Review One year in review 2021: pathogenesis of rheumatoid arthritis
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Review
One year in review 2021: pathogenesis of rheumatoid arthritis
D. Testa1, S. Calvacchi2, F. Petrelli1, D. Giannini1, S. Bilia1, A. Alunno2, I. Puxeddu1
1
Immuno-Allergology Unit, Department ABSTRACT P36L1 and LINC00158 may be new
of Clinical and Experimental Medicine, Rheumatoid arthritis (RA) is a chronic RA-risk loci in a large Korean cohort
University of Pisa, Italy; autoimmune disease characterised by (4) and IL12RB2, BOLL-PLCL1,
2
Rheumatology Unit, Department of
local and systemic inflammation where CCR2, TCF7 and IQGAP1 in a Chinese
Medicine, University of Perugia,
Perugia, Italy. the close interaction between immune cohort (5).
cells and soluble mediators leads to It is well established that among differ-
Davide Testa, MD
Santina Calvacchi, MD amplification and perpetuation of in- ent alleles conferring RA susceptibility,
Fiorella Petrelli, MD flammatory and remodelling processes. the major histocompatibility complex
Daiana Giannini, MD The research carried out in the last year (MHC) genes, including class I (HLA-
Silvia Bilia, MD in the field of RA has made it possible A, B, C), class II (HLA-DR, DP, DQ),
Alessia Alunno, MD, PhD to identify new mechanisms involved and class III sub-regions, are the most
Ilaria Puxeddu, MD, PhD in the pathogenesis of the disease, relevant ones. Within the HLA alleles,
Please address correspondence to: enabling the discovery of new poten- HLA-DRB1*04 has recently been con-
Ilaria Puxeddu, tial therapeutic targets. Thus, in this firmed to increase the risk of developing
Dipartmento di Medicina
Clinica e Sperimentale,
review we summarise new insights in RA in a southern Mexican population,
Via Roma 67, RA pathogenesis, resulting from a lit- while HLA-DRB1*08 allele seems to
56126 Pisa, Italy. erature research date published in the exert a protective effect (6).
E-mail: ilaria.puxeddu@unipi.it last year. In addition to HLA loci, several ge-
Received on March 11, 2021; accepted netic variants of non-HLA loci have
in revised form on May 4, 2021. Introduction been associated with some aspects of
Clin Exp Rheumatol 2021; 39: 445-452. Rheumatoid arthritis (RA) is a com- RA pathogenesis such as the role of im-
© Copyright Clinical and plex autoimmune disease characterised mune cells (B cells, T cells and mast
Experimental Rheumatology 2021. by local and systemic inflammation cells) and pro-inflammatory cytokines
(1-3). In the last year, advances have that actively regulate some relevant in-
Key words: rheumatoid arthritis, been made in the knowledge of RA flammatory mechanisms. The genetic
genes, environmental factors, innate pathogenesis, in particular in the field variants of genes encoding for soluble
immunity, adaptive immunity, of genetics and environmental factors mediators regulating immune cells ac-
pathogenesis that can influence the development of tivities have been the focus of several
the disease. Due to advanced research recent investigation.
techniques, it has been possible to bet- For instance, it is well recognised that
ter characterise cellular and molecular IL-1β plays a crucial role in joint in-
processes involved in the dysregula- flammation and tissue damage in RA,
tion of innate and acquired immune re- and several polymorphisms of its gene
sponses with the identification of new have been widely investigated. Among
pathways useful for the development of these, three single nucleotide polymor-
new therapeutic approaches in RA. In phisms, rs2853550, rs1143643, and
this review article we summarised the rs16944, have been recently associated
results of a Medline search of original with RA susceptibility in a Chinese Han
research articles in English published population (7).
in the PubMed database from January In parallel to IL-1β, the TGF-β1
1 to December 31, 2020. +869C/T gene polymorphism was re-
ported to increase susceptibility to RA
Genetic aspects with significant association with in-
To date, several genome-wide associa- flammatory parameters, such as eryth-
tion studies (GWAS) and meta-analyses rocyte sedimentation rate (ESR), C-
identified more than 100 alleles associ- reactive protein (CRP), and with the
ated with RA susceptibility. Recently, disease activity (8). Interestingly, eval-
it has been reported that SLAMF6, uation of the innate gene expression
Competing interests: none declared. CXCL13, SWAP70, NFKBIA, ZF- signature, including 10 Toll-like recep-
Clinical and Experimental Rheumatology 2021 445One year in review 2021: pathogenesis of RA / D. Testa et al. tors (TLRs), 7 IL1/IL1R family mem- phate. In this regard, Zhang TP et al. lncRNA may also exert their biological bers and the chemokine CXCL8/IL8 in demonstrated that gene polymorphisms function by sponging target miRNA. the peripheral blood mononuclear cells of NCF4 rs4821544 and rs729749, but For example, the lncRNA PVT1 was (PBMC) from active and inactive RA not of NCF2 and CYBA, contribute to shown to regulate the proliferation patients, revealed a certain heterogenei- RA susceptibility (12). and pro-inflammatory activity of RA ty with an association with up-regulated In parallel to gene polymorphisms, epi- FLS by targeting microRNA-145-5p TLR2, TLR4, TLR6, TLR8 and down- genetic mechanisms, including DNA (17), while the lncRNA Growth Arrest- regulated TLR10 (9). methylation, histone modifications, Specific Transcript 5 (GAS5) is mainly Besides the innate immune system, and small (s) and long (l) non-coding involved in promoting the release of lymphocytes play a fundamental role RNAs (ncRNA) play important roles pro-inflammatory mediators in the RA- in orchestrating the production of au- in mechanisms underlying RA patho- derived synovial tissues (18). toantibodies in the context of the adap- genesis. Among sncRNA, micro-RNAs Furthermore, several genetic polymor- tive immunity. Due to their crucial role (miRNA) are sncRNA molecules with phisms within these lncRNA genes in RA, during the last year increasing lengths of 18–25 nucleotides regulating might also contribute to RA suscepti- attention has been given to novel vari- target messenger RNA (mRNA) and the bility or disease severity. For instance, ants in genes encoding for lymphocyte translation of the corresponding pro- the lncRNA 00305 (LINC00305), a signalling regulating molecules, which teins. Accumulating evidence suggests pro-inflammatory atherosclerosis-asso- may control cell survival and activity. that miRNA exert important effects on ciated lncRNA, and its rs2850711 ge- For example, cytotoxic T-lymphocyte some mechanisms regulating RA patho- netic variant, seems to contribute to the antigen-4 (CTLA4), also known as genesis. For example, miR-150-5p is activity and severity of the disease (19). CD152, is an inhibitory glycoprotein able to promote the growth of RA fibro- The role of various gene polymor- present on the surface of T cells that blast-like synoviocytes (FLS) probably phisms in the pathogenetic mecha- regulates the activation of autoreactive by inhibiting the suppressor of cytokine nisms of RA are under investigation, T cells. The CTLA4 gene polymor- signalling 1 (SOCS1) molecule (13). particularly in Asian countries. Com- phism rs11571319 was found to be as- On the other hand, a recent analysis of paring the results obtained in the differ- sociated with RA susceptibility in the miRNA and mRNA expression profiles ent populations can contribute to better Pakistani population (10). VAV1, an in RA PBMC, demonstrated that miR- understanding the close interaction be- intracellular signal transduction pro- 99b-5p is a novel post-transcriptional tween gene profiles and inflammatory tein, that plays an important role in de- mediator involved in different cellu- and autoimmune processes in RA. velopment, proliferation and activation lar activities, including T cell growth, of T cells, was widely investigated and activation, and expression of multiple Take home messages patients carrying VAV1 252546133T pro-inflammatory cytokines (IL-2, IL- • GWAS and meta-analyses of GWAS and 252617822G allele presented an 6, TNF-α and IFN-γ) (14). identify multiple novel susceptibil- increased frequency of extra-articular However, some miRNAs may also play ity loci in RA. manifestations (11). a protective role in RA by inhibiting • HLA-DRB1 alleles may play a pro- Furthermore, several variants may con- pro-inflammatory mediators. For in- tective role in RA. tribute to disease susceptibility by regu- stance, miRNA-17-5p is able to reduce • Variants of genes encoding for cyto- lating molecules involved in oxidative inflammation and bone erosions in kines and lymphocyte signalling stress or bone homeostasis. In fact, collagen-induced arthritis (CIA) mice regulating molecules may contrib- increased oxidative stress and aberrant model, by inhibiting the IL-6 family ute to disease susceptibility and/or generation of reactive oxygen species autocrine-amplifying loop via JAK1 severity. (ROS) may occur in RA pathogenesis. and STAT3 pathways (15). • lnc-AL928768.3 and lnc-AC091493.1 In particular, the NADPH-oxidase As far as lncRNA are concerned, these may be novel biomarkers for RA sus- (NOX) complex is critical for ROS are a heterogeneous class of molecules ceptibility and activity. generation and several studies suggest- defined by a lack of protein-coding ed that NOX gene variations could af- potential and a minimum transcribed Environmental factors fect the risk of developing autoimmune length of 200 nucleotides. LncRNA It is now well established that RA is diseases by orchestrating ROS produc- are able to interact with RNA, DNA the result of a close interaction between tion. NOX complex is composed of and proteins to regulate gene expres- susceptibility genes and environmental gp91phox, p22phox, IM7phox, p67ph- sion at multiple levels, thus critically factors, including cigarette smoking ox, and p40phox encoded by CYBB, orchestrating immune cells differentia- (CS), air pollutants, diet, obesity, mi- CYBA, NCF1, NCF2, and NCF4 genes. tion and activation. Notably, a recent crobiota and infections. CS is involved Among these, NCF4 has been proven to analysis of lncRNA expression profiles in autoimmunity processes due to its regulate the production of intracellular demonstrated a potential role of lnc- ability to promote the production of ROS by inducing the NOX complex AL928768.3 and lnc-AC091493.1 as rheumatoid factor (RF) and anti-cit- to phagosome membranes through the novel biomarkers for RA susceptibil- rullinated peptide antibodies (ACPA), binding of phosphatidylinositol 3-phos- ity and disease activity (16). However, which are linked to joint destruction 446 Clinical and Experimental Rheumatology 2021
One year in review 2021: pathogenesis of RA / D. Testa et al. and systemic bone loss in RA, even in the development and activity of RA, improve intestinal barrier function, and the early phases of the disease (2, 3). mainly based on case-control studies. larazotide acetate, a zonulin antagonist, Recently, Regueiro et al. confirmed Recently, a meta-analysis, including 13 was able to attenuate arthritis. In fact, that in RA patients CS is the strong- cohort studies, investigating the link high levels of Zonula occludens toxin est risk factor for triple-seropositivity between adiposity and RA, proved a (zonulin), a microbial protein which to RF, ACPA and anti-carbamylated correlation between body mass index disrupts epithelial tight junctions, have protein antibodies, and it is exclusively (BMI) and the risk to develop the dis- been recently liked to disease progres- associated with the presence of RF in ease. In this meta-analysis the asso- sion from preclinical to clinical stage of patients with positivity to one or two ciation was more significant in women RA in both human and animal models, autoantibodies (20). Besides CS, ex- than men, probably due to the lack of and treatment with a zonulin agonist posure to air pollutants appears to af- available accurate indicators of male peptide in CIA mice has been shown to fect some of the mechanisms involved adiposity. According to these results, worsen joint inflammation (29). There- in RA pathogenesis. In fact, a recent it can be assumed that adiposity may fore, these results highlight the funda- cross-sectional study demonstrated be target for primary prevention in RA mental role of the intestinal epithelial that exposure to fine particulate matter (25). barrier in protection from systemic in- (PM 2.5) is an independent predictor of In this context, the role of microbiome flammatory processes and partially ex- ACPA titres (21). This result has been has been extensively investigated. A re- plain how certain dietary components confirmed by a meta-analysis that was cent comprehensive metagenome-wide can improve microbiota homeostasis also able to recognise ozone exposure association study (MWAS), conducted with beneficial effects on RA. and living in proximity to high-traffic in Japan, demonstrated more bacteria roads as risk factors for developing belonging to the genus Prevotella in the Take home messages RA (22). Furthermore, it appears that a stool samples of RA patients compared • Smoking is a risk factor for triple- pro-inflammatory diet may worsen the to healthy subjects. On the other hand, seropositive RA. activity of the disease. This hypothesis R6FCZ7, a bacterial gene involved in • PM 2.5 and ozone exposure and liv- has been supported by a recent ran- redox reactions and possessed by many ing near busy roads are risk factors domised, controlled cross-over trial, species within the genus Bacterioides, for RA. showing beneficial effects of an anti- was underrepresented in RA samples • An anti-inflammatory diet and pro- inflammatory dietary on clinical out- compared with controls (26). These biotics supplementation may reduce comes of RA. Such intervention was results strongly support the role of mi- disease activity. able to induce an improvement of the crobiome and microbiota in the mecha- • Overweight and obesity have been disease, in terms of Disease Activity nisms underlying RA pathogenesis. In proven to be associated with RA, Score 28-joint count indices (DAS28) addition, novel therapeutic approaches particularly in women, by a meta- calculated with ESR. Furthermore, the can be introduced in clinical settings, analyses of cohort studies. patients with the higher activity score such as pregnancy or lactation, where achieved the greater disease improve- pharmacological treatments encounter Innate immune response ment following this anti-inflammatory limitations (27). It has been proven that Cells and soluble mediators of the in- diet. However, some relevant informa- a high-fat diet can promote the devel- nate immune system play a key role in tion such as the ongoing pharmaco- opment of a pro-inflammatory gut mi- the pathogenesis of RA and all these logical therapy of the patients, useful crobiota, that microbial-derived short- singular components