Progranulin antibodies in autoimmune diseases

Thurner, Lorenz; Preuss, Klaus‐Dieter; Fadle, Natalie; Regitz, Evi; Klemm, Philipp; Zaks, Marina; Kemele, Maria; Hasenfus, Andrea; Csernok, Elena; Gross, Wolfgang L.; Pasquali, Jean‐Louis; Martin, Thierry; Bohle, Rainer M.; Pfreundschuh, Michael

doi:10.1016/j.jaut.2012.10.003

Cited by 65 publications

(78 citation statements)

References 42 publications

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“…These antibodies had the direct effect of lowering plasma PGRN levels by about 50% compared with NC,8 mirroring the haploinsufficiency effects of PGRN mutations 9. The presence of anti-PGRN antibodies in autoimmune disease provides a direct mechanism of action for how sustained autoimmune pathology would precipitate FTLD-TDP disease and supports our findings of increased rates of these related autoimmune disorders in FTLD-TDP populations.…”

Section: Discussionsupporting

confidence: 80%

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TDP-43 frontotemporal lobar degeneration and autoimmune disease

Miller

Rankin

Graff‐Radford

et al. 2013

Journal of Neurology, Neurosurgery & Psychiatry

148

132

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Background The aetiology and pathogenesis of non-genetic forms of frontotemporal dementia (FTD) is unknown and even with the genetic forms of FTD, pathogenesis remains elusive. Given the association between systemic inflammation and other neurodegenerative processes, links between autoimmunity and FTD need to be explored. Objective To describe the prevalence of systemic autoimmune disease in semantic variant primary progressive aphasia (svPPA), a clinical cohort, and in progranulin (PGRN) mutation carriers compared to neurologically healthy normal controls (NC) and Alzheimer’s disease (AD) as dementia controls. Design Case control. Setting Academic medical centres. Participants 129 svPPA, 39 PGRN, 186 NC, and 158 AD patients underwent chart review for autoimmune conditions. A large subset of svPPA, PGRN, and NC cohorts underwent serum analysis for tumor necrosis factor α (TNF-α) levels. Outcome Measures Chi-square comparison of autoimmune prevalence and follow up logistic regression. Results There was a significantly increased risk of autoimmune disorders clustered around inflammatory arthritides, cutaneous disorders, and gastrointestinal conditions in the svPPA and PGRN cohorts. Elevated TNF-α levels were observed in svPPA and PGRN compared to NC. Conclusions svPPA and PGRN are associated with increased prevalence of specific and related autoimmune diseases compared to NC and AD. These findings suggest a unique pattern of systemic inflammation in svPPA and PGRN and open new research avenues for understanding and treating disorders associated with underlying transactive response DNA-binding protein 43 (TDP-43) aggregation.

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Section: Discussionsupporting

confidence: 80%

“…PGRN knockout mice develop inflammatory arthritis and PGRN has demonstrated antagonistic effects on TNF-α signalling 7. Recently, antibodies to PGRN have been demonstrated in patients with histories of particular autoimmune conditions, lowering systemic PGRN levels by half, similar to levels found in PGRN mutation carriers 8 9…”

Section: Introductionmentioning

confidence: 93%

TDP-43 frontotemporal lobar degeneration and autoimmune disease

Miller

Rankin

Graff‐Radford

et al. 2013

Journal of Neurology, Neurosurgery & Psychiatry

148

132

View full text Add to dashboard Cite

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“…However, this finding does not belittle the role of T cells- and B cells-derived PGRN in chronic DSS colitis and other IBD models. Several recent articles have indicated that PGRN contributes to the pathogenesis of chronic autoimmune diseases193940. In CD4+CD45Rb high T cells transfer colitis model, transfer of PGRN −/− CD4+CD45Rb high T cells leads to more severe intestinal inflammation (Fig.…”

Section: Discussionmentioning

confidence: 96%

PGRN protects against colitis progression in mice in an IL-10 and TNFR2 dependent manner

