Review One year in review 2019: pathogenesis of rheumatoid arthritis
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Review
One year in review 2019: pathogenesis of rheumatoid arthritis
C. Croia1, R. Bursi2, D. Sutera1, F. Petrelli1, A. Alunno2, I. Puxeddu1
1
Immuno-Allergology Unit, Department ABSTRACT the disease. In the current review we
of Clinical and Experimental Medicine, Rheumatoid arthritis (RA) is a chronic reported a Medline search of articles in
University of Pisa, Italy; inflammatory autoimmune disease in- English published in the PubMed data-
2
Rheumatology Unit, Department of
fluenced by both genetic and environ- base from 1st January 2018 to 31st De-
Medicine, University of Perugia, Italy.
mental factors. Over the last few years, cember 2018. The new insights in the
Cristina Croia, PhD
particular attention has been given to field of RA pathogenesis may improve
Roberto Bursi, MD
Donatella Sutera, MD novel genes and to the close interaction current knowledge of the disease and
Fiorella Petrelli, MD between genetic factors and epigenetic contribute to identifying new targets
Alessia Alunno, MD, PhD mechanisms. Research has also fo- for the development of novel disease-
Ilaria Puxeddu, MD, PhD cused on the influence of environmen- modifying therapies.
Please address correspondence to: tal factors on disease development, and
Dr Ilaria Puxeddu, on new mechanisms of the innate and Genetic aspects
Department of Clinical adaptive immune system that can influ- Genome-wide association studies
and Experimental Medicine, ence the different stages of RA. Howev- (GWAS) and independent replication
University of Pisa,
Via Roma 67,
er, there are still several aspects of the studies identified potential genes as-
56126 Pisa, Italy. disease that need further investigation. sociated with RA susceptibility, espe-
E-mail: ilaria.puxeddu@unipi.it Shedding some light on the different cially major histocompatibility com-
Received on April 26, 2019; accepted aspects of RA pathogenesis will help plex (MHC) genes, divided into class I
in revised form on April 30, 2019. to improve the current diagnostic tools (HLA-A, B, C), class II (HLA-DR, DP,
Clin Exp Rheumatol 2019; 37: 347-357. and to identify new targets for the de- DQ), and class III sub-regions. It has
© Copyright Clinical and velopment of disease-modifying thera- been established that HLA-DR, espe-
Experimental Rheumatology 2019. pies. Thus, in this review we summarise cially HLA-DRB1 locus, provides im-
the new insights in RA pathogenesis, portant genetic contribution for the risk
Key words: rheumatoid arthritis, resulting from literature research data of development of RA, by encoding
genes, environmental factors, innate published in the last year. the MHC class II antigen-presenting
immunity, adaptive immunity molecules which can accommodate a
Introduction widely range of peptide ligands. So far,
Rheumatoid arthritis (RA) is a chronic it is well known that most of the RA-
inflammatory autoimmune disease in- associated HLA-DRB1 alleles share
fluenced by both genetic and environ- similar amino acid sequences at posi-
mental factors. Over the last few years, tion 70–74 on the HLA-DR β chain,
particular attention has been given to named shared epitope (SE), which is
novel genes encoding for lymphocyte highly prevalent among anti-citrulli-
signalling, affecting molecules or en- nated protein antibodies (ACPA)-pos-
zymes that are involved in cell regula- itive patients. By investigating the in-
tory networks and oxidative stress. The teraction between RA associated anti-
development of RA cannot be fully ex- gens and HLA-SE allomorphs, Ting et
plained by the tight regulation of genet- al. identified a preferential binding of
ic factors and epigenetic mechanisms. three HLA-DRB1 allomorphs (HLA-
The environment, including smoking, DRB1*04:01/*04:04/*04:05) by self-
diet, obesity, infections and microbiota antigens implicated in RA. In particu-
have been proposed to trigger the dis- lar, a strong correlation between bind-
ease in genetically predisposed indi- ing affinity and citrullination at P4 of
viduals. The clinical picture of RA is the bound peptide ligand was reported
the result of a close interaction between for all three HLA-DRB1 allomorphs.
