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Review

The adenosinergic system: a potential player in the pathogenesis of ANCA-associated vasculitis? L. Kling, B.K. Krämer, B.A. Yard, A.-I. Kälsch

Vth Department of Medicine (Nephrology/ ABSTRACT peripheral blood (1). It is a life-threat- Endocrinology/Rheumatology), University Antineutrophil cytoplasmic antibody ening disease potentially affecting all Medical Centre Mannheim, University of (ANCA)-associated vasculitis (AAV) organs (2), but necrotising vasculitis is Heidelberg, Germany. is a potentially lethal autoimmune most commonly found in the respira- Lovis Kling disease whose pathology comprises tory tract and the kidneys (as reviewed Bernhard K. Krämer, Prof. Dr. med. disturbed T cell differentiation and previously) (3). Its pathogenesis is not Benito A. Yard, Prof. Dr. rer. nat. Anna-Isabelle Kälsch, PD Dr. med. functionality accompanied by dysfunc- completely elucidated yet, but increas- tional autoreactive immunoglobulin Please address correspondence to: ing experimental evidence and under- Dr Anna-Isabelle Kälsch, development, culminating in destruc- standing of the disease resulted in the Theodor-Kutzer-Ufer 1-3, tive innate immune response as well. current pathogenetic model summa- 68167 Mannheim, Germany. Purines, and rised by the extended ANCA-cytokine E-mail: [email protected] in particular, have been sequence theory (4, 5). In short, AAV Received on October 26, 2017; accepted in elucidated as potent extracellular me- patients present with disturbed adap- revised form on February 1, 2018. diators for fine adjustment of these tive immunity forming dysfunctional Clin Exp Rheumatol 2018; 36 (Suppl. 111): pivotal processes establishing human lymphocyte populations (for example S143-S151. immunity. Therefore, the extracellular persistently activated T cell subsets, © Copyright Clinical and purinergic microenvironment is under impaired regulatory T lymphocytes, Experimental Rheumatology 2018. control of ectonucleotidases CD39 autoreactive Th17 as well as B cells) and CD73 degrading pro-inflamma- and producing ANCA which are able Key words: ANCA-associated tory (ATP) to to trigger neutrophil driven inflamma- vasculitis, adenosine, CD73 antigen, anti-inflammatory adenosine as well tion of the vessel walls by binding their CD26 antigen, purinergic effects as adenosine deaminase bound to epitopes (mainly proteinase 3 (PR3) or CD26 deactivating adenosine. Accord- myeloperoxidase (MPO)) expressed on

ingly, the ATP P2X7 was elic- the activated neutrophil cell surface. ited to be responsible for promotion of Subsequently, released cytokines and inflammation, while predominantly the chemokines (e.g., TNF-α, IL-6, IL-8,

adenosine A2A receptor demonstrated C5a, monocyte chemoattractant pro- the opposite. Recent reports pointed tein 1/CCL2) (6) cause other immune at the adenosinergic system to be cru- cells including lymphocytes to migrate cially involved in AAV pathogenesis. to the damaged vessel wall, thus, main- Here, experimental evidence on ecto- taining the inflammatory destruction of controlling extracellular ad- vascular tissue and surrounding paren- enine concentrations and chyma. purinergic signalling in the immune More recently, purinergic signalling system with respect to its contribu- was recognised as a key player involved tion to the AAV pathomechanism is in homeostasis of immunity. Specifi- reviewed besides unsolved problems cally, adenosine triphosphate (ATP) is being identified that require further generally perceived to enhance inflam- investigation in order to develop new mation, while adenosine demonstrated treatment strategies for AAV. the opposite. This review focuses on ecto-enzymes controlling extracel- Introduction lular concentrations of indispensable Antineutrophil cytoplasmic antibody adenine nucleotides for purinergic sig- (ANCA)-associated vasculitis (AAV) is nalling (such as ATP, ADP, AMP, NAD defined as small vessel vasculitis highly and the nucleoside adenosine) and both associated with presumably pathogenic their contribution to pathogenic pro- Competing interests: none declared. auto-antibodies detectable in patients’ cesses in AAV.

