K/BxN Serum-Transfer Arthritis as a Model for Human Inflammatory Arthritis

Anne D. Christensen; Claus Haase; Andrew D. Cook; John A. Hamilton

doi:10.3389/fimmu.2016.00213

Christensen, Anne D.;Haase, Claus;Cook, Andrew D.;Hamilton, John A.;

2016-06-02 00:00:00

Review published: 02 June 2016 doi: 10.3389/fimmu.2016.00213 K/BxN Serum-Transfer Arthritis as a Model for Human inflammatory Arthritis 1,2 2 1 1 Anne D. Christensen *, Claus Haase , Andrew D. Cook and John A. Hamilton 1 2 Department of Medicine, University of Melbourne, Parkville, VIC, Australia, Novo Nordisk A/S, Måløv, Denmark The K/BxN serum-transfer arthritis (STA) model is a murine model in which the immu- nological mechanisms occurring in rheumatoid arthritis (RA) and other arthritides can be studied. To induce K/BxN STA, serum from arthritic transgenic K/BxN mice is transferred to naive mice and manifestations of arthritis occur a few days later. The inflammatory response in the model is driven by autoantibodies against the ubiquitously expressed self-antigen, glucose-6-phosphate isomerase (G6PI), leading to the formation of immune complexes that drive the activation of different innate immune cells such as neutrophils, macrophages, and possibly mast cells. The pathogenesis further involves a range of immune mediators including cytokines, chemokines, complement factors, Toll-like Edited by: Pierre Miossec, receptors, Fc receptors, and integrins, as well as factors involved in pain and bone University of Lyon, France erosion. Hence, even though the K/BxN STA model mimics only the effector phase of Reviewed by: RA, it still involves a wide range of relevant disease mediators. Additionally, as a murine Christian Jorgensen, Institut National de la Santé et de la model for arthritis, the K/BxN STA model has some obvious advantages. First, it has a Recherche Médicale, France rapid and robust onset of arthritis with 100% incidence in genetically identical animals. Erik Lubberts, Second, it can be induced in a wide range of strain backgrounds and can therefore Erasmus MC University Medical Center, Netherlands also be induced in gene-deficient strains to study the specific importance of disease Gilles Chiocchia, mediators. Even though G6PI might not be an essential autoantigen, for example, in Institut National de la Santé et de la Recherche Médicale, France RA, the K/BxN STA model is a useful tool to understand how autoantibodies, in general, *Correspondence: drive the progression of arthritis by interacting with downstream components of the Anne D. Christensen innate immune system. Finally, the model has also proven useful as a model wherein [email protected] arthritic pain can be studied. Taken together, these features make the K/BxN STA model a relevant one for RA, and it is a potentially valuable tool, especially for the preclinical Specialty section: This article was submitted to Inflammation, Abbreviations: ACPA, anti-citrullinated protein antibodies; APC, antigen-presenting cell; C5aR, C5a receptor; CAIA, collagen a section of the journal antibody-induced arthritis; CFA, complete Freund’s adjuvant; CGRP, calcitonin-gene-related peptide; CIA, collagen-induced Frontiers in Immunology arthritis; CII, type II collagen; COX, cyclooxygenase; DCs, dendritic cells; DMARDs, disease-modifying anti-rheumatic Received: 22 February 2016 drugs; FcγR, Fcγ receptor; G6PI, glucose-6-phospate isomerase; G-CSF, granulocyte colony-stimulating factor; GM-CSF, Accepted: 17 May 2016 granulocyte–macrophage colony-stimulating factor; ICA, immune complex-induced arthritis; ICs, immune complexes; IFA, Published: 02 June 2016 incomplete Freund’s adjuvant; IFNγ, interferon γ; IgGs, immunoglobulins; IL, interleukin; IRF, interferon regulator factor; IVIG, intravenous immunoglobulin; KO, knockout; LPS, lipopolysaccharide; mAb, monoclonal antibodies; MHC, major Citation: histocompatibility complex; MIF, macrophage migration inhibitory factor; MMP, matrix metalloproteinase; MyD88, myeloid Christensen AD, Haase C, Cook AD differentiation factor 88; NK cells, natural killer cells; NK T cells, natural killer T cells; NOD, non-obese diabetic; NSAIDs, and Hamilton JA (2016) K/BxN non-steroidal anti-inflammatory drugs; PAMP, pathogen-associated molecular pattern; PGs, prostaglandins; RA, rheumatoid Serum-Transfer Arthritis as a Model arthritis; RANKL, receptor-activator-of-nuclear-factor-κβ ligand; RF, rheumatoid factor; STA, serum-transfer arthritis; Syk, for Human Inflammatory Arthritis. spleen tyrosine kinase; TCR, T-cell receptor; TLR, Toll-like receptor; TNF, tumor necrosis factor; TGF-β1, transforming growth Front. Immunol. 7:213. factor β1; WT, wild-type. doi: 10.3389/fimmu.2016.00213 Frontiers in Immunology | www.frontiersin.org 1 June 2016 | Volume 7 | Article 213 Christensen et al. Mechanisms in Immune Complex-Driven Arthritis screening of new therapeutic targets for RA and perhaps other forms of inflammatory arthritis. Here, we describe the molecular and cellular pathways in the development of K/BxN STA focusing on the recent advances in the understanding of the important mechanisms. Additionally, this review provides a comparison of the K/BxN STA model to some other arthritis models. Keywords: K/BxN serum-transfer arthritis model, immune complex-driven arthritis, animal model, autoantibodies, rheumatoid arthritis addressed, with focus on driver mechanisms responsible for iNTRODUCTiON progression of arthritis aer s ft erum transfer. Since B- and T-cells Research into the pathogenesis of rheumatoid arthritis (RA) has are not thought to play a major role in mediating arthritis aer ft benefited enormously from a vast number of animal models, serum transfer they are not addressed in detail. wherein mechanisms governing arthritis can be studied. These Since its discovery in 1996, the model has been used increas- include both spontaneous models, such as the tumor necrosis ingly. From 2000 to 2005, only 15 papers were published about factor (TNF) transgenic and interleukin-1 (IL-1) receptor antag- the K/BXN STA model (pubmed.com search under “KBxN onist-deficient mice, as well as induced models, most notably the serum transfer arthritis”); from 2005 to 2010, 53 papers were collagen-induced arthritis (CIA) model. published, and from 2010 to 2015, the number was 87 with 18 In 1996, the K/BxN model of arthritis was reported for the first papers published in 2015. Nonetheless, a thorough review of the time by the Mathis/Benoist laboratory (1). This model was dis- literature about the model has not been published since 2004 (3). covered by crossing T-cell receptor (TCR) transgenic KRN mice In addition to updating the literature on the K/BxN STA model, on a C57BL/6 background (transgenic for a TCR) recognizing a this review discusses the relevance of the model in relation to RA bovine ribonuclease peptide (RNase 43–56) presented by I-Ak and provides a comparison to other RA models. It should also major histocompatibility complex (MHC) class II molecule with be noted that immune complexes (ICs) have been implicated in autoimmune-prone non-obese diabetic (NOD) mice. Surprisingly, other arthritides, such as systemic lupus erythematosus (7) and the F1-generation, called K/BxN mice, developed severe arthritis ankylosing spondylitis (8); thus, though the focus on this review by the age of 4–5 weeks, which rapidly evolved until mobility was is on RA, it could also be relevant to other arthritides. significantly suppressed ( 1). Arthritis progression in the K/BxN mice is driven by activation of T cells expressing the KRN TCR g7 THe iNiTiATiON PHASe OF THe K/BxN that recognizes a self-peptide bound to the NOD-derived I-A STA MODe L molecule on MHC class II antigen-presenting cells (APCs). The g7 peptide recognized by the K/BxN TCR, in the context of I-A , e Th main features of what we have termed for convenience, albeit is the ubiquitously expressed self-antigen, glucose-6-phosphate somewhat arbitrary, the “initiation phase” of the K/BxN STA isomerase (G6PI) (2), a cytosolic glycolytic enzyme catalyzing model, are depicted in the literature-based schematic in Figure 1 the inter-conversion of d-glucose-6-phosphate and d-fructose- and summarized below. 