Spondylarthritides Research Articles

Illuminating the impact of γδ T cells in man and mice in spondylarthritides.

Spondylarthritides (SpA) are a group of autoinflammatory diseases affecting the spine, peripheral joints, and entheses, including axial spondyloarthritis (axSpA) and psoriatic arthritis. AxSpA has a multifactorial etiology that involves genetic predispositions, such as HLA-B27 and IL-23R. Although HLA-B27 is strongly associated with axSpA, its role remains unclear. GWAS studies have demonstrated that genetic polymorphisms related to the IL-23 pathway occur throughout the spectrum of SpA, including but not limited to axSpA and PsA. IL-23 promotes the production of IL-17, which drives inflammation and tissue damage. This pathway contributes not only to peripheral enthesitis but also to spinal inflammation. γδ T cells in axSpA express IL-23R and RORγt, crucial for their activation, although specific pathogenic cells and factors remain elusive. Despite drug efficacy in PsA, IL-23R inhibition is ineffective in axSpA. Murine models provide valuable insights into the intricate cellular and molecular interactions that contribute to the development and progression of SpA. Those models are useful tools to elucidate the dynamics of γδ T cell involvement, offering insights into disease mechanisms and potential therapeutic targets. This review aims to illuminate the complex interplay between IL-23 and γδ T cells in SpA pathogenesis, emphasizing their roles in chronic inflammation, tissue damage, and disease heterogeneity.

History of reactive arthritis. Historical milestones and future

Die Einführung der Bezeichnung reaktive Arthritis (ReA) für die nach Infektion mit Yersinia enterocolitica beobachtete Gelenkentzündung, bei der „ein ursächlicher Erreger nicht aus der Gelenkflüssigkeit isoliert werden kann“, und die Assoziation mit dem HLA-B27 waren die historischen Wegmarken für eine neue Klassifikation und Zuordnung zu den Spondyloarthritiden (SpA). Die 1976 vorgeschlagene Unterteilung in postinfektiöse und reaktive Arthritiden erfuhr in den 1990er-Jahren durch Untersuchungen mit der neu verfügbaren molekularbiologischen Methode der Polymerasekettenreaktion eine Relativierung. Aus Gelenkproben von Patienten mit ReA konnten mikrobielle Produkte identifiziert werden. Deshalb wurde vorgeschlagen, die Unterscheidung zwischen den beiden Erkrankungsgruppen aufzugeben und für beide den Begriff „ReA“ vorzuziehen. Daraus ist eine terminologische und nosologische Problematik entstanden. Einerseits existieren Klassifikations- und Diagnosekriterien für die klassische HLA-B27-assoziierte ReA, die der SpA zugeordnet und allgemein akzeptiert sind. Andererseits sind eine zunehmende Zahl von bakteriellen Erregern, Viren, Amöben, Helminthen, aber auch antivirale und antibakterielle Impfungen als Auslöser einer Arthritis beschrieben, die unter der Bezeichnung ReA publiziert wurden. Seit dem Beginn der SARS-CoV-2-Pandemie werden Fälle einer akuten Post-COVID-19-Arthritis beschrieben, die wegen der vergleichbaren klinischen Merkmale ebenfalls als ReA klassifiziert wurden.

IL-17A and TNF Modulate Normal Human Spinal Entheseal Bone and Soft Tissue Mesenchymal Stem Cell Osteogenesis, Adipogenesis, and Stromal Function.