cells, soluble mediators, autoantibod- However, we have to take in account
ies and signal transduction pathways that not all HLA-DRB1 allomorphs
of the innate and adaptive immune sys- were shown to bind citrullinated anti-
Competing interests: none declared. tem, all involved at different stages of gens with the same affinity, probably
Clinical and Experimental Rheumatology 2019 347One year in review 2019: pathogenesis of RA / C. Croia et al. due to β-chain polymorphisms residing ligand 1A (TL1A), encoded by TNF su- cells such as natural killer (NK) cells, outside the SE motif (1). Furthermore, perfamily member 15, located on chro- T lymphocytes and monocytes. Its role the SE alleles are associated with RA mosome 9q32, is known to exert pleio- is primarily linked to intercellular adhe- susceptibility as well as with the sever- tropic effects on cell proliferation and sion and lymphocyte signalling and the ity of the disease, and they can help activation as well as on differentiation T allele of the CD226 gene has recently to identify different genetic profiles in of immune cells, such as T helper cells. been identified as a potential suscepti- subsets of RA patients. HLA-DRB1 In this regard, the TL1A rs3810936 and bility risk factor for the development analysis performed in different RA sub- rs7848647 polymorphisms were shown of RA in a cohort of Egyptian patients groups, allowed the identification of to be protective genotypes against the (10). a genetically unique subset of RA pa- development of the disease (7). In addi- In parallel, particular attention has been tients and distinct genetic background tion, both TNF receptor and TNF recep- given to Caspases (CASPs), a family (2). In addition to the well-recognised tor-associated factors have been also of cystein proteases that are known to role of HLA-DRB1, increasing atten- extensively investigated in RA. TNF regulate apoptotic signalling (apoptotic tion has recently been given to HLA- receptor-associated factors (TRAF) CASPs) or to mediate host defence DP genes for their role in infection pro- were initially identified as adaptor pro- against microbial infection and pro- cesses and autoimmunity. In this regard, teins for TNF receptor (TNFR) family cessing pro-inflammatory cytokines single-nucleotide polymorphism (SNP) in the signalling of intracellular path- (inflammatory CASPs). The latter, have rs9277535 in HLA-DPB1, a subunit of ways. However, they were subsequent- been widely investigated in inflamma- HLA-DP, was shown to be strongly ly shown to be signal transducers for tory diseases such as intestinal bowel associated with RA susceptibility in a a wide variety of receptors that are in- diseases and in neoplastic conditions. West Chinese population (3). volved in regulating cell death and sur- Only recently has their involvement in Beyond HLA loci, a number of non- vival and cellular responses to stress. autoimmune diseases been proposed. HLA genes have also been implicated Within the TRAF family, TNF receptor Interestingly, among the main genes in the susceptibility to RA. For exam- associated factor 6 (TRAF6) was found encoding the inflammatory CASPs ple, polymorphisms in the promoter to induce NF-κB activation, resulting (CASP1, CASP4 and CASP5), the regions of cytokine genes may modu- in the transcription and secretion of a CASP5 rs9651713 polymorphism has late cytokine expression, thus affecting variety of inflammatory mediators, in- been correlated with an increased risk of disease susceptibility. It is recognised volved not only in synovial inflamma- RA in a Chinese population, supporting that IL-1β plays a key role in mediat- tion, but also in cartilage and bone de- the involvement of these enzymes in the ing joint inflammation and destruction struction. In addition, TRAF6 rs540386 pathogenesis of RA (11). in RA, and the role of polymorphisms SNP has been recently associated with Increased oxidative stress, decreased of the IL-1β gene within the promoter low bone mineral density (BMD) in a antioxidant levels, and impaired anti- region -511(C/T) has been recently cohort of RA patients (8). oxidant defenses might occur during investigated in RA. The mutant allele Besides cytokines and growth factors, RA pathogenesis. In particular, Par- (T) of IL-1β-511 promoter SNP was chemokines play an important role in aoxonase (PON) is a group of proteins reported to be associated not only with the inflammatory state of RA and SNP present in three forms (PON1, PON2, elevated anti-CCP and IL-1β levels, of chemokine-encoding genes have PON3) encoded by genes PON1, but also with disease susceptibility in a been extensively studied in RA. For in- PON2, and PON3, located on the long cohort of North Indian RA patients (4). stance, the chemokine C-C motif ligand arm of chromosome 7 between q21.3 Among members of IL1 gene family, 4 (CCL4), secreted under mitogenic and q22.1. Among them, PON1 and the IL37 gene, particularly IL37 gene signals and acting as a chemo-attract- PON3 are plasma enzymes, structur- rs3811047 SNP, was found to be asso- ant factor for different immune cells, ally and functionally related to HDL, ciated with more severe disease activ- was widely investigated. Analysis of while PON2 is characterised by an in- ity in an Egyptian RA population (5). SNP of the CCL4 gene showed that tracellular location. A positive associa- In parallel with the IL1 family genes, the nucleotide T over the rs1719153 is tion between PON1 L55M (rs854560) polymorphisms of IL10 gene have been associated with decreased CCL4 gene polymorphism and an increased sever- also investigated, since IL10 exerts im- expression with consequent decreased ity of the disease was observed in RA munoregulatory as well as anti-inflam- risk for RA development (9). patients with moderate or high activity matory functions in the rheumatoid Over the last few years, particular at- of the disease in the presence of anti- synovial. Also, an association of IL10- tention has been given to novel genes CCP antibodies. Furthermore, the poly- 1082 A/G promoter SNP with the sus- encoding for lymphocyte signalling morphisms of PON1 L55M (rs854560) ceptibility to RA has been reported in regulating molecules or enzymes that and Q192R (rs662) act in synergy in a North Indian population (6). Genetic are involved in cell regulatory net- increasing disease activity in anti- variants in TNF superfamily genes are works and oxidative stress. In this CCP-positive patients and in those also under investigation due to the key context, CD226, a 67-kDa type I trans- patients with moderate or high active role of their encoded proteins in disease membrane glycol-protein encoding by disease (12). pathogenesis. For instance, TNF-like CD226 gene, is expressed on immune Although HLA and non-HLA loci are 348 Clinical and Experimental Rheumatology 2019
