Author's Accepted Manuscript

The TL1A/DR3/DcR3 Pathway in Autoimmune Rheumatic Diseases Spyros I. Siakavellas MD, Petros P. Sfikakis MD, Giorgos Bamias MD

www.elsevier.com/locate/semarthrit

PII: DOI: Reference:

S0049-0172(15)00017-7 http://dx.doi.org/10.1016/j.semarthrit.2015.02.007 YSARH50900

To appear in:

Seminars in Arthritis and Rheumatism

Cite this article as: Spyros I. Siakavellas MD, Petros P. Sfikakis MD, Giorgos Bamias MD, The TL1A/DR3/DcR3 Pathway in Autoimmune Rheumatic Diseases, Seminars in Arthritis and Rheumatism, http://dx.doi.org/10.1016/j.semarthrit.2015.02.007 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

THE TL1A/DR3/DcR3 PATHWAY IN AUTOIMMUNE RHEUMATIC DISEASES

Spyros I. Siakavellas, MDa, Petros P. Sfikakis, MDb, Giorgos Bamias, MDa a

Academic Department of Gastroenterology, Kapodistrian University of Athens, Laikon

Hospital, 17 Agiou Thoma St, Athens 11527, Greece b

First Department of Propaedeutic and Internal Medicine, Kapodistrian University of

Athens, Laikon Hospital, 17 Agiou Thoma St, Athens 11527, Greece

Corresponding author: Dr Giorgos Bamias, MD, Academic Department of Gastroenterology, Kapodistrian University of Athens, Laikon Hospital, 17 Agiou Thoma St, Athens 11527, Greece Tel: +30-210-7456504 Fax: +30-210-7791839 E-mail: [email protected]

Abstract IMPORTANCE: TNF-like cytokine 1A (TL1A) and its receptors, death receptor 3 (DR3) and decoy receptor 3 (DcR3) are members of the TNF and TNF receptor superfamilies of proteins, respectively. They constitute a cytokine system that actively interferes with the regulation of immune responses and may participate in the pathogenesis of autoimmune diseases. OBJECTIVES: This review aims to present the current knowledge on the role of the TL1A/DR3/DcR3 system in the pathophysiology of autoimmune rheumatic diseases, with a focus on rheumatoid arthritis (RA). METHODS: An extensive literature search was performed in the PubMed database using the following keywords: TL1A, death receptor 3, DR3, decoy receptor 3, DcR3, TNFSF15, TNFRSF25, and TNFSF6B. Studies were assessed and selected in view of their relevance to autoimmune rheumatic diseases. RESULTS: The TL1A/DR3/DcR3 system of cytokines is upregulated both at the tissue and/or systemic levels in several rheumatologic diseases, including rheumatoid arthritis, ankylosing spondylarthropathy, systemic lupus erythematosus, and systemic sclerosis. Preclinical and clinical studies indicate that these proteins are involved in several immunological pathways that are considered central to the pathogenesis of chronic inflammatory arthritis. In particular, they mediate the shaping of effector immunity, more specifically of Th1 and Th17 responses and participate in the remodeling processes observed in RA.

CONCLUSION: The TL1A/DR3/DcR3 axis is a novel immune pathway that participates in the pathogenesis of a variety of autoimmune rheumatic diseases. These molecules may be promising therapeutic targets for inflammatory arthritis.

KEYWORDS: TL1A; DR3; DcR3; autoimmune disease; rheumatic disease

1. INTRODUCTION The superfamilies of tumor necrosis factor (TNF) ligands and their corresponding receptors (TNFSF and TNFRSF, respectively) consist of several proteins, which are critically involved in the regulation of innate and adaptive immunity(1). Ligand/receptor binding activates signaling pathways that shape several aspects of the immune response, ranging from apoptosis to autoimmunity. One such TNFSF/TNFRSF system comprises of the TNF-like ligand, TL1A and its two receptors DR3 and DcR3. The immunological pathways that are mediated by these proteins will be the subject of our review with a focus on their involvement in the pathogenesis of autoimmune rheumatic diseases.

2. METHODS A systematic literature search was conducted on the PubMed database. We searched for articles published until September 2014, using the following keywords: TNF-like cytokine 1A, TL1A, death receptor 3, DR3, decoy receptor 3, DcR3, TNFSF15,

TNFRSF25, TNFSF6B, VEGI, all separately as well as in different combinations. The reference lists of identified articles were searched for further relevant articles. The retrieved articles were assessed according to their applicability to the review subject. Thus, only articles pertaining to the TL1A/DR3/DcR3 axis and its involvement in the subset of autoimmune rheumatic diseases were selected. Studies from animal models and clinical studies were both included. The central findings and main conclusions from this multitude of recent data are summarized in the following parts of the article. 3. DISCOVERY AND CHARACTERIZATION OF TL1A AND ITS RECEPTORS DR3 AND DCR3 TNF-like protein 1A (TL1A) was first described in 2002(2). In their seminal paper, Migone et al., reported that TL1A is a longer variant of the previously described protein TL1 (alternative name vascular endothelial growth inhibitor - VEGI). The gene that encodes for both variants is designated TNFSF15 in humans (located on chromosome 9q32) and Tnfsf15 in mice (chromosome 4). TL1A is translated from all four exons of the gene, whereas VEGI is encoded by a continuous DNA sequence spanning from the third to the end of the fourth exon(2). The C-terminal regions of TL1 and TL1A are identical, whereas no similarity occurs for the N-terminal regions. The produced TL1A protein is a trimeric 28-kDa, type II transmembrane protein, which contains 251 aminoacids. Its extracellular part contains the characteristic TNF homology domain(3). The shorter variant, TL1, lacks a transmembrane region. Like most TNF-like cytokines, the membrane-bound form of TL1A (mTL1A) can be cleaved by enzymes of the matrix metalloproteinases family and released as a soluble 20-kDa protein (sTL1A), which retains full functionality(3).

TL1A is the only known ligand for death receptor 3 (DR3, designated TNFRSF25)(4). The first reports of DR3 date from 1996 and a variety of names were assigned to this protein (Wsl-1, Apo3, LARD, TRAMP, TNFRSF25, and TR3)(5-9). DR3 is a type I membrane protein comprised of 417 amino-acids with a molecular weight of 45 kDa and contains a death domain (DD) in its cytoplasmic region(7). The respective gene was mapped in the human genome at the 1p36.3 position (5-7, 9, 10). Both the long (TL1A) and short (TL1) variants of the TNFSF15 products signal through DR3. The effects of ligation by each isoform to DR3-expressing cells have not been tested comparatively. In an isolated exception, Tian et al. reported that VEGI/TL1 (but not TL1A) induced DR3-mediated signals to bone marrow-derived immature dendritic cells, leading to their maturation(11). Nevertheless, TL1 has been studied for its role in carcinogenesis, almost exclusively, whereas TL1A mostly for its function in the immune system. DR3 is the member of the TNFRSF with the highest homology to TNFR1(5). Nevertheless, in contrast to TNFR1 that is expressed ubiquitously, expression of DR3 appears to be restricted to the lymphocytic compartment. Indeed, abundant expression of DR3 was detected both in tissues enriched for lymphocytes (thymus, spleen) and in peripheral blood lymphocytes(6-8). In particular, DR3 is expressed on CD4+ and CD8+ cells as well as natural killer (NK) cells, and is upregulated during activation of the respective populations(5-8, 12, 13). Furthermore, although DR3 is not expressed by resting B-cells, it is induced by anti IgM stimulation and becomes detectable on plasma cells(14). Apart from lymphocytes there have been reports of DR3 expression in endothelial cells and osteocytes(15, 16). On the other hand, TL1A was first reported to be produced in endothelial cells after stimulation by TNF and IL1β(2). Subsequent

