| 1. |
- Bersellini Farinotti, Alex, et al.
(author)
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Cartilage-binding antibodies induce pain through immune complex-mediated activation of neurons
- 2019
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In: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 216:8, s. 1904-1924
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Journal article (peer-reviewed)abstract
- Rheumatoid arthritis-associated joint pain is frequently observed independent of disease activity, suggesting unidentified pain mechanisms. We demonstrate that antibodies binding to cartilage, specific for collagen type II (CII) or cartilage oligomeric matrix protein (COMP), elicit mechanical hypersensitivity in mice, uncoupled from visual, histological and molecular indications of inflammation. Cartilage antibody-induced pain-like behavior does not depend on complement activation or joint inflammation, but instead on tissue antigen recognition and local immune complex (IC) formation. smFISH and IHC suggest that neuronal Fcgr1 and Fcgr2b mRNA are transported to peripheral ends of primary afferents. CII-ICs directly activate cultured WT but not FcRγ chain-deficient DRG neurons. In line with this observation, CII-IC does not induce mechanical hypersensitivity in FcRγ chain-deficient mice. Furthermore, injection of CII antibodies does not generate pain-like behavior in FcRγ chain-deficient mice or mice lacking activating FcγRs in neurons. In summary, this study defines functional coupling between autoantibodies and pain transmission that may facilitate the development of new disease-relevant pain therapeutics.
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| 2. |
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| 3. |
- Lloyd, Katy A., et al.
(author)
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Differential ACPA Binding to Nuclear Antigens Reveals a PAD-Independent Pathway and a Distinct Subset of Acetylation Cross-Reactive Autoantibodies in Rheumatoid Arthritis
- 2019
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In: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 9, s. 1-22
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Journal article (peer-reviewed)abstract
- Rheumatoid arthritis (RA) associated anti-citrullinated protein autoantibodies (ACPA) target a wide range of modified proteins. Citrullination occurs during physiological processes such as apoptosis, yet little is known about the interaction of ACPA with nuclear antigens or apoptotic cells. Since uncleared apoptotic cells and neutrophil extracellular trap (NET) products have been postulated to be central sources of autoantigen and immunostimulation in autoimmune disease, we sought to characterize the anti-nuclear and anti-neutrophil reactivities of ACFA. Serology showed that a subset of anti-CCP2 seropositive RA patients had high reactivity to full-length citrullinated histones. In contrast, seronegative RA patients displayed elevated IgG reactivity to native histone compared to controls, but no citrulline-specific reactivity. Screening of 10 single B-cell derived monoclonal AGFA from RA patients revealed that four ACPA exhibited strong binding to apoptotic cells and three of these had anti-nuclear (ANA) autoantibody reactivity. Modified histones were confirmed to be the primary targets of this anti-nuclear ACPA subset following immunoprecipitation from apoptotic cell lysates. Monoclonal ACPA were also screened for reactivities against stimulated murine and human neutrophils, and all the nuclear-reactive monoclonal ACPA bound to NETs. Intriguingly, one ACPA mAb displayed a contrasting cytoplasmic perinuclear neutrophil binding and may represent a different NET-reactive ACPA subset. Notably, studies of CRISPR-Cas9 PAD4 KO cells and cells from PAD KO mice showed that the cytoplasmic NET-binding was fully dependent on PAD4, whilst nuclear- and histone-mediated NEI reactivity was largely PAD-independent. Our further analysis revealed that the nuclear binding could be explained by consensus-motif driven ACPA cross-reactivity to acetylated histones. Specific acetylated histone peptides targeted by the monoclonal antibodies were identified and the anti-modified protein autoantibody (AMPA) profile of the ACPA was found to correlate with the functional activity of the antibodies. In conclusion, when investigating monoclonal ACPA, we could group ACPA into distinct subsets based on their nuclear binding-patterns and acetylation-mediated binding to apoptotic cells, neutrophils, and NETs. Differential anti-modified protein reactivities of RA-autoantibody subsets could have an important functional impact and provide insights in RA pathogenesis.
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| 4. |
- Su, Jie, et al.
(author)
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Pain-like behavior in the collagen antibody-induced arthritis model is regulated by lysophosphatidic acid and activation of satellite glia cells.