Objective: The spondylarthritides (SpA) are intimately linked to new bone formation and IL-17A and TNF pathways. We investigated spinal soft tissue and bone mesenchymal stem cell (MSC) responses to IL-17A and TNF, including their osteogenesis, adipogenesis, and stromal supportive function and ability to support lymphocyte recruitment. Methods: Normal spinal peri-entheseal bone (PEB) and entheseal soft tissue (EST) were characterized for MSCs by immunophenotypic, osteogenic, chondrogenic, and adipogenic differentiation criteria. Functional and gene transcriptomic analysis was carried out on undifferentiated, adipo- differentiated, and osteo-differentiated MSCs. The enthesis C-C Motif Chemokine Ligand 20-C-C Motif Chemokine Receptor 6 (CCL20-CCR6) axis was investigated at transcript and protein levels to ascertain whether entheseal MSCs influence local immune cell populations. Results: Cultured MSCs from both PEB and EST displayed a tri-lineage differentiation ability. EST MSCs exhibited 4.9-fold greater adipogenesis (p < 0.001) and a 3-fold lower osteogenic capacity (p < 0.05). IL-17A induced greater osteogenesis in PEB MSCs compared to EST MSCs. IL-17A suppressed adipogenic differentiation, with a significant decrease in fatty acid-binding protein 4 (FABP4), peroxisome proliferator-activated receptor gamma (PPARγ), Cell Death Inducing DFFA Like Effector C (CIDEC), and Perilipin-1 (PLIN1). IL-17A significantly increased the CCL20 transcript (p < 0.01) and protein expression (p < 0.001) in MSCs supporting a role in type 17 lymphocyte recruitment. Conclusions: Normal spinal enthesis harbors resident MSCs with different in vitro functionalities in bone and soft tissue, especially in response to IL-17A, which enhanced osteogenesis and CCL20 production and reduced adipogenesis compared to unstimulated MSCs. This MSC-stromal-enthesis immune system may be a hitherto unappreciated mechanism of “fine tuning” tissue repair responses at the enthesis in health and could be relevant for SpA understanding.

Establishment of the current classification criteria for axial spondylarthritis, rheumatoid arthritis and SLE in routine practice of German rheumatologists

In Germany, the numbers of patients with spondylarthritides (SpA) and rheumatoid arthritis (RA) have increased. This rise was possibly promoted by the introduction of new classification criteria (CC) that enable an earlier recognition and the inclusion of less severe cases. The study explores how the new CC for axial SpA (axSpA) are incorporated into the clinical practice, compared with the CC for RA and systemic lupus erythematosus (SLE). In addition, the study investigated whether the new entity of non-radiographic axSpA (nr-axSpA) is accepted and used in Germany. In 2016, an online survey was performed among all rheumatologists registered in the German Society of Rheumatology (DGRh). In addition, 150 rheumatologists were invited to the survey at the national meeting of the DGRh in 2016. Among 119 participating rheumatologists, 99% were familiar with the new CC for SpA and 82% applied them in practice (RA 99% and 80%, SLE 50% and 56%). 78% differentiated between radiographic and nr-axSpA and 80% believed that asignificant proportion of patients with nr-axSpA will never develop radiographic changes. 91% agreed that the new CC facilitated an earlier treatment start and 58% that the CC enabled more patients to receive biologicals. 50% shared the opinion that the criterion "chronic back pain" could lead to the classification of too many patients as having axSpA. It deemed possible to 65% that patients with nr-axSpA would be treated with biologicals in whom the diagnosis of axSpA could not be confirmed later on. 81% voted against the initiation of TNF inhibitors in nr-axSpA patients with normal CRP levels and normal MRI. 67% interpreted the MRI themselves and 30% stated that the MRI is evaluated according to validated standards by the radiologists. Among all axSpA criteria, HLA B27 and inflammatory back pain received the highest significance and the response to NSAID the lowest. The new CC and the entity of nr-axSpA are accepted by German rheumatologists. Arelevant proportion saw weaknesses of the new CC in the differentiation between nr-axSpA and non-specific chronic back pain. In practise, the interpretation of the CC with respect to the start of biologics is relatively strict, especially in cases with normal CRP and MRI. A ranking of axSpA criteria is commonly applied, although this was not initially intended in the CC.

