Andeen N.K., Kung V.L., Robertson J., Gurley S.B., Avasare R.S., Sitaraman S.: Fibrillary Glomerulonephritis, DNAJB9, and the Unfolded Protein Response. Glomerular Diseases DOI 10.1159/000525542
Fibrillary glomerulonephritis (FGN) is a rare form of primary glomerular disease defined by the common co-deposition of IgG and DNAJB9 and fibril formation. Its etiology and pathogenesis are unknown. DNAJB9 deposition is a highly sensitive and specific biomarker for FGN. The role of DNAJB9 (a chaperone regulating heat shock protein responding to endoplasmic reticulum stress) in the pathogenesis of the lesion of FGN is largely unknown.
In a very scholarly and well-written review article, Andeen and colleagues from the University of Oregon analyze FGN from the perspective of protein folding with a particular emphasis on DNAJB9. FGN is seen in about 1% of kidney biopsies performed for evaluation of suspected glomerular disease. The IgG deposits are nearly always polyclonal, although rarely they may be monoclonal. The fibrils are typically small (10–20 nm in width). Serological evaluation shows concomitant autoimmunity in up to about 15% of patients (positive FANA or ANCA). Hypocomplementemia is seen in 5% or less. HLA DR7 is found in about 50% of patients. Paraffin immunofluorescence can be required for unmasking of polyclonality of the IgG as frozen immunofluorescence may commonly show light chain monotypism. Rarely, IgG may be absent in the deposits. DNAJB9 is nearly always present in the deposits, and serum levels of DNAJB9 are elevated in 30–50% of patients. No circulating antibody to DNAJB9 has yet been described in FGN. Rarely, AA amyloid may also be DNAJB9 positive. The disease can recur in kidney allografts, but this is usually very delayed and very indolent in its clinical features. Donor-derived FGN has also been described in kidney transplantation.
The authors suggest that misfolded or unfolded proteins may be part of the pathogenesis of the FGN lesions. Such misfolding can unleash a series of molecular and cellular responses covered under the rubric of the “unfolded protein response.” Fibril formation and upregulation of DNAJB9 formation ispart of this cascade of events. Data suggests that DNAJB9 binds to misfolded IgG, but the reverse may also occur. Mutations of the DNAJB9 gene have not yet been found. DNAJB9 deposits are only very rarely seen in other protein misfolding disorders, such as amyloidosis. Studies so far have failed to show upregulation of DNAJB9 in glomeruli, so a post-transcriptional event is likely involved in DNAJB9 deposition seen in FGN.
Collectively, these features suggest that a post-transcriptional defect in DNAJB9 itself is deeply involved in the pathogenesis of FGN. This is perhaps mediated by the “unfolded protein response” to misfolded IgG or DNAJB9 or both. Targeted therapy for FGN will depend upon further unraveling of this complicated cascade. At present, there is no proven effective therapy for FGN, although preliminary, uncontrolled observations suggest a possible beneficial effect of rituximab, which has no known effect on DNAJB9 itself. Stay tuned as this mystery “unfolds.”