One year in review 2019: pathogenesis of RA / C. Croia et al. well recognised to be involved in RA, good epigenetic indicators of chroma- in the pathogenesis of RA and in the they cannot explain disease suscepti- tin state associated with gene activation development of the disease (19). bility alone. A fundamental contribu- or repression. In this regard, aberrant tion in understanding the mechanisms histone lysine methylation (HKM) has Environmental factors of gene modulation comes from epi- been reported in RA FLS. Specifically, Cigarette smoking genetic studies. This field deals in the dysregulated gene expression of The environment, including smoking, particular with inheritable and poten- HKM-modifying enzymes, including diet, obesity, infections and microbiota tially reversible modification of DNA histone lysine methyltransferases and have been proposed to induce the de- which can modulate gene expression demethylases, have been implicated velopment of RA in genetically predis- without altering DNA sequence and in the alteration of HKM, leading to posed individuals. Cigarette smoking which may be influenced by environ- changes in the gene expression of FLS, (CS) is the most known external factor mental factors. Among the distinct epi- contributing to the amplification and identified as trigger of RA (20). The di- genetic mechanisms, growing interest perpetuation of inflammation and re- rect effect of cigarette smoke conden- has recently been given to the possible modelling of RA synovia (15). sate (CSC) on the development of ar- contribution of DNA methylation in Another class of heredity variants that thritis has recently been demonstrated RA pathogenesis. Through genome- has recently been the objective of at- in the CIA model. Inoculating intraperi- wide analysis of DNA methylation in tention is the class of DNA polymor- tonally of CSC one day before immu- disease-discordant monozygotic twins, phisms affecting microRNA (miRNA). nisation of the animal model was suf- Webster et al. identified a differentially These belong to a class of small, non- ficient to promote arthritis. Therefore, variable DNA methylation signature in coding RNA molecules with approxi- the analysis of a single CSC compound the absence of differential methylation, mately 21 nucleotides in length that using sequential fractionation, silica gel supporting the importance of epige- can regulate gene expression by reduc- column chromatography, Mass Spec- netic variability in the pathogenesis of ing the ability of their target messen- trometer and the Gas Chromatograph, RA as well as of other autoimmune dis- ger RNA (mRNA) to promote proteins revealed that the compound potential- eases (13). Novel methodologies have synthesis. Altered miRNA expression ly relevant for inducing arthritis was been developed in order to better char- has been reported in RA patients and 5-hydroxy-2-methylpyridine (5H2MP) acterise the epigenomic landscape in SNP in miRNA have been investigat- which was not mutagenic and did not RA, in particular in fibroblast-like syn- ed in humans and in animal models. exert its activity via aryl hydrocarbon oviocytes (FLS), structural synovial For instance, SNPs of miRNA-146a receptor (AHR). The authors hypoth- cells that play active role in the inflam- (rs2910164 and rs2710164) and miR- esised that this effect may be the result matory and remodelling processes. In NA-499 (rs3746444) have been as- of an amplification of the AHR pathway order to cluster the RA genome into re- sociated with RA susceptibility in an or even of an independent mechanism gions with similar epigenomic profiles, Egyptian population (16) (17). In par- with production of an active metabo- a large collection of epigenomes for RA allel, Fernandes et al. have analysed lite. Activation of this receptor seems to FLS has been generated by profiling miRNA and gene expression profiles in play a key role in the pathogenesis of six histone modification patterns, open peritoneal cells of the two mouse lines RA and in CS-induced arthritis. Chen et chromatin regions, RNA expression AIRmax and AIRmin, which differ in al. observed that the AHR and its down- and whole-genome DNA methylation. their susceptibility to experimental ar- stream gene expression were present in Subsequently, these epigenomic data thritis after pristane injection (Pristane- both smoking and non-smoking rheu- have been integrated into a single anal- induced arthritis model) (PIA). This is matoid peripheral blood mononuclear ysis. It was therefore possible to identi- a mouse model resembling histopatho- cells (PBMC) with significantly higher fy several RA-specific pathways, some logical, immunological and clinical expression in smoking patients (21). of which are unexpected. In particular, aspects of RA. They demonstrated that Therefore, administrating AHR path- the “Huntington’s Disease Signalling”, cells from susceptible AIRmax mice way agonists to transgenic mice carry- specific to the Huntingtin-interacting had higher gene and miRNA modula- ing human SE-coding alleles resulted protein-1, seems to modulate the FLS tion than cells from resistant AIRmin in a robust increase in arthritis severity, capacity to invade the extracellular mice, suggesting that miRNA expres- bone destruction, overabundance of os- matrix (ECM), contributing to tissue sion may be responsible for the differ- teoclasts, and IL17-expressing cell infil- remodelling. These intriguing results ent PIA susceptibility in these strains. tration in the inflamed joints, providing allowed the introduction of novel diag- Moreover, miR-132-3p/212-3p, miR- new insights into the well-described, nostic approaches and the identification 106-5p, miR-27b-3p and miR-25-3p but poorly understood amplification of of new potential targets for the develop- were the miRNAs with the highest ex- the genetic risk for RA upon exposure ment of further treatments (14). In addi- pression in susceptible animals (18). to environmental pollutants (22). tion to DNA methylation, the evaluation Moreover, the down-regulation of The molecular mechanisms underlying of histone modifications may be useful MiR-338-5p, involved in the initiation, smoking-induced arthritis were further to understand the epigenomic profile progression and metastasis of many investigated. By using in-vivo model of in RA subtypes. These may represent human cancers, seems to be implicated IL17ra KO mice and in-vitro systems, Clinical and Experimental Rheumatology 2019 349
One year in review 2019: pathogenesis of RA / C. Croia et al.
Talbot et al. found that smoking is able increases the risk of RA compared to colitis by reducing STAT3 activation.
to exacerbate arthritis and to increase normal weight, mainly in the female Kim et al. have recently shown in the
Th17 differentiation of T cells via AHR population (28). Adipokines are key CIA model that Metformin was able to
activation (23). players in the activity of the adipose ameliorate the development of arthritis
Among the CSC that might contribute tissue and they seem to exert direct ef- in obese mice by reducing autoantibod-
to the induction of arthritis, Hydroqui- fects on the immune system. Among ies expression and joint inflammation.
none (HQ) was recently identified as an adipokines, it has recently been pro- Thus, these results strongly support the
active player in the early phase of the posed that leptin plays an active role in beneficial effect of this treatment in RA
disease, by increasing the infiltration RA with higher levels detected in the when it is associated with metabolic
of inflammatory cells, the levels of IL6 circulation of RA patients compared to disorders (33).