The Microbiome and Psoriatic Arthritis

Psoriatic arthritis is a chronic inflammatory joint disease, seen in combination with the chronic inflammatory skin disease psoriasis and belonging to the family of spondylarthritides (SpA). A link is recognized between psoriatic arthritis and inflammatory bowel disease (IBD). Environmental factors seem to induce inflammatory disease in individuals with underlying genetic susceptibility. The microbiome is a subject of increasing interest in the etiology of these inflammatory immune-mediated diseases. The intestinal microbiome is able to affect extra-intestinal distant sites, including the joints, through immunomodulation. At this point, evidence regarding a relationship between the microbiome and psoriatic arthritis is scarce. However, we hypothesize that common immune-mediated inflammatory pathways seen in the "skin-joint-gut axis" in psoriatic arthritis are induced or at least mediated by the microbiome. Th17 has a crucial function in this mechanism. Further establishment of this connection may lead to novel therapeutic approaches for psoriatic arthritis.

Inhibiting HLA–B27 homodimer–driven immune cell inflammation in spondylarthritis

Spondylarthritides (SpA), including ankylosing spondylitis (AS), are common inflammatory rheumatic diseases that are strongly associated with positivity for the HLA class I allotype B27. HLA-B27 normally forms complexes with β(2) -microglobulin (β(2) m) and peptide to form heterotrimers. However, an unusual characteristic of HLA-B27 is its ability to form β(2) m-free heavy chain homodimers (HLA-B27(2) ), which, unlike classic HLA-B27, bind to killer cell immunoglobulin-like receptor 3DL2 (KIR-3DL2). Binding of HLA-B27(2) to KIR-3DL2-positive CD4+ T and natural killer (NK) cells stimulates cell survival and modulates cytokine production. This study was undertaken to produce an antibody to HLA-B27(2) in order to confirm its expression in SpA and to inhibit its proinflammatory properties. We generated monoclonal antibodies by screening a human phage display library positively against B27(2) and negatively against B27 heterotrimers. Specificity was tested by enzyme-linked immunosorbent assay (ELISA), surface plasmon resonance (SPR) assay, and fluorescence-activated cell sorting (FACS) analysis of B27(2) -expressing cell lines and peripheral blood mononuclear cells (PBMCs) and synovial fluid mononuclear cells (SFMCs) from patients with SpA. Functional inhibition of KIR-3DL2-B27(2) interactions was tested using cell lines and PBMCs from patients with SpA. Monoclonal antibody HD6 specifically recognized recombinant HLA-B27(2) by ELISA and by SPR assay. HD6 bound to cell lines expressing B27(2) . FACS revealed binding of HD6 to PBMCs and SFMCs from patients with AS but not from controls. HD6 inhibited both the binding of HLA-B27(2) to KIR-3DL2 and the survival and proliferation of KIR-3DL2-positive NK cells. Finally, HD6 inhibited production of the proinflammatory disease-associated cytokine interleukin-17 by PBMCs from patients with AS. These results demonstrate that antibody HD6 has potential for use in both the investigation and the treatment of AS and other B27-associated spondylarthritides.

Is there subclinical enthesitis in early psoriatic arthritis? A clinical comparison with power doppler ultrasound.

Enthesitis is a recognized feature of spondylarthritides (SpA), including psoriatic arthritis (PsA). Previously, ultrasound imaging has highlighted the presence of subclinical enthesitis in established SpA, but there are little data on ultrasound findings in early PsA. The aim of our study was to compare ultrasound and clinical examination (CE) for the detection of entheseal abnormalities in an early PsA cohort. Forty-two patients with new-onset PsA and 10 control subjects underwent CE of entheses for tenderness and swelling, as well as gray-scale (GS) and power Doppler (PD) ultrasound of a standard set of entheses. Bilateral elbow lateral epicondyles, Achilles tendons, and plantar fascia were assessed by both CE and ultrasound, the latter scored using a semiquantitative (SQ) scale. Inferior patellar tendons were assessed by ultrasound alone. A GS SQ score of >1 and/or a PD score of >0 was used to describe significant ultrasound entheseal abnormality. A total of 24 (57.1%) of 42 patients in the PsA group and 0 (0%) of 10 controls had clinical evidence of at least 1 tender enthesis. In the PsA group, for sites assessed by both CE and ultrasound, 4% (7 of 177) of nontender entheses had a GS score >1 and/or a PD score >0 compared to 24% (9 of 37) of tender entheses. CE overestimated activity in 28 (13%) of 214 of entheses. All the nontender ultrasound-abnormal entheses were in the lower extremity. The prevalence of subclinical enthesitis in this early PsA cohort was low. CE may overestimate active enthesitis. The few subclinically inflamed entheses were in the lower extremity, where mechanical stress is likely to be more significant.