studies detected high TL1A expression in antigen presenting cells (monocytes, dendritic cells, macrophages), which is induced via Fcγ­receptor and Toll­like receptor signaling(17-19). In addition, TL1A may also be expressed by T lymphocytes under inflammatory conditions, via T-cell receptor- or cytokine-mediated stimulation(20). In general, expression of TL1A by these cells is transient, with the exception of the T cells(20). In addition to DR3, which is the functional receptor, TL1A may also bind to decoy receptor 3 (DcR3, designated TNFSF6B, also known as TR6 or M68)(21). DcR3 protein has 300 amino acids, with a molecular size of 33 kDa, and is encoded by the tnfrsf6b gene, which is located on chromosome 20 (20q13.3)(22). DcR3 exists only in soluble form and is detectable in biological fluids(23-25). There is no murine analogue for human DcR3. The main characteristics of the three molecules of the TL1A/DR3/DcR3 system are summarized in Table 1.

4. FUNCTIONS OF THE TL1A/DR3/DcR3 PATHWAY TL1A/DR3 binding has been associated with two distinct downstream signaling cascades (Figure 1). In the first, the adapter protein TNFR-associated death domain protein (TRADD) binds to the cytoplasmic death domain. This, in turn, recruits the TNFR-associated factor (TRAF) proteins, subsequently stimulating mitogen-activated protein kinases (MAPK) and leading to activation of the nuclear factor kappa-light-chainenhancer of activated B cells (NF-κB)(26, 27). The end-point of this process is T-cell co-stimulation. The second cascade differs in that TRADD associates not with TRAF

proteins but with Fas-associated death domain (FADD) and caspase 8. This initiating step activates effector caspases such as caspase 3, ultimately leading to cell apoptosis(26, 28). It appears that ligation of TL1A to DR3 that is expressed on lymphocytes preferentially induces co-stimulation rather than apoptosis. A previous study reported that stimulation by TL1A of DR3-expressing TF-1 cells resulted in upregulation of cellular inhibitor of apoptosis proteins (c-IAP), especially c-IAP2(29). These proteins prevent apoptotic death by constraining the effector caspases. Interestingly, when c-IAP function was aborted, TL1A stimulation led to apoptosis of TF1 cells. A positive feedback loop existed between c-IAPs and NF-κB and inhibition of the latter also promoted apoptosis. Therefore, it is possible that the fate of TL1A-DR3 signaling may be dictated by the effective co-production of antiapoptotic proteins. Recent functional studies strongly support a pro-inflammatory role for TL1A/DR3 signaling during immunological responses. DR3 induces the proliferation of CD4+ T cells and the secretion of interferon (IFN)­γ and granulocyte­macrophage colony stimulating factor (GM-CSF)(18). Moreover, sTL1A increased the responsiveness of TCR-stimulated T cells to IL-2 and IL-15 and acted in concordance with IL-12 and IL-18 to increase the expression of IFN-γ from T and NK cells(2, 30). Similarly, TL1A acting in tandem with IL-12, IL-15 and IL-18 induced the expression of co-stimulatory molecules CD154 (CD40 ligand) and CD134 (OX40) on activated CD4+ T cells, thus, decreasing the activation threshold(31). Initially, it was proposed that the co-stimulatory effect of TL1A/DR3 signaling resulted in specific enhancement of Th1 effector responses. Nevertheless, newer studies have produced data that support a broader role for TL1A and DR3 as universal co-stimulators of immunological responses.

First, three

independent

groups

reported

that,

TL1A

transgenic

mice

develop

intestinal

inflammation, that is characterized by predominant Th2 type responses with a marked elevation of IL-13(32-34). Second, in other studies, DR3 was found to be selectively elevated in Th17 cells and TL1A enhanced the proliferation of effector Th17 cells(35, 36). Finally, TL1A may also modulate the expansion and function of regulatory T cells (Tregs)(32, 33, 37, 38). The aforementioned immunomodulatory effects of the TL1A/DR3 axis are, at least, partially reverted when the decoy receptor DcR3 binds to TL1A. In fact, it has been shown that DcR3 restricts the function of the TL1A/DR3 complex, attenuating T-cell activation and downregulating the secretion of pro-inflammatory cytokines(2). DcR3 has also the ability to bind to other TNFSF ligands, in particular, Fas ligand(21) and receptor homologous to lymphotoxins that exhibits inducible expression, competes with HSV glycoprotein D for the HVEM, and is expressed by T lymphocytes (LIGHT)(39). DcR3 acts competitively towards the natural binding of these ligands to their cognate receptors. Finally, recent data have demonstrated that DcR3 can also exert non-decoy, immunomodulatory functions. The effects of TL1A on B-cells remain largely unknown. As previously said, B cells upregulate DR3 expression upon polyclonal stimulation via the B-cell receptor(14). In the same study, it was shown that TL1A stimulation resulted in blockade of B-cell proliferation without affecting B-cell survival. Therefore, it appears that TL1A may affect humoral responses directly by acting to DR3-expressing B-cells. Taken together, the aforementioned findings indicate that the TL1A/DR3/DcR3 pathway is a crucial mediator of inflammatory responses and, as a consequence, may be

involved in the pathogenesis of a variety of chronic inflammatory diseases. Furthermore, essential roles for these molecules have been demonstrated in murine models of experimental autoimmune encephalomyelitis (EAE)(20), colitis(40), and allergic lung inflammation(13). In the remaining of this review, we will examine the involvement of this immunologic system in rheumatologic disease with particular focus on rheumatoid arthritis. 5. THE TL1A/DR3 AXIS IN HUMAN RHEUMATIC DISEASE (Table 2) 5.1 RHEUMATOID ARTHRITIS Rheumatoid arthritis (RA) is a chronic, immune-mediated disease of the joints that is characterized by persistent synovial hyperplasia and inflammation, which leads to cartilage and bone destruction. The inflammatory process at the synovium is mediated by a diverse network of cytokines, including several members of the TNF superfamily(41, 42). While RA was initially thought to be mediated primarily by Th1 cells, newer studies have also implicated the Th17 immune responses in its pathogenesis(43). As TL1A/DR3 signaling was shown to bolster both Th1 and Th17 responses and participate in the development of experimental arthritis (see below), an active role for these proteins in the pathogenesis of RA has been hypothesized. Several converging lines of genetic, immunological and clinical data support this hypothesis. Several independent groups have reported upregulated TL1A expression in the peripheral blood and, more importantly, the inflamed joints and synovial fluid of patients with RA (18, 44, 45). Interestingly, this was particularly evident in rheumatoid factor (RF) seropositive RA patients(18).

In several of these studies, a correlation was

reported between TL1A serum concentrations and RA severity. Original studies by Cassatella et al. demonstrated that human monocytes express and release significant amounts of soluble TL1A when stimulated with insoluble immune complexes, polyethylene glycol precipitates from the serum of RF positive patients, or with insoluble immune complexes purified from RA synovial fluids(18). The authors concluded that the main source of TL1A in RA are mononuclear phagocytes. Nevertheless, other reports indicated that TL1A may also be produced by chondrocytes and synovial fibroblasts, following stimulation with TNF-α and/or IL-1β(19). In turn, sTL1A protein functions as perpetuator of auto-inflammation. Studies from our group confirmed the presence of elevated concentrations of TL1A protein in inflamed synovia but also in the serum of patients with RA as compared to healthy controls(44).

