Differential Protein Expression in Rheumatoid Arthritis Interstitial Lung Disease

Wu, Xian; Frias, S. Poli De; Taheri, Sahar; Hoffman, Katherine L.; Easthausen, Imaani; Esposito, Anthony J.; Arias, Lucas; Ayaub, Ehab; Maurer, Rie; Gill, Ritu R.; Hatabu, Hiroto; Nishino, Mizuki; Frits, Michelle; Iannaccone, Christine; Weinblatt, Michael E.; Shadick, Nancy A.; Dellaripa, Paul F.; Rosas, Iván O.; Martínez, Fernando J.; Choi, Augustine M.K.; Doyle, Tracy J.

doi:10.1164/ajrccm-conference.2020.201.1_meetingabstracts.a7796

Cited by 2 publications

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“…We also found elevated MMP7 in autoimmune/hereditary PAP, and both ICAM5 and MMP7 were elevated in a few patients with SAVI-related ILD ( online supplemental figure S9 ). Elevation of ICAM5 was also reported in idiopathic pulmonary fibrosis (IPF) 18 19 , rheumatoid arthritis-associated ILD (RA-ILD) 17 , and bronchoalveolar lavage (BAL) fluid from neuroendocrine hyperplasia of infancy (NEHI) 20 . In these reports, the tissue of origin of ICAM5 is unclear.…”

Section: Discussionmentioning

confidence: 89%

“…However, an autopsy dataset of healthy adults (GTEx) 16 showed ICAM5 expression in the lung comparable to that seen in the CNS ( figure 5A, online supplemental figure S10A ). Indeed, serum ICAM5 is elevated in several interstitial lung diseases (ILDs) 17-20 . MMP7, a matrix metallopeptidase (MMP) that efficiently cleaves ICAM5 in vitro 21 , is also significantly elevated in sJIA-PAP sera ( online supplemental table S4, online supplemental figure S9 ), and we found a significant correlation between serum concentrations of ICAM5 and MMP7 ( figure 5B ).…”

Section: Resultsmentioning

confidence: 99%

“…We found ICAM5 predominantly in interstitial fibroblasts by immunostaining ( figures 5D ), and in fibroblasts, type II alveolar (AT2) cells, and ciliated cells by RNA-sequencing 11 ( online supplemental figure S14 ). MMP7 has been shown to efficiently cleave ICAM5 and is also elevated in various other ILDs 17 19 31 . We hypothesize that ICAM5 elevation in blood may be traced back to lung-specific activity of MMP7 in sJIA-PAP, and the marker pair may be elevated in a variety of lung diseases.…”

Section: Discussionmentioning

confidence: 99%

“…In line with our hypothesis, ICAM5 appeared also to be elevated in cases with pneumonia or pulmonary hypertension, but normal in an sJIA patient with a distant history of lung disease that had resolved at sampling (Figure 5D, Supplementary Table 1). Elevation of ICAM5 was reported in idiopathic pulmonary fibrosis (IPF) [33,34], rheumatoid arthritis-associated ILD (RA-ILD) [35], and bronchoalveolar lavage (BAL) fluid from neuroendocrine hyperplasia of infancy (NEHI) [36] (Supplementary Table 8).…”

Section: Discussionmentioning

confidence: 99%

“…Cytokines/chemokines contributing to the sJIA-PAP component, particularly CCL17/TARC, CCL7/MCP3, CCL25, GDF15/MIC-1 [39] and CCL11/eotaxin-1 (Supplementary Table 8), could be part of pro-fibrotic and/or type 2 immune responses. They, along with MMP7, have been elevated in the proteomic profiles of other ILDs [33][34][35][36]. In a mouse model, expression of a PAP-causing surfactant mutant led to overexpression of CCL17, CCL7, and MMP7 proteins in AT2 cells [40].…”

Section: Discussionmentioning

confidence: 99%

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Serum proteome analysis of systemic JIA and related pulmonary alveolar proteinosis identifies distinct inflammatory programs and biomarkers

