Mechanisms of pain in autoimmunity : the role of antibodies

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.

List of scientific papers

I. Wigerblad G, Bas, DB, Fernandes-Cerqueira C, Krishnamurthy A, Nandakumar KS, Rogoz K, Kato J, Sandor K, Su J, Jimenez-Andrade JM, Finn A, Bersellini Farinotti A, Amara K, Lundberg K, Holmdahl R, Jakobsson PJ, Malmström V, Catrina AI, Klareskog L, Svensson CI. Autoantibodies to citrullinated proteins induce joint pain independent of inflammation via a chemokine-dependent mechanism. Annals of the Rheumatic Diseases. 2016 Apr;75(4):730-8.
https://doi.org/10.1136/annrheumdis-2015-208094

II. Krishnamurthy A, Joshua V, Haj Hensvold A, Jin T, Sun M, Vivar N, Ytterberg AJ, Engström M, Fernandes-Cerqueira C, Amara K, Magnusson M, Wigerblad G, Kato J, Jimenez-Andrade JM, Tyson K, Rapecki S, Lundberg K, Catrina SB, Jakobsson PJ, Svensson CI, Malmström V, Klareskog L, Wähämaa H, Catrina AI. Identification of a novel chemokine-dependent molecular mechanism underlying rheumatoid arthritis-associated autoantibody-mediated bone loss. Annals of the Rheumatic Diseases. 2016 Apr;75(4):721-9.
https://doi.org/10.1136/annrheumdis-2015-208093

III. Wigerblad G, Bas D, Nandakumar KS, Sinclair J, Sandor K, Abdelmoaty S, Su J, Khmaladze I, Collin M, Bersellini Farinotti A, Baharpoor A, Kultima K, Jardemark K, Lanner JT, Holmdahl R, Svensson CI. Collagen type II specific antibodies induce pain through immune complex mediated stimulation of neurons. [Manuscript]