6-phosphate (3). It was demonstrated that the activated T cells g7 subsequently interact with B cells through TCR:A –MHC class II molecules and CD40:CD40L engagement, thereby promoting immune Complexes polyclonal B-cell activation and T-helper cell-dependent produc- To address why the autoimmune inflammatory attack against the tion of disease-inducing immunoglobulins (IgGs) (1, 3–5). ubiquitously expressed enzyme, G6PI, occurs only in the distal Importantly, it was further shown that transfer of purified joints, it was first shown that G6PI was present on the articular IgGs or serum from arthritic K/BxN mice led to a robust and surface in ankle joints in normal mice and, most importantly, that reproducible arthritis in many mouse strains, such as BALB/c, its expression was amplified in arthritic mice (9). Second, it was C57BL/6, and DBA/1 mice (6), as well as B-cell- and lymphocyte- demonstrated that purified anti-G6PI IgGs localized specifically deficient mice (4). Since transfer of K/BxN sera leads to reproduc - to the distal joints in the front and rear limbs within minutes of ible disease in several mouse strains, it is an ideal model to study intravenous injection, while control IgGs could not be detected the effector mechanisms involved in progression of disease. As in any joints. Binding of anti-G6PI IgGs reached saturation aer ft expected, arthritis induced by serum transfer is transient and 20 min and remained localized within the joints for at least 24 h wanes aer 15–30 ft days but can be made persistent by repeated (10). This led to the conclusion that anti-G6PI antibodies bind administration of antibody or serum (4). Overall, the discovery directly to extracellular G6PI in normal non-inflamed mouse of K/BxN arthritis showed that joint-specific disease can be the joints, thereby forming anti-G6PI/G6PI ICs directly on the consequence of systemic self-reactivity. The ability to transfer cartilage surface. The importance of these ICs was emphasized arthritis using pooled K/BxN sera has been widely used by many by the observation that pathogenicity aer ft transfer of a pool of researchers to dissect several important effector pathways of anti-G6PI monoclonal antibodies (mAb) was directly dependent arthritis in vivo. In the following sections, current knowledge on their ability to form mAb/G6PI ICs (11). Furthermore, it about the K/BxN serum-transfer arthritis (STA) model is was demonstrated that soluble ICs, formed between anti-G6PI Frontiers in Immunology | www.frontiersin.org 2 June 2016 | Volume 7 | Article 213 Christensen et al. Mechanisms in Immune Complex-Driven Arthritis FiGURe 1 | The “initiation phase” of the K/BxN STA model. A summary of some of the literature on the early stages of K/BxN STA progression, leading to the formation of anti-G6PI/G6PI ICs in the joint, is depicted. (1) In the blood, the anti-G6PI antibodies (Ab) bind to G6PI and form the ICs. (2) On neutrophils, for example, the ICs bind to Fcγ-receptors (FcγR) triggering the release of vasoactive mediators and the local increase in vascular permeability, thus allowing ICs and anti-G6PI Abs to enter the perivascular tissue in the joint. (3) In the perivascular tissue, the ICs might bind to FcγRs on mast cells causing them to degranulate, resulting in enhanced vascular permeability. (4) ICs, anti-G6PI Abs, non-specific Abs (not shown) and serum proteins (not shown) enter the joint cavity, where (5) anti-G6PI Abs bind to G6PI expressed on the cartilage surface. promote arthritis development, indicating that simple access to antibodies and G6PI in serum, played a central role in facilitat- ing access for antibodies to the distal joints by binding to Fcγ- the joint is not pathogenic, but there must be a targeting of ICs to some joint structures, for example, G6PI expressed on cartilage, receptor (FcγR) III (12) possibly expressed on neutrophils in the blood (12, 13) (see also Fc Receptors below) but probably also on to induce arthritis (14). Thus, it appears for reasons unknown that the distal extremities are especially prone to respond to systemic radio-resistant cells in an organ distant from the joint (14). It was further suggested that the activation of neutrophils subsequently circulating ICs by vascular leakage, which subsequently facilitates access of arthritis-inducing antibodies into the joint. triggers the release of vasoactive mediators, which leads to a local increase in vascular permeability, thus allowing ICs to enter the Fc Receptors perivascular tissue in the joint and possibly bind to FCγRIII on mast cells found in close proximity to the microvasculature in An important link between antibodies and activation of the immune system is Fc receptors. Four types of murine FcγR have the synovium (12). If this occurs, it would cause mast cells to degranulate, which results in an even larger and more widespread been identified. FcγRI, FcγRIII, and FcγRIV mediate activating signals via the common γ-chain when cross-linked with ICs, increase in the vascular permeability, thus allowing anti-G6PI antibodies, non-specific antibodies, and serum proteins to enter while FcγRII inhibits cellular activation upon ligation (15). The role of the different Fc γRs in the K/BxN STA model was explored the joint. Once in the joint, the anti-G6PI antibodies bind to G6PI expressed on the articular cartilage surface and thereby mediate using knockout (KO) mice. FcγR KO mice were protected from arthritis demonstrating the crucial role of FcγRs in this model activation of different components of the innate immune system, for example, neutrophils (12) (discussed in Figure 2 below). (16). Lack of FcγRI had no influence on arthritis development (16), whereas FcγRIII-deficient mice developed reduced arthritis It is difficult to explain why ICs in serum facilitate access of antibodies exclusively to the distal joints, but it was suggested that with delayed onset (13, 16, 17). The importance of Fc γRIV was demonstrated by Mancardi et al. (18), who showed that blockade arthritogenic antibodies cause an increase in the macromolecular vasopermeability in sites destined to develop arthritis (14). This of FcγRIV with anti-FcγRIV mAb prevented development of arthritis. Additionally, it has been demonstrated that mice with increased vascular leakage in the distal joints mediated by anti- G6PI:G6PI ICs seemed to involve vasoactive amines, histamine, a specific deletion of FcγRIV on osteoclasts were protected from arthritis induced by K/BxN serum suggesting an important and serotonin. An increased vasopermeability was also induced by G6PI-non-specific ICs. However, the non-specific ICs did not role for FcγRIV in maturation and activation of osteoclasts and Frontiers in Immunology | www.frontiersin.org 3 June 2016 | Volume 7 | Article 213 Christensen et al. Mechanisms in Immune Complex-Driven Arthritis FiGURe 2 | The “effector phase” of the K/BxN STA model. A summary of some of the literature on the subsequent stages of K/BxN STA progression, driven by joint-localized anti-G6PI/G6PI ICs and their proposed interaction with innate immune cells, such as neutrophils and macrophages, is depicted. (1) The alternative complement pathway is activated by the ICs, leading to C3 cleavage and eventually to the generation of C5a. Subsequently, C5a activates neutrophils via C5aR, which leads to their release of LTB . (2) Activation of neutrophils by the LTB /BLT1 interaction and (3) by Fcγ-receptors (FcγRs) leads to the release of interleukin 1β 4 4 (IL-1β), which then induces neutrophil-attracting chemokines, for example, CXCL1, CXCL5, and CCL9, from resident tissue cells. Additionally, neutrophils participate in their own recruitment by releasing the chemokine CXCL2 (CXCR2 ligand) and to a lesser extent, CCL3 (CCR1 ligand). (4) IL-1β, and other pro-inflammatory cytokines, mediates the release of G-CSF locally in the joint, leading to neutrophil mobilization. (5) Leukocyte, for example, neutrophil, recruitment into the joint is facilitated by their LFA-1 binding to its ligands (ICAM1, ICAM2, and JAM-A) expressed on the activated vascular endothelium; Ly6C blood monocytes are also recruited (not shown). (6) Cartilage loss in the inflamed joint is mediated by, for example, IL-1β and macrophage-derived macrophage migration inhibitory factor (MIF). (7) Bone erosion upon osteoclast activation by RANK ligand/RANK interaction and release of MIF; MMP8 can protect against bone erosion and arthritis. (8) Both TNF and the prostaglandin, PGI2, are produced in the joint and either directly or indirectly mediate pain. ultimately bone destruction (19). When addressing the impact of CSF-1-dependent macrophages, which by acting as “sensors” the inhibitory FcγRIIB, it was first observed that mice lacking this for the Fc fragments of IVIG, lead to the induction of FcγRIIB receptor developed arthritis similar to wild-type (WT) mice (6); expression on CSF-1-independent “effector” macrophages at however, three later studies demonstrated an enhanced disease the site of inflammation, thereby raising the threshold for their progression in FcγRIIB KO mice compared to WT mice, indicat- activation by ICs (20). The immunoregulatory effect of IVIG has ing that this inhibitory Fc receptor has an immunosuppressive also been investigated in immune thrombocytopenia in mice and role in the model (13, 17, 20). In conclusion, these results reveal was shown, as in the K/BxN STA model, to result in an induc- that in the K/BxN STA model FcγRIII is the dominant activating tion of FcγRIIB on splenic macrophages, thereby preventing Fc receptor, FcγRIV is contributing to a minor extent, and FcγRII FcγRIII-mediated clearance of IgG-opsonized platelets (24). has an inhibitory role in disease development. Later, the anti-inflammatory effect was claimed to result from As an indication of the importance of Fc receptors in arthritis, the presence of sialylated IgGs which are IgGs with sialic acid intravenous immunoglobulin (IVIG) is widely used as a thera- bound to glycan on their Fc region (23). These sialylated IgGs peutic strategy for suppression of autoantibody-triggered inflam- were shown to bind to the C-type lectin receptor SIGN-R1 on mation in a variety of clinical settings. The immunoglobulins are regulatory myeloid cells resulting in IL-33 release, which in administered in a dose of 1–2 g/kg, and their anti-inflammatory turn stimulated IL-4 secretion from basophils; this IL-4 further effect has been proposed to be the result of several different promoted expression of the inhibitory Fc receptor, FcγRIIB, mechanisms (21). In the K/BxN STA model, IVIG has been on effector macrophages ( 23). The