Moreover, TL1A levels

correlated with advanced stage of disease. Similarly to our studies, TL1A was found to be more elevated in RA patients than in patients with osteoarthritis(45).

This

upregulation of TL1A was more prominent in the synovial fluid than in the peripheral circulation(45).

Again, TL1A expression was higher in patients with RA-specific

autoantibodies such as RF(44, 45) and anti-citrullinated protein antibodies(45). The functional effects of the reported elevation of TL1A protein in RA are still largely unknown.

In one study, TL1A stimulated antibody production by peripheral blood

mononuclear cells in RA patients(45). In a different perspective, it was suggested that TL1A induces Th17 differentiation via RORc activation in naive T cells and increased IL17A levels in cell supernatants from RA patients(46). Therefore, TL1A-DR3 interactions seem to be important in both adaptive (that functions through a mixed Th1/Th17 phenotype) and innate immunity in RA. Regarding the potential role of TL1A as a

marker of disease activity, this remains a matter of debate, since some studies report a correlation of its levels with disease severity(18, 44, 47), while in others this finding has not been confirmed(45). In all, the aforementioned findings strongly indicate a crucial role for the TL1A axis in the shaping of the immune response and the inflammatory process in RA. This mediation seems to be achieved mainly through effects in the adaptive Th1/Th17 immune response that underlies the disease. Support for the functional implication of the TL1A/DR3 system in RA also comes from genetic studies. In particular, a duplication of the DR3 gene in the chromosome region 1p36.3 was shown to be more prevalent in patients with RA when compared to healthy individuals(48). The functional implications of this genetic derangement have not been elucidated, although it may predict the presence of soluble or transmembrane forms of DR3 protein. DcR3, the decoy receptor for TL1A, is also significantly upregulated in peripheral blood and synovial fluid from patients with RA, as compared to healthy controls, or patients with osteoarthritis(44, 49). Moreover, in one of these studies, average DcR3 levels were found to be associated with RA disease stage(44). In another study, it was shown that DcR3 was secreted from fibroblast-like synoviocytes isolated from patients with RA(50). Expression of DcR3 in synoviocytes was highly induced by TNF-α, an effect that seems specific for RA, as it was not observed in osteoarthritis. Moreover, findings from another group further characterized the distribution of DcR3 expression in the inflamed synovium(51). It was shown that no significant differences were observed in synovial lining layer between RA, ankylosing spondylitis (AS) and osteoarthritis, while at

the sublining layer, the expression of DcR3 was more upregulated in RA and AS than in osteoarthritis. As in the case of TL1A, the functional role of DcR3 in RA has not been clarified, yet. The primary function of DcR3 is of a decoy receptor that prevents TL1A/DR3 binding; this would imply a protective role during chronic synovial inflammation. This hypothesis is indeed supported by recent reports.

In the CIA murine model of arthritis, over-

expression of DcR3 via plasmid transfer resulted in significantly downregulated immunological responses and attenuated severity of arthritis(52). Similarly, a protective role for DcR3 was also implied by a recent in vitro study. It was reported that DcR3 was capable of binding to TL1A expressed on fibroblast-like synoviocytes from RA patients and inhibited their proliferation induced by pro-inflammatory cytokines(53). In follow-up work from the same group, the results of a cDNA microarray study on the expression profiles of genes in fibroblast-like synoviocytes under the effect of DcR3, were reported(54). Among the 100 genes most significantly regulated by DcR3, 45 were upregulated and 55 were downregulated and a variety of cellular functions were affected. DcR3 may also exert pro-inflammatory functions, as indicated by its ability to bind Fas ligand on fibroblast-like synoviocytes and inhibit apoptosis of the latter(50). Such an effect may prevent the elimination of inflammatory cells and result in perpetuation of the autoimmune process, contributing to the pathogenesis of RA. A final point of interest related to the possible utility of circulating TL1A and DcR3 levels as markers of disease activity/severity in RA. We have already mentioned that in some studies TL1A levels were associated with advanced stages of RA. This association was further supported by the fact that treatment of RA patients with adalimumab was

associated with a significant decrease of the circulating levels of TL1A(44).

More

interesting are our findings that TL1A and DcR3 may be used as predictive markers for atheromatic plaque formation in patients with RA(55). In this prospective study, we followed 45 patients (that had a baseline measurement of serum TL1A and DcR3 concentrations) for more than 3 years with ultrasound of carotid and femoral arteries. We found that a serum phenotype of “low TL1A and undetectable DcR3” was predictive of significantly fewer newly formed carotid plaques during the follow-up period and a stable atherosclerosis profile in carotid or carotid and/or femoral arteries.

As a

pathogenetic link to our clinical observation, TL1A was recently reported to induce the expression of proteases in macrophages found in atherosclerotic plaques, thus, affecting plaque stability in atherosclerosis(56). These findings expand previous work on the role of the TL1A/DR3/DcR3 pathway in the atherogenetic process(57, 58), and suggest that measurements of these proteins in the serum may not only serve as biomarkers of organ-specific disease but also of low-grade systemic inflammation and possibly as predictors of the future risk for plaque formation in this subset of patients.

5.2. EXPERIMENTAL INFLAMMATORY ARTHRITIS The animal models that are most commonly used for the study of inflammatory arthritis are collagen-induced arthritis (CIA) and antigen induced arthritis (AIA). Several studies in these rodent models have brought about a significant role for TL1A and its receptors in the pathogenesis of experimental arthritis (Table 3).

In one of the first studies, Zhang et al. used the CIA model to study the potential role of TL1A in the pathogenesis of RA-like murine arthritis(19). Daily administration of TL1A was shown to aggravate CIA in a dose-dependent manner. It was further shown that macrophage-derived TNF-α and IL-1β induced the secretion of TL1A by synovial fibroblasts, which, in turn, mediated the production of TNF-α and IL-17 by T-cells attracted to the synovium. These immunological effects may explain the increased severity and speed of onset of arthritis as well as the greater bone and cartilage damage that accompanied TL1A administration. In the same study it was shown that treatment with TL1A was associated with substantial increase in the size of the germinal centers in the spleen and with elevated titers of serum anti-collagen antibodies. These findings are in line with a recent publication by Wang et al. on the characteristics of CIA in TL1A knockout (TL1A KO) mice(59). Indeed, it was reported that TL1A KO mice developed significantly ameliorated disease. In this study, plasma cells (but not B cells) expressed DR3 in high levels and were the target of TL1A. Thus, it seems that the TL1A/DR3 axis influences not only cellular but also humoral immunological pathways that are involved in the pathogenesis of joint inflammation. Following a different experimental design, Bull et al. studied the effects of TL1A neutralization via administration of a monoclonal antagonistic antibody against TL1A on the severity of CIA(60). The authors reported that blockade of the TL1A/DR3 pathway in the first stages of disease development ameliorated significantly the severity of arthritis. This was indicated by reduced swelling, bone damage and leukocyte infiltration in the affected joints following anti-TL1A treatment. The same group also studied the role of TL1A/DR3 in the pathogenesis of joint disease in the AIA model. The authors