Clinical and Experimental Rheumatology 2018 S-143 Adenosine in ANCA-associated vasculitis / L. Kling et al.

The extracellular adenosine CD26 is an exopeptidase, also known as Belonging to the same gene family as microenvironment: dipeptidyl peptidase-4 (DPP-4), which CD38, CD157 (also known as bone CD39, CD73, CD26 cleaves dipeptides from proteins that marrow stromal cell antigen 1/BST-1) The fate of extracellular adenine de- contain alanine or proline in the second (38) metabolises extracellular NAD+ rivatives including ATP, ADP, AMP and last N-terminal position (22). Its tran- to either ADP (ADPR) or cyclic adenosine is determined by the local scriptional regulation is influenced by ADP ribose (cADPR) as well (39-41). expression of ectonucleotidases CD39 inter alia hepatocyte nuclear factor 1 al- CD38, formerly referred to as T10 mol- and CD73 degrading nucleotides, aden- pha (HNF-1α) (23). Considerable CD26 ecule (thymic cell surface antigen) (42), osine deaminase metabolising adeno- expression is known in human epithelial is expressed on human thymocytes and sine as well as receptors binding - thus (24) and endothelial cells (25) as well as lymphocytes (43). In contrast to CD38, capture - the different purine molecules lymphocytes (26) with regards to CD26 CD157 is reported not to be expressed mentioned with various affinity (7, 8). serving as a potent co-stimulatory recep- on lymphocytes, eosinophils and den- The intracellular location of ATP is well tor in the activation of T cells (27). Al- dritic cells (44), but on human mono- established and its involvement in cel- though CD26 has no related enzymatic cytes and neutrophils, synovial as well lular energy supply is undoubted (9). activity to nucleotides, it strongly binds as follicular dendritic cells (44) besides However, compelling evidence describ- adenosine deaminase and therefore is human endothelium (45). Conceivably, ing different mechanisms of ATP trans- pivotal for purine metabolism (28). purine metabolism in the extracellular port into the extracellular compartment Adenosine deaminase is ubiquitously compartment shapes the immune re- including exocytosis and secretion was expressed in the cytoplasm with its pri- sponse since activation of the different discussed in the literature. Moreover, mary structure lacking a transmembra- purinergic receptors heavily depends on data on its extracellular presence and nous domain. However, its ecto- the enzymatic activity of CD39, CD73, function in intercellular signalling is activity degrading adenosine to adenosine deaminase bound to CD26 available (9, 10). and ammonia has been detected re- (29), CD38/CD157 and CD203a (36, CD39 belongs to the group of ecto- peatedly (29). Consistently, membrane 46) determining concentrations. nucleoside triphosphate diphosphohy- bound CD26 has previously been used drolases (E-NTPDases) with different as surrogate parameter for the presence Purinergic receptors and their names used in the literature, e.g., ecto- and enzymatic activity of adenosine expression in the immune system apyrase, ecto ATP diphosphohydrolase deaminase as it is considered to be an Purinergic receptors are