same group further showed shown to suppress the progression of arthritis indicating that Fc that IVIG or sialylated Fcs activated and expanded regulatory receptors are important; however, the mechanisms of action have T cells in mice injected with K/BxN serum (22). However, the been the subject of disagreement (20–23). First, the mechanism importance of sialylation has been questioned by the finding behind the immunosuppression was reported to be induced by that removal of sialic acid residues by neuraminidase did not Frontiers in Immunology | www.frontiersin.org 4 June 2016 | Volume 7 | Article 213 Christensen et al. Mechanisms in Immune Complex-Driven Arthritis affect the suppression of K/BxN STA by IVIG ( 21); furthermore, STA model will be discussed in further detail later). Moreover, the depletion of basophils did not abrogate the immunosup- neutrophils could directly participate in their own recruitment pression exerted by IVIG (21). The reason for the discrepancy by expressing the CXCR2 ligand, CXCL2, and to a lesser extent between these results is currently unknown; however, it could the CCR1 ligand, CCL3 (33). Recruitment of neutrophils was be due to differences in, for example, the source of IVIG, route demonstrated to be dependent on their expression of CXCR2 of administration, mouse strain, or experimental setup. and partly of CCR1 (33, 34). Recently, the link between release of LTB and IL-1β from neutrophils and the requirement for C5a receptor (C5aR) and FcγR was addressed. It was demonstrated THe e FFe CTOR PHASe OF THe K/BxN that C5aR- and FcγR activation on neutrophils were necessary STA MODe L for the initiation and progression of arthritis, and that C5aR acti- vation of neutrophils was required for their LTB release, while e es Th sential link in the K/BxN STA model between antibody- FcγR engagement mediated IL-1β release (35) (complement dependent components, such as ICs, complement, and Fc recep- activation is discussed below and in Figure 2). Activation of the tors, and arthritis progression, is the activation of innate effector two receptors occurred independently from each other without cells such as neutrophils, macrophages, and possibly mast cells. any cross-regulation between the two receptor classes. This is a e m Th ain features of what we have termed for convenience the unique observation compared to other models of autoantibody- “effector phase” of the K/BxN STA model, involving the main induced inflammation where C5aR signaling is thought to set effector cells and their responses, are depicted in the literature- the threshold for subsequent sustained activation of FcγRs on based schematic in Figure 2 and are summarized below. resident tissue immune cells (36). The importance of neutrophil expression of FcγR and C5aR as well as their release of LTB4 and Neutrophils IL-1β in the K/BxN STA model was confirmed by Monach et al. Neutrophils are readily activated by ICs and play an important (28). Furthermore, it was shown that C5aR and FcγR on mast role in the induction of arthritis in the K/BxN STA model. Their cells did not contribute significantly to arthritis ( 35). Some of essential role was illustrated by Wipke et al. (25), who showed that these neutrophil-dependent cascades are depicted in Figure 2. mice depleted of neutrophils failed to develop arthritis – even at Th Fc γR-expression on neutrophils is of crucial importance neutrophil depletion aer t ft he onset of arthritis could reverse for the recognition of ICs was further addressed through the use disease (25). This study used the neutrophil-depleting anti- of the spleen tyrosine kinase (Syk)-deficient mouse strain. Syk is Ly6G/C (Gr-1) mAb (clone RB6.8C5). However, the use of this required for signaling through FcγRs, integrins, and other scav- antibody was recently challenged as it is thought to deplete not enger receptors by using ITAMs to initiate intracellular signaling. + + neutrophils but also a fraction of the Ly6C monocytes only LyG First, it was shown that mice lacking Syk in all hematopoietic and macrophages (26). Specific depletion with anti-Ly6G mAb lineages were resistant to disease in the K/BxN STA model (37). (clone 1A8) confirmed a role for neutrophils in the model and Second, specific deletion of Syk in neutrophils was sufficient to also showed that non-depleting doses of anti-Ly6G mAb (clone block the initiation of arthritis, which emphasizes the impor- 1A8) attenuated progression of arthritis due to blockade of neu- tance of FcγR signaling in neutrophils aer en ft gagement with trophil migration into the joint (27). A crucial role of neutrophils ICs (38). Furthermore, we have recently shown that granulocyte was further supported by the observation that Gfi-1 KO mice, colony-stimulating factor (G-CSF), possibly produced from which have a selective defect in their ability to generate mature IL-1β activation of a resident cell population, is a pivotal driver neutrophils, were resistant to arthritis (28). of the disease progression in the K/BxN STA model and possibly To further understand the role of neutrophils and how they acts, in part, by regulating neutrophil numbers in the circulation contribute to the induction of arthritis, different neutrophil- (39) (Figure 2). related effector mechanisms have been investigated, including the In conclusion, it is evident that neutrophils are a pivotal cell ) and its receptor, BLT1. neutrophil-derived leukotriene B4 (LTB4 type in the K/BxN STA model and play an essential role in pro- LTB is a highly potent lipid chemoattractant produced by cells gression of arthritis. In addition, release of LTB and IL-1β ampli- 4 4 of the innate immune system (for example, neutrophils, mac- fies arthritis by driving the ongoing recruitment of neutrophils. rophages, and mast cells). BLT1 is expressed on neutrophils and induces chemotaxis and adhesion in response to LTB (29, 30). It Macrophages appeared that the arthritis progression in the K/BxN STA model Macrophages are present in high numbers in the inflamed was critically dependent on the generation of neutrophil-derived joint tissue in RA, and activation of macrophage FcγRs by ICs LTB (31), while neutrophil expression of BLT1 was required for at the site of inflammation has been demonstrated to be crucial arthritis generation as well as chemokine production, suggesting in the pathogenesis of an immune complex-induced arthritis that neutrophils recruit other neutrophils in an autocrine manner (ICA) model (40). In the K/BxN STA model, the importance (32). On further examination, BLT1-expression on neutrophils of macrophages has been demonstrated by depletion studies was found crucial for their release of the pro-inflammatory showing that a lack of macrophages resulted in complete resist- cytokine, IL-1β, into the joint which induced the production ance to arthritis (41). Importantly, subsequent studies showed of neutrophil-active chemokines, for example, CXCL1, CXCL5, that arthritis could be induced in macrophage-depleted mice and CCL9, from resident tissue cells of the joint (33) (the role by reconstitution with peritoneal macrophages, hence confirm - and impact of IL-1 β in the progression of arthritis in the K/BxN ing a key role for macrophages (41). However, it has also been Frontiers in Immunology | www.frontiersin.org 5 June 2016 | Volume 7 | Article 213 Christensen et al. Mechanisms in Immune Complex-Driven Arthritis shown that K/BxN serum-induced arthritis is independent of and transfer of mast cells into both strains restored their ability CSF-1-dependent macrophages since op/op mice, which lack to develop arthritis (46). It was also shown that mast cells in the CSF-1, were fully susceptible to arthritis (20). This suggests that initiation phase of the disease were activated through FcγRIII, CSF-1-independent macrophages are the effector macrophages which led to release of IL-1 (47), and arthritis could be suppressed in this model. Moreover, a recent study by Misharin et al. (42) by preventing the activation-induced degranulation of mast cells demonstrated that non-classical Ly6C blood monocytes were by treatment with the cAMP-inducing agent, salbutamol (48). recruited to the joint during inflammation in the K/BxN STA Another way that mast cells might drive arthritis was proposed model where they gave rise to inflammatory macrophages, a to be through the release of tryptase/heparin complexes, which subtype known as M1 macrophages, and were shown to be crucial were shown to induce the expression of the neutrophil chemoat- for development of arthritis (42). Additionally, they showed that tractants, CXCL1, CXCL5, and CXCL8, in cultured fibroblast-like tissue-resident macrophages in the joint played an important role synoviocytes (49). Recently, the use of the mast-cell-deficient W/W-v in maintaining joint integrity and resolution of inflammation -strain has been questioned, since it also shows defects in Kit and that they thereby belong to the M2 subtype of macrophages many other cell lineages, such as red blood cells and neutrophils W/W-v (45). When K/BxN STA arthritis in the Kit -strain was com- (42). Interestingly, their data further suggested that the recruited W-Sh macrophages initially expressed a complex set of both M1 and pared with another mast cell-deficient strain, the Kit -strain, it W/W-v was found that arthritis did not develop in the Kit -strain but M2 genes followed by a shift