reported that DR3 deficient mice presented with substantially milder pathological features of joint disease and displayed faster resolution of synovial inflammation in conjunction with reduced leukocyte infiltration, when compared to wild-type mice(60). The role of DR3 in early stages of arthritis has been explored further in the AIA model. It was shown that DR3 may drive early cartilage destruction by maximizing neutrophil accumulation into the inflamed tissue and this correlated closely with a reduction in the neutrophil chemoattractant protein CXCL1 in DR3 deficient mice(61, 62). Impairment in neutrophil recruitment may be one of the main reasons for the mild AIA that was observed in DR3 deficient mice(61, 62). In line with these observations, TL1A administration in the AIA model was shown to exacerbate the inflammatory process, especially when bone destruction was the main denominator(60). This effect was not seen in DR3 deficient mice and was associated with higher injection doses of TL1A. It may be possible TL1A promotes osteoclastogenesis, leading to increased bone erosions, in the context of the disease. Additional data indicating an effect of the TL1A/DR3 axis on bone turnover support this hypothesis. Activation of DR3 has been suggested to regulate osteoblast maturation and control the decision to exit the precursor pool of differentiation-competent preosteoblasts(62). This direct effect of TL1A on osteoclastogenesis and bone resorption is thought to be mediated through an early increase in the cytokine CCL2(64).

5.3 OTHER RHEUMATOLOGIC DISEASES

Through the studies for the involvement of TL1A in the pathogenesis of RA, an additional role of this cytokine in the regulation of osteoclastogenesis and bone resorption was also suggested(60, 63, 64). This may also have therapeutic implications, as a recent study reported that Atsttrin, a progranulin-derived molecule, that is therapeutic against inflammatory arthritis, binds to the DR3 receptor and neutralizes TL1A associated osteoclastogenesis(65). Similarly, DcR3 may also promote formation of osteoclasts from monocytes, macrophages, and bone stromal marrow cells. This was proven in an experimental model DcR3 transgenic mice displayed significantly lower bone mineral density and total body bone mineral content when compared with controls(66). Furthermore, local administration of DcR3 resulted in decreased bone volume. Taken together, these data indicate an effector role for the TL1A/DR3/DcR3 system in promoting osteoclast formation and bone resorption activity, and suggest that manipulation this pathway may be a viable option for restoring bone metabolism and prevent/reverse osteoporosis. Recently, an association was also described between serum TL1A and ankylosing spondylitis (AS)(67). It was found that patients with AS had significantly higher serum TL1A concentrations than healthy controls. In addition, the circulating TL1A levels in AS patients after anti-TNF treatment, were significantly lower compared to those in treatment-naive patients and became comparable to those in healthy controls. No significant association was found between TL1A levels and functional status (BASFI score, AS Metrology parameters) or CRP measured in the same sera. In contrast, a positive correlation was observed between individual circulating levels of TL1A and both

the BASDAI and ASDAS-CRP disease activity scores. These results indicate a possible role for the TL1A axis in the pathogenesis of AS. Another form of joint disease that belongs to the family of spondyloarthropathies is psoriatic arthritis. It was recently reported that in psoriatic skin lesions the expression of TL1A and both of its receptors is significantly upregulated in comparison to normal skin(68). Moreover, TL1A levels were found to be increased in the serum of patients with psoriasis when compared to patients with atopic dermatitis. Furthermore, TL1A serum levels decreased after appropriate antipsoriatic treatment(69). In the same study peripheral blood mononuclear cells from patients with psoriasis were isolated and showed significantly increased TL1A mRNA levels, while soluble TL1A in conjunction with IL-23 seems to stimulate these very same cells to produce IL-17(69). DcR3 is expressed in primary human epidermal keratinocytes and becomes upregulated in skin lesions in psoriasis, a phenomenon driven primarily by epidermal growth factor receptor(70). Finally, a case-control genetic study from Hungary reported that certain variants of the TNFSF15 gene, may modify the risk for developing psoriasis(71). Spondylathropathy is also a common complication of Inflammatory Bowel Disease, namely Crohn’s Disease and Ulcerative Colitis.

Multiple reports from both animal

models and patient studies have established that the TL1A/DR3 axis is involved in the pathogenesis of inflammatory bowel diseases(24, 25, 72). Taken together, the overexpression of TL1A and its receptors in inflammatory bowel disease, psoriasis and spondylathropathies, raise the possibility that this immunological axis may be the common denominator in the joint, gut and skin inflammation, which frequently is observed in clinical practice.

A potential association was observed between serum DcR3 and systemic sclerosis (SSc)(73).

Patients with diffuse cutaneous SSc were reported to have significantly

higher serum DcR3 concentrations than healthy controls or those with limited cutaneous disease. While the authors could not fully explain the immune pathways through which DcR3 exerts its influence on the evolution of SSc, they suggested that TL1A blockade may be implicated in the activation of the pathological angiogenesis observed in SSc, as TL1A is known to be a potent anti-angiogenic factor(2). Thus, not only the TL1A system may be involved in SSc, but also soluble DcR3 values may serve as a surrogate biomarker of pulmonary arterial hypertension and systemic inflammation due to its significant correlation with indicators of right ventricular function or of systemic inflammation (CRP, ESR, and IgG), respectively. Several studies have provided evidence for an association between DcR3 and systemic lupus erythematosus (SLE)(74, 75). This role seems to be more of a result from the function of DcR3 as a decoy receptor for the Fas ligand cytokine, and no involvement of the TL1A axis has been proven. In light of the fact that the main interest of our review is the TL1A system, we will not expand more on the subject. Finally, another study focused on the role of DR3 in experimental autoimmune uveitis (EAU)(76). Experimental autoimmune uveitis (EAU) is a T cell–mediated autoimmune disease that serves as a model for several human posterior uveitis such as Behcet’s disease. In EAU, DR3 and TL1A expression was found to be upregulated, compared to the control group. This finding, coupled with the increased IL-17 levels obtained from the EAU mice, suggests an involvement of the TL1A/DR3 pair, possibly through the Th17 immune response in the development of uveitis. Although, uveitis may not be a

rheumatic disease per se, as a common manifestation in autoimmune disease it falls within the scope of our review.

6. CLINICAL CONSIDERATIONS A significant change has taken place in recent years, regarding the treatment of immune-mediated, chronic inflammatory diseases. In particular, the use of non-specific, generalized immunosuppression has been replaced by targeted therapies which aim to neutralize single or limited immunological pathways. These biological therapies not only induce the amelioration of clinical symptoms but also modify the natural course of disease. There are currently several such medications that are used for the treatment of rheumatic diseases(77). As the molecular targets of such therapies are considered essential for disease progression, the effect of their blockade on the expression of TL1A/DR3/DcR3 activity may provide support for the pathogenetic significance of the latter. Nonetheless, very few studies have reported relevant information and only related to anti-TNF treatment; it should be noted, however, that all of them report downregulation of TL1A and/or DcR3. In the aforementioned study by Bamias et al. treatment with the anti-TNF agent adalimumab resulted in significantly lower serum TL1A levels(44).

In the study of

Konsta et al., patients with AS who were treated with anti-TNF-treated had significantly lower serum TL1A levels than anti-TNF-treatment-naïve patients(67). Notably, similar responses to anti-inflammatory treatment (although not exclusively with anti-TNF

agents) were reported in psoriasis(69) as well as in patients with ulcerative colitis or Crohn’s disease(24, 25). The aforementioned studies show that TNF may affect the activity of the TL1A/DR3/DcR3 system.