- 2022
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In: Brain, behavior, and immunity. - : Elsevier. - 0889-1591 .- 1090-2139. ; 101, s. 214-230
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Journal article (peer-reviewed)abstract
- Inflammatory and neuropathic-like components underlie rheumatoid arthritis (RA)-associated pain and lysophosphatidic acid (LPA) is linked to both joint inflammation in RA patients and to neuropathic pain. Thus, we investigated a role for LPA signalling using the collagen antibody-induced arthritis (CAIA) model. Pain-like behavior during the inflammatory phase and the late, neuropathic-like phase of CAIA was reversed by a neutralizing antibody generated against LPA and by an LPA1/3 receptor inhibitor, but joint inflammation was not affected. Autotaxin, an LPA synthesizing enzyme was upregulated in dorsal root ganglia (DRG) neurons during both CAIA phases, but not in joints or spinal cord. Late-phase pronociceptive neurochemical changes in the DRG were blocked in Lpar1 receptor deficient mice and reversed by LPA neutralization. In vitro and in vivo studies indicated that LPA regulates pain-like behavior via the LPA1 receptor on satellite glia cells (SGCs), which is expressed by both human and mouse SGCs in the DRG. Furthermore, CAIA-induced SGC activity is reversed by phospholipid neutralization and blocked in Lpar1 deficient mice. Our findings suggest that the regulation of CAIA-induced pain-like behavior by LPA signalling is a peripheral event, associated with the DRGs and involving increased pronociceptive activity of SGCs, which in turn act on sensory neurons.
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| 5. |
- Wigerblad, Gustaf
(author)
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Mechanisms of pain in autoimmunity : the role of antibodies
- 2016
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Doctoral thesis (other academic/artistic)abstract
- Chronic pain in autoimmune diseases, like rheumatoid arthritis (RA), is a common and life- changing problem for many patients. Treatment is usually aimed at reducing inflammation and preserving the function of affected tissues. Chronic pain, however, often persists despite optimal disease control. Autoimmune pain arises from multiple mechanisms with a wide range of characteristics that differs between individuals. For effective management of the pain, it is essential to understand these mechanisms. One of the hallmarks in the pathogenesis in most autoimmune diseases is the presence of autoantibodies. In RA, several types of antibodies are well characterized, but little is known about their interaction with the sensory system. Thus, the aim of this thesis is explore mechanisms involved in pain signaling, specifically the role of disease-relevant antibodies as inducers of pain. In Paper I and II, we investigate the effect of anti-citrullinated protein antibodies (ACPA) on pain behavior and interaction with immune cells. When injected into mice, both polyclonal human ACPA or murinized monoclonal ACPA induces spontaneous and evoked pain-like behavior in the absence of inflammation. Additionally, the antibodies induce trabecular bone loss measured with micro-CT. The antibodies localize to joint and bone marrow, binding osteoclasts and its precursors. Using cultures of mice and human osteoclasts, we show that ACPA bind structures on the cells, causing proliferation and release of the chemokine CXCL1/IL-8. The effect of the release is increased bone resorption and activation of sensory neurons, causing pain-like behavior, which can be reversed by treating the mice with the CXCR1/2 blocker reparixin. In Paper III, we demonstrate that mice injected with antibodies specific to the cartilage protein collagen type II (anti-CII mAbs) displays pronounced mechanical hypersensitivity and reduction in locomotion at time points when visual, histological and molecular indications of inflammation were completely absent. Further, this effect was not mediated by the activation of complement factors or by changes in the cartilage structure. Instead our data point to a direct action of anti-CII mAb/collagen immune complexes on the sensory neurons through neuronally expressed Fc-gamma receptor IIb (FcγRIIb), causing increased inward currents, intracellular Ca2+ levels, and calcitonin-gene related peptide (CGRP) release. Importantly, the nociceptive properties of anti-CII mAbs were lost when the Fc-FcγR interaction was disrupted in vivo. In summary, we have described two novel mechanisms of how disease-relevant antibodies can activate sensory neurons, causing pain-like behavior. These results deepen the understanding of pain mechanisms in autoimmune disease and potentially to new ways of treating the pain component in patients.
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