toward a more M2 phenotype where W-sh they, together with the tissue-resident macrophages, attenuated that the Kit -strain was fully susceptible. This was explained by W/W-v W- the neutropenia found in the Kit -strain but not in the Kit the severity of arthritis (42). Taken together, these data suggest − sh that circulating Ly6C non-classical monocytes are recruited to -strain (18, 38). A dispensable role for mast cells was confirmed the joint in the initiation phase of arthritis, where they orchestrate by the use of a non-kit mutated mast-cell-deficient mouse strain, cre/+ both the development and resolution of the joint inflammation. the Cpa3 -mouse, which developed arthritis and, besides a e r Th ole of granulocyte–macrophage colony-stimulating fac- lack of mast cells, display a normal immune system (45). The cre/+ tor (GM-CSF) has also been examined in the K/BxN STA model discrepancy between arthritis-susceptible Cpa3 -mice and W/W-v (43). GM-CSF is considered to be an important differentiation/ arthritis-resistant Kit -mice suggests an important role for Kit W/W-v activation factor for macrophages and granulocytes and is also in this model. Also, since transfer of mast cells rendered Kit - mice susceptible to arthritis (46), it is possible that mast cells have a pro-inflammatory mediator ( 43), with encouraging RA trials targeting it or its receptor having been completed (44). Its impor- pro-pathogenic effects when Kit is missing. In combination, these experiments suggest that the previous conclusion regarding the tance in arthritis progression was illustrated by the observation that in the K/BxN STA model, both GM-CSF KO mice and WT importance of mast cells in the K/BxN STA model could be based W/W-v on a misinterpretation of the lack of arthritis in the Kit -strain. mice treated with anti-GM-CSF mAb showed less severe arthritis but with a similar time of onset compared to WT control mice Mast cells might contribute, but based on the recent study in the cre/+ mast cell-deficient Cpa3 -strain (45), they appear dispensable. (43). This was suggested to be a consequence of a reduced number of monocytes in the circulation and a decline in the number of Natural Killer T Cells synovial macrophages. The data indicated that in the absence of GM-CSF, the early neutrophil-mediated response was still A role for natural killer (NK) T cells in the K/BxN STA model was suggested by the observation that arthritis was attenuated in present, whereas later, the macrophage-driven response was defective (43). Another aspect of the role of macrophages in the CD1d KO and Jα281 KO mice, both deficient in NKT cells (50). e m Th echanism was thought to involve NKT-mediated suppres- K/BxN STA model has been revealed through studying the effect of IVIG treatment as described previously (20). It was shown sion of transforming growth factor β1 (TGF-β1) production in the joint tissue, which in turn was dependent on release of IL-4 that IVIG protected against arthritis induced by K/BxN serum through a macrophage-specific induction of FcγRIIB expression and interferon γ (IFNγ) from the NKT cells (51). Furthermore, it at the site of inflammation, which raised the threshold for their was shown that CD1d KO mice exhibited less severe arthritis and activation by ICs (20). that arthritis could only be restored with transfer of NKT cells Taken together, these results suggest that macrophages consti- from WT mice and not with transfer of cells from FcγR KO mice. tute an important cell type in the K/BxN STA model. es Th e findings indicate that binding of IgG to Fc γRIII on NKT cells in the joint induces their activation and participation in the Mast Cells induction of arthritis (50). e r Th ole of mast cells in the K/BxN STA model has been contro - versial mainly due to the different KO strains used in the various Complement studies. Insights into the role of mast cells in many inflammatory Development of arthritis in the K/BxN STA model involves responses relies predominately on a mouse strain deficient in activation of the complement cascade. It is believed that the mast cells due to a mutation in the gene encoding the receptor alternative pathway is important, since mice lacking comple- tyrosine kinase Kit, referred to as the white-spotted (W) Kit allele ment factor B did not develop arthritis (16). The classical pathway or the mannose-binding pathway is not thought to (45). The K/BxN STA model was initially induced in two versions W/W-v of this strain, the mast cell-deficient Kit strain and the mast be relevant, since transfer of K/BxN sera to mice deficient in Sl/Sl-d cell-deficient Kit-ligand (Kitl)-mutated Kitl strain (46). Both C1q, C4, and mannose-binding-protein A (MBP-A) resulted strains displayed little or no clinical or histologic signs of arthritis, in normal arthritis development (16). This conclusion was Frontiers in Immunology | www.frontiersin.org 6 June 2016 | Volume 7 | Article 213 Christensen et al. Mechanisms in Immune Complex-Driven Arthritis further supported by Solomon et al. (52) who showed that mice mouse strains deficient in one or more inflammatory cytokines deficient in C4 or the complement receptors 1 and 2, all compo - or their receptors. These results demonstrated a critical role for nents of the classical pathway, were susceptible to K/BxN STA IL-1, since no clinical signs of disease were observed aer t ft ransfer (52). All three pathways of the complement system lead to the of K/BxN serum into IL-1R-deficient mice, in which both IL-1 α- generation of C3, which has been shown to be indispensable for and IL-1β-mediated signaling are blocked. In relation to IL-1, it arthritis induction, thus emphasizing the general importance should also be mentioned that IL-1 receptor antagonist, which is of complement activation in this model (16, 53); in contrast, a well-known anti-inflammatory mediator, controlled articular the C3-receptor seems to be dispensable (16). C3 deposits inflammation during the acute phase of K/BxN STA ( 59). The have been found locally in the arthritic joints (9, 16), and it results obtained for TNF involvement in the model were mixed, has been suggested that during the inflammatory response, C3 since arthritis developed in one-third of the TNF-deficient mice, is produced by parenchymal cells distant from the joint and indicating that TNF is an important, but dispensable, driver of transported to the joints via the circulation (53). In addition, it disease development (57). In contrast to TNF and IL-1, IL-6 did has been shown that circulating C3 is necessary and sufficient not play a role in driving the inflammatory response (57). This for arthritis induction (53). Downstream of C3, the complement suggests that in the K/BxN STA model, IL-1 signaling is crucial cascade, leads to activation of C5 that is a central mediator in (Figure 2), TNF plays an important but partial, role, and IL-6 is the complement network. In the joints of the K/BxN STA model, completely dispensable. the alternative complement pathway is activated by the anti- e r Th ecently discovered IL-17 family of cytokines, especially G6PI/G6PI ICs, leading to C3 cleavage and generation of C5 IL-17A and IL-17F, which are the most homologous members of (Figure 2). The importance of C5 in the K/BxN STA model was the family, has been shown to be implicated in the pathogenesis demonstrated by the fact that C5 KO mice showed no signs of of many autoimmune diseases including RA (60, 61). They have disease (16). This was further confirmed by blockade of C5 with also been investigated in the K/BxN STA model. First, it was anti-C5 mAb, which both prevented disease by treatment prior shown that administration of anti-IL-17A mAb did not exert any to onset and reversed ongoing disease when injected several effect on arthritis progression ( 62). Later, it was found that mice days after arthritis onset ( 16). C5 is cleaved by C5 convertase deficient in IL-17 receptor subunit A were protected from the into the soluble component, C5a, and the C5b fragment that serum-induced arthritis, while recently, it was further demon- remains bound to the cell surface and initiates the formation strated that IL-17A KO mice exhibited reduced arthritis (63). The of the membrane attack complex, the final step of complement same study additionally showed that neutrophils are an essential activation. Formation of the membrane attack complex is not source of IL-17 in the model (63). It has further been found that required in the K/BxN STA model since C6 deficiency (a com - local administration of IL-17 via intra-articular injection of an ponent of the complex) did not influence disease progression adenovirus vector increased the severity of arthritis in the K/BxN (16). In contrast, C5a is crucial for the development of arthritis STA model (64). e Th discrepancy between the anti-IL-17 mAb illustrated by the fact that C5a–C5aR KO mice were completely study and mice deficient in IL-17A or IL-17 receptor subunit A resistant to arthritis (16). C5a functions as a chemoattractant might be explained by insufficient antibody dosing or incomplete and inducer of acute inflammation, for example, by activating blocking of IL-17 arising from the tight interaction between effec- neutrophils and mast cells, stimulating endothelial cells to tor cells. express P-selectin and increasing vascular permeability (3). In addition to increased levels of pro-inflammatory