categorised in or NTPDase1 (11). CD39 is able to hy- adenosine deaminase receptor (as also two families by their activating ligands: drolyze ATP to expressed by its other name adenosine P1 or adenosine receptors and P2 re- (ADP) and subsequently to adenosine deaminase-binding protein) (29, 30). ceptors recognising purine and pyrimi- monophosphate (AMP) with a resulting dine nucleotides, inter alia ATP, ADP, product ratio of 1:10 (ADP:AMP) (11). Alternative sources of extracellular triphosphate (UTP) and uridine Several pro-inflammatory cytokines adenosine: CD38, CD157, CD203a diphosphate (UDP). The P2 receptor (e.g., TGFβ, IL-6 (12)), oxidative stress In addition, extracellular adenosine group comprises of diverse ionotropic and hypoxia, involving transcription can also be synthesised from nicoti- P2X and metabotropic P2Y receptors. factors STAT3 and Sp1, control CD39 namide dinucleotide (NAD+) by the To date, the P1 family contains four expression (12, 13). CD39 expression concerted action of CD38 and CD203a different adenosine receptors (A1, A2A, has been widely observed, including (also known as plasma cell membrane A2B and A3) which were reported to be the endothelium (14) and lymphocytic glycoprotein (31)/PC-1 (32), NPPase expressed in different tissues and al- populations (15). (33), NPPγ (34), major aFGF stimu- most all cells of the immune system. CD73, or ecto-5’-nucleotidase, also be- lated protein/MAFP (35)) together with The majority of cells express more than longs to the group of ectonucleotidases CD73 (36). Evidence from in vitro one subtype of the P1 and P2 receptors (16). Its enzymatic activity dephospho- experiments with canine and murine simultaneously (47). Expression of the rises AMP to adenosine (17). Its expres- vessel and bladder specimen suggests immunomodulatory A2A receptor (48, sion is reduced by pro-inflammatory NAD+ is constitutively released into 49) was reported in human endothe- cytokines like IL-6, IFNγ and IL-12, the extracellular space (37). Data sup- lial cells (50, 51), neutrophils (52, 53), but enhanced by TGFβ (18). Expres- ports NAD+ first is converted to adeno- monocytes (54), platelets (55), T cells sional increase was demonstrated upon sine diphosphate ribose (ADPR) - with (56), B cells (56, 57) and dendritic cells hypoxia involving oxygen-sensitive nicotinamide as side product - by CD38 (58). IFNγ was found to downregulate transcription factor hypoxia-inducible which subsequently is digested into A2A receptor expression, while TNF-α factor-1α (HIF-1α) (19) in addition to AMP and pyrophosphate by activity and IL-1 stimulation were described cyclic AMP response element binding of CD203a (36). Furthermore, NAD+ to enhance it (48). The lower affinity protein (CREB) (19, 20). Various tis- was demonstrated to be also a direct A2B and the A3 receptor were detected sues including human lymphocytes and substrate for CD203a, which is able to in dendritic cells (59, 60), T cells (61, endothelial cells are described to ex- cleave it into AMP and nicotinamide 62), monocytes (54, 62) and human press CD73 (15, 21). mononucleotide (NMN) as well (36). neutrophils (62, 63). Expression of the