were deeply in- for a better interpretation of the results chain fatty acids (SCFAs) are reduced vestigated during this last year. obtained, was not included in the study in RA patients and in animal models of It is well known that neutrophils are the (23). Moreover, two independent meta- arthritis, and that in the CIA model bu- most abundant immune cells in RA in- analyses, systematically reviewing all tyrate supplementation was able to im- flamed joints and their ability to form randomised clinical trials (RCTs) on prove the disease activity. It has been neutrophil extracellular traps (NETs) the effects of anti-inflammatory dietary hypothesised that this was due to the actively contributes to RA pathogen- and RA, confirmed a moderate benefi- ability of SCFAs to activate regulatory esis, via autoantigen production and ac- cial effect of certain foods on disease B cells (Bregs), inducing IL-10 release tivation of FLS. Recently, NET produc- activity, although further studies are with consequent inhibition of germinal tion has been linked to cartilage dam- needed for better clarifying the direct centre B cell and plasmablast differ- age in RA. In particular, NET-derived contribution of nutrients to the devel- entiation and a probable effect on au- elastase seems to be able to disrupt car- opment and severity of RA, taking in toantibodies production (28). It is well tilage matrix, leading to citrullination of account the timing of dietary interven- known that dysregulation of gut micro- cartilage components, with subsequent tion, the ongoing therapy and the phase biota may affect the whole organism internalisation by FLS and presenta- of the disease (24). Overall, dietary and may lead to RA development in pa- tion to CD4+ T cells. In fact, transgenic habits seem to be relevant in the man- tients showing preclinical evidence of mice immunised with NETs developed agement of RA patients. In fact, over- autoimmunity. Furthermore, diet sup- autoantibodies against citrullinated car- weight and obesity have been linked to plementation with butyrate, known to tilage fragments and inhibition of NET- Clinical and Experimental Rheumatology 2021 447
One year in review 2021: pathogenesis of RA / D. Testa et al. derived elastase proved to rescue NET- of cytokines and chemokines such as of RA was associated with increased mediated cartilage damage (30). IL-6 and IL-8, as well as the metal- risk of disease flare, suggesting that Besides NETs, extracellular vesicles loproteinases MMP-1 and MMP-13 modulation of these two macrophages (EVs), derived from different cell (37). Moreover, CXCL1/CXCR2 axis subsets could be a potential therapeutic types, seem to promote inflammation (chemokine-ligand 1 and its receptor) strategy in RA (43). Given the key role in RA joints by stimulating the release activation may induce IL-6 production of macrophages in joint inflammation, of pro-inflammatory cytokines. EVs in FLS derived from both RA and os- modulation of certain apoptotic pro- were isolated from the synovial fluid teoarthritis (38) and the alarmin IL-33 cesses has been proposed as alternative and characterised by proteomic analy- is able to modulate some mechanisms therapeutic approach. In particular, the sis but these results were in contrast regulating proliferation and apoptosis pro-apoptotic BCL-2 family protein with previous data. In fact, while ear- in RA-derived FLS via NF-κB path- BAD has been suggested as potential lier studies pointed at B cells and plate- way (39). The central role of FLS in pharmacological target in RA, given lets as the main EVs-releasing cells, RA pathogenesis is also supported by that its inactivation confers the apop- new evidence identified neutrophils recent findings showing that these cells tosis resistance on synovial sub-lining and FLS as major sources of EVs (31). are source of local production of CRP. macrophages, thereby contributing to In addition, the co-culture of CD14+ It is well-known that synovial fluid the development of arthritis (44). cells with small EVs containing miR- from RA patients contains high levels Monocytes have also been investigat- 574-5p purified from RA synovial of CRP, mainly derived from FLS. At ed in order to better characterise their fluid , demonstrated the ability of EVs the same time, FLS have been recog- phenotype in different mechanisms to promote osteoclast differentiation, nised as the major cell-type expressing underlying RA pathogenesis. Mono- mainly via TLR 7/8 signalling (32). CD32 and CD64, receptors for CRP, cytes are the main PB cells that can Activated FLS contribute to the for- involved in FLS proliferation, invasion differentiate in macrophages or den- mation of synovial pannus and bone and production of CCL2, CXCL8, IL- dritic cells. Monocyte subpopulations destruction and it has been recently 6, MMP-2 and MMP-9 (40). can be divided, based on the different observed that FLS-derived adiponectin In addition to FLS, several studies dem- expression of CD14 and CD16, into (AD), already known as a promoter of onstrated the pivotal role of macrophag- classical (CD14++CD16-), intermedi- inflammation in RA, is able to induce es in joint inflammation and bone ero- ate (CD14++CD16+/++) and nonclas- in-vitro and in-vivo T-follicular helper sion. Synovial macrophages (SM) are sical (CD14-/+CD16++) monocytes. cell (Tfh) activity via the release of a type of tissue macrophages deriving Recently, differences in monocytes soluble IL-6 (33). from bone marrow cells orchestrating subpopulations with a shift towards In parallel, certain intracellular path- joint inflammation and tissue remod- nonclassical subset have been detected ways of FLS were identified as respon- eling. Immunofluorescent comparison in individuals at high risk of develop- sible of their aggressive phenotype in of synovial tissue from CIA and control ing RA, especially in ACPA+ subjects, RA. Particularly, WNTS5A, a mem- mice proved that a tight crosstalk be- priming the progression from early ber of the secreted glycoproteins fam- tween SM and FLS takes place in RA. phase to the active disease (45). ily Wingless/integrase 1, up-regulated Under inflammatory conditions, the Further studies aimed to characterise in RA-derived FLS and involved in tight interaction between these two cell inflammatory and structural cells of cytoskeleton remodelling, seems to types in murine arthritis leads to meta- the innate immune system will allow to strongly enhance migration and in- bolic reprogramming of SM with con- better understand the mechanisms un- vasion of RA FLS, but not of those sequent increase of their cell viability. derlying RA pathogenesis. isolated by patients with other types Several soluble mediators, such as IL- of arthritis (34). In parallel, c-Jun N- 26 (41), and receptors, such as Angio- Take home messages terminal kinase (JNK) was identified tensin II Type 2 receptor (AT2R) (42), • NETs actively contribute to RA as one of the downstream molecules are able to modulate SM polarisation in pathogenesis, via autoantigens pro- mediating the sonic hedgehog (SHH) RA-derived synovia, contributing to the duction and activation of FLS. signaling pathway in patients with RA amplification and perpetuation of tissue • EVs, produced mainly by neutro- (35), and IL-34 has been proven as inflammation. phils and FLS in RA, promote in- one of a key soluble mediator in con- Furthermore, different SM subsets, par- flammation and osteoclast differen- trolling migration and proliferation of ticularly MerTKposTREM2high and tiation. RA-derived FLS via ERK1/2 and AKT MerTKposLYVE1pos, seems to regu- • Intracellular pathways such as signalling pathways (36). Furthermore, late inflammatory processes in the ac- WNTS5A, JNK, ERK1/2, AKT and studies performed in humans and ani- tive as well as in the remission phase of DELR3 actively regulate FLS activ- mal models demonstrated that DELR3, the disease. In-vitro, these two SM types ities in inflammatory and remodel- an endoplasmic reticulum-associated producing inflammation-resolving lipid ling processes. degradation protein, expressed in RA- mediators are responsible for repair re- • Synovial macrophages (SM) interact derived FLS, is involved in inflamma- sponse of FLS, and low proportion of with FLS through IL-26 and AT2R, tory processes by increased production MerTKpos SMs in the remission phase perpetuating tissue inflammation. 448 Clinical and Experimental Rheumatology 2021