cytokines, Since antibodies generally activate complement through C1q high levels of prostaglandins (PGs) are also found in RA patients. and the classical pathway, it was a surprise that this pathway They are lipid mediators that, besides having a role in many was not involved in driving the disease. However, the dominant physiologic activities, also play an important role in pathologic isotype in anti-G6PI antibodies is the IgG1-subclass (11) and, inflammation (65). In the K/BxN STA model, high levels of since mouse IgG1 is a weak activator of C1q, a component of PGE , as well as the stable metabolite of PGI , 6-keto-PGF1α, 2 2 were found in inflamed joints, although only PGI appeared the classical pathway (54), it may explain why the alternative 2 pathway is the one important for arthritis induction in the K/ to be indispensable for arthritis development (65) (Figure 2). Furthermore, it was demonstrated that arthritis was reduced by BxN STA model. Additionally, multimerized IgG1 is efficient in activating FcγRIII, which is also an important driver of the pharmacological inhibition of PG synthesis by administration of a potent inhibitor of both cyclooxygenase (COX) 1 and 2. inflammatory response in the model, as described above (11). Interestingly, it was additionally shown that even though both Pro-inflammatory Mediators COX isoforms were found in the inflamed joints in the model, Pro-inflammatory cytokines, such as TNF, IL-1, and IL-6, are only COX1 contributed substantially to disease (65). Inhibition pathogenic drivers in both RA and in many mouse models of of COX1 and/or COX2 is the mechanism of action behind the arthritis; however, the impact of each cytokine on the disease pro- immunosuppressive effect of non-steroidal anti-inflammatory gression can differ from patient to patient ( 55) and from model to drugs (NSAIDs) that have been used frequently for amelioration model (56). In the K/BxN STA model, studies have indicated that of symptoms in RA patients (66). TNF, IL-1β, and IL-6 were released in the inflamed joint ( 57), but a role for TNF could not initially be proven (58). Subsequently, the Toll-Like Receptors Toll-like receptors (TLRs) are a group of receptors that serve significance of different selected cytokines was studied in further detail by Ji et al. (57) who induced the K/BxN STA in a panel of to recognize pathogen-associated molecular patterns (PAMPs), Frontiers in Immunology | www.frontiersin.org 7 June 2016 | Volume 7 | Article 213 Christensen et al. Mechanisms in Immune Complex-Driven Arthritis which oen co ft mprise microbial products such as lipopolysac- (CD11b), α (CD11c), or α (CD11d). Ligands for CD11a/ X D charide (LPS) and peptidoglycans. When one of these ligands CD18 (LFA-1) include ICAM-1, -2, -3, and junctional adhesion binds to TLRs on cells of the innate immune system, it leads to molecule (JAM)-A (75), while ICAM-1 and iC3b are ligands for a range of responses, including the release of different cytokines CD11b/CD18 (Mac-1, CR3) (76). In the K/BxN STA model, it and activation of APCs (67). The TLRs differ in their extracel - was demonstrated that β -deficient mice were resistant to arthritis lular structure from the receptors for IL-1 and IL-18; however, and that CD11a α-chain (LFA-1) was critical for this process (77). they share the same intracellular signaling pathway, which Moreover, blockade of LFA-1 with an anti-LFA-1 mAb reduced includes myeloid differentiation factor 88 (MyD88) ( 68). In the already ongoing inflammation, and functional blockade of the K/BxN STA model, the role of TLR4 was first investigated. its counter-receptors, ICAM-1, ICAM-2, and JAM-A, provided It was shown that arthritis progression in TLR4 KO mice had a a reduction, but not complete amelioration, of arthritis (77). similar initiation phase but was not sustained compared to WT It was also shown that ICAM-1, ICAM-2, and JAM-A were mice, suggesting that TLR4 plays a role in the later phase in the mainly expressed by the vascular endothelium, while LFA-1 was model (69). Additionally, the same study showed that MyD88 is expressed on leukocytes within the synovial lining and within a key molecule and confirmed the essential role of IL-1 since no the inflammatory synovial fluid ( 77). This study did not inves - arthritis was observed in either MyD88- or IL-1R KO mice (69). tigate which subtype of leukocytes expressed LFA-1; however, Interestingly, LPS, a TLR4 ligand, circumvented the requirement another study subsequently demonstrated that LFA-1 expression for IL-1R signaling (69). However, recent studies reported that on neutrophils was crucial for arthritis development in the K/ TLR4 KO mice exhibited either a similar progression of arthritis BxN STA model (28). It is reasonable to consider that LFA-1 (70, 71) or a reduced arthritis even in the early induction phase expression on monocytes/macrophages might also contribute (72) compared to WT mice. These discrepancies demonstrate to arthritis progression. In this context, LFA-1 was shown not that the impact of TLR4 on arthritis development in the K/BxN to be important for monocyte migration in an acute murine STA model varies from study to study and that further studies are peritonitis model, suggesting that LFA-1 does not play a role therefore needed to clarify its role. in infiltration of monocytes into inflamed tissue ( 78). However, The role of another TLR and its ligands in the K/BxN STA whether this is the same for the K/BxN STA model should be model has been investigated by Wu et al. (73) who, surprisingly, examined. discovered that certain unmethylated DNA CpG motifs (CpGs), In conclusion, recruitment of leukocytes into the joints with their signaling being mediated through TLR9, were able and the ensuing arthritis in the K/BxN STA model seem to be to inhibit arthritis. This inhibition relied on cells of the innate dependent on the expression of LFA-1 on leukocytes, especially immune system and, specifically, on crosstalk between dendritic neutrophils, and the binding to its ligands, ICAM-1, ICAM-2, cells (DCs) and NK cells. It was suggested that CpGs bind to and JAM-A, expressed on the activated vascular endothelium DCs via TLR9, which in return release IL-12 that further (Figure 2). stimulates NK cells to produce IFNγ. IFNγ subsequently inhibits neutrophil migration into the joint (73). These observations describe a potential anti-inflammatory role for both CpGs and DiSe ASe MANiFe STATiONS IFNγ in this model underlining the complexity of the innate Cartilage Loss and Bone e rosion effector mechanisms driving the pathogenesis. Additionally, an inhibitory role has been suggested for TLR2, which was shown Cartilage loss is a well-studied pathological manifestation of arthritis in the K/BxN STA model (57, 79). IL-1β is oen a ft to regulate arthritis in the model by controlling the inhibitory FcγRIIB on macrophages (71). Finally, a recent study showed crucial mediator of cartilage destruction in arthritis models (80), and aer ft induction of K/BxN STA, IL-1R KO mice showed, in that both TLR3 KO and TLR7 KO mice developed reduced K/ BxN serum-induced arthritis (74) and that the transcription fac- addition to complete arthritis suppression, no signs of cartilage destruction (57), suggesting that IL-1β is a crucial driver of tor, interferon regulatory factor 5 (IRF5), contributed to disease progression by mediating pro-inflammatory cytokine produc- cartilage destruction also in this model. Additionally, bone ero- sion, via osteoclast activation in inflamed joints, is involved in tion, mainly that of IL-1β generated downstream of TLR3 and TLR7 (74). the pathogenesis of RA and has also been studied in the K/BxN STA model. One of the essential factors for osteoclast differentia - Taken together, these studies suggest that TLR3, TLR7, and possibly TLR4 play a pro-inflammatory role in the K/BxN STA tion and activation is the receptor activator of nuclear factor-κβ ligand (RANKL), and it was shown that RANKL KO mice were model, while TLR9 and TLR2 mediate an anti-inflammatory effect. protected from bone erosion aer t ft ransfer of K/BxN serum ( 81) (Figure 2). In contrast, a deficiency in matrix metalloproteinase-8 (MMP8) increased joint inflammation and bone erosion in the iNTe GRiNS model, suggesting that MMP8 protects against the inflammatory Leukocyte infiltration into the synovial tissue is a crucial step synovitis and bone erosion (79). A cytokine that could also play in the pathogenesis of inflammatory arthritis and involves a a role in RA is macrophage migration inhibitory factor (MIF) range of different integrins and their ligands. The β integrins (82). It was first demonstrated that this cytokine was essential are heterodimeric cell proteins consisting of a common β-chain for disease development in the K/BxN STA model since both (CD18) that pairs with one of four α-chains: α (CD11a), α joint inflammation and cartilage destruction were significantly L M Frontiers in Immunology | www.frontiersin.org 8 June 2016 | Volume 7 | Article 213 Christensen et al. Mechanisms in Immune Complex-Driven Arthritis reduced in MIF KO mice (83) (Figure 2). Furthermore, the same and could be a potential model to explore novel pain-modulating study demonstrated that adoptive transfer of WT macrophages treatment strategies for RA. could restore the sensitivity of MIF KO mice to arthritis develop- ment (83). Recently, it