Wei

Zhang

Jian

et al. 2014

Sci Rep

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This study was aimed to determine the role and regulation of progranulin (PGRN) in the pathogenesis of inflammatory bowel diseases (IBD). Dextran sulfate sodium (DSS)−, picrylsulfonic acid (TNBS)-induced, bone marrow chimera and CD4+CD45Rbhi T cell transfer colitis model were established and analyzed in wild-type and several genetically-modified mice, including PGRN, IL-10 and TNFR2 deficient mice. Elevated levels of PGRN were found in colitis samples from human IBD patients and mouse colitis models in comparison to the corresponding controls. PGRN-deficient mice became highly susceptible to DSS- and TNBS-induced colitis, whereas recombinant PGRN ameliorated the pathology and reduced the histological score in both DSS and TNBS colitis models. In addition, hematopoietic-derived PGRN was critical for protection against DSS-induced colitis, and lack of PGRN signaling in CD4+ T cells also exacerbated experimental colitis. PGRN-mediated protective effect in colitis was compromised in the absence of IL-10 signaling. In addition, PGRN's effect was also largely lost in the TNFR2-deficient colitis model. Collectively, these findings not only provide the new insight into PGRN's anti-inflammatory action in vivo, but may also present PGRN and its derivatives as novel biological agent for treating IBD.

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“…A similar implication was depicted by Hu and co-workers [18], where they identified salivary proteomic and genomic biomarkers for SS showing upregulation of genes involved in the IFN pathway, thereby suggesting a potential role for viral infection in SS. Moreover, both GRN, a cytokine-like peptide that is central in inflammation due to its active role in wound repair and tissue remodelling [51], and CALML5, a calcium-binding protein that plays a central role in the differentiation of keratinocytes [52], were also upregulated in our patient group. This finding in turn provides evidence of acinar damage and oral environment alteration.…”

Section: Discussionmentioning

confidence: 99%

Identification of potential saliva and tear biomarkers in primary Sjögren’s syndrome, utilising the extraction of extracellular vesicles and proteomics analysis

et al. 2017

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BackgroundThere is a long-lasting need for non-invasive, more accurate diagnostic techniques when evaluating primary Sjögren’s syndrome (pSS) patients. Incorporation of additional diagnostics involving screening for disease-specific biomarkers in biological fluid is a promising concept that requires further investigation. In the current study we aimed to explore novel disease biomarkers in saliva and tears from pSS patients.MethodsLiquid chromatography-mass spectrometry (LC-MS) was performed on stimulated whole saliva and tears from 27 pSS patients and 32 healthy controls, and salivary and tear proteomic biomarker profiles were generated. LC-MS was also combined with size exclusion chromatography to isolate extracellular vesicles (EVs) from both fluids. Nanoparticle tracking analysis was conducted on joint fractions from the saliva and tears to determine size distribution and concentration of EVs. Further EV characterisation was performed by immunoaffinity capture of CD9-positive EVs using magnetic beads, detected by flow cytometry. The LC-MS data were analysed for quantitative differences between patient and control groups using Scaffold, and the proteins were further analysed using the Database for Annotation, Visualization and Integrated Discovery (DAVID), for gene ontology overrepresentation, and the Search Tool for the Retrieval of Interacting Genes/Proteins for protein-protein interaction network analysis.ResultsUpregulation of proteins involved in innate immunity (LCN2), cell signalling (CALM) and wound repair (GRN and CALML5) were detected in saliva in pSS. Saliva EVs also displayed biomarkers critical for activation of the innate immune system (SIRPA and LSP1) and adipocyte differentiation (APMAP). Tear analysis indicated overexpression of proteins involved in TNF-α signalling (CPNE1) and B cell survival (PRDX3). Moreover, neutrophil gelatinase-associated lipocalin was upregulated in saliva and tears in pSS. Consistently, DAVID analysis demonstrated pathways of the adaptive immune response in saliva, of cellular component assembly for saliva EVs, and of metabolism and protein folding in tears in pSS patients.ConclusionsLC-MS of saliva and tears from pSS patients, solely and in combination with size-exclusion chromatography allowed screening for possible novel biomarkers encompassing both salivary and lacrimal disease target organs. This approach could provide additional diagnostic accuracy in pSS, and could possibly also be applied for staging and monitoring the disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-017-1228-x) contains supplementary material, which is available to authorized users.

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Progranulin antibodies in autoimmune diseases

Cited by 65 publications

References 42 publications

TDP-43 frontotemporal lobar degeneration and autoimmune disease

TDP-43 frontotemporal lobar degeneration and autoimmune disease

PGRN protects against colitis progression in mice in an IL-10 and TNFR2 dependent manner

Identification of potential saliva and tear biomarkers in primary Sjögren’s syndrome, utilising the extraction of extracellular vesicles and proteomics analysis

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