S-144 Clinical and Experimental Rheumatology 2018 Adenosine in ANCA-associated vasculitis / L. Kling et al. fourth member of the P1 family, the A1 Adenosine guarding the recently presumed to drive the patho- receptor, was found in neutrophils (64), blood-vascular-tissue barrier genesis of AAV (78). In addition, aden- peripheral blood mononuclear cells Different scientific approaches allowed osine potentially decreases formation (PBMC) (65) and dendritic cells (58). to conclude adenosine is involved in the of granulomatous tissue, a core aspect Ionotropic as well as metabotropic ATP very first onset of inflammation due to of granulomatosis with polyangiitis receptors from the P2 family also are its immunosuppressive effect not only (GPA) and eosinophilic GPA (EGPA) expressed in various immune cell types. on infiltrating immune cells character- pathology, given that A2A antagonists For example, there is data available on ising the peak of inflammatory condi- added to cultured human monocytes neutrophils, monocytes and lympho- tions (as elaborated on below) (70), but during stimulation increased formation cytes expressing the P2X1, P2X4, P2X5, also on the endothelium which is able of giant cell like macrophages (79). P2X7 and P2Y11 subtypes (as reviewed to trigger local as well as systemic in- in (7)). flammatory response. Specifically, cul- Adaptive immunity under control The co-expression of a myriad of dif- tured human umbilical vein endothelial of adenosine ferent receptor subtypes from the P1 cells demonstrated a reduced vascular Adenosinergic signalling is probably and P2 family on immune cells im- cell adhesion molecule-1 induction best investigated in the context of adap- plies the high complexity of puriner- and endothelial release of pro-inflam- tive immunity. Several studies con- gic signal transduction. In conclusion, matory IL-6 and IL-8 upon stimula- cluded CD39 and CD73 expression of the intracellular signal resulting from tion when treated with adenosine (71). lymphocytes (e.g. CD8+ cells (80-82), extracellular stimuli originating from Moreover, adenosine limited diapede- regulatory T cells (80) and B cells (83)) extracellular ATP depends not only on sis by mainly acting on the A2A and A2B were responsible for the generation of expression of purinergic ecto-enzymes receptors (72), correspondingly, pro- adenosine, thus its mediatory effects controlling concentrations of the differ- moting the tightness of the endothelial (84, 85) such as reducing the functional- ent receptor ligands, but also on the co- barrier (73) and decreasing neutrophil ity of antigen-presenting cells like den- expression and density of the individual adhesion to endothelial cells as well as dritic cells (58, 86). In murine dendritic purinergic receptors showing different neutrophil damage to the endothelium cells, the activation of the A2A receptor affinities to their ligands (7). In system- in vitro (74). An airpouch mice model resulted in tolerogenic dendritic cells ic inflammation, e.g. as found in AAV underscored this concept of adenosine with decreased secretion of IL-6 and and other rheumatologic disorders or invigorating vascular integrity, since it IL-12 (87). Consistent with this find- sepsis (49), cytokines modify both the reduced the accumulation of inflam- ing, mature dendritic cells from human expressional level of purinergic recep- matory cells at the inflamed tissue site donors shifted to an anti-inflammatory tors and ectonucleotidases providing (72). Therefore, endothelial cells are phenotype under A2A activation upon purinergic ligands. Hence, complexity able to produce adenosine themselves stimulation showing enhanced IL-10, of the extracellular purinergic microen- (75) in order to protect them from in- diminished IL-12 (88) and reduced vironment even increases and is prone flammatory damage as adenosine was TNF-α production (86). Thus, environ- to pathologic alteration. found to inhibit the oxidative burst mental adenosine was observed to limit in human neutrophils (74-76). Thus, Th1 differentiation of T cells in co-cul- Adenosine inhibits pivotal processes adenosine additionally interferes dur- ture with mature dendritic cells (86). In of immunity ing the initial phase of inflammation addition, direct stimulation of the A2A Adenosinergic signalling is believed to representing a negative feedback mech- receptor expressed on T cells inhibited represent a potent negative feedback anism also on innate immunity directly both Th1 and Th2 T cell differentiation mechanism protecting tissue from fur- at the vascular interface. Explicitly, our and proliferation by reducing produc- ther inflammatory damage highlighted group was able to demonstrate produc- tion of IL-4, IL-5, IL-10 and IFNγ under by its anti-inflammatory characteristics tion of reactive oxygen species (ROS) the appropriate stimulating conditions in as demonstrated by inhibition of activat- was reduced by extrinsic adenosinergic order to skew towards a Th1 or Th2 phe- ed immune cells (47) and upregulation stimulation of activated neutrophils not notype (66, 67, 89). Both these Th sub- of A2A receptor on murine T cells upon only from healthy controls, but also populations seem to be involved in the T cell receptor activation (66, 67). Con- from AAV patients highlighting local pathology of AAV as analysis of granu- sistently, the A2A receptor currently is ectonucleotidase expression determin- lomas and peripheral T cells from GPA suspected to be predominantly respon- ing adenosine generating capacity to be and MPA patients indicated predomi- sible for anti-inflammatory transduction pivotal for adenosinergic hindrance of nance of a Th1 cytokine profile (90, 91) on immune cells (68, 69). However, in- inadequate inflammatory response in accompanied with elevated counts of volvement of AAV pathomechanism is AAV rather than neutrophil adenosine the Th1 phenotype in peripheral blood not only restricted to lymphocytes, but receptor responsiveness (76). Further- of GPA patients (92). Nonetheless, GPA also encompasses compartments of in- more, ROS produced by neutrophils are patients also disclosed a Th2 phenotype nate immunity which all dramatically known to be indispensable for NETo- (as defined by expression of surface respond to purinergic signalling as de- sis (77). Hence, adenosine might also marker ST2L) among the effector mem- picted in the following sections. prevent NETosis, which has been just ory T cell population (92).