was further demonstrated that MIF KO A COMPARiSON OF THe K/BxN STA mice transferred with arthritic K/BxN serum, in addition to MODe L wi TH OTHe R ARTHRiTiS reduced joint inflammation, exhibited markedly reduced bone erosion compared to WT mice. It was also shown in vitro that MODe LS MIF facilitated RANKL-induced osteoclastogenesis, which sug- Collagen Antibody-induced Arthritis Model gests that MIF contributes directly to bone erosion as well as to Among the many different mouse models of arthritis, the K/BxN inflammation in arthritis (84) (Figure 2). Taken together, these STA model is most similar to the collagen antibody-induced studies suggest that the K/BxN STA model can also be used as arthritis (CAIA) model. The main similarities and differences an animal model, wherein the different mechanisms behind between the features of the CAIA and K/BxN STA models are bone erosion can be studied in addition to those governing listed in Table 1. In the former model, arthritis develops aer ft cartilage loss. administration of a defined cocktail of anti-collagen type II mAb (anti-CII mAb), most oen t ft ogether with LPS ( 91). When LPS PAiN is administered with the antibody cocktail, it enhances the inci- Recently, an increasing focus has been on the interface between dence and severity of the disease and thereby reduces the amount the immune and nervous systems in inflammatory pain, with pain of mAb required to induce arthritis. Both models represent the being a clinical symptom with high negative impact on patients effector phase of arthritis, work in many mouse strains, and have suffering from different autoimmune diseases and especially RA. a similar time scale. Both the CAIA and K/BxN STA models are Pain in RA is difficult to control and oen p ft ersists aer r ft esolu - driven by antibodies and the formation of ICs (91), and both tion of joint swelling with anti-inflammatory treatments ( 85). can be induced in T cell- and B cell-deficient mice ( 4, 92, 93). In To address the unmet need for pain relief, inflammatory pain both models, ICs initiate the inflammatory response either via has lately been investigated in several arthritis models including activation of the complement system or by direct engagement and activation of Fc receptor-bearing immune cells (91). As to the role the K/BxN STA model (86, 87). Christianson et al. (86) showed that arthritis in the K/BxN STA model led to persistent pain of Fc receptors, the two models also share similar dependencies since CAIA mice lacking the general FcγR-chain were highly with mechanical hypersensitivity not returning to baseline and outlasting the inflammation by 2 weeks ( 86). Moreover, the pain resistant to arthritis, but FcγRIII-deficient mice were only partially resistant (94), an observation also seen in the K/BxN STA model was shown in the inflammatory phase to be sensitive to treat - ment with NSAIDs and etanercept (TNF blocker) (Figure 2), (16). Additionally, complement activation and the downstream effects of C5a and C5aR are key factors in the pathogenesis of and this was not the case in the post-inflammatory phase ( 86). Furthermore, the same group showed that during the persistent arthritis in both models (16, 95, 96). As in the K/BxN STA model (16), the alternative complement activation pathway has been pain seen aer r ft esolution of inflammation, spinal TLR4 played an important role (70). suggested to be the dominant pathway for inflammation and joint destruction in the CAIA model (97–99). However, in the CAIA An interesting aspect of pain is the involvement of capsaicin- sensitive neurons that not only can mediate pain but also contrib- model, the classical pathway additionally seemed to participate in complement activation, which indicates that both pathways ute to inflammatory processes by release of neuropeptides such as substance P and calcitonin-gene-related peptide (CGRP) (88). might play a role (98), an observation different from that in the K/BxN model. This difference could be explained by the fact that In the K/BxN STA model, it was demonstrated that in the early phase, capsaicin-sensitive neurons played an anti-inflammatory IgG1 is the dominant isotype of the anti-G6PI antibodies (11), whereas IgG2a and IgG2b are the most widely used for the induc - role, while in the later phase (10 days post-serum injection), they contributed to mechanical hyperalgesia (88). Furthermore, the tion of CAIA (93). Murine IgG2a, IgG2b, and IgG3 isotypes have been shown to activate the classical pathway, whereas IgG1 has neuropeptide, neuromedin U, which has pro-inflammatory activ- ity, was shown to promote arthritis in the K/BxN STA model (89). been suggested to activate the alternative pathway (54). As in the K/BxN STA model, neutrophils play an essential e eff Th ect of denervation on arthritis progression has also been explored in the K/BxN STA model. Interestingly, it was found that role in the CAIA model and were indispensable both for the development and maintenance of arthritis (96). With regard to denervation of one limb prior to the serum transfer protected that limb from arthritis via an impact on the microvasculature. The effector cytokines, both TNF and IL-1β have been shown to be the major effector cytokines in CAIA, and blockade of either of these joint-localized vascular leak that normally causes swelling and edema in the ae ff cted joint was compromised in the denervated cytokines ameliorated the disease, whereas IL-6 blockade had no effect (92). Hence, TNF seems to be more crucial in the CAIA limbs (90). This finding underlines the fact that arthritis, even in a rather simple model system as the K/BxN STA model, results model than in the K/BxN model where, as mentioned, divergent results were obtained aer n ft eutralizing TNF ( 57). Another from complex interactions between the nervous, immune, and vascular systems. cytokine that has been shown to play different roles in the two models is IL-4. It was reported to be an important cytokine in the Overall, these recent studies within pain suggest that the K/ BxN STA model is useful for the exploration of pain mechanisms CAIA model, and its neutralization greatly reduced the severity Frontiers in Immunology | www.frontiersin.org 9 June 2016 | Volume 7 | Article 213 Christensen et al. Mechanisms in Immune Complex-Driven Arthritis TABLe 1 | Similarities and differences between the K/BxN STA, CAiA, and CiA models. Feature K/BxN STA model CAiA model CiA model Phase(s) Effector Effector Immunization and effector Susceptible strains Multiple strains (6) Multiple strains (100) DBA1, B10Q, B10.QRIII, and C57BL/6 (less severe) (101) Time to termination 10–15 days normally (102) 10–15 days normally (91) 5–6 weeks (101) Immunization (involvement of No (4) No (93) Yes (101) T- and B-cells) Antigen G6PI (2) Collagen II (91) Collagen II (101) Immunostimulatory components None (102) LPS (91) CFA (103) Autoantibodies Main drivers – ICs formed Main drivers – ICs formed in Yes (104) systemically and in the joint (9) the joint (12) Isotype of autoantibodies IgG1 (11) • IgG2a IgG2a (104) • IgG2b (93) Fc receptors • FcγR • FcγR • FcγR (105) • FcγRIII • FcγRIII (94) • FcγRIII (106) • FcγRIIB (16) • FcγRII (105) Complement system • C5aR (16) • C5aR (95) • C5aR (107) • Alternative pathway (16) • Alternative and classical • Alternative and classical pathways (98) pathways (108) Important immune cells • Neutrophils (25) • Neutrophils (96) • Neutrophils (109) • Macrophages (41) • Macrophages (110) • Mast cells? (45, 46) • T cells (101) • B cells (101) Pro-inflammatory cytokines • TNF (57) • TNF (92) • TNF (80) • IL-1β (57) • IL-1β (92) • IL-1β (80) • G-CSF (39) • IL-4 (111) • G-CSF (109) • GM-CSF (43) • GM-CSF (112) • MIF (83, 84) • IL-6 (113) • IL-17? (62, 63) • IL-17 (114) and ICs cannot be formed systemically (12), which means that of the disease (111), whereas IL-4 was shown to play no role in the anti-CII mAb given systemically do not readily localize in the K/BxN model (115). the joints without any additional trigger. Therefore, LPS or a high e m Th ost significant difference between the two models is dose of antibody is needed to ensure that the anti-CII mAb enter the specificity of the antibodies driving the disease. In the CAIA the joints (12). Overall, despite many similarities between the two model, the antibodies are anti-CII mAb (91), whereas the K/ BxN STA model is driven by arthritogenic serum containing models, differences also exist such that each model can be used to inform on different aspects of arthritis progression. polyclonal antibodies directed toward G6PI (3). This difference, among other aspects, leads to different localization of the respec- Collagen-induced Arthritis Model tive antibodies in the joints. Both types of antibodies bind to e CI Th A model is one of the most widely used animal models for the cartilage surface (10, 116); however, the anti-CII mAb also RA and shares many similarities with it. It is, therefore, relevant penetrate the cartilage (117). Anti-G6PI serum is more effective to highlight the similarities and differences between the CIA and at inducing arthritis than anti-CII mAb as illustrated by the fact K/BxN STA models and the advantages of each model. e Th main that the K/BxN STA model does not need the co-injection of LPS similarities and differences between the features of the CIA and as the CAIA model does, and a lower dose of purified