One year in review 2021: pathogenesis of RA / D. Testa et al. Adaptive immune response able to independently produce RF over after the adoptive transfer of WT (wild- As far as B cells are concerned, Riv- time (50). type) mouse Treg and an hypermeth- ellese et al. observed that B cell rich A peculiar B cell subset, CD19+ ylation of Foxp3 gene in comparison of synovitis is associated with high levels CD24hiCD38hi regulatory B cells (cTr WT mice was detected in experimental of disease activity and seropositivity for B cells), was found to be increased in models of TNFRII deletion (homozy- RF and ACPA, particularly in early RA naïve early RA (51). cTr B cells display gous mice TNFRII-/-) (55). and in patients with treatment-resistant anti-inflammatory properties, such as The involvement in RA pathogenesis disease (46). When comparing B cells the production of IL-10, and are associ- of phospholipase (PL) D1, a molecule from the synovial tissue with those ated with ACPA titres and the response responsible for Treg cells immuno- from the PB, the latter showed a more to methotrexate at 1 year. Another suppressive action, was observed in pronounced complexity in their clonal IL-10 producing B cell subset charac- CIA model. PLD1 inhibition leads families, supporting the hypothesis that terised by the co-expression of CD27 to suppression of autoantibodies and the small subset of clonal families pre- and high levels of CD24, are reduced inflammatory cytokines production, sent in the synovial tissue and the an- as a consequence of disease activity. In ultimately determining a reciprocal tibodies produced here, mainly ACPA, fact, pro-inflammatory cytokines like regulation of Th17/Treg balance. The may have a role in RA pathogenesis due TNF-α and IL-1β cause the overexpres- Th17/Treg cell ratio was decreased in to both the persistent peripheral antigen sion of the CD70 on both CD4+T cells RA, especially in early, active and se- stimulation in this site and the capabili- and CD8+B cells, causing the CD27/ vere disease (56). PLD1 inhibition de- ty to indirectly stimulate the production CD70 interaction and the increase of termined an increase of Treg cells with of TNF-α (47). the soluble form of CD27 (52). enhanced anti-inflammatory effect, and In addition, Kissel et al. demonstrated As far as T lymphocytes are con- reduction of Th17 effector cells, lead- that ACPA have a broad cross-reactiv- cerned, a relationship between signal- ing to a decrease of the inflammatory ity towards several post-translationally ing lymphocytic activation molecule, state. PLD1 effect on the Th17/Treg modified antigens, not only citrulli- SLAM associated protein (SAP) and balance also affects osteoclastogenesis nated, but also carbamylated and/or programmed cell death (PD)-1 was ob- and bone resorption. Furthermore, Treg acetylated antigens that can be present served. SAP is an adaptor molecule im- cells were found to be negatively corre- in the inflammatory sites and could portant in T cells signalling and in the lated with signs of high disease activity be involved in the autoimmune pro- contest of self-tolerance, while PD-1 like DAS28, but also white blood cells cesses. These findings shed some light is a receptor that has a role in the pre- count, percentage of neutrophils, plate- on B cells tolerance (48) and the pro- vention of autoimmunity. RA T cells let count, while Th17 cells were in- duction of these autoantibodies was display higher levels of SAP and since creased in the same disease stage (57). explained by the classical theory of it renders the PD-1 ineffective, this ul- With regard to the imbalance of Treg “shared epitope”. However, Auger et timately prevents the PD-1 mediated and other T cell subsets, Cao et al. al. put forward a new hypothesis and T-cell exhaustion. Despite its function investigated the role of an imbalance speculated that peptidyl arginine deimi- is hampered, PD-1 expression is in- between a subpopulation of Treg cells, nase (PAD)4-specific T cells may help creased in RA synovial fluid and PB follicular regulatory T cells (Tfreg), PAD4-specific B cells leading to the T cells with a positive correlation with found in germinal centres, and Tfh that production of anti-PAD4 antibodies and disease activity (53). resulted in the expansion of autoreac- ACPA. This is explained by the hapten- CD4+Foxp3+regulatory T cells (Treg) tive B cells and autoantibody produc- carrier mechanism, where PAD4 acts absolute number, percentage and acti- tion. The Tfreg/Tfh ratio is decreased as carrier and haptens are the proteins vation are reduced in the PB of early in RA patients and it is negatively cor- bound and citrullinated by PAD. More- untreated RA patients in comparison related with ESR, CRP, RF, IL-21 and over, it has been demonstrated that the to healthy controls a negative correla- disease activity while being positively peptide of PAD4 that triggers T cells tion between the percentage of these correlated with TGF-β, produced by proliferation in 40% of the RA patients, cells and the disease activity, the ESR, Tfreg. In normal subjects, TGF-β can peptide 8, is associated with PAD4- the CRP and the RF (IgM) levels has inhibit the function of Tfh cells, pre- antibodies, HLA-DRB1 shared epitope also been described. The importance of venting their germinal centre response and RA, giving a chance to prevention Treg cells is further underlined by the and antibodies production (58). in these high-risk individuals (49). observation that a specific Treg subset Developmental plasticity of T cell sub- B cells are involved also in the produc- expressing TNF receptor (TNFRII) and sets is a pivotal phenomenon in the field tion of RF, and a longitudinal study associated with a Foxp3 TSDR (fork- of autoimmunity. As far as RA is con- across 5 years demonstrated that in the head box P3 Treg specific demethyla- cerned, Leipe et al. detected that Th1/ first stage of RA T helper cells are re- tion region) hypomethylation, the latter Th2 subsets can differentiate in Th17 quired for IgG RF production, while determining Treg cells stability, is in- cells in early RA, while Th17 cells do after 5 years there is a dissociation be- creased after treatment with methotrex- not change their phenotype towards tween T cell reactivity and RF status, ate (54). In addition, an exacerbation Th1/Th2 cells (59). Furthermore, when suggesting that B cells may become of inflammatory state that ameliorates assessing classic (CD161-/CCR6-) and Clinical and Experimental Rheumatology 2021 449
One year in review 2021: pathogenesis of RA / D. Testa et al.