Clinical and Experimental Rheumatology 2018 S-145 Adenosine in ANCA-associated vasculitis / L. Kling et al.

Transcription of IL-2 (93) and TNFα of murine regulatory T cells accompa- Antibody formation involves production in human T cells were nied by active A2A receptor transduction adenosinergic signalling both inhibited via the A2A receptor in caused expansion of these regulatory T Animal studies unveiled purines were HIV positive patients (93). Adenosine cells and enhanced their immunosup- fundamentally involved in forma- and its analogs additionally impeded pressive activity, too (104). Murine reg- tion of immunoglobulins, too. Murine CD25 upregulation due to stimulation ulatory T cells were elicited to express B cells were found to express CD39 of murine T cell receptors (94). Thus, CD39 and CD73, thus produce adeno- and CD73, thus were able to generate adenosine prohibited expansion of T sine in order to suppress effector T adenosine from ATP released into the cell clones upon activation by reduc- cells in mice (85). Subsequently, it was extracellular space upon B cell stimu- ing levels of IL-2 as well as its receptor shown adenosine also was an immuno- lation in culture (83). Thus, adenosine CD25 (95). By contrast, AAV patients suppressive mediator produced by regu- was found to influence class switch of showed a lymphocytic phenotype in- latory T cells isolated from healthy hu- antibody subtype produced by the in- dicative of persistent T cell activation mans (105). Intriguingly, AAV patients vestigated B cells. Namely, CD73+ B evident by high frequency of CD25 ex- (GPA specifically) were demonstrated cells tended to produce rather IgG and pression as well as decreased naïve T with both altered relations of T helper IgA immunoglobulins compared to cells which also was associated with a and regulatory T cells in the peripheral CD73- subpopulations (83). Further- more severe course of AAV (96). blood (106) as well as functional defi- more, in a human cohort of patients

A2A receptor activation was also shown ciencies of regulatory T cells. How- with combined immunodeficiency syn- to reduce Th17 differentiation of na- ever, evidence providing an underlying drome, a lack of CD73 expression on B

ïve T cells (97). Instead, in vivo A2A mechanism explicating this intrinsic cells combined with decreased produc- receptor stimulation in a C3HA mice regulatory T cell defect remained lack- tion of IgG and IgA immunoglobulins model demonstrated differentiation of ing (107, 108). Nonetheless, our group was measured (83). In AAV, antibody T lymphocytes predominantly towards lately discovered impaired lymphocytic class switch is reported to be pivotal as a regulatory T cell phenotype (97). In- adenosine generating capacity in AAV ANCA can also be detected in healthy terestingly, Th17 cells were suggested patients due to downregulation of CD39 individuals without clinical evidence to be pathogenic in AAV (98) as GPA and CD73 combined with upregulation of AAV (often referred to as natural au- patients disclosed higher frequencies of CD26, most imposing in CD4- lym- to-antibodies). Surprisingly, these clin- of Th17 cells than healthy controls in phocytic subsets (109). Enthrallingly, ically irrelevant ANCA showed lower the peripheral circulation (98, 99) as this pattern of ectonucleotidase expres- avidity and preferentially belonged to well as PR3-specific Th17 cells in PR3- sion in our AAV cohort is in line with the IgG1 subclass (111) whereas PR3- ANCA positive patients implicating previous studies reporting altered Th17 ANCA of active patients were most the pivotal involvement of Th17 cells and regulatory T cell populations in abundant in the IgG3 fraction (112). also in formation of ANCA (100). Ac- AAV, as both subsets were unveiled to cordingly, levels of IL-17 (produced be responsive to adenosinergic signal- Cytokine secretion responds by Th17 cells) and IL-23 (stimulating ling. Moreover, our study implied dis- to adenosinergic signalling the differentiation and activity of Th17 rupted ectonucleotidase expression con- The influence of adenosine on lympho- cells) were found elevated in AAV pa- tributed not only to the pathogenesis, cytic cytokine production has already tients with active disease as well as in but also to the clinical picture of AAV as been described above. Nevertheless, remission (98) supporting the idea of it was independent from disease activ- cytokine release of other immune com- Th17 cells maintaining AAV. This is ity, but linked to decreased renal func- partments was reported to be respon- also supported by an animal model of tion and systemic inflammation. sive to adenosine as well. In detail, MPO-ANCA glomerulonephritis using Further details underscoring adenosine adenosine reduced leukotriene B4 syn- C57BL/6 mice knocked out for the IL- as an immunosuppressive agent itself thesis in neutrophils (113), TNF-α se- 17A gene (C57BL/6 IL-17A-/-), since it were given by investigations on T cell cretion (114), transcription and release revealed the knockout mice had been anergy. In patients with follicular lym- of chemokines CXCL2, CCL3, CCL4 protected from renal injury (101). phoma, adenosine was produced in and CCL20 (114) implying adenosine