Chen

Deutsch

Schulert

et al. 2021

Preprint

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ObjectivesRecent observations in systemic Juvenile Idiopathic Arthritis (sJIA) suggest an increasing incidence of high-mortality interstitial lung disease (ILD), characterized pathologically by a variant of pulmonary alveolar proteinosis (PAP). The co-occurrence of macrophage activation syndrome (MAS) and PAP in sJIA suggested a shared pathology, but features of drug reaction such as anaphylaxis, rashes, and eosinophilia are also common in these patients. We sought to investigate immunopathology and identify biomarkers of this lung disease.MethodsWe used SOMAscan to measure >1300 analytes in serum samples from healthy controls and patients with sJIA-PAP, sJIA, sJIA-MAS, and other associated diseases, and verified selected findings by ELISA and lung immunostaining. Because a sample’s proteome may reflect multiple states (SJIA, MAS, SJIA-PAP), we used linear regression modeling to identify subsets of altered proteins associated with each state.ResultsMarkers identified for sJIA, including SAA, S100A9, and S100A12, were consistent with previous reports. Proteome alterations in sJIA and MAS overlapped substantially, including new findings of heat shock proteins and glycolytic enzymes. sJIA, MAS, and sJIA-PAP shared elevation of IL-18. Importantly, we identified a unique sJIA-PAP signature whose expression was independent of sJIA-MAS activity. Key proteins were ICAM5 and MMP7, previously observed markers of fibrotic ILD. Immunohistochemistry showed expression of these proteins in sJIA-PAP lung, supporting a pulmonary source. The eosinophil chemoattractant CCL11 was elevated in sJIA-PAP, but not sJIA/MAS or other PAP.ConclusionsWe found novel circulating proteins associated specifically with sJIA, sJIA/MAS and sJIA-PAP. Select biomarkers, such as ICAM5, could aid in early detection and management of sJIA-PAP.Key MessagesPulmonary Alveolar Proteinosis (PAP) occurring in the setting of Systemic Juvenile Idiopathic Arthritis (sJIA) is an increasingly-noted, dangerous condition that has been associated with Macrophage Activation Syndrome (MAS).We evaluated >1300 serum proteins by aptamer array, verifying and localizing key proteins, and identified novel pathways associated with MAS (HSPs, glycolysis), candidate pathways/proteins associated with PAP in sJIA (e.g., ICAM5, MMP7, and type 2 chemokines), and divergence of the sJIA/MAS and sJIA-PAP proteomes.This analysis supports the evaluation of novel pathways in MAS, the validation of screening/monitoring biomarkers in sJIA-PAP, and the management of PAP as a disease process enmeshed with, but distinct from, sJIA and MAS.

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Section: Discussionmentioning

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Serum proteome analysis of systemic JIA and related pulmonary alveolar proteinosis identifies distinct inflammatory programs and biomarkers

Chen

Deutsch

Schulert

et al. 2021

Preprint

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Identification of Distinct Inflammatory Programs and Biomarkers in Systemic Juvenile Idiopathic Arthritis and Related Lung Disease by Serum Proteome Analysis

Chen

Deutsch

Schulert

et al. 2022

Arthritis & Rheumatology

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Objective Recent observations in systemic juvenile idiopathic arthritis (JIA) suggest an increasing incidence of high‐mortality interstitial lung disease often characterized by a variant of pulmonary alveolar proteinosis (PAP). Co‐occurrence of macrophage activation syndrome (MAS) and PAP in systemic JIA suggests a shared pathology, but patients with lung disease associated with systemic JIA (designated SJIA‐LD) also commonly experience features of drug reaction such as atypical rashes and eosinophilia. This study was undertaken to investigate immunopathology and identify biomarkers in systemic JIA, MAS, and SJIA‐LD. Methods We used SOMAscan to measure ~1,300 analytes in sera from healthy controls and patients with systemic JIA, MAS, SJIA‐LD, or other related diseases. We verified selected findings by enzyme‐linked immunosorbent assay and lung immunostaining. Because the proteome of a sample may reflect multiple states (systemic JIA, MAS, or SJIA‐LD), we used regression modeling to identify subsets of altered proteins associated with each state. We tested key findings in a validation cohort. Results Proteome alterations in active systemic JIA and MAS overlapped substantially, including known systemic JIA biomarkers such as serum amyloid A and S100A9, and novel elevations in the levels of heat‐shock proteins and glycolytic enzymes. Interleukin‐18 levels were elevated in all systemic JIA groups, particularly MAS and SJIA‐LD. We also identified an MAS‐independent SJIA‐LD signature notable for elevated levels of intercellular adhesion molecule 5 (ICAM‐5), matrix metalloproteinase 7 (MMP‐7), and allergic/eosinophilic chemokines, which have been previously associated with lung damage. Immunohistochemistry localized ICAM‐5 and MMP‐7 in the lungs of patients with SJIA‐LD. The ability of ICAM‐5 to distinguish SJIA‐LD from systemic JIA/MAS was independently validated. Conclusion Serum proteins support a systemic JIA–to‐MAS continuum; help distinguish systemic JIA, systemic JIA/MAS, and SJIA‐LD; and suggest etiologic hypotheses. Select biomarkers, such as ICAM‐5, could aid in early detection and management of SJIA‐LD.

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Differential Protein Expression in Rheumatoid Arthritis Interstitial Lung Disease

Cited by 2 publications

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Serum proteome analysis of systemic JIA and related pulmonary alveolar proteinosis identifies distinct inflammatory programs and biomarkers

Serum proteome analysis of systemic JIA and related pulmonary alveolar proteinosis identifies distinct inflammatory programs and biomarkers

Identification of Distinct Inflammatory Programs and Biomarkers in Systemic Juvenile Idiopathic Arthritis and Related Lung Disease by Serum Proteome Analysis

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