Table I. Studies on gene susceptibility. number, and particularly that of the ar-
thritogenic clones specific for a citrulli-
Genetic features Associations or roles References
nated vimentin epitope, is significantly
SLAMF6 Susceptibility (4) increased in RA patients while being
CXCL13 Susceptibility (4) reduced by treatment with anti-TNF
SWAP70 Susceptibility (4) agents (65).
NFKBIA Susceptibility (4)
ZFP36L1 Susceptibility (4) CCL21, a chemokine that binds to
LINC00158 Susceptibility (4) CCR7, is abundantly present in RA
IL12RB2 Susceptibility (5) synovial tissue being expressed by
BOLL-PLCL1 Susceptibility (5) dendritic cells, macrophages and en-
CCR2 Susceptibility (5)
TCF7 Susceptibility (5) dothelial cells. CCR7+ cells are there-
IQGAP1 Susceptibility (5) fore recruited to the synovial microen-
HLA-DRB1*04 Susceptibility (6) vironment modulating, among other
HLA-DRB1*08 Protective role (6) tasks, the immune response. In the ear-
IL1B (rs2853550) Susceptibility (7)
IL1B (rs1143643) Susceptibility (7) ly phase of RA, the presence of CCL21
IL1B (rs16944) Susceptibility (7) in the synovial fluid induces the forma-
TGF-β1 +869C/T polymorphism Susceptibility (8) tion of an inflammatory infiltrate main-
CTLA4 (rs11571319) Susceptibility (10) ly constituted by CCR7+ monocytes
VAV1 (rs2617822) Susceptibility (11)
NCF4 (rs4821544) Susceptibility (12) that, as RA progresses, are committed
miR-150-5p Pro-inflammatory role (13) towards an M1 phenotype (classically
miR-99b-5p Pro-inflammatory role (14) activated macrophages), able to pro-
miRNA-17-5p Protective role (15) duce IL-6 and IL-23. Such mediators
lnc-AL928768.3 Susceptibility and disease activity (16)
lnc-AC091493.1 Susceptibility and disease activity (16) ultimately promote the differentiation
lncRNA PVT1 Pro-inflammatory role (17) of Th17 cells that are strongly involved
lncRNA GAS5 Pro-inflammatory role (18) in RA pathogenesis. A positive feed-
LINC00305 (rs2850711) Severity and disease activity (19) back mechanism has also been iden-
tified in this scenario since IL-17 can
non-classic (CD161+/CCR6+) Th1 cell (sEPCR) forms, the former being ex- further promote the function of the
subtypes, they observed that CCR6+ pressed by CD4+ T cells. Lower levels CCL21/CCR7 axis. In the erosive, fi-
cells display an increased plasticity of CD4+EPCR+Tcells and higher levels nal stages, these cytokines and CCL21
towards IL17 producing cells, while of sEPCR have been observed in RA directly and indirectly participate in
CCR6- seemed to show higher plastic- compared to osteoarthritis and sEPCR osteoclastogenesis and bone resorption
ity towards IL-4 producing cells (60). showed a positive correlation with clin- (66).
This finding is of particular importance ical and laboratory parameters of RA Another study reported that hypoxic
also in light of the demonstration that (63). In-vitro experiments demonstrat- conditions in RA synovial tissue led
Th1 and Th17 cells not only are in- ed that sEPCR inhibited Th17 activa- to reduced indoleamine 2,3-dioxyge-
creased in RA compared to normal sub- tion, modifying the Th17/Treg balance nase-1 expression, namely tryptophan
jects but that among patients, increased alleviating disease progression. Hence, metabolism, thereby interfering with
frequencies were found in carriers of higher levels of sEPCR in RA may ex- the interaction between FLS and T cells
HLA-DRB1 genotypes that have a plain a compensatory, albeit not suffi- (67). In particular, while normally FLS
shared epitope (HLA-SE), the strongest cient, compensatory mechanism lead- act as immunomodulators, suppressing
genetic risk factor for RA, involved in ing to limit disease progression (51). T cell responses, hypoxia may repre-
ACPA production but also in the induc- RA patients also displayed an increase sent a pathogenic mechanism prevent-
tion of innate and adaptive response, of the γδTcells, a small T cell sub- ing such interaction. In addition, a re-
through IL-17a and IFN-γ producing set that has a role in RA pathogenesis lationship between anaerobic metabo-
CD4+T cells (61). through release of pro-inflammatory cy- lism, through glycolysis, as it happens
Other studies have also assessed the tokines such as IL-17 and the support of in hypoxic microenvironment like the
mechanism of Th17 regulation in RA antibody production by B cells. These synovial membrane and the inflamma-
showing that the expression of USF2, effects seem to be mediated by prosta- tory features of CD8+ T cells has been
a transcription factor fundamental glandin (PG) E2 since the addition of reported (68). In fact, the inhibition of
in maintaining inflammatory Th17 this molecule leads to an increased ex- glycolysis leads to a of the proinflam-
cells, is increased in RA patients non- pression of CD80 and CD86 on γδTcells matory CD8+ T cell phenotype in RA.