Nevertheless, the opposite may also be true as it was

indicated in a recent study in mice(78). Indeed, it was reported that TL1A may act upstream of TNF-α, as it was able to induce the production of proinflammatory cytokines, including TNF-α, from human CD4+CD161+ T cells. On the other hand, TNF-α failed to stimulate these cells, whereas anti-TNF-α had no effect on TL1A function.

These results show that TL1A may act directly on effector cells and

independently of TNF-α. TL1A was also found to promote the differentiation of Th17 cell from naive precursors and also augment the production of IL-17A level in cell supernatants from RA patients(46). Interestingly, treatment with anti-TNF suppressed these TH17-inducing functions of TL1A. These are clinically relevant data, given the current focus on Th17-mediated pathways in autoimmune rheumatic disease(79). In all these data indicate that the interactions between the TL1A/DR3 system and the major effector pathways in rheumatic diseases (including anti-TNF-α- and TH17-mediated) are complex.

In turn, the therapeutic manipulation of such complexity will also be

demanding. Another implication of these experimental findings is the potential utility of TL1A and DcR3 as biomarkers. Both TL1A and DcR3 exist in soluble forms and can be measured in biological fluids, with the use of homemade or commercially available assays. In patients with RA, both are increased in the peripheral blood of patients and show a significant correlation with advanced disease(18, 44, 47).

Moreover, their levels

substantially fall after anti-inflammatory treatment(44).

Nevertheless, the critical

question of whether a fall in TL1A and/or DcR3 levels may predict response to treatment has not been answered yet, as no study compared responders to nonresponders. Furthermore, it should be kept in mind that TL1A and, even more, DcR3 serum levels are affected by several other factors, such as the co-existence of infective complications(80, 81).

Nonetheless, of particular importance are recent findings

connecting serum TL1A/DcR3 levels with increased cardiovascular risk in patients with RA. It should be noted that in some of the studies these markers performed better that C-reactive protein(55). Taken together, more work is required to accurately delineate the exact clinical application of TL1A and DcR3 as inflammatory biomarkers. In conclusion, the TL1A/DR3/DcR3 system is a novel immunological pathway, with increasing importance for the pathogenesis of chronic inflammation that occurs in several autoimmune conditions, most prominently RA. This system exerts a tight regulatory control resulting from a combination of pro-inflammatory signaling mediated by the TL1A/DR3 interaction and the decoy function of DcR3. A clearer understanding of this immune pathway not only will facilitate the understanding of pathogenetic aspects of chronic inflammation, but also raises the possibility for unique therapeutic approaches.

REFERENCES 1.

Locksley RM, Killeen N, Lenardo MJ. The TNF and TNF receptor superfamilies:

integrating mammalian biology. Cell. 2001;104(4):487-501. 2.

Migone TS, Zhang J, Luo X, Zhuang L, Chen C, Hu BG, et al. TL1A is a TNF-like

ligand and functions as a T cell for DR3 and TR6/DcR3 costimulator. Immunity. 2002;16(3):479-92. 3.

Zhan CY, Yan QR, Patskovsky Y, Li ZH, Toro R, Meyer A, et al. Biochemical and

Structural

Characterization

of

the

Human

TL1A

Ectodomain.

Biochemistry.

2009;48(32):7636-45. 4.

Al-Lamki RS, Wang J, Tolkovsky AM, Bradley JA, Griffin JL, Thiru S, et al. TL1A

both promotes and protects from renal inflammation and injury. Journal of the American Society of Nephrology. 2008;19(5):953-60. 5.

Kitson J, Raven T, Jiang YP, Goeddel DV, Giles KM, Pun KT, et al. A death-

domain-containing receptor that mediates apoptosis. Nature. 1996;384(6607):372-5. 6.

Marsters SA, Sheridan JP, Donahue CJ, Pitti RM, Gray CL, Goddard AD, et al.

Apo-3, a new member of the tumor necrosis factor receptor family, contains a death domain

and

activates

apoptosis

and

NF-kappa

B.

Current

biology

:

CB.

1996;6(12):1669-76. 7.

Chinnaiyan AM, O'Rourke K, Yu GL, Lyons RH, Garg M, Duan DR, et al. Signal

transduction by DR3, a death domain-containing receptor related to TNFR-1 and CD95. Science. 1996;274(5289):990-2.

8.

Bodmer JL, Burns K, Schneider P, Hofmann K, Steiner V, Thome M, et al.

TRAMP, a novel apoptosis-mediating receptor with sequence homology to tumor necrosis factor receptor 1 and Fas(Apo-1/CD95). Immunity. 1997;6(1):79-88. 9.

Screaton GR, Xu XN, Olsen AL, Cowper AE, Tan R, McMichael AJ, et al. LARD:

a new lymphoid-specific death domain containing receptor regulated by alternative premRNA splicing. Proceedings of the National Academy of Sciences of the United States of America. 1997;94(9):4615-9. 10.

Wang EC, Thern A, Denzel A, Kitson J, Farrow SN, Owen MJ. DR3 regulates

negative selection during thymocyte development. Molecular and cellular biology. 2001;21(10):3451-61. 11.

Tian F, Grimaldo S, Fujita M, Cutts J, Vujanovic NL, Li LY. The endothelial cell-

produced antiangiogenic cytokine vascular endothelial growth inhibitor induces dendritic cell maturation. Journal of immunology. 2007;179:3742-51. 12.

Tan KB, Harrop J, Reddy M, Young P, Terrett J, Emery J, et al. Characterization

of a novel TNF-like ligand and recently described TNF ligand and TNF receptor superfamily genes and their constitutive and inducible expression in hematopoietic and non-hematopoietic cells. Gene. 1997;204(1-2):35-46. 13.

Fang L, Adkins B, Deyev V, Podack ER. Essential role of TNF receptor

superfamily 25 (TNFRSF25) in the development of allergic lung inflammation. The Journal of experimental medicine. 2008;205(5):1037-48.

14.

Cavallini C, Lovato O, Bertolaso A, Pacelli L, Zoratti E, Zanolin E, et al. The TNF-

family cytokine TL1A inhibits proliferation of human activated B cells. PloS one. 2013;8:e60136. 15.

Al-Lamki RS, Wang J, Thiru S, Pritchard NR, Bradley JA, Pober JS, et al.

Expression of silencer of death domains and death-receptor-3 in normal human kidney and in rejecting renal transplants. The American journal of pathology. 2003;163(2):40111. 16.

Bu R, Borysenko CW, Li Y, Cao L, Sabokbar A, Blair HC. Expression and

function of TNF-family proteins and receptors in human osteoblasts. Bone. 2003;33(5):760-70. 17.

Prehn JL, Thomas LS, Landers CJ, Yu QT, Michelsen KS, Targan SR. The T cell

costimulator TL1A is induced by FcgammaR signaling in human monocytes and dendritic cells. Journal of immunology. 2007;178(7):4033-8. 18.

Cassatella MA, Pereira-da-Silva G, Tinazzi I, Facchetti F, Scapini P, Calzetti F, et

al. Soluble TNF-like cytokine (TL1A) production by immune complexes stimulated monocytes in rheumatoid arthritis. Journal of immunology. 2007;178(11):7325-33. 19.

Zhang J, Wang X, Fahmi H, Wojcik S, Fikes J, Yu Y, et al. Role of TL1A in the

pathogenesis of rheumatoid arthritis. Journal of immunology. 2009;183(8):5350-7. 20.