The interferon signature and STAT1 expression in rheumatoid arthritis synovial fluid macrophages are induced by tumor necrosis factor α and counter‐regulated by the synovial fluid microenvironment

Type I interferons (IFNs) have emerged as potential activators of the IFN signature and elevated STAT-1 expression in rheumatoid arthritis (RA) synovium, but mechanisms that induce synovial IFN expression are unknown. Recently, tumor necrosis factor α (TNFα) was shown to induce a delayed IFN response in macrophages. We undertook this study to test whether TNFα, classically thought to activate inflammatory NF-κB target genes in RA, also contributes to the "IFN signature" in RA synovial macrophages. Synovial fluid (SF) macrophages purified from 24 patients with RA and 18 patients with spondylarthritides (SpA) were lysed immediately after isolation or were cultured ex vivo in the absence or presence of blockade of endogenous type I IFN or TNFα. Expression of IFN-inducible target genes was measured by quantitative reverse transcription-polymerase chain reaction, and expression of their corresponding proteins was measured by enzyme-linked immunosorbent assay. Expression of an IFN signature and STAT1 in RA synovial macrophages was suppressed when type I IFNs or TNFα were blocked, whereas TNFα blockade did not affect expression of IFN response genes or STAT1 in SpA synovial macrophages. RA SF suppressed the IFN signature in RA synovial macrophages and in TNFα-, IFNα-, and IFNβ-stimulated control macrophages. Type I IFNs suppressed expression of IL8 and MMP9 in RA synovial macrophages and in TNFα-stimulated control macrophages. Our findings identify a new function of TNFα in RA synovitis by implicating TNFα as a major inducer of the RA synovial IFN response. The results suggest that the expression of IFN response genes in RA synovium is regulated by interplay between TNFα and opposing homeostatic factors expressed in the synovial microenvironment.

β‐glucan triggers spondylarthritis and Crohn's disease–like ileitis in SKG mice

The spondylarthritides (SpA), including ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis, and arthritis associated with inflammatory bowel disease, cause chronic inflammation of the large peripheral and axial joints, eyes, skin, ileum, and colon. Genetic studies reveal common candidate genes for AS, PsA, and Crohn's disease, including IL23R, IL12B, STAT3, and CARD9, all of which are associated with interleukin-23 (IL-23) signaling downstream of the dectin 1 β-glucan receptor. In autoimmune-prone SKG mice with mutated ZAP-70, which attenuates T cell receptor signaling and increases the autoreactivity of T cells in the peripheral repertoire, IL-17-dependent inflammatory arthritis developed after dectin 1-mediated fungal infection. This study was undertaken to determine whether SKG mice injected with 1,3-β-glucan (curdlan) develop evidence of SpA, and the relationship of innate and adaptive autoimmunity to this process. SKG mice and control BALB/c mice were injected once with curdlan or mannan. Arthritis was scored weekly, and organs were assessed for pathologic features. Anti-IL-23 monoclonal antibodies were injected into curdlan-treated SKG mice. CD4+ T cells were transferred from curdlan-treated mice to SCID mice, and sera were analyzed for autoantibodies. After systemic injection of curdlan, SKG mice developed enthesitis, wrist, ankle, and sacroiliac joint arthritis, dactylitis, plantar fasciitis, vertebral inflammation, ileitis resembling Crohn's disease, and unilateral uveitis. Mannan triggered spondylitis and arthritis. Arthritis and spondylitis were T cell- and IL-23-dependent and were transferable to SCID recipients with CD4+ T cells. SpA was associated with collagen- and proteoglycan-specific autoantibodies. Our findings indicate that the SKG ZAP-70W163C mutation predisposes BALB/c mice to SpA, resulting from innate and adaptive autoimmunity, after systemic β-glucan or mannan exposure.