responders to treatment (62). Fur- and, consequently, of secreted IL-17 Furthermore, CD4+ T cells directly
thermore, Bai et al. have assessed the in-vitro (64). Another subset of CD4+ impact the metabolic profile of RA-
role of an endothelial receptor EPCR T cells, the CD45RA+CD62L+CD95+ derived FLS, promoting a glycolytic
(endothelial protein C receptor) in its memory stem T cells (Tscm), may play phenotype to meet increased metabolic
membranous (mEPCR) and soluble a role in RA pathogenesis since their demand in a reciprocal activating re-
450 Clinical and Experimental Rheumatology 2021One year in review 2021: pathogenesis of RA / D. Testa et al.
lationship (69). Taken together, these tion identifies six novel susceptibility loci for 19. WAHBA AS, IBRAHIM ME, MESBAH NM,
rheumatoid arthritis. Ann Rheum Dis 2020; SALEH SM, ABO-ELMATTY DM, MEHANNA
findings suggest glycolytic manipula-
79: 1438-45. ET: Serum LINC00305 expression and its
tion as possible new therapeutic strat- 5. LENG RX, DI DS, NI J et al.: Identification of genetic variant rs2850711 are associated
egy in RA. new susceptibility loci associated with rheu- with clinical and laboratory features of rheu-
matoid arthritis. Ann Rheum Dis 2020; 79: matoid arthritis. Br J Biomed Sci 2020; 77:
1565-71. 142-7.
Take home messages 6. SEPÚLVEDA-DELGADO J, RIZO-PINTO A, 20. REGUEIRO C, RODRIGUEZ-RODRIGUEZ L,
• B cell rich synovitis is associated GRANADOS-ARRIOLA J et al.: Role of HLA- LOPEZ-MEJIAS R et al.: A predominant in-
with high levels of disease activity DRB1*04 in the susceptibility and HLA- volvement of the triple seropositive patients
and seropositivity for RF and ACPA. DRB1*08 in the protection for development and others with rheumatoid factor in the as-
of rheumatoid arthritis in a population of sociation of smoking with rheumatoid arthri-
• peptidyl arginine deiminase (PAD)4- Southern Mexico: brief report. Clin Rheuma- tis. Sci Rep 2020; 10: 3355.
specific T cells may help PAD4-spe- tol 2020; 39: 2875-9. 21. ALEX AM, KUNKEL G, SAYLES H, FLAUTERO
cific B cells leading to the production 7. RONG H, HE X, WANG L et al.: Association ARCOS JD, MIKULS TR, KERR GS: Exposure
of anti-PAD4 antibodies and ACPA. between IL1B polymorphisms and the risk of to ambient air pollution and autoantibody
rheumatoid arthritis. Int Immunopharmacol status in rheumatoid arthritis. Clin Rheuma-
• Tfreg/Tfh ratio is decreased in RA 2020; 83: 106401. tol 2020; 39: 761-8.
patients and it is negatively corre- 8. PATEL SL, PRAKASH J, GUPTA V: TGF-β1 22. DI D, ZHANG L, WU X, LENG R: Long-term
lated with ESR, CRP, RF, IL-21 and +869C/T polymorphism increases suscepti- exposure to outdoor air pollution and the risk
disease activity while being positive- bility to rheumatoid arthritis in North Indian of development of rheumatoid arthritis: a
population. Clin Rheumatol 2020; 39: 2881- systematic review and meta-analysis. Semin
ly correlated with TGF-β, produced 8. Arthritis Rheum 2020; 50: 266-75.
by Tfreg. 9. PETRACKOVA A, HORAK P, RADVANSKY M 23. VADELL AKE, BÄREBRING L, HULANDER E,
• CCR6+ cells display an increased et al.: Revealed heterogeneity in rheumatoid GJERTSSON I, LINDQVIST HM, WINKVIST A:
arthritis based on multivariate innate signa- Anti-inflammatory Diet In Rheumatoid Ar-
plasticity towards IL17 producing
ture analysis. Clin Exp Rheumatol 2020; 38: thritis (ADIRA) – a randomized, controlled
cells, while CCR6- seemed to show 289-98. crossover trial indicating effects on disease
higher plasticity towards IL-4 pro- 10. ASLAM MM, JALIL F, JOHN P et al.: activity. Am J Clin Nutr 2020; 111: 1203-13.
ducing cells. A sequencing study of CTLA4 in Pakistani 24. GENEL F, KALE M, PAVLOVIC N, FLOOD VM,
rheumatoid arthritis cases. PLoS One 2020; NAYLOR JM, ADIE S: Health effects of a low-
15: e0239426. inflammatory diet in adults with arthritis: a
Conclusions 11. PAWLIK A, MALINOWSKI D, PARADOWSKA- systematic review and meta-analysis. J Nutr
In the last year several studies have GORYCKA A, SAFRANOW K, DZIEDZIEJKO Sci 2020: 11.
been published in order to better under- V: VAV1 gene polymorphisms in patients 25. OHNO T, AUNE D, HEATH AK: Adiposity and
with rheumatoid arthritis. Int J Environ Res the risk of rheumatoid arthritis: a systematic
stand the pathogenic mechanisms un- Public Health 2020; 17: 3214. review and meta-analysis of cohort studies.
derlying RA. In particular, studies on 12. ZHANG T-P, LI R, HUANG Q, PAN H-F, YE D-Q, Sci Rep 2020; 10: 16006.
gene susceptibility (Table I), epigenet- LI X-M: Association of NCF2, NCF4, and 26. KISHIKAWA T, MAEDA Y, NII T et al.: Meta-
ic mechanisms and different environ- CYBA gene polymorphisms with rheuma- genome-wide association study of gut micro-
toid arthritis in a Chinese population. J Im- biome revealed novel aetiology of rheuma-
mental factors allowed us to recognise munol Res 2020; 2020: 8528976. toid arthritis in the Japanese population. Ann
additional mechanisms underlying the 13. QIU M, MO L, LI J et al.: Effects of miR-150- Rheum Dis 2020; 79: 103-11.
disease, useful for building new thera- 5p on the growth and SOCS1 expression 27. YAO Y, CAI X, FEI W et al.: Regulating gut
peutical strategies. In parallel, interest- of rheumatoid arthritis synovial fibroblasts. microbiome: therapeutic strategy for rheu-
Clin Rheumatol 2020; 39: 909-17. matoid arthritis during pregnancy and lacta-
ing and promising results for future 14. ZHU X, WU L, MO X et al.: Identification of tion. Front Pharmacol 2020; 11: 594042.