in the synovial fluid, the deposition of healthy controls. Wang et al. demon- Recently, diet and nutritional supple-
ECM proteins, proliferation of synovio- strated that in RA patients leptin was ments has been the subject of investiga-
cytes and by promoting higher frequen- able to increase the number of circulat- tion for their protective roles in several
cy of AHR and neutrophils expressing ing follicular T helper cells, the levels pathological conditions. The Mediterra-
IL17 in the synovial membrane (24). of IL6, IL21 and IL12, mainly through nean diet is commonly known as one of
CS seems to be involved in RA not only activation of STAT1 and STAT3 path- the healthiest dietary patterns existing,
for its role in inflammatory and remod- ways (29). While leptin seems to be influencing the gut microbioma and in-
elling processes, but also for its capac- involved in the inflammatory process, directly modulating the immune system.
ity to influence autoantibodies produc- adiponectin seems to increase bone This diet regime seems to exert benefi-
tion. It has been observed that a subset erosions in the CIA model. This may cial effects on RA, mainly through the
of patients with anti-Peptidyl arginine be due to the induction of osteopontin intake of antioxidant elements such as
deiminase 4 (PAD4) antibodies that expression by synovial FLS, which re- vitamin C, retinol and omega-3 polyun-
cross-react with PAD3 (anti-PAD3/4) cruits osteoclasts with consequent bone satured fatty acids (PUFA). In addition,
are at the highest risk for interstitial erosion (30). The role of adiponectin in high dietary quality with a high intake
lung disease, and this risk is increased RA was also studied in humans, par- of fish, whole grains, fruit and vegeta-
by a history of CS. Therefore, Cap- ticularly in first-degree relatives of bles and low intake of meat and sweets
pelli et al. aimed to investigate whether subjects at high risk of RA who have seems to be negatively associated with
smoking is aetiologically linked to the not yet developed the disease (31). The inflammatory markers such as CRP and
development of anti-PAD4 antibodies, chemokine C-X-C motif chemokine ESR (34). Erythrocyte levels of the n-6
but they did not demonstrate in the RA ligand 5 (CXCL5), also known as epi- PUFA linoleic acid are inversely as-
patients any association of anti-PAD4 thelial neutrophil activating peptide sociated with risk of RA, whereas no
antibodies with smoking, suggesting 78 (ENA78) represent a link between associations were observed for other
that other environmental factors might obesity, inflammation and insulin re- n-6 or n-3 PUFA (35). Up to now, it
be involved in these processes (25). sistance (IR) in the general population. is not known which component of the
Among environmental factors, hypoxia Since CXCL5 has also been found to Mediterranean diet is responsible for
seems to be a prominent feature in RA, play a role in the inflammatory process their beneficial effect on RA. Recently,
by modulating the activity of FLS via of RA, and chronic inflammation pro- particular attention was given to the
hypoxia-inducible factor 1α (HIF1α). motes IR with impairment of pancreat- monounsaturated fatty acid (MUFA),
Interestingly, Yu et al. have discovered ic β-cells in RA patients, Tejera-Segura an important component of this diet.
that hypoxia is able to promote RA de- et al. have hypothesised a role of this Daily MUFA intake might suppress dis-
velopment not only because it induces chemokine in the development of IR ease activity in RA patients, supporting
inflammation and angiogenesis, but in RA. However, they showed that in the potential benefits of the components
also because it induces the process of RA patients, unlike the general popula- of the Mediterranean diet in controlling
citrullination in human FLS. In particu- tion, the CXCL5 is not related to IR, RA (36).
lar, they found that PAD2 and citrulli- suggesting that other mechanisms are
nated proteins were increased in human involved in the development of IR in Microbiota
FLS after exposure to hypoxia and this RA (32). It has also been hypothesised The inflammatory state underlying RA
was down-regulated by knocking down that the possibility of non-response to seems to be closely linked to the mi-
HIF1α using HIF1α siRNA (26). RA treatment might be linked to meta- crobiota. Many studies suggest that
bolic disorders and that the treatment a chronic inflammatory response in-
Obesity and diet of these disorders might exert positive duced by gut dysbiosis can critically
An association between RA and obesi- effects on RA as well. In fact, Met- contribute to the pathogenesis of some
ty has been demonstrated, but the pre- formin, a biguanide anti-diabetic drug autoimmune diseases. Diet can modify
cise mechanisms involved have not yet mainly used in type 2 diabetes, exerts intestinal microbiota and can influence
been elucidated (27). A meta-analysis therapeutic efficacy in other diseases intestinal barrier strength, integrity and
based on over 350,000 patients showed besides type 2 diabetes, such as ex- permeability. We know that the micro-
that higher body mass index (BMI) perimental autoimmune arthritis and biota of RA patients differs from the
350 Clinical and Experimental Rheumatology 2019One year in review 2019: pathogenesis of RA / C. Croia et al. general population and that anti-rheu- Infections (MAP) and host peptides has been con- matic drugs can exert positive effects In parallel to the gut microbiota, sev- sidered as an RA pathogenetic mecha- on its regulation. Recently, analysis of eral viral and bacterial infections seem nism. By using bio-informatic analy- the components of microbiota enabled to be responsible for the development sis, Bo et al. identified high sequence a better understanding of the link be- of autoimmune diseases, including RA. homology among interferon regulatory tween inflammation and microbiota. In Arleevskaya et al. characterised the in- factor 5 (IRF5), EBV antigen BOLF1 particular, Muniz Pedrogo et al. dem- fection events in a longitudinal cohort and MAP antigen MAP_4027. They onstrated an increase of Clostridiacee of first-degree relatives of patients with have also evaluated in the sera of RA in the stool samples of RA and inflam- RA, evaluating their associations with patients the presence of antibodies di- matory bowel disease-associated ar- the development