Mucosal Inflammation in Spondylarthritides: Past, Present, and Future

Spondylarthritides (SpA) and inflammatory bowel disease (IBD) are idiopathic, chronic inflammatory disorders. Although they are very distinct and well-defined entities, there is clinical and genetic evidence supporting some degree of overlap between the pathogenesis of the two. Subclinical gut inflammation is present in up to two thirds of all SpA patients and can evolve into IBD. This subclinical gut inflammation has been shown to be strongly associated with joint inflammation, providing a clue for a common pathophysiologic background. Despite extensive research progress in the field over the past few years, many questions remain unanswered. In this paper, we focus on the clinical, genetic, and pathophysiologic overlap of SpA and IBD. Furthermore, we discuss some of the targets that may influence therapeutic decision making.

The HLA–B*2705 peptidome

The HLA-B27 allele is strongly associated with the group of inflammatory diseases known as the spondylarthritides (SpA). The aim of this study was to perform a large-scale, direct biochemical analysis of the HLA-B*2705 peptidome in order to identify candidates for mimicry between HLA-B27 peptides derived from cartilage proteins and arthritogenic bacterial sequences and to refine the consensus binding motif of this important allele. The peptides were recovered by recombinant expression of soluble HLA-B27 molecules secreted from cultured chondrocytic cells or HeLa cells. Analysis was based on capillary chromatography and tandem mass spectrometry in combination with stable isotope labeling with amino acids in cell culture or chemical labeling with iTRAQ to enhance the validity of the data. Over 1,268 B27 peptides were identified, with 569 of them at high certainty, thus enabling better refinement of the B27 motif. This enabled the prediction of both short peptides and long peptides whose middle residues likely bulge out of the binding groove. Moreover, we identified a number of human B27 peptide sequences derived from human cartilage proteins, some of which are similar to common bacterial sequences. The peptides we identified may provide the missing link between bacterial infections and the resulting SpA.