anti-G6PI K/BxN STA models are also listed in Table 1. The CIA model IgGs is required to induce arthritis compared to the dose of anti- is induced by immunization of susceptible mouse strains, such CII mAb routinely used (11). as DBA/1, B10.Q, and B.10RIII, with CII in complete Freund’s Another important difference between the two models is the adjuvant (CFA) (103). However, it can also be established in way the antibodies enter the joints. In the K/BxN STA model, ICs C57BL/6 mice, thereby increasing the range of KO mice that can are formed systemically due to the fact that G6PI is ubiquitously be studied, although the incidence and severity are less than in present (9) (Figure 1). As mentioned, the systemic ICs activate the DBA/1 or B10.RIII strains (101). Typically, chicken or bovine inflammatory cells, such as neutrophils, which subsequently CII is used. The mice can be boosted with CII emulsified in release mediators that increase the vascular permeability, thereby incomplete Freund’s adjuvant (IFA) 3 weeks later; however, this giving ICs and antibodies access to the joint (Figure 1). In CAIA is usually only necessary when using specific types of collagen model, the collagen II (CII) antigen is mainly present in the joint, Frontiers in Immunology | www.frontiersin.org 10 June 2016 | Volume 7 | Article 213 Christensen et al. Mechanisms in Immune Complex-Driven Arthritis such as α1(II) chains or purified cyanogen bromide fragments answer to a potential question can be obtained much quicker than of CII (101). Additionally, occasionally LPS is given around the what is the case with the CIA model. Furthermore, the K/BxN time of the boost to induce the disease to occur more rapidly and STA model is independent of an immunostimulatory component, with less variability in onset (118). Normally, arthritis appears such as CFA, which induces a severe stimulation of the innate 3–5 weeks after immunization and usually peaks by week 6 immune system. (101). It presents as a polyarthritis most prominently in the Another important difference between the models is that the limbs and characterized by inflammatory synovial infiltration, CIA model represents both the priming and effector phases of cartilage and bone erosion, and synovial hyperplasia similar to arthritis and therefore mimics more features of RA than the K/ RA (119). Generally, susceptibility has been linked to strains BxN STA model; nonetheless, since the K/BxN STA model only q r that have MHC class II I-A and I-A haplotypes; however, it represents the effector phase, one of its advantages is that it can is evident that many mouse strains have variable degrees of be used to study the biology of this phase. The above discussion susceptibility to CIA (119). The biggest difference between indicates that even though the CIA model oen i ft s the first choice K/BxN STA and CIA is of course that CIA is the result of an for a murine model for RA, the K/BxN STA model does oer ff active immunization, while arthritis in the K/BxN STA model is some advantages and can be a valuable supplement to the CIA induced by passive transfer of autoantibodies. Since an immuni- model. zation takes place in the induction phase of CIA, arthritis in this model is dependent on stimulation of collagen-specific T cells and the production of high titers of autoantibodies specific for THe K/BxN STA MODe L AS A CII by B cells (101). As mentioned, in the K/BxN STA model, MODe L FOR RA both T cells and B cells are dispensable (4). However, similar to what is the case in the K/BxN STA model (25, 41), both The K/BxN STA model is a valuable tool in understanding the pathogenic mechanisms behind autoantibody-driven neutrophils (109) and macrophages (110) have been shown to be important cell types in the CIA model. With regard to the arthritis. However, it is essential to consider in what aspects the K/BxN STA model resembles RA and where it differs. The role of Fc receptors, the two models show similar dependencies since mice lacking the general FcγR-chain were highly resistant main similarities and differences between the features of the K/ BxN STA model and RA are listed in Table 2. When looking to CIA (105) and FcγRIII-deficient mice were partially resistant (106). Additionally, FcγRII-deficient mice exhibited increased at the clinical manifestations and histopathological findings, arthritis, suggesting an inhibitory role of this FcRII in CIA (105) it is evident that this murine arthritis exhibits many features as for the K/BxN STA model (16). Like the CAIA model, both similar to RA such as leukocyte invasion, synovitis, pannus the classical and alternative complement pathways have been formation, cartilage and bone destruction, and remodeling of shown to be important in the CIA model (108) and, like in the the joint (4). However, the progression of arthritis in the K/ K/BxN STA model (14), C5a and C5aR are key factors in the BxN STA model is more aggressive developing over a few days, pathogenesis of the CIA model (107). whereas the development of RA disease is a very long process e t Th wo models share the involvement of autoantibodies, with a peak incidence between 30 and 50 years of age (121). although the specificity of the autoantibodies varies between the When considering the disease drivers, arthritis in the K/BxN two. In the CIA model, the antibodies are directed against CII, STA model is solely mediated by autoantibodies, while in RA, while in the K/BxN STA model, the antibodies are anti-G6PI. even though autoantibodies are present and known to partici- Moreover, in the CIA model, the autoantibodies predominantly pate in the pathogenesis, the disease is additionally driven by belong to the IgG2a subclass (104), while in the K/BxN STA other mechanisms involving, for example, CD4 T cells (122). model, they mainly consist of IgG1 (11). With respect to the An important role for antibodies in RA is, nevertheless, sug- involvement of cytokines, TNF (80), IL-1β (80), G-CSF (109), gested by the success of anti-CD20 therapy (91). Moreover, GM-CSF (112), IL-6 (113), and IL-17 (114) are all important autoantibodies of several different specificities have been found drivers in the pathogenesis in CIA, while IL-4 has been shown in RA patients, including antibodies against citrullinated filag - to mediate a suppressive effect ( 120). In the K/BxN STA model, grin, the Fc portion of IgG [rheumatoid factor (RF)], keratin, it appears that IL-1β (57) and G-CSF (39) are crucial for arthritis chondrocyte gp39, and heat-shock protein 60 (123). Anti- progression, TNF (57) and GM-CSF (43) have a partial role, and citrullinated filaggrin antibodies have been shown to be useful both IL-6 (57) and IL-4 (115) play no role. as a prognostic marker in patients with early RA (124), while A major practical advantage of the K/BxN STA model over the in general, the anti-citrullinated protein antibodies (ACPA) are CIA model is that it induces a robust inflammatory response in found in 60% of RA patients and are believed to be a critical a range of different mouse strains with 100% incidence and with hallmark in the pathogenesis of RA (125). Moreover, anti-type a similar onset. As mentioned previously, the CIA model, on the II collagen antibodies may contribute to disease development other hand, induces a robust response mainly in susceptible strains, even though they are not primary drivers of disease (123). RF such as DBA1, B10.Q, and B10.QRIII, while in C57BL/6 mice, the is found in 80% of RA patients, and patients with a positive test incidence and severity are less pronounced with a variable time of result for RF in blood have more severe clinical disease and onset (101). Moreover, the CIA model runs for 5–6 weeks, while complications than seronegative patients (126, 127), although the K/BxN STA model is normally terminated 10–15 days aer ft the pathophysiological role of RF in RA is still unclear. Of note, serum injection. This means that with the K/BxN STA model, an RF is not present in the K/BxN STA model (126). Frontiers in Immunology | www.frontiersin.org 11 June 2016 | Volume 7 | Article 213 Christensen et al. Mechanisms in Immune Complex-Driven Arthritis TABLe 2 | Similarities and differences between the K/BxN STA and RA the different types of autoantibodies, it is likely that, as in the models. K/BxN STA model, autoantibodies in RA drive the inflammatory response by IC formation and deposition, complement activation Feature K/BxN STA model RA as well as activation of Fc receptors on innate immune cells such Histopathological • Leukocyte invasion • Leukocyte invasion as neutrophils, macrophages and mast cells (122). However, in manifestations • Synovitis • Synovitis contrast to disease progression relying entirely on autoantibodies • Pannus formation • Pannus formation and their activation of innate immune cells as found in the K/ • Cartilage and bone • Cartilage and bone destruction BxN STA model, RA is driven by complex interactions between a destruction • Joint remodeling (4) • Joint remodeling (4) range of different cell types from both the innate and the adaptive immune systems, such as T cells, B cells, macrophages, DCs, and Autoantibodies Main driver (9) Present – role unknown (122) neutrophils (55). Specificity of G6PI (2) • G6PI With regard to disease mediators, TNF is an important media- autoantibodies • Citrullinated filaggrin tor in many, but not all, cases of RA, as