of the disease (41). rected against human homologous thropathy, suggesting a potential com- Interestingly, they observed that an an- IRF5 cross-reacting with BOLF1 and mon microbial link between the two nual increase of respiratory tract infec- MAP_4027. According to their results, forms of arthritis (37). Interestingly, tions was found at the pre-clinical stage they suggested that IRF5 might be a po- both gut microbiota and arthritis have of RA, probably due to alteration in the tential target of RA, supporting the hy- been studied in the murine model of immune system, resulting in suscep- pothesis that EBV and MAP infections CIA in which broad-spectrum antibiot- tibility to infection. The authors also may be involved in the pathogenesis of ics were administered 7 days before or hypothesised that the infectious events the disease, leading to a secondary im- 21 days after immunisation with type can predispose to the development of mune response, cross-reacting against II collagen (38). Interestingly, a deple- RA. In particular, the role of Epstein- RA self-peptides (44). tion of the microbiota prior induction Barr virus (EBV) in the pathogenesis of CIA resulted in reduction in dis- of RA has been demonstrated, although Innate immune response ease severity by 40% with a decrease some aspects need to be better defined. The innate immune system plays a in circulating inflammatory cytokines. Recently, Kuusela et al. have investi- key role in non-specific recognition of In parallel, a delay in the production gated the prevalence of asymptomatic pathogens and represents the first de- of IL17A and IL22 in intestinal tissue activation of EBV in RA patients and fence against viruses or bacteria. Fol- has been observed. In the other group the correlation of serum EBV DNA lowing the identification of microbial of mice treated 21 days after immun- with disease activity. Interestingly, they substances, the phagocytosis process is issation, a greater reduction in sever- observed that active RA was associated activated by innate immune cells with ity was even observed, suggesting that with a lytic EBV infection which may the release of specific cytokines and intestinal dysbiosis is able to trigger play an active role in the pathogenesis of chemokines at the site of infection. Sev- mucosal immune responses. In addition RA (42). Subsequently, to better charac- eral cells of the innate immune system to the commensal bacteria and their terise the influence of EBV infection in are involved, including macrophages, pathogenic components present in the the development of RA, Masuoka et al. monocytes, dendritic cells, neutrophils, gastrointestinal tract, the bacteria pre- evaluated the EBV gene in the synovial natural killer cells, mast cells, eosino- sent in the oral cavity exert pathologi- tissue of RA patients by using nested phils, innate lymphoid cells (ILCs) and cal activity in autoimmune diseases. PCR for the amplification of EBV nu- myeloid-derived suppressor cells (MD- An interesting study showed that mul- clear antigen-1 (EBNA-1). Interest- SCs). All these cells act through a large tiple environmental pathogens contrib- ingly, they observed that EBV infection number of specialised receptors, such ute independently or concomitantly to can contribute to the onset of RA and as pattern recognition receptors (PRRs) reaching worse disease activity, and chronic inflammation in synovial tis- expressed on different immune cells. to affecting the outcomes of RA (39). sue and that the frequency of EBNA-1 Among PRRs, the Toll-like receptors Subsequently, Ceccarelli et al. analysed gene variants was low and not signifi- (TLRs) are able to recognise several tongue Porphiromonas (P) gingivalis cantly different between RA and control microbial epitopes on pathogens with presence and quantification in a large groups, suggesting that EBNA-1 gene subsequent activation of the inflamma- cohort of healthy subjects and RA pa- variants are not a risk factor for RA. In some. tients, comparing these data to those addition, they demonstrated that HLA- Several studies have thoroughly inves- obtained in patients with periodontitis, DRB1 with SE was a genetic risk factor tigated the role of monocytes in RA knee osteoarthritis or fibromyalgia. for the development of RA, but neither pathogenesis, recognising the role of They showed a similar prevalence of the presence of EBV nor EBNA-1 gene these cells in the joint inflammation and P.gingivalis in RA and periodontitis, variants differed between SE-positive bone erosion. Smiljanovic et al. have with higher prevalence in these groups and SE-negative patients. According to recently analysed the role of monocytes compared to the control group. In addi- their results, it is possible to hypothesise in RA by using transcriptome technolo- tion, the P.gingivalis/total bacteria rate that these two risk factors, SE and EBV, gy and by performing a cytometric pro- was lower in RA patients in the remis- may be independent and not related to filing of monocytes from bone marrow sion phase of the disease and was posi- each other (43). (BM) and from peripheral blood (PB) tively correlated to the disease activity Molecular mimicry among EBV, My- of RA patients. The main pattern found (40). cobacterium avium paratuberculosis in both RA-BM and RA-PB was similar Clinical and Experimental Rheumatology 2019 351
One year in review 2019: pathogenesis of RA / C. Croia et al. to the one of less mature and differenti- and bone erosion, down-regulation of energy-demanding process and conse- ated precursors, i.e. the “left-shift pat- monocytes activation can be another quently it requires a strict regulation tern”. Based on these observations the possible way of inhibiting inflamma- of their metabolic programmes. They authors suggested an increased turno- tion and bone erosion in RA. It has been observed that RA monocytes express ver of RA monocytes, which migrate shown that FLS from RA synovia ex- a higher level of SLC7A5, a key regu- from BM into the blood stream and pressed higher levels of CXCL12, and lator of the uptakes of different amino from the circulation into the inflamed the over-expression of this chemokine acids, and that the SLC7A5-mediated synovia. The authors confirmed the would in turn increase the recruitment leucine uptake promotes the produc- transcriptome data in RA by cytometry of monocytes via CXCR4. Thus, once