The HLA–B27 peptidome: Building on the cornerstone

The pathogenetic role of HLA–B27 in the spondylarthritides (SpA) is an elusive problem that remains unsolved 37 years after the discovery of the extraordinary association of this antigen with ankylosing spondylitis (AS) (1,2) and almost 20 years after the establishment of a transgenic animal model (3) in which the direct involvement of B27 in the pathogenesis of these diseases was demonstrated. In the absence of definitive evidence for the mechanism of this association, 3 major hypotheses are currently the focus of intense debate. First is the arthritogenic peptide hypothesis (4), which is based on the canonical antigen-presenting properties of B27. This hypothesis assumes that there is an autoimmune mechanism involving specific T cell recognition and molecular mimicry between microbial and selfantigens presented by this molecule. Second is the misfolding hypothesis (5), which proposes an autoinflammatory mechanism (independent of antigen presentation) following activation of the unfolded protein response upon accumulation of misfolded B27 heavy chain in the endoplasmic reticulum. Third is the surface homodimer hypothesis (6), which is based on the expression of covalent B27 heavy-chain homodimers at the cell surface that can be recognized by leukocyte receptors, providing the basis for an immunomodulatory role of noncanonical B27 forms with potentially pathologic consequences (7). Recently, we proposed that the pathogenesis of SpA might be better explained not on the basis of just a particular feature of B27, but from a comprehensive consideration of its whole biology, which is determined by the interdependency of multiple molecular properties (8). In adopting this viewpoint, peptide binding is recognized as an essential feature of HLA–B27, largely determining its immunologic specificity, as well as its folding and stability, which are critical to the formation of heavy-chain homodimers. Thus, peptides emerge as the cornerstone of HLA–B27 biology and pathophysiology (8). This idea might be supported by the identification of endoplasmic reticulum aminopeptidase 1 (ERAP-1), which is involved in the processing of HLA class I ligands, as a susceptibility factor for AS (9). Therefore, the characterization of the B27 peptidome becomes a critical issue in our search for an understanding of the pathogenesis of AS. What can be expected from a knowledge of the B27-bound peptide repertoire that may be relevant to the pathogenesis of SpA? It would be naive to assume that a purely proteomic approach may lead to a straightforward identification of putative arthritogenic peptides because, among other reasons, we ignore the features these peptides might have or the proteins from which they arise. However, other basic issues that are critical to a proper assessment of the very concept of arthritogenic peptide and to its potential features can be addressed. Some of these issues are as follows: 1) the accurate establishment of the B27 binding motif and its variation as a function of peptide size, which would improve the prediction of B27 epitopes and help in their identification as naturally processed antigens; 2) the influence of the binding motif, and deviations therefrom, on the molecular stability of B27; 3) the characterization of peptide features that influence the binding mode and presentation to T cells, as shown for Arg5 residues among B*2705 ligands (10); 4) the identification of the parental proteins of B27-bound peptides, including tissue-specific ones, that might be targets of site-specific autoimmune attack; 5) the identification of self-derived B27 ligands with similarity to microbial epitopes, which may provide a basis for molecular/antigenic mimicry; 6) an estimation of the frequency of such peptides, which would inform us of the likelihood that molecular mimSupported by grant SAF2008/00461 from the Ministry of Science and Innovation and by an institutional grant from the Fundacion Ramon Areces to the Centro de Biologia Molecular Severo Ochoa. Jose A. Lopez de Castro, PhD: Centro de Biologia Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientificas, and Universidad Autonoma de Madrid, Madrid, Spain. Address correspondence and reprint requests to Jose A. Lopez de Castro, PhD, Centro de Biologia Molecular Severo Ochoa, Calle Nicolas Cabrera No. 1, Universidad Autonoma, 28049 Madrid, Spain. E-mail: aldecastro@cbm.uam.es. Submitted for publication August 25, 2009; accepted in revised form October 2, 2009.

Synovial fluid is a site of citrullination of autoantigens in inflammatory arthritis

To examine synovial fluid as a site for generating citrullinated antigens, including the candidate autoantigen citrullinated alpha-enolase, in rheumatoid arthritis (RA). Synovial fluid was obtained from 20 patients with RA, 20 patients with spondylarthritides (SpA), and 20 patients with osteoarthritis (OA). Samples were resolved using sodium dodecyl sulfate-polyacrylamide gel electrophoresis, followed by staining with Coomassie blue and immunoblotting for citrullinated proteins, alpha-enolase, and the deiminating enzymes peptidylarginine deiminase type 2 (PAD-2) and PAD-4. Proteins from an RA synovial fluid sample were separated by 2-dimensional electrophoresis, and each protein was identified by immunoblotting and mass spectrometry. Antibodies to citrullinated alpha-enolase peptide 1 (CEP-1) and cyclic citrullinated peptide 2 were measured by enzyme-linked immunosorbent assay. Citrullinated polypeptides were detected in the synovial fluid from patients with RA and patients with SpA, but not in OA samples. Alpha-enolase was detected in all of the samples, with mean levels of 6.4 ng/microl in RA samples, 4.3 ng/microl in SpA samples, and <0.9 ng/microl in OA samples. Two-dimensional electrophoresis provided evidence that the alpha-enolase was citrullinated in RA synovial fluid. The citrullinating enzyme PAD-4 was detected in samples from all 3 disease groups. PAD-2 was detected in 18 of the RA samples, in 16 of the SpA samples, and in none of the OA samples. Antibodies to CEP-1 were found in 12 of the RA samples (60%), in none of the SpA samples, and in 1 OA sample. These results highlight the importance of synovial fluid for the expression of citrullinated autoantigens in inflammatory arthritis. Whereas the expression of citrullinated proteins is a product of inflammation, the antibody response remains specific for RA.