Meylan F, Davidson TS, Kahle E, Kinder M, Acharya K, Jankovic D, et al. The

TNF-family receptor DR3 is essential for diverse T cell-mediated inflammatory diseases. Immunity. 2008;29(1):79-89.

21.

Pitti RM, Marsters SA, Lawrence DA, Roy M, Kischkel FC, Dowd P, et al.

Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer. Nature. 1998;396(6712):699-703. 22.

Bai C, Connolly B, Metzker ML, Hilliard CA, Liu X, Sandig V, et al.

Overexpression of M68/DcR3 in human gastrointestinal tract tumors independent of gene amplification and its location in a four-gene cluster. Proceedings of the National Academy of Sciences of the United States of America. 2000;97(3):1230-5. 23.

Lin WW, Hsieh SL. Decoy receptor 3: a pleiotropic immunomodulator and

biomarker for inflammatory diseases, autoimmune diseases and cancer. Biochemical pharmacology. 2011;81(7):838-47. 24.

Bamias G, Kaltsa G, Siakavellas SI, Papaxoinis K, Zampeli E, Michopoulos S, et

al. High intestinal and systemic levels of decoy receptor 3 (DcR3) and its ligand TL1A in active ulcerative colitis. Clinical immunology. 2010;137(2):242-9. 25.

Bamias G, Kaltsa G, Siakavellas SI, Gizis M, Margantinis G, Zampeli E, et al.

Differential expression of the TL1A/DcR3 system of TNF/TNFR-like proteins in large vs. small intestinal Crohn's disease. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2012;44(1):30-6. 26.

Aiba Y, Nakamura M. The role of TL1A and DR3 in autoimmune and

inflammatory diseases. Mediators of inflammation. 2013;2013:258164.

27.

Pobezinskaya YL, Choksi S, Morgan MJ, Cao X, Liu ZG. The adaptor protein

TRADD is essential for TNF-like ligand 1A/death receptor 3 signaling. Journal of immunology. 2011;186(9):5212-6. 28.

Micheau O, Tschopp J. Induction of TNF receptor I-mediated apoptosis via two

sequential signaling complexes. Cell. 2003;114(2):181-90. 29.

Wen L, Zhuang L, Luo X, Wei P. TL1A-induced NF-kappaB activation and c-IAP2

production prevent DR3-mediated apoptosis in TF-1 cells. The Journal of biological chemistry. 2003;278:39251-8. 30.

Papadakis KA, Zhu D, Prehn JL, Landers C, Avanesyan A, Lafkas G, et al.

Dominant role for TL1A/DR3 pathway in IL-12 plus IL-18-induced IFN-gamma production by peripheral blood and mucosal CCR9+ T lymphocytes. Journal of immunology. 2005;174(8):4985-90. 31.

Reichwald K, Jorgensen TZ, Skov S. TL1A Increases Expression of CD25, LFA-

1, CD134 and CD154, and Induces IL-22 and GM-CSF Production from Effector CD4 TCells. PloS one. 2014;9(8):e105627. 32.

Taraban VY, Slebioda TJ, Willoughby JE, Buchan SL, James S, Sheth B, et al.

Sustained TL1A expression modulates effector and regulatory T-cell responses and drives intestinal goblet cell hyperplasia. Mucosal immunology. 2011;4(2):186-96. 33.

Meylan F, Song YJ, Fuss I, Villarreal S, Kahle E, Malm IJ, et al. The TNF-family

cytokine

TL1A drives IL-13-dependent small intestinal inflammation.

immunology. 2011;4(2):172-85.

Mucosal

34.

Shih DQ, Michelsen KS, Barrett RJ, Biener-Ramanujan E, Gonsky R, Zhang X,

et al. Insights into TL1A and IBD pathogenesis. Advances in experimental medicine and biology. 2011;691:279-88. 35.

Pappu BP, Borodovsky A, Zheng TS, Yang X, Wu P, Dong X, et al. TL1A-DR3

interaction regulates Th17 cell function and Th17-mediated autoimmune disease. The Journal of experimental medicine. 2008;205(5):1049-62. 36.

Takedatsu H, Michelsen KS, Wei B, Landers CJ, Thomas LS, Dhall D, et al.

TL1A (TNFSF15) regulates the development of chronic colitis by modulating both Thelper 1 and T-helper 17 activation. Gastroenterology. 2008;135(2):552-67. 37.

Schreiber TH, Wolf D, Tsai MS, Chirinos J, Deyev VV, Gonzalez L, et al.

Therapeutic Treg expansion in mice by TNFRSF25 prevents allergic lung inflammation. The Journal of clinical investigation. 2010;120(10):3629-40. 38.

Khan SQ, Tsai MS, Schreiber TH, Wolf D, Deyev VV, Podack ER. Cloning,

expression, and functional characterization of TL1A-Ig. Journal of immunology. 2013;190(4):1540-50. 39.

Yu KY, Kwon B, Ni J, Zhai Y, Ebner R, Kwon BS. A newly identified member of

tumor necrosis factor receptor superfamily (TR6) suppresses LIGHT-mediated apoptosis. The Journal of biological chemistry. 1999;274(20):13733-6. 40.

Bamias G, Mishina M, Nyce M, Ross WG, Kollias G, Rivera-Nieves J, et al. Role

of TL1A and its receptor DR3 in two models of chronic murine ileitis. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(22):8441-6.

41.

Scrivo R, Di Franco M, Spadaro A, Valesini G. The immunology of rheumatoid

arthritis. Annals of the New York Academy of Sciences. 2007;1108:312-22. 42.

Firestein

GS.

Biomedicine.

Every

joint

has

a

silver

lining.

Science.

2007;315(5814):952-3. 43.

Hirota K, Yoshitomi H, Hashimoto M, Maeda S, Teradaira S, Sugimoto N, et al.

Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model. The Journal of experimental medicine. 2007;204(12):2803-12. 44.

Bamias G, Siakavellas SI, Stamatelopoulos KS, Chryssochoou E, Papamichael

C, Sfikakis PP. Circulating levels of TNF-like cytokine 1A (TL1A) and its decoy receptor 3 (DcR3) in rheumatoid arthritis. Clinical immunology. 2008;129(2):249-55. 45.

Sun X, Zhao J, Liu R, Jia R, Sun L, Li X, et al. Elevated serum and synovial fluid

TNF-like ligand 1A (TL1A) is associated with autoantibody production in patients with rheumatoid arthritis. Scandinavian journal of rheumatology. 2013;42(2):97-101. 46.

Zhou M, Liu R, Su D, Feng X, Li X. TL1A increased the differentiation of

peripheral Th17 in rheumatoid arthritis. Cytokine. 2014;69(1):125-30. 47.

Bayry J. Immunology: TL1A in the inflammatory network in autoimmune

diseases. Nature reviews Rheumatology. 2010;6(2):67-8. 48.

Osawa K, Takami N, Shiozawa K, Hashiramoto A, Shiozawa S. Death receptor 3

(DR3) gene duplication in a chromosome region 1p36.3: gene duplication is more prevalent in rheumatoid arthritis. Genes and immunity. 2004;5(6):439-43.

49.

Hayashi S, Miura Y, Tateishi K, Takahashi M, Kurosaka M. Decoy receptor 3 is

highly expressed in patients with rheumatoid arthritis. Modern rheumatology / the Japan Rheumatism Association. 2010;20(1):63-8. 50.