tion of pro-inflammatory cytokines in analysis and showed that monocytes monocytes migrate to the synovia, they human monocytes/macrophages. By are activated in the joint tissue, thereby differentiate into pro-inflammatory blocking SLC7A5, IL1β is reduced and supporting the relevant role for local macrophages, releasing several cyto- this effect seems to be due to the inhibi- disease-specific stimuli (45). It is well kines and chemokines that contribute tion of the leucine-mediated activation known that monocytes can differenti- to the amplification and perpetuation of of mTORC1, the master regulator of ate into M1 macrophages with a pro- local inflammation and tissue damage cellular metabolism (52). inflammatory phenotype or into M2 (48). Thus, the recruitment of mono- Several in-vivo models have been used macrophages with an anti-inflammato- cytes into the joint of RA patients can to analyse the role of macrophages ry phenotype. Fukui et al. showed that be regulated by the interaction between in RA. Hagert et al. developed a new in RA patients M1/M2 ratio positively monocytes and FLS in the inflamed tis- mouse model of chronic arthritis by correlate with the rate of differentiation sue. In particular, it has recently been injecting 4 monoclonal anti-type II col- of osteoclasts. In particular, they found demonstrated that the disintegrin and lagen antibodies followed by mannan that in ACPA-positive patients the M1/ metalloprotease ADAM17 might play injection in RA B10.Q mice. Interest- M2 ratio is higher than in ACPA-nega- an important role in monocyte-FLS ingly, they found that this model devel- tive patients and that a higher M1/M2 interaction. The levels of this media- oped the disease independently of the ratio also had a higher levels of ESR tor are increased in both the serum and contribution of T and B lymphocytes. and CRP, suggesting that the modula- synovial fluid of RA patients. In ad- Instead, macrophages and the com- tion of M1 and M2 subsets could repre- dition, ADAM17 is expressed in FLS plement cascade seem to play crucial sent a potential therapeutic target in RA and knocking down this molecule leads roles in driving RA in this model. The (46). Several soluble mediators orches- to a drastic reduction in the adhesion authors suggest that mannan is able to trate monocyte recruitment in the in- of monocytes to FLS (49). Besides activate macrophages via TLR4, sug- flamed tissue. In particular, Cecchinato ADAM17, circulating immune com- gesting that the innate immunity can et al. proved that high mobility group plexes (ICs) purified from RA patients, induce a chronic active arthritis, also protein (HMG) B1, a damage-associat- but not those from healthy donors, without the involvement of the adaptive ed molecular pattern (DAMP) released were able to promote a pro-inflamma- response (53). by necrotic cells after tissue injury, and tory phenotype in monocytes with an An interesting discovery linking mac- the chemokine CXCL12, might act in over-production of TNF-α in response rophages, fat tissue and the mecha- synergy, increasing the migration of to a variety of innate stimuli (50). nisms involved in RA pathogenesis has monocytes to the site of inflammation Recently, Masako et al. evaluated the been reported by Giles et al. Adipose and promoting the progression and impact of different monocyte popula- tissue macrophages (ATM) are a strong amplification of the inflammatory pro- tions on disease activity in RA. By source of pro-inflammatory cytokines, cesses. Monocytes purified from RA flow cytometry analysis they divide regulating the functions of the adipose patients in clinical remission compared the monocytes into CD14brightCD16-, tissue. The authors demonstrated for the to those from RA patients with an ac- CD14brightCD16+ and CD14dim- first time that adipose tissue from RA tive disease, require 10-fold less con- CD16+ subsets and they observed that patients show 76% more macrophages centration of HMGB1 to enhance CX- the CD14brightCD16+ subset is in- than adipose tissue from normal pa- CL12-induced monocyte migration. creased in the PB of RA patients, but tients. In addition, RA patients have Therefore, it has been hypothesised decreased following anti-IL6 or anti- 1.5-fold higher number of crown-like that the activity of this heterocomplex TNF treatment together with the de- structure, formed by ATM surrounding might depend on COX2 and JAK/ crease of disease activity (51). dead adipocytes and secreting inflam- STAT pathways and are affected by the As previously reported, circulating matory cytokines, with association with redox potential of the microenviron- monocytes can infiltrate inflamed joint IR. Importantly, among RA patients ment. Thus, modulation of the hetero- in RA and differentiate into M1 and into there was a striking correlation between complex CXCL12/HMGB1 might be M2 macrophages. Interestingly, Yoon the levels of ATM and/or crown-like an alternative tool in RA patients that et al. investigated the metabolic repro- structures, systemic inflammation and poorly respond to conventional treat- gramming of monocytes/machrophag- autoantibodies production. Moreover, ments (47). Since monocytes are im- es expression, since their participation levels of ATM and/or crown-like struc- portant players in local inflammation in a specific immune response is an tures were significantly lower in pa- 352 Clinical and Experimental Rheumatology 2019