development of therapeutic approaches PBMC-expressed miRNAs for rheumatoid 28. ROSSER EC, PIPER CJM, MATEI DE et al.:
have been reported in the context of the arthritis. Epigenetics 2020; 15: 386-97. Microbiota-derived metabolites suppress
15. NAJM A, MASSON FM, PREUSS P et al.: arthritis by amplifying aryl-hydrocarbon re-
innate and adaptive immune systems
MicroRNA-17-5p reduces inflammation and ceptor activation in regulatory B cells. Cell
with particular attention to novel path- bone erosions in mice with collagen-induced Metab 2020; 31: 837-851.e10.
ways regulating the activity of FLS, arthritis and directly targets the JAK/STAT 29. TAJIK N, FRECH M, SCHULZ O et al.: Target-
different phenotypes of monocytes and pathway in rheumatoid arthritis fibroblast- ing zonulin and intestinal epithelial barrier
like synoviocytes. Arthritis Rheumatol 2020; function to prevent onset of arthritis. Nat
macrophages and different subsets of B 72: 2030-9. Commun 2020; 11: 1995.
and T lymphocytes. 16. DING J, SHI C, BOWES J, EYRE S, OROZCO G: 30. CARMONA-RIVERA C, CARLUCCI PM, GOEL
Exploring the overlap between rheumatoid RR et al.: Neutrophil extracellular traps
References arthritis susceptibility loci and long non-cod- mediate articular cartilage damage and en-
1. McINNES IB, SCHETT G: The pathogenesis ing RNA annotations. PLoS One 2020; 15: hance cartilage component immunogenicity
of rheumatoid arthritis. N Engl J Med 2011; e0223939. in rheumatoid arthritis. JCI Insight 2020; 5:
365: 2205-19. 17. TANG J, YI S, LIU Y: Long non-coding RNA e139388.
2. CROIA C, BURSI R, SUTERA D, PETRELLI F, PVT1 can regulate the proliferation and in- 31. FOERS AD, DAGLEY LF, CHATFIELD S et al.:
ALUNNO A, PUXEDDU I: One year in review flammatory responses of rheumatoid arthritis Proteomic analysis of extracellular vesicles
2019: pathogenesis of rheumatoid arthritis. fibroblast-like synoviocytes by targeting mi- reveals an immunogenic cargo in rheumatoid
Clin Exp Rheumatol 2019; 37: 347-57. croRNA-145-5p. Hum Cell 2020; 33: 1081- arthritis synovial fluid. Clin Transl Immunol
3. GIANNINI D, ANTONUCCI M, PETRELLI F, 90. 2020; 9: e1185.
BILIA S, ALUNNO A, PUXEDDU I: One year in 18. LI M, WANG N, SHEN Z, YAN J: Long non- 32. HEGEWALD AB, BREITWIESER K, OTTINGER
review 2020: pathogenesis of rheumatoid ar- coding RNA growth arrest-specific transcript SM et al.: Extracellular miR-574-5p Induces
thritis. Clin Exp Rheumatol 2020; 38: 387-97. 5 regulates rheumatoid arthritis by targeting Osteoclast Differentiation via TLR 7/8 in
4. KWON Y-C, LIM J, BANG S-Y et al.: Genome- homeodomain-interacting protein kinase 2. rheumatoid arthritis. Front Immunol 2020;
wide association study in a Korean popula- Clin Exp Rheumatol 2020; 38: 1145-54. 11: 585282.
Clinical and Experimental Rheumatology 2021 451One year in review 2021: pathogenesis of RA / D. Testa et al.
33. LIU R, ZHAO P, ZHANG Q et al.: Adiponectin rheumatoid arthritis: relationship to disease between blood CD4+CXCR5+Foxp3+ Tfr
promotes fibroblast-like synoviocytes pro- stages and drug exposure. Arthritis Rheuma- cells and CD4+CXCR5+Tfh cells may con-
ducing IL-6 to enhance T follicular helper tol 2020; 72: 714-25. tribute to the immunopathogenesis of rheu-
cells response in rheumatoid arthritis. Clin 47. ELLIOTT SE, KONGPACHITH S, LINGAM- matoid arthritis. Mol Immunol 2020; 125:
Exp Rheumatol 2020; 38: 11-8. PALLI N et al.: B cells in rheumatoid arthri- 1-8.
34. RODRIGUEZ-TRILLO A, MOSQUERA N, PENA tis synovial tissues encode focused antibody 59. LEIPE J, PIRRONELLO F, SCHULZE-KOOPS
C et al.: Non-canonical WNT5A signaling repertoires that include antibodies that stimu- H, SKAPENKO A: Altered T cell plasticity fa-
through RYK contributes to aggressive phe- late macrophage TNF-α production. Clin Im- vours Th17 cells in early arthritis. Rheuma-
notype of the rheumatoid fibroblast-like syn- munol 2020; 212: 108360. tology 2020; 59: 2754-63.
oviocytes. Front Immunol 2020; 11: 555245. 48. KISSEL T, REIJM S, SLOT LM et al.: Antibod- 60. LEIPE J, PIRRONELLO F, KLOSE A, SCHULZE-
35. ZHU S, YE Y, SHI Y et al.: Sonic hedgehog ies and B cells recognising citrullinated pro- KOOPS H, SKAPENKO A: Increased plasticity
regulates proliferation, migration and inva- teins display a broad cross-reactivity towards of non-classic Th1 cells toward the Th17
sion of synoviocytes in rheumatoid arthritis other post-translational modifications. Ann phenotype. Mod Rheumatol 2020; 30: 930-6.
via JNK signaling. Front Immunol 2020; 11: Rheum Dis 2020; 79: 472-80. 61. ALVANDPUR N, TABATABAEI R, TAHAM-
1300. 49. AUGER I, BALANDRAUD N, MASSY E et OLI-ROUDSARI A et al.: Circulating IFN-γ
36. ELKHIDER A, WEI J, AL-AZAB M et al.: IL-34 al.: Peptidylarginine deiminase autoimmun- producing CD4+ T cells and IL-17A produc-
modulates rheumatoid synovial fibroblasts ity and the development of anti-citrullinated ing CD4+ T cells, HLA-shared epitope and
proliferation and migration via ERK/AKT protein antibody in rheumatoid arthritis: the ACPA may characterize the clinical response
signalling pathway. Clin Exp Rheumatol Hapten-Carrier model. Arthritis Rheumatol to therapy in rheumatoid arthritis patients.
2020; 38: 479-87. 2020; 72: 903-11. Hum Immunol 2020; 81: 228-36.