Prolonged A2A receptor stimulation of the extracellular space by subsequent is able to reduce recruitment of im- murine CD4+ cells led to expansion activity of CD39 and CD73 from ATP mune cells to sites of inflammatory le- of regulatory T cells and an increase and was reported to suppress cytokine sion, hence limiting not only the onset, of their immunosuppressive capacity production of T cells infiltrating the but also the maintenance of inflamma- + while it impaired CD8 cell stimulation malignant tissue (110). Similarly, A2A tion. Similar results were obtained in and activation (102). A2A activation of receptor activation during stimulation BALB/c mice with murine CD4+ and CD8+ T cells resulted of a A.E7 CD4+ T cell line resulted in decreasing peripheral TNF-α in upregulation of both immunosuppres- hyporesponsiveness of these cells re- levels and enhancing secretion of anti- sive surface proteins CTLA-4 and pro- sembling features of T cell anergy as inflammatory IL-10 after intraperito- grammed death-1 (PD-1) (103). Under- assessed by stimulation assays using neal LPS application (115). Not only lying these findings, selective activation their designated antigen (97). adenosinergic inhibition of TNF-α and

S-146 Clinical and Experimental Rheumatology 2018 Adenosine in ANCA-associated vasculitis / L. Kling et al.

IL-12 release in murine macrophages overcome by P2X7 receptor blockade minating autoreactive lymphocytes in (116), but also enhancement of IL- (125). Accordingly, ATP was shown to the state of anergy which is reported to 10 synthesis in these cells and in a induce Th17 differentiation of murine depend at least partially on extracellu- RAW264.7 macrophage cell line was T cells in vitro (126) and in vivo using lar adenosine. By contrast, we suggest elicited (116-118). Direct, functional a germ-free mice model for peritoneal the disrupted adenosinergic negative effects of adenosinergic signalling and rectal treatment with non-degrada- feedback mechanism promotes con- were shown in in vitro experiments as ble ATP derivatives (126). In systemic tinuous, therefore persistent, activation - well: unselective A2 receptor agonists lupus erythematosus, the literature re- of T lymphocytes and pathologic CD4 , and adenosine impaired phagocytic ac- cently supported the hypothesis that Th1, Th2, Th17 or regulatory T cell dif- tivity of human monocytes cultured for ATP activating the P2X7 receptor seems ferentiation. Besides, the adenosiner- more than 48 hours (119). likely to contribute dually to the pro- gic negative feedback appears to be of motion of this inflammatory disease by particular interest in AAV as the blood- ATP as promotor of inflammation leading to pyroptotic cell death on the vascular-tissue-barrier cannot be main- In general, ATP can be perceived as the one hand, and directly stimulating the tained in the phase of disease onset and antipode of adenosine, and A2A activa- inflammasome on the other (127). during the chronically maintained vas- tion respectively, being an extracellular culitic process (for example showing pro-inflammatory mediator (84) with Prospects of adenosinergic granuloma in GPA and EGPA). On the well described effects on lymphocytes signalling in the context of AAV contrary, absence of adenosine might and cytokine secretion. Specifically, its Although primary data on adenosin- prolong vasculitis due to unresisted