Hayashi S, Miura Y, Nishiyama T, Mitani M, Tateishi K, Sakai Y, et al. Decoy

receptor 3 expressed in rheumatoid synovial fibroblasts protects the cells against Fasinduced apoptosis. Arthritis and rheumatism. 2007;56(4):1067-75. 51.

Chen MH, Chen WS, Tsai CY, Liao HT, Chen CH, Chou CT. Overexpression of

decoy receptor 3 in synovial tissues of inflammatory arthritis. Clinical and experimental rheumatology. 2012;30(2):171-7. 52.

Cheng CP, Sytwu HK, Chang DM. Decoy receptor 3 attenuates collagen-induced

arthritis by modulating T cell activation and B cell expansion. The Journal of rheumatology. 2011;38(12):2522-35. 53.

Takahashi M, Miura Y, Hayashi S, Tateishi K, Fukuda K, Kurosaka M. DcR3-

TL1A signalling inhibits cytokine-induced proliferation of rheumatoid synovial fibroblasts. International journal of molecular medicine. 2011;28(3):423-7. 54.

Fukuda K, Miura Y, Maeda T, Takahashi M, Hayashi S, Kurosaka M. Decoy

receptor 3 regulates the expression of various genes in rheumatoid arthritis synovial fibroblasts. International journal of molecular medicine. 2013;32(4):910-6. 55.

Bamias G, Stamatelopoulos K, Zampeli E, Protogerou A, Sigala F, Papamichael

C, et al. Circulating levels of TNF-like cytokine 1A correlate with the progression of atheromatous lesions in patients with rheumatoid arthritis. Clinical Immunology. 2013;147(2):144-50.

56.

Ashlin TG, Kwan AP, Ramji DP. Regulation of ADAMTS-1, -4 and -5 expression

in human macrophages: differential regulation by key cytokines implicated in atherosclerosis

and

novel

synergism

between

TL1A

and

IL-17.

Cytokine.

2013;64(1):234-42. 57.

Kang YJ, Kim WJ, Bae HU, Kim DI, Park YB, Park JE, et al. Involvement of TL1A

and DR3 in induction of pro-inflammatory cytokines and matrix metalloproteinase-9 in atherogenesis. Cytokine. 2005;29(5):229-35. 58.

McLaren JE, Calder CJ, McSharry BP, Sexton K, Salter RC, Singh NN et al. The

TNF-like protein 1A-death receptor 3 pathway promotes macrophage foam cell formation in vitro. Journal of immunology. 2010; 184: 5827-34. 59.

Wang X, Hu Y, Charpentier T, Lamarre A, Qi S, Wu J, et al. TNF-like ligand 1A

(TL1A) gene knockout leads to ameliorated collagen-induced arthritis in mice: implication of TL1A in humoral immune responses. Journal of immunology. 2013;191(11):5420-9. 60.

Bull MJ, Williams AS, Mecklenburgh Z, Calder CJ, Twohig JP, Elford C, et al.

The Death Receptor 3-TNF-like protein 1A pathway drives adverse bone pathology in inflammatory arthritis. The Journal of experimental medicine. 2008;205(11):2457-64. 61.

Perks WVT, Newton Z, Clark SR, Collins F, Singh RK, Twohig JP, et al.

Investigating the function of Death Receptor 3 (DR3) and its ligand TNF-like protein 1A (TL1A) during the early stages of inflammation. Immunology. 2012;137:133-.

62.

Wang EC, Newton Z, Hayward OA, Clark SR, Collins F, Perks WV, et al.

Regulation of early cartilage destruction in inflammatory arthritis by Death Receptor 3. Arthritis & rheumatology. 2014. 63.

Robinson LJ, Borysenko CW, Blair HC. Tumor necrosis factor family receptors

regulating bone turnover - New observations in osteoblastic and osteoclastic cell lines. In: Zaidi M, editor. Skeletal Biology and Medicine, Pt A: Aspects of Bone Morphogenesis and Remodeling; 2007. p. 432-43. 64.

Collins F, Stone M, Wang E, Williams A. DEATH RECEPTOR 3 AND TL1A: A

REGULATORY

PATHWAY

OF

BONE

TURNOVER

AND

TARGET

FOR

OSTEOPOROSIS THERAPY? Osteoporosis International. 2012;23:S528-S. 65.

Liu C, Li XX, Gao W, Liu W, Liu DS. Progranulin-derived Atsttrin directly binds to

TNFRSF25 (DR3) and inhibits TNF-like ligand 1A (TL1A) activity. PloS one. 2014;9(3):e92743. 66.

Tang CH, Hsu TL, Lin WW, Lai MZ, Yang RS, Hsieh SL, et al. Attenuation of

bone mass and increase of osteoclast formation in decoy receptor 3 transgenic mice. The Journal of biological chemistry. 2007;282(4):2346-54. 67.

Konsta M, Bamias G, Tektonidou MG, Christopoulos P, Iliopoulos A, Sfikakis PP.

Increased levels of soluble TNF-like cytokine 1A in ankylosing spondylitis. Rheumatology. 2013;52(3):448-51. 68.

Bamias G, Evangelou K, Vergou T, Tsimaratou K, Kaltsa G, Antoniou C, et al.

Upregulation and nuclear localization of TNF-like cytokine 1A (TL1A) and its receptors DR3 and DcR3 in psoriatic skin lesions. Experimental dermatology. 2011;20(9):725-31.

69.

Li L, Fu L, Lu Y, Wang W, Liu H, Li F, et al. TNF-like ligand 1A is associated with

the pathogenesis of psoriasis vulgaris and contributes to IL-17 production in PBMCs. Archives of dermatological research. 2014. 70.

Wu NL, Huang DY, Hsieh SL, Hsiao CH, Lee TA, Lin WW. EGFR-driven up-

regulation of decoy receptor 3 in keratinocytes contributes to the pathogenesis of psoriasis. Biochimica et biophysica acta. 2013;1832(10):1538-48. 71.

Kepiro L, Szell M, Kovacs L, Keszthelyi P, Kemeny L, Gyulai R. Genetic risk and

protective factors of TNFSF15 gene variants detected using single nucleotide polymorphisms in Hungarians with psoriasis and psoriatic arthritis. Human immunology. 2014;75(2):159-62. 72.

Bamias G, Martin C, 3rd, Marini M, Hoang S, Mishina M, Ross WG, et al.

Expression, localization, and functional activity of TL1A, a novel Th1-polarizing cytokine in inflammatory bowel disease. Journal of immunology. 2003;171(9):4868-74. 73.

Yamada D, Asano Y, Takahashi T, Masui Y, Aozasa N, Akamata K, et al. Clinical

significance of serum decoy receptor 3 levels in patients with systemic sclerosis. European journal of dermatology : EJD. 2012;22(3):351-7. 74.

Lee CS, Hu CY, Tsai HF, Wu CS, Hsieh SL, Liu LC, et al. Elevated serum decoy

receptor 3 with enhanced T cell activation in systemic lupus erythematosus. Clinical and experimental immunology. 2008;151(3):383-90. 75.

Han B, Moore PA, Wu J, Luo H. Overexpression of human decoy receptor 3 in

mice results in a systemic lupus erythematosus-like syndrome. Arthritis and rheumatism. 2007;56(11):3748-58.

76.

