 m/z) of the most intense peaks in the mass spectrometry scan. The m/z values of isolated peaks would be excluded for 10 seconds.

Protein Identification and Quantification

Mass spectrometry raw data files were converted to .ms1 and .ms2 format using MSConvertor26 and subject to an in-house version of Bullseye27 for accurate precursor monoisotopic mass assignment on tandem mass spectrometry scans. The processed .ms2 files were searched using COMET28 with trypsin specificity against a human protein fasta database that consisted of UniportKB/Swiss-Prot protein sequences and known amyloidosis-relevant sequence variants collected from the Uniport variant file and the literature.29,30 Search parameters include static carbamidomethyl modification (57.02 D) of cysteine, maximum of one miss cleavage and one nontryptic end, and 10 ppm and 0.1-D tolerance for precursor and tandem mass spectrometry matching, respectively. The target decoy database strategy was performed with Percolator v2.0431 for false discovery rate estimation. Identified spectra with false discovery rate of 1% or lower were subject to MSDaPl32 for protein inference and quantification. Relative protein abundance in each sample was presented with normalized spectra abundance factor33 to account for different protein sizes and total amount of proteins in the sample. Data analysis was performed on Graphpad Prism, version 6.

IHC and IF

IHC and IF were performed using anti-DNAJB9 antibody (HPA041533; Sigma-Aldrich), a polyclonal rabbit antibody. Formalin-fixed, paraffin-embedded tissue was cut at 4 μm, deparaffinized in xylene, and rehydrated. Endogenous peroxidase was blocked with hydrogen peroxide. Slides were incubated in HIER-L antigen retrieval solution at 120°C for 2 minutes in a pressure cooker and then blocked with Background Buster (Innovex). Slides were incubated with anti-DNAJB9 (dilution 1:200) overnight in a moist chamber at 4°C. After equilibration at room temperature, they were washed with PBS , incubated with ImmPress anti-rabbit reagent for 30 minutes at room temperature in a moist chamber, and then washed with PBS. Slides were then incubated with DAB, washed in deionized water, counterstained with hematoxylin, dehydrated, cleared with xylene, and coverslipped. For IF, frozen tissue was cut at 4 μm and incubated with ice cold acetone for 10 minutes. Slides were incubated with anti-DNAJB9 at a dilution of 1:200 overnight in a moist chamber at 4°C. Slides were washed with PBS. Slides were then incubated with ImmPress anti-rabbit reagent for 30 minutes at room temperature in a moist chamber. Slides were washed with PBS and then coverslipped with aqueous mounting reagent with 4',6-diamidino-2-phenylindole. Dual immunofluorescence was performed by sequentially staining sections with anti-DNAJB9 as described above followed by mouse biotinylated anti-human IgG (dilution 1:100; Clone G18–145; BD Biosciences) for 1 hour at 4°C and then streptavidin-FITC (dilution 1:100; Sigma-Aldrich) for 30 minutes at 4°C.

Disclosures

None.

Acknowledgments

We thank to the talented and dedicated people in the University of Washington Renal and Electron Microscopy laboratories, our renal pathology colleagues, and Kelly Hudkins-Loya and James Li for their technical expertise.

This work was supported by the University of Washington Department of Pathology (N.K.A. and K.D.S.) and National Institutes of Health grants R21 CA192983 (to M.J.M.), P41 GM103533 (to M.J.M.), and P30 AG013280 (to M.J.M.).

Footnotes

  • Published online ahead of print. Publication date available at www.jasn.org.

  • See related editorial, “Glomerular Disease Pathology in the Era of Proteomics: From Pattern to Pathogenesis,” on pages 2–4.

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DnaJ Homolog Subfamily B Member 9 Is a Putative Autoantigen in Fibrillary GN
Nicole K. Andeen, Han-Yin Yang, Dao-Fu Dai, Michael J. MacCoss, Kelly D. Smith
JASN Jan 2018, 29 (1) 231-239; DOI: 10.1681/ASN.2017050566
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