One year in review 2019: pathogenesis of RA / C. Croia et al. tients using methotrexate, leflunomide, (56). Recently, neutrophils have been able to induce the same effects, along TNF inhibitors or statins, suggesting linked to the formation of ACPA in RA. with the inhibition of CD4+ T cell pro- that adipose tissue may be the target Gorlino et al. found that in the pres- liferation. β2-AR mediates all these ef- of pharmacological therapies used in ence of ACPA in the synovial fluid of fects through a cAMP-protein kinase RA (54). Besides monocytes and mac- RA patients, the number of neutrophils A signalling, and β2-AR antagonist rophages, neutrophils play important was increased in the joint and corre- ICI118551 prevents the effects of NE roles in the immune system and they lates with the levels of IL8, the main and the PKA inhibitor H-89 blocks the represent around 80–90% of the total chemokine involved in neutrophil mi- effects of Terb, suggesting new poten- cells in RA synovial fluid/joints. These gration. By in-vitro and in-vivo stud- tial therapeutic approaches via modula- cells have been linked to the pathogen- ies, they also demonstrated that higher tion of β2-AR. (59). esis of RA for their release of pro-in- synovial ACPA levels induce ROS IL-34 does not directly influence Th17 flammatory cytokines, reactive oxygen production, DNA extracellular release CD4+ T cells from RA patients, how- species (ROS), granules containing and the induction of ICAM-1 expres- ever, if they are co-cultured with stimu- degradative enzymes and neutrophils sion in neutrophils (57). Subsequently, lated monocyte-like cell line (THP-1) extracellular traps (NETs) which can by studying the binding of ACPA-IgG in the presence of anti-CD3/CD28 cause further damage to the tissue IC to individual Fc gamma receptors antibodies, it can stimulate THP1 CS- and amplify the neutrophil response. (FcγR), Kempers et al. identified a piv- F1R. This treatment induces the up- Like any other cells, neutrophils can otal role for the neutrophil-expressed regulation of ROS production which, undergo autophagy, a self-protective FcγRI receptor in binding the ACPA- in turn, leads to increasing the release mechanism where the cell disassembles IgG IC. Since neutrophils isolated from of IL6 with the consequent enhance- and gets rid of unnecessary or dysfunc- the synovial fluid exhibit an activated ment of the Th17 cell generation. In tional components. Recent studies have state and express FcγRI, this strongly this co-culture system, the levels of the reported that autophagy is involved in suggests that the binding of FcγRI to pro-inflammatory mediators TNF-α the pathogenesis of RA, but the clear IC could contribute to local inflam- and IL1β are up-regulated, indicating mechanisms have yet to be elucidated. matory processes and therefore to the their possible role in Th17 generation. Qiyuan et al. found that neutrophils un- mechanisms underlying the pathogen- The use of TNFRII antagonist, but not dergo a higher rate of autophagy in RA esis of RA (58). of IL1βR, can reduce ROS production synovia as indicated by the increase in from THP1 and CD4+ T cells and con- the autophagy-related protein LC3 and Adaptive immune response sequently the release of IL6 and the a lower lysosomal PH in neutrophils. Different studies have demonstrated formation of Th17 (60). Recently, It has Several cytokines such as IL6, IL8, that a dysregulation of adaptive im- been demonstrated that IL-17-produc- IL10 and MCP1 were higher in RA mune response plays an important role ing CD4+CD161+ T cell subset can also synovial fluid and correlate with the au- in the pathogenesis of RA and that sev- play a role in RA pathogenesis. The tophagy rate, suggesting that these cy- eral mediators and cellular components level of CD4+CD161+ T cells, along tokines are possible driving factors for may be involved. Among the adaptive with their level of expression of CD98 neutrophil autophagy. In addition, this immune cells, T and B lymphocytes and CD147, is significantly increased process may be regulated by different might contribute to the pathogenesis of in the synovial fluid of RA patients signalling pathways, including those of RA at different levels. Liu et al. have compared to the PB. CD4+CD161+ T IL17 (55). discovered that β2-adrenergic receptor cells in the synovial fluid can be used A fascinating study by Rhys et al. has (β2-AR) expressed by CD4+ T cells is as an indicator of RA disease activity investigated the potential role of neu- reduced in the ankle and in the spleen since their expression of CD98 and trophils microvesicle on the inflam- of CIA model, compared to the healthy CD147 is directly correlated with the matory activation of macrophages. mice. In mice with CIA, Th17 cells, disease activity index (DAS) on 28 By combining in-vitro and ex-vivo the Th17-related transcriptional factor joints. CD147 expression is also asso- techniques, the authors demonstrated retinoic acid related orphan receptor-gt ciated to the levels of the CRP, thereby that a specific subset of neutrophils (ROR-gt) and also IL17 and IL22 cy- suggesting a potential function of this microvesicle (expressing annexin A1 tokines, are more consistently present factor in T cell behaviour in local in- and phosphatidylserine) can attenuate compared to healthy mice. Treatment flammation (61). macrophages activation in response to of these mice with norepinephine (NE), The presence of the PTP22 risk allele LPS and IFNγ. In co-culture experi- which signals through the β2-AR ex- is associated with several autoimmune ments, the authors also demonstrated pressed by lymphocytes, blocks Th17 diseases, including RA. Naive human that classically activated macrophages cell differentiation and consequently CD4+T cells homozygous for that allele stimulated with neutrophil-derived mi- reduces ROR-gt, IL17 and IL22 pro- over-express a set of genes which are crovesicles no longer activate adjacent duction, ultimately leading to an anti- important for cytotoxic T cell differen- fibroblasts, suggesting that modulation inflammatory microenviroment. Treat- tiation. Moreover, the protein expres- of neutrophil vesicles might be a new ing CD4+ T cells from CIA mice with sion of the T-box transcription factor therapeutic approach for joint disease β2-AR agonist terbutaline (Terb) is eomesodermin (EOMES) is increased Clinical and Experimental Rheumatology 2019 353
