Patients with enthesitis related arthritis show similar monocyte function pattern as seen in adult axial
Shruti Bhattacharya1, Ramnath Misra1, Amita Aggarwal2
1Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.
Background:
Axial SpA and Enthesitis related arthritis (ERA) patients show strong HLA-B27 association, gut dysbiosis, high toll like receptor (TLR)2 and 4 expression on monocytes, pro-inflammatory cytokine production and elevated levels of TLR4 endogenous ligands [tenascin-c (TNC) and myeloid related protein (MRP)8/14] in serum. Hence, we aimed to understand if these diseases have similar or different monocyte response.
Methods:
Fifty adult axial SpA, 52 ERA patients and 25 healthy controls (HC) were enrolled. Cytokine-producing monocyte frequency before and after stimulation with lipopolysaccharide (LPS), peptidoglycan (PG), TNC or MRP8 were measured in whole blood (WB) and synovial fluid mononuclear cells (SFMC) by flow cytometry. Also, IL-6, TNF, MMP3, TNC and MRP8/14 levels were measured in unstimulated and TLR ligand stimulated WB cultures supernatant by ELISA. Finally, the mRNA expression levels of TNF and IL-6 were measured post stimulation with LPS, TNC and MRP8.
Results:
At baseline, ERA and axial SpA patients showed similar TNF-α producing monocyte frequency which was higher than HC. MRP8 simulation led to increased TNF-α producing monocyte frequency in ERA than axial SpA. TNC and MRP8 stimulation led to similar IL-6 producing monocyte frequency in axial SpA and ERA patients. Baseline TNF and IL-6 producing monocyte frequency also modestly correlated with disease activity scores. TNF and IL-6 producing monocyte frequency increased in response to TLR stimulation in SFMC from both patients. In culture supernatants, axial SpA and ERA patients showed similar TNF production at baseline. MRP8 and TNC stimulation led to higher TNF production from ERA. Baseline IL-6 and MMP3 production was higher in ERA while TLR stimulation led to similar IL-6 and MMP3 production from axial SpA and ERA. TNC stimulation led to higher MMP3 production in ERA. mRNA expression in response to TLR stimulation was observed to be similar in axial SpA and ERA. TNC production was higher in ERA at baseline, while MRP8/14 production was higher in axial SpA than ERA post stimulation.
Conclusion:
ERA patients have similar monocyte response to exogenous and endogenous TLR ligands as patients with axial SpA. This suggests that differences between pediatric and adult-onset SpA are minimal and they may have a common pathogenesis.
Insights
Enthesitis-related arthritis (ERA) and axial spondyloarthritis (SpA) patients exhibit similar monocyte responses to toll-like receptor (TLR) ligands, suggesting a shared pathogenesis. These findings indicate minimal differences between pediatric and adult-onset SpA, supporting a common underlying disease mechanism.
Area of Science:
- Immunology
- Rheumatology
- Molecular Biology
Background:
- Axial spondyloarthritis (SpA) and Enthesitis-related arthritis (ERA) share associations with HLA-B27, gut dysbiosis, and heightened toll-like receptor (TLR) expression on monocytes.
- Elevated levels of TLR4 endogenous ligands, tenascin-C (TNC) and myeloid-related protein (MRP)8/14, are observed in the serum of these patients.
- Understanding the similarities and differences in monocyte responses is crucial for elucidating the pathogenesis of these related arthritic conditions.
Purpose of the Study:
- To investigate and compare the monocyte response to exogenous and endogenous toll-like receptor (TLR) ligands in patients with axial spondyloarthritis (SpA) and Enthesitis-related arthritis (ERA).
- To determine if observed differences in monocyte activation and cytokine production reflect distinct or common pathogenic pathways in these conditions.
Main Methods:
- Flow cytometry was used to quantify cytokine-producing monocyte frequencies in whole blood and synovial fluid mononuclear cells (SFMC) from 50 axial SpA patients, 52 ERA patients, and 25 healthy controls (HC) before and after stimulation with TLR ligands (LPS, PG, TNC, MRP8).
- Enzyme-linked immunosorbent assay (ELISA) measured IL-6, TNF, MMP3, TNC, and MRP8/14 levels in unstimulated and stimulated whole blood culture supernatants.
- Messenger RNA (mRNA) expression of TNF and IL-6 was assessed post-stimulation with LPS, TNC, and MRP8.
Main Results:
- Both axial SpA and ERA patients showed similar baseline frequencies of TNF-α producing monocytes, which were higher than in HC. MRP8 stimulation increased TNF-α producing monocytes more in ERA than axial SpA.
- TNC and MRP8 stimulation resulted in comparable IL-6 producing monocyte frequencies in both patient groups. Baseline TNF and IL-6 producing monocyte frequencies correlated with disease activity.
- While baseline TNF production was similar, ERA patients showed higher TNF and MMP3 production after MRP8 and TNC stimulation. mRNA expression responses to TLR stimulation were similar in both groups.
Conclusions:
- Enthesitis-related arthritis (ERA) patients demonstrate a monocyte response to exogenous and endogenous TLR ligands that is comparable to patients with axial spondyloarthritis (SpA).
- These findings suggest that the differences between pediatric-onset (ERA) and adult-onset (axial SpA) spondyloarthritis are minimal.
- The study supports the hypothesis that axial SpA and ERA share a common underlying pathogenesis, driven by similar inflammatory pathways involving monocyte responses to TLR activation.
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