P2X7 receptor was found to transduce ergic signalling in AAV specifically cytokine release. Nonetheless, these induction of pro-inflammatory cy- still has to be judged scarce in general hypotheses not only require further in- tokines, chemokines and leukotrienes (and mainly is focused on regulatory vestigation, but also impose on other (120, 121). Moreover, extracellular ATP T cells), reports on purinergic effects questions: Ecto-enzyme expression activating the P2X7 receptor induced on key players of the immune system, enabling adenosinergic signalling may lytic cell death in murine T cells with which are known to be involved in AAV also contribute to better understanding regulatory T cell subsets being more pathogenesis, is strongly suggestive of of organ selectivity in AAV syndromes susceptible to this treatment than other dysfunctional adenosinergic signalling which frequently affect e.g. renal and lymphocyte subtypes as a key finding in AAV. This is further underscored by pulmonary vessels. Our own data im- (122). Consistently, mice knocked out a CD73 knockout (CD73-/-) mice model plied AAV patients potentially benefit for the P2X7 gene disclosed higher reg- that presented with typical findings of from treatment targeting their disrupted ulatory T cell frequencies in lymphatic AAV pathology including glomerular adenosinergic system as lymphocytic tissue as well as peripheral blood than and peritubular capillaritis, deposi- CD73 expression was associated with wild-type mice (122). Investigating tion of IgG and complement as well as renal function and systemic inflam-

P2X7 knockout mice in a model of in- proteinuria besides features of autoim- mation (109). Fortunately, a myriad of flammatory bowel disease, the control munity (128). Purinergic signalling and substances engaging in adenosinergic group was observed with higher neu- adenosine producing capacity through signalling became a matter of interest trophil infiltration and mast cell activa- ecto-enzyme activity has already been for drug developers more recently. Spe- tion in the bowel (120). Involving its linked to other autoimmune diseases, cific adenosine receptor agonists and other receptors P2X1 and P2X4, ATP for example Sjögren’s syndrome (121, antagonists have been and are currently was also reported to act as a co-stim- 129) and systemic lupus erythemato- studied in registered clinical trials, al- ulatory molecule on T cells (123, 124) sus with decreased lymphocytic CD39 beit these do not study the agents in the with T cells showing active ATP release (130) and CD73 levels (131). This context of AAV. However, one study in- at the immune synapse themselves in suggests alterations of the adenosin- vestigating the anti-inflammatory effect order to amplify T cell activation in an ergic system are possibly a common of P2Y12 antagonist in meth- autocrine manner (124). In contrast to feature of autoimmunity in general. otrexate refractory patients with rheu- the A2A receptor, this specific receptor However, this review identified sev- matoid arthritis on disease activity has activation also coded for enhancement eral complex relationships between been launched lately (NCT02874092). of IL-2 transcription during T cell ac- AAV pathogenesis and adenosinergic Our study group is convinced further tivation (124). Furthermore, ATP was signalling. Our group hypothesises the investigation of adenosinergic signal- described not only to enhance T cell intercellular microenvironment in AAV ling in AAV is imperative on the means activation, but also driving T cell dif- patients demonstrates an adenosine to launch clinical studies developing ferentiation fate. Exposure to ATP, thus deficit caused by defective extracellular future therapies of the disease. Finally,

P2X7 receptor activation resulted in IL- adenosine metabolism which is likely if purinergic signalling is pathogenic 17 synthesis in human T cells and sub- to enable expansion of autoreactive in AAV, it still remains to elucidate its sequent induction of a Th17 resembling dendritic cells and in consequence, T aetiology with prospects to evolve ad- phenotype (125) while regulatory T cell and B lymphocytes as well. Addition- equate measures to prevent pathogenic function was suppressed, but could be ally, AAV patients seem to fail in ter- alteration.

Clinical and Experimental Rheumatology 2018 S-147 Adenosine in ANCA-associated vasculitis / L. Kling et al.

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