One year in review 2019: pathogenesis of RA / C. Croia et al. in T cells from healthy donors ho- function. Zafari et al. analysed the epi- 1, Matsuda et al. showed that over 60% mozygous for the PTPN22 risk allele genetic modulation of the Foxp3 Treg- of synovial CD3+ cells in RA express and correlates with a decreased num- specific demethylated region (TSDR) CD3 which is otherwise undetectable ber of naıve CD4+ T cells. In PTPN22 and Helios gene expression to deter- in osteoarthritis and that the majority risk allele carriers an accumulation of mine Treg cell alteration in RA pa- of the RA synovial lining cells express EOMES+CD4+ T cells in synovial fluid tients. Interestingly, they demonstrated PD-L1, one of PD-1 ligands. The ex- of RA patients was observed, together that both epigenetic modifications and pression of this ligand is significantly with a more pronounced production of Helios gene expression may have im- correlated with the amount of synovial perforine (62). portant roles in the pathogenesis of RA T cells, inflammatory markers such as It has also been observed that in RA through their effects on Foxp3 gene ex- CRP, autoantibodies such as RF and patients the proportion of Th17 cells pression (65). Krenn’s synovitis score, supporting the and the chemokine CCL20, ligand of The dysregulation of the Treg cells in idea that the expression of PD-L1 may CCR6, is higher in the mononuclear the RA was also supported by recent reflect the state of the disease (70). cells from the synovial fluid than in studies by Wang et al. They showed The infections are connected to RA those from the PB, while Th1 cells that an increase of miRNA, in particu- not only for the close interaction with manifest the opposite behaviour. Th17 lar the exosome miRNA, a negative the innate immune system, but also cells display higher levels of RORγt regulator of cellular gene expression, for their possible interactions with the and CCR6 expression compared to can downregulate the differentiation adaptive one. Autoantibodies are pro- the cells from healthy subjects and of Treg cells in RA patients compared duced in lymphoid tissue where lymph osteoarthritis patients, and this is par- to healthy subjects. In particular, they node stromal cells (LNSCs) regulate ticularly evident in the synovial fluid. discovered that the miRNA 17 can sup- lymphocyte function. Infections can Thus, It has been hypothesised that this press the induction of Treg by inhibit- alter the interaction between LNSCs can lead to a selective increase of Th17 ing the expression of the receptor II of and lymphocytes resulting in defective cells migrating to the inflamed joint. In TGFβ (TGFBRII) (66). In support of immune responses. Interestingly, Han- addition, treatment with anti-rheumat- these studies, it was also reported that hlein et al. showed that upon TLR3 ic drugs such as methotrexate for 24 CD3+CD4+CD25+CD127low Treg cells triggering, human LNSCs from RA- weeks is able to reduce the presence of increased in the PB of RA, together risk individuals and RA patients pro- RORγt and CCR6 in Th17 cells, as well with an increased level of IL6, TNF-α, duce fewer T cell guiding chemokines as CCL20 expression in the synovial IL37 and the cell immunoglobulin and as well as the antiviral molecule MxA, fluid of RA patients, thereby reducing mucin-domain containing-3 (TIM-3). compared with healthy controls, sug- the migration of Th17 cells to target However, no association with disease gesting that during systemic autoim- tissues. Surprisingly, this treatment is activity was found, suggesting that this munity human LNSCs attempt to in- also able to increase the levels of the dysregulation may be involved in the hibit immune responses when activated chemokine CXCL10 in Th1 cells. mechanisms that regulate the pathogen- through TLR3 (71). Taken together, these results support esis of RA, but are not implicated in the Analysis of transcription factors related the hypothesis that the CXCR3-CX- disease activity (67). By analysis of T to CXCL13-producing CD4+T cells at CL10 axis and RORγt -CCR6-CCL20 cell subsets in RA, it has been observed local inflammatory sites has highlight- axis may play important roles in the that CD4+ Tim-3+/PD-1+/CD4+ T cell ed the role of SOX 4 in RA. In fact, it pathogenesis of RA and the latter could subset is higher in the circulation of has been shown that this transcription represent a potential therapeutic target RA patients compared to healthy sub- factor is more consistently expressed in in RA (63). jects (68). In addition, a role of PD‑1, CD4+T cells from the synovial fluid of In addition, the in-vitro stimulation one of the main immunosuppressive RA compared to the PB and that it can with IL2 of either PBMC or purified co-stimulatory molecules, which medi- induce the production of the chemokine CD4+ T cells, but not of lymph-node ates an inhibitory effect, has been also CXCL13 in the PD-1hiCXCR5−CD4+ derived T cells from healthy subjects demonstrated. In fact, Luo et al. found T cell subset in-vitro. This effect is par- and RA patients promotes a significant that the expression of PD-1 on T cells ticularly evident in a pro-inflammatory increase of Foxp3+CD25+CD4+CD127 in the PB of RA patients was increased environment, contributing to the de- low regulatory T cells (Treg) cells significantly in subjects with a high RF velopment of ectopic lymphoid-like which is not observed if cells are only titre, high levels of inflammatory mark- structures in the inflamed tissues. At pre-treated with IL2. Conversely, the ers and a high DAS28. The expression the same time, SOX 4 can have a role rise in Treg cells after treatment with of PD-1 on T cells in the synovial fluid in the commitment of Th1, but not of low dose of IL2 could be related to an of was also increased significantly in Th2 cells, by increasing the produc- unmasking of latent Treg cells already those RA patients with a high DAS28, tion of IFNγ and the expression of present in the PB (64). Recently, it has indicating that the expression of PD-1 CXCL13 under Th1-polarising condi- been demonstrated that in RA the con- on T cells might be closely linked to tion. To note, the effect of SOX 4 has trol of auto-reactive cells is defective the activity of the disease (69). not been observed in mouse models and that Treg cells have an impaired Subsequently, to support the role of PD- of RA, opening the way to new stud- 354 Clinical and Experimental Rheumatology 2019
One year in review 2019: pathogenesis of RA / C. Croia et al.
ies to better understand the difference involvement of CD8+ memory T cells explain the development of the disease.
in the regulation of SOX 4 in humans in the development of bone erosions in Research aimed at better clarifying the
compared to animal models of RA (72). RA patients. The study revealed that B mechanisms underlying the pathogene-
Prado et al. demonstrated that not all cells are able to inhibit bone formation sis of RA, will enable the development
the inflammatory features of RA are in the animal model of RA, by produc- of novel and more specific disease-
directly linked with the severity of the ing multiple inhibitors of osteoblasts, modifying therapies.
disease, since dendritic cells can lead to including CCL3 and TNF (76) (77). It
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