shown by the success of • Fc portion of IgG (rheumatoid factor) TNF blockade in treating the disease. In contrast, neutralizing • Keratin IL-1 in clinical settings has been shown to have only a limited • Chondrocyte gp39 effect (140). As mentioned, in the K/BxN STA model, IL-1 is • Heat-shock protein absolutely required for arthritis development, and TNF appears • Collagen II (123) to play an important, but partial, role in the disease pathogenesis Important • Neutrophils (25) • Neutrophils (57). Additionally, blockade of GM-CSF or its receptor are cur- immune cells • Macrophages (41) • Macrophages rently being tested in RA trials with encouraging results (44), and • Mast cells? (45, 46) • CD4 T cells GM-CSF has also been shown to be an important cytokine in • B cells • Dendritic cells (55) the K/BxN STA model (43). The crucial role of macrophages and neutrophils in the K/BxN STA model (25, 41) and the fact that Pro-inflammatory • TNF (57) • TNF (55) cytokines • IL-1β (57) • IL-6 (55) both cell types are found in increased numbers in the inflamed • GM-CSF (43) • GM-CSF (44) synovia in RA patients (55) suggest that they are also likely • G-CSF (39) important cell types in RA. • MIF (83, 84) As mentioned previously, the most severe symptom frequently • IL-17? (62, 63) reported in RA patients is pain, which can persist aer t ft he reso - Pain Present and persists Present and persists after lution of joint swelling following anti-inflammatory treatment after resolution of resolution (85). Arthritis in the K/BxN STA model led to persistent pain inflammation (87) of joint swelling with anti- inflammatory treatment (85) with mechanical hypersensitivity, unlike the joint swelling, not returning to baseline but outlasting the inflammation by 2 weeks Common • NSAIDs (65) • NSAIDs (86). Moreover, the pain was in the inflammatory phase shown therapies • TNF blockade (57) • TNF blockade • Glucocorticoids • Glucocorticoids to be sensitive to treatment with NSAIDs and etanercept (TNF (128, 129) • Methotrexate blocker) (86), suggesting that the K/BxN STA model might be • Methotrexate (130) • Tacrolimus (66) useful for the exploration of the mechanisms and novel treatment • Tacrolimus (131) strategies for RA pain. Current treatment strategies for RA include NSAIDs, gluco- corticoids, disease-modifying anti-rheumatic drugs (DMARDs), Given the essential role of anti-G6PI antibodies in the K/BxN such as methotrexate, and biologic response modifiers, for STA model, antibody titers to G6PI have also been investigated example, the blockade of TNF and IL-6 (66). When considering in RA patients, however with conflicting results. Initially, it was the relevance of the K/BxN STA model as a tool to identify drug reported that 64% of RA patients had high levels of anti-G6PI candidates with potential therapeutic effect in RA, it is noticeable antibodies, which were significantly different from healthy that several of the approved drugs to treat RA have also been controls (132), but subsequent studies could not reproduce these shown to have immunosuppressive effects in the K/BxN STA findings (133–136). A later study suggested that autoantibodies model. Besides the already mentioned effect of blocking TNF, to G6PI were associated with the occurrence of extra-articular glucocorticoids, which are widely used in RA, also suppress complications, such as Felty’s syndrome characterized by neutro- progression of arthritis (128, 129). Additionally, abrogation of penia and an enlarged spleen (137); another study showed that arthritis was obtained with inhibition of COX1 and COX2 by autoantibodies to G6PI were not unique to patients with RA but treatment with NSAIDs (65). Finally, the widely used DMARD were found in many patients with inflammatory arthritis (138). for RA, methotrexate (130), as well as another DMARD, the es Th e results indicate that G6PI might be one of the several calcineurin inhibitor, Tacrolimus (131), had a therapeutic effect autoantigens able to serve as a target for autoantibodies in RA, in the model. This indicates that the model can have a predictive but their pathogenic and diagnostic relevance is currently not value in the preclinical screening of drug candidates for RA. clear. In this context, G6PI has recently been shown to promote In summary, the K/BxN STA model provides a useful tool for proliferation and to inhibit apoptosis in fibroblast-like synovio- studying certain aspects of RA including autoantibodies, comple- cytes from RA patients (139). Despite the uncertain relevance of ment, ICs, Fc receptors, and innate cell types, such as neutrophils Frontiers in Immunology | www.frontiersin.org 12 June 2016 | Volume 7 | Article 213 Christensen et al. Mechanisms in Immune Complex-Driven Arthritis and macrophages. The increasing focus on autoantibodies and in RA, the K/BxN STA model is a useful tool to understand how especially ACPA in the pathogenesis in RA potentially raises autoantibodies, in general, drive the progression of arthritis by the relevance of the K/BxN STA model as the one to study how interacting with different downstream components of the innate autoantibodies drive autoimmune disease. RA is a heterogeneous immune system. A further advantage of the K/BxN STA model disease involving multiple different immunological pathways and is that it provides an opportunity to study only the effector phase accumulation of multiple autoantibody specificities, which differ of arthritis without involving the priming phase of the immune from patient to patient (66). Therefore, it is not possible to find an response. Finally, the model has also proven useful for the study animal model that covers all phases and aspects of RA. Thus, as of arthritic pain. Taken together, these features make the K/BxN for any animal model, the K/BxN STA model does not encompass STA model a relevant one for RA and, even though not discussed, all of the features of RA, but mimics several facets of the effector other arthritides; it is also a potentially valuable tool for the phase. A useful exercise would be to create a “pathogenesis map” preclinical screening of new therapeutic targets. Although the outlining the current knowledge of RA (and other types of arthri- model has been characterized to a great extent, many aspects of tis) and align the various animal models according to the specific arthritis and pain development, including the roles of regulatory aspect/subset of the disease that each of them reflects. This “map” components, different chemokines, and other pro-inflammatory would facilitate choosing the most appropriate model to address cytokines, are still unknown and need to be addressed. a given question or to study a particular pathway (141, 142). In such a “map,” the K/BxN STA model would be highly relevant as AUTHOR CONTRiBUTiONS a model to study the effector phase of RA and how autoantibodies drive joint inflammation. A.D.Christensen participated in the design and wrote the manu- script. CH and A.D.Cook participated in the design and helped draft the manuscript. JH provided intellectual support and helped CONCLUSiON draft the manuscript. All authors read and approved the final As an arthritis model, the K/BxN STA model has some obvious manuscript. advantages. First, it has a rapid onset beginning 2–3 days aer ft transfer of serum with 100% incidence in genetically identical FUNDiNG animals. The arthritis is very robust and reproducible, even though minor inter-individual variability can be seen. Second, This work is the result of a PhD project funded by the Novo it can be induced in a wide range of strain backgrounds and Nordisk & Life In Vivo Pharmacology Centre (LIFEPHARM), therefore also in different KO strains to study the importance Denmark (to A.D.Christensen). CH is employed by Novo Nordisk A/S. This work was also supported by a Senior Principal Research of different disease mediators. Furthermore, the model is inde - pendent of immunostimulatory components, such as LPS and Fellowship (to JH) and a Project Grant (to A.D.Cook) from the National Health and Medical Research Council of Australia. CFA. Even though G6PI might not be an essential autoantigen 9. Matsumoto I, Maccioni M, Lee DM, Maurice M, Simmons B, Brenner M, Re Fe Re NCe S et al. How antibodies to a ubiquitous cytoplasmic enzyme may provoke joint-specific autoimmune disease. 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Zong M, Lu T, Fan S, Zhang H, Gong R, Sun L, et al. Glucose-6-phosphate Copyright © 2016 Christensen, Haase, Cook and Hamilton. This is an open-access isomerase promotes the proliferation and inhibits the apoptosis in fibro- article distributed under the terms of the Creative Commons Attribution License (CC blast-like synoviocytes in rheumatoid arthritis. Arthritis Res Ther (2015) BY). The use, distribution or reproduction in other forums is permitted, provided the 17(1):100. doi:10.1186/s13075-015-0619-0 original author(s) or licensor are credited and that the original publication in this 140. van den Berg WB. Anti-cytokine therapy in chronic destructive arthritis. journal is cited, in accordance with accepted academic practice. No use, distribution Arthritis Res (2001) 3(1):18–26. doi:10.1186/ar303 or reproduction is permitted which does not comply with these terms. Frontiers in Immunology | www.frontiersin.org 17 June 2016 | Volume 7 | Article 213

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