The concept of a “synovio‐entheseal complex” and its implications for understanding joint inflammation and damage in psoriatic arthritis and beyond

The pathogenesis of tissue inflammation and damage in rheumatic diseases that are associated with the major histocompatibility complex (MHC), including rheumatoid arthritis (RA) and the spondylarthritides (SpA), has mainly been viewed in relation to an autoimmune effector mechanism (1–3). However, because synovial joints serve to promote movement, it is logical to assume that aberrant functioning of their constituent parts could contribute to inflammation. Although such “wear and tear” mechanisms are well recognized as contributory factors in osteoarthritis (OA), it is less clear that factors intrinsic to the biomechanical functioning of synovial joints could be significant in diseases considered to be autoimmune. Investigators in our group previously proposed that the primary basis for the pathogenesis of psoriatic arthritis (PsA) and SpA could be biomechanical rather than autoimmune (4–6). This was based on our interpretation of magnetic resonance imaging (MRI) in knee disease in early SpA, which showed specific patterns of inflammation. Moreover, such observations were not confined to SpA, because the anatomic locations of ligaments and tendons also affected both the magnitude of synovitis and the propensity for erosions in early RA (7). This concept of such tissue-specific factors or “autoinflammatory factors” (as distinct from autoimmunity, which is principally played out in the primary and secondary lymphoid organs) allowed for the development of a new classification scheme for all inflammatory disorders (8). Such tissue-specific factors might also underscore common inflammatory or tissue repair pathways that may be shared by both inflammatory and degenerative disorders (9). Thus, the purpose of the present article is to develop the idea that joint-specific factors could trigger innate immune responses and may be pivotal players in the phenotypic expression of PsA, the related SpA, RA, and even OA. The concept is centered on an anatomic unit we have called the synovio-entheseal complex (SEC) and is described in relation to PsA and other types of arthropathy.

Expansion and enhanced survival of natural killer cells expressing the killer immunoglobulin-like receptor KIR3DL2 in spondylarthritis.

The spondylarthritides (SpA) are strongly associated with possession of HLA-B27. We hypothesized that the expression of abnormal forms of HLA-B27 in SpA may have a pathogenic role through interaction with cells bearing natural killer (NK) receptors, in particular, killer immunoglobulin-like receptor (KIR) KIR3DL2, a receptor for HLA-B27 homodimer (B27(2)). We therefore undertook the present study to determine the number and function of NK and T cells bearing KIR3DL2 in SpA. Expression of KIR3DL2 on NK and T cells was quantified in peripheral blood (PB) from 35 patients with SpA and 5 patients with juvenile enthesitis-related arthritis (juvenile ERA); samples were compared with samples from healthy and rheumatoid arthritis (RA) controls. Paired synovial fluid (SF) was studied where available. Expression of other KIRs as well as activation, memory, and homing markers on KIR3DL2+ NK and T cells was quantified. NK cell survival was assessed using the apoptotic markers annexin V and 7-aminoactinomycin D, and cytotoxicity by (51)Cr release assay. In SpA, an increased number of PB and SF NK and CD4+ T cells expressed the KIR3DL2 receptor compared with controls. In ERA, KIR3DL2 expression was increased in PB and SF CD4 T cells (and SF NK cells) compared with RA controls. KIR3DL2+ NK cells had an activated phenotype, and were protected from apoptosis by culture with a cell line expressing B27(2). SpA PB mononuclear NK cells from SpA patients showed greater cytotoxicity than those from controls. KIR3DL2 expression on NK cells and CD4 lymphocytes is increased in SpA and ERA. These cells are activated and may have a pathogenic role.