37. GENG M, XU K, MENG L et al.: Up-regulated 50. DAVIS JM, CROWSON CS, KNUTSON KL et 62. HU D, TJON EC, ANDERSSON KM et al.:
DERL3 in fibroblast-like synoviocytes exac- al.: Longitudinal relationships between rheu- Aberrant expression of USF2 in refractory
erbates inflammation of rheumatoid arthritis. matoid factor and cytokine expression by rheumatoid arthritis and its regulation of pro-
Clin Immunol 2020; 220: 108579. immunostimulated peripheral blood lympho- inflammatory cytokines in Th17 cells. Proc
38. HOU S-M, CHEN P-C, LIN C-M, FANG M-L, cytes from patients with rheumatoid arthritis: Natl Acad Sci U S A 2020; 117: 30639-48.
CHI M-C, LIU J-F: CXCL1 contributes to IL-6 New insights into B-cell activation. Clin Im- 63. BAI L, LIU W, GUO P et al.: Elevated levels
expression in osteoarthritis and rheumatoid munol 2020; 211: 108342. of soluble Endothelial protein C receptor in
arthritis synovial fibroblasts by CXCR2, c- 51. FORTEA-GORDO P, VILLALBA A, NUÑO L et rheumatoid arthritis and block the therapeu-
Raf, MAPK, and AP-1 pathway. Arthritis al.: Circulating CD19+CD24hiCD38hi regu- tic effect of protein C in collagen-induced
Res Ther 2020; 22: 251. latory B cells as biomarkers of response to arthritis. Int Immunopharmacol 2020; 81:
39. WU S, JIANG Y, TENG Y, LIU X, ZHOU L, LI methotrexate in early rheumatoid arthritis. 106255.
W: Interleukin-33 promotes proliferation and Rheumatology 2020; 59: 3081-91. 64. DU B, ZHU M, LI Y, LI G, XI X: The prostaglan-
inhibits apoptosis of fibroblast-like synovio- 52. SHI L, HU F, ZHU L et al.: CD70-mediated din E2 increases the production of IL-17 and
cytes in rheumatoid arthritis. Clin Exp Rheu- CD27 expression downregulation c-ntrib- the expression of costimulatory molecules
matol 2020; Oct 9 PMID 33124 566 [Online uted to the regulatory B10 cell impairment on γδ T cells in rheumatoid arthritis. Scand J
ahead of print.] in rheumatoid arthritis. Mol Immunol 2020; Immunol 2020; 91: e12872.
40. FANG Z, LV J, WANG J et al.: C-reactive pro- 119: 92–100. 65. CIANCIOTTI BC, RUGGIERO E, CAMPOCHIA-
tein promotes the activation of fibroblast-like 53. SANDIGURSKY S, PHILIPS MR, MOR A: RO C et al.: CD4+ memory stem T cells rec-
synoviocytes from patients with rheumatoid SAP interacts with CD28 to inhibit PD-1 ognizing citrullinated epitopes are expanded
arthritis. Front Immunol 2020; 11: 958. signaling in T lymphocytes. Clin Immunol in patients with rheumatoid arthritis and
41. LIN Y-H, WANG Y-H, PENG Y-J et al.: Inter- 2020; 217: 108485. sensitive to tumor necrosis factor blockade.
leukin 26 skews macrophage polarization 54. AVDEEVA A, RUBTSOV Y, DYIKANOV D, Arthritis Rheumatol 2020; 72: 565-75.
towards M1 phenotype by activating cJUN POPKOVA T, NASONOV E: Regulatory T cells 66. van RAEMDONCK K, UMAR S, PALASIE-
and the NF-κB pathway. Cells 2020; 9: 938. in patients with early untreated rheumatoid WICZ K et al.: CCL21/CCR7 signaling in
42. WANG X, TU J, JIANG J et al.: Angiotensin arthritis: Phenotypic changes in the course macrophages promotes joint inflammation
II type 2 receptor modulates synovial mac- of methotrexate treatment. Biochimie 2020; and Th17-mediated osteoclast formation in
rophage polarization by inhibiting GRK2 174: 9-17. rheumatoid arthritis. Cell Mol Life Sci 2020;
membrane translocation in a rat model of 55. SANTINON F, BATIGNES M, MEBREK ML et 77: 1387-99.
collagen-induced arthritis. J Immunol 2020; al.: Involvement of Tumor Necrosis Factor 67. KAUL N-C, MOHAPATRA SR, ADAM I et al.:
205: 3141-53. Receptor Type II in FoxP3 Stability and as a Hypoxia decreases the T helper cell-sup-
43. ALIVERNINI S, MACDONALD L, ELMES- Marker of Treg Cells Specifically Expanded pressive capacity of synovial fibroblasts by
MARI A et al.: Distinct synovial tissue mac- by Anti–Tumor Necrosis Factor Treatments downregulating IDO1-mediated tryptophan
rophage subsets regulate inflammation and in Rheumatoid Arthritis. Arthritis Rheumatol metabolism. Rheumatology 2020; 59: 1148-
remission in rheumatoid arthritis. Nat Med 2020; 72: 576-87. 58.
2020; 26: 1295-306. 56. YOO HJ, HWANG WC, MIN DS: Targeting of 68. SOUTO-CARNEIRO MM, KLIKA KD, ABREU
44. LI J, ZHANG L, ZHENG Y et al.: BAD inacti- Phospholipase D1 Ameliorates Collagen- MT et al.: Effect of increased lactate dehy-
vation exacerbates rheumatoid arthritis pa- Induced Arthritis via Modulation of Treg drogenase A activity and aerobic glycolysis
thology by promoting survival of sublining and Th17 Cell Imbalance and Suppression of on the proinflammatory profile of autoim-
macrophages. Elife 2020; 9: e56309. Osteoclastogenesis. Int J Mol Sci 2020; 21: mune CD8+ T cells in rheumatoid arthritis.
45. PRAJZLEROVÁ K, KRYŠTŮFKOVÁ O, 3230. Arthritis Rheumatol 2020; 72: 2050-64.
KOMARC M et al.: The dysregulation of 57. HUANG Y, WANG H, BA X et al.: Decipher 69. PETRASCA A, PHELAN JJ, ANSBORO S,
monocyte subpopulations in individuals at manifestations and Treg /Th17 imbalance in VEALE DJ, FEARON U, FLETCHER JM: Tar-
risk of developing rheumatoid arthritis. Rheu- multi-staging rheumatoid arthritis and cor- geting bioenergetics prevents CD4 T cell-
matology 2021; 60: 1823-31. relation with TSDR/RORC methylation. Mol mediated activation of synovial fibroblasts
46. RIVELLESE F, HUMBY F, BUGATTI S et al.: Immunol 2020; 127: 1-11. in rheumatoid arthritis. Rheumatology 2020;
B cell synovitis and clinical phenotypes in 58. CAO G, WANG P, CUI Z et al.: An imbalance 59: 2816-28.
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