Qin T. Upregulation of DR3 expression in CD4(+) T cells promotes secretion of

IL-17 in experimental autoimmune uveitis. Molecular vision. 2011;17:3486-93. 77.

Furst DE, Keystone EC, So AK, Braun J, Breedveld FC, Burmester GR, et al.

Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2012. Annals of the rheumatic diseases. 2013;72 Suppl 2:ii2-34. 78.

Jin S, Chin J, Seeber S, Niewoehner J, Weiser B, Beaucamp N, et al.

TL1A/TNFSF15 directly induces proinflammatory cytokines, including TNFalpha, from CD3+CD161+ T cells to exacerbate gut inflammation. Mucosal immunology. 2013;6:886-99. 79.

Annunziato F, Cosmi L, Liotta F, Maggi E, Romagnani S. Type 17 T helper cells-

origins,

features

and

possible

roles

in

rheumatic

disease.

Nature

reviews

Rheumatology. 2009;5:325-31. 80.

Twohig JP, Marsden M, Cuff SM, Ferdinand JR, Gallimore AM, Perks, WV, et al.

The death receptor 3/TL1A pathway is essential for efficient development of antiviral CD4(+) and CD8(+) T-cell immunity. FASEB journal: official publication of the Federation of American Societies for Experimental Biology. 2012;26:3575-86. 81.

Kim S, Mi L, Zhang L. Specific elevation of DcR3 in sera of sepsis patients and

its potential role as a clinically important biomarker of sepsis. Diagnostic microbiology and infectious disease. 2012;73:312-7.

Figure Legends Figure 1. Ligation of TL1A to DR3 activates two distinct downstream signaling pathways. Both pathways involve binding of adapter protein TNFR-associated death

domain protein (TRADD) to the cytoplasmic death domain of DR3. The next step determines the end result of TL1A/DR3 interaction. In the first pathway, the recruitment of the TNFR-associated factor (TRAF) and receptor-interacting (RIP) proteins by TRADD, stimulates mitogen-activated protein kinases (MAPK). This in turn, induces activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). The final outcome of this process is a pro-inflammatory signal, leading to T cell costimulation, with enhancement of T effector via cytokine secretion, cell proliferation and activation. The function of regulatory T-cell responses is also affected. In the second pathway, TRADD associates with the Fas-associated death domain (FADD) and caspase 8, resulting in the activation of the effector caspases. This pathway will ultimately trigger cell apoptosis. So far, TL1A/DR3 interaction was shown to promote apoptosis only in experimental models of transient overexpression of DR3. In contrast, in primary T lymphocytes, the main pathway is the induction of pro-inflammatory signals. This seems to be mediated by the TL1A-induced production of cellular inhibitor of apoptosis proteins (c-IAP) that is upregulated by NF-κB. Therefore, a feedback loop is created that inhibits apoptosis and perpetuates T-cell co-stimulation. TL1A; TNF-like cytokine 1A, DR3; death receptor 3, TRADD; TNFR-associated death domain protein, TRAF; TNFR-associated factor, RIP; receptor-interacting protein, MAPK; mitogen-activated protein kinase, NF-κB; nuclear factor kappa-light-chainenhancer of activated B cells, FADD; Fas-associated death domain, c-IAP; cellular inhibitor of apoptosis protein, Teff; T effector cells, Treg; T regulatory cells

Fig 1

Table 1. Characteristics of members of the TL1A/DR3/DcR3 system Codin g gene locatio n

Alternativ e names

Molecula r Weight (kDa)

TL1A

TNFSF15

28 (membran e form), 20 (soluble form)

TNFSF15

9q32

DR3

Wsl-1, Apo3, LARD, TRAMP, TNFRSF2 5, TR3

45

TNFRSF2 5

1p36.3

Molecul e

DcR3

TR6, M68

33

Coding gene

TNFRSF6 b

20q13. 3

Membran e bound form

Cells expressed in

Yes

Yes

endothelial cells, monocytes, dendritic cells, macrophages, T cell lymphocytes

No

Yes

T cell lymphocytes, endothelial cells, osteocytes

No

tumor cells, T cell lymphocytes, antigen presenting cells (monocytes/macrophag es, myeloid-derived dendritic cells, intestinal epithelial cells), synoviocytes, variety of normal tissue (colon, lung, stomach, spleen, lymph node, pancreas, and spinal cord)

Solubl e form

Yes

Table 2. Animal models for the study TL1A/DR3 interactions in inflammatory arthritis Mouse disease model

Antigeninduced arthritis

Phenotype of disease

Intervention in TL1A axis

Effect

Refere nce

DR3−/− mice

Significantly milder joint disease, faster resolution of synovitis, less cartilage damage

60, 61, 62

Exogenous TL1A administration

Dose - dependent exacerbation of inflammation (especially regarding bone destruction)

60

No exacerbation of inflammation observed

60

Exogenous TL1A administration

Disease aggravation, upregulated anti-collagen antibody expression

18

TL1A−/− mice used

Significant amelioration of joint disease

59

TL1A antagonistic antibody administration

Decrease of disease severity

60

Over-expression of DcR3

Significantly attenuated disease severity

52

Acute inflammatory arthritis similar to rheumatoid arthritis (rapidly progressive to joint destruction, secondary to Arthus reaction)

DR3−/− mice used + Exogenous TL1A administration

Collageninduced arthritis

Autoimmune polyarthritis similar to rheumatoid arthritis (intense synovitis that corresponds precisely with the clinical onset of arthritis)

(via plasmid transfer)

Table 3. The TL1A pathway in human rheumatic diseases Findings regarding TL1A/DR3/DCR3 axis

Suggested TL1A axis role

High concentrations of TL1A in synovial fluid, tissue and serum in patients, correlation with disease severity, downregulation of TL1A after anti-TNF treatment, association with RA specific autoantoibodies

Perpetuation of autoinflammatory process (mediates production of TNF-α and IL-1β, enhances chemotaxis of inflammatory cells to tissue)

Increased levels of DcR3 in synovial fluid and blood in patients, mean DcR3 levels associated with disease stage

"Double agent” role of DcR3: downregulation of immunologic response but perpetuation of autoinflammation due to inhibition of apoptosis

Serum levels of low TL1A and DcR3 predict lower incidence of new atheromatic events

Participation in inflammatory component of atherogenesis, modulation of atheromatic plaques

55,56,5 7,58

Ankylosing spondylitis

Increased levels of TL1A in active disease, return to normal levels after anti-TNF treatment, correlation with disease activity scores

Participation in the inflammatory response in various tissues (joint, intestine, skin) in seronegative spondyloarthropathies

67

Psoriasis/Psori atic arthritis

TL1A, DR3, DcR3 expression upregulated in psoriatic skin lesions, TL1A increased in blood of psoriasis patients, DcR3 expression regulated by EGFR, tnfsf15 polymorphisms implicated in pathogenesis of disease

Participation in the inflammatory response in various tissues (joint, intestine, skin) in seronegative spondyloarthropathies

68,69,7 0,71

Systemic sclerosis

Higher levels of DcR3 in diffuse cutaneous disease compared to limited cutaneous form

Inhibits pathological angiogenesis

73

Systemic lupus erythematosus

Increased levels of DcR3 in active disease

Unclear role

74, 75

DR3 and TL1A expression upregulated

TL1A participating in Th17 response

76

Disease

Rheumatoid arthritis

Experimental autoimmune uveitis

Referen ces

18,19,4 4,45, 46,48

44,49,5 0,51, 52,53,5 4