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One year in review 2018: pathogenesis of rheumatoid arthritis

E. Calabresi1, F. Petrelli2, A.F. Bonifacio3, I. Puxeddu2, A. Alunno3

Rheumatology Unit, and ABSTRACT the breakdown of immune tolerance,
Immuno-Allergology Unit, Rheumatoid arthritis (RA) is a chronic autoantigen presentation with antigen-
Department of Clinical and Experimental inflammatory autoimmune disease that specific T and B cells activation and
Medicine, University of Pisa, Italy;
primarily affects joints. The several aberrant inflammatory cytokines pro-
Rheumatology Unit, Department of
Medicine, University of Perugia, Italy. mechanisms involved in the develop- duction. The cascade of events leads to
ment of the disease are not completely synovitis, proliferation of synovia and
Emanuele Calabresi, MD*
Fiorella Petrelli, MD* understood. It has been proposed that cartilage and subchondral bone destruc-
Angelo Francesco Bonifacio, MD different environmental factors, such as tion. RA can also involve extra-articu-
Ilaria Puxeddu, MD, PhD cigarette smoking, occupational and at- lar organs, mainly skin, lung, eyes and
Alessia Alunno, MD, PhD mospheric agents act as trigger stimuli cardiovascular system. The better un-
*These authors contributed equally. for the development of RA in genetically derstanding of pathogenetic pathways
Please address correspondence to: predisposed individuals, leading to syn- underlying RA, may be relevant to ob-
Dr Ilaria Puxeddu, ovial hyperplasia and bone destruction. tain more targeted and safer therapies,
Department of Clinical and The initial disease stage of RA is associ- to improve diagnosis in the early stage
Experimental Medicine, ated with alteration of innate and adap- of the disease with consequent better
Università di Pisa, tive immune system with consequent disease control.
Via Roma 67,
56126 Pisa, Italy.
production of autoantibodies, targeting The aim of this review is to provide
E-mail: various molecules including modified an overview of the new insights in RA
Received and accepted on April 12, 2018.
self-epitopes. In the following stages of pathogenesis, summarising the most
the disease, both the innate (e.g. den- relevant studies published over the last
Clin Exp Rheumatol 2018; 36: 175-184.
dritic cells, macrophages and neutro- year.
© Copyright Clinical and
phils) and adaptive immune cells (e.g.
Experimental Rheumatology 2018.
B and T lymphocytes) contribute to the Genetic aspects
Key words: rheumatoid arthritis, amplification and perpetuation of the Congenital predisposition is a well
ACPA, NETosis, microbiota, chronic inflammatory state. The recog- known risk factor for RA development.
immune system, pathogenesis nition of key cells, mediators and mech- Several studies are focusing on iden-
anisms implicated in the pathogenesis tifying new genetic clues that can be
of RA could provide the basis for the de- involved in the pathogenetic processes,
velopment of new and precise disease- leading to the development of RA.
modifying anti-rheumatic drugs. A subgroup of the non-canonical Wnt
Therefore, we reviewed the literature of molecule, named Wnt5a, has been re-
the last year in order to find the new cently identified. This molecule is able
insights in RA pathogenesis. to modulate cellular differentiation, mi-
gration and inflammation. In particular,
Introduction Wnt5a is up-regulated in fibroblast-like
Rheumatoid arthritis (RA) is a chronic synoviocytes (FLS) of RA patients and
systemic inflammatory autoimmune it has been implicated as a possible
disorder characterised by a persistent player of arthritis. MacLauchlan et al.
joint inflammation leading to cartilage described for the first time a role for
and bone damage, disability and even- endogenous Wnt5a in autoimmune
tually to systemic complications. The disease. They studied two population
progression of the disease may lead to of Tamoxifen-inducible mice, Wnt5a
lose functionality, reduce quality of life knockout (Wnt5a cKO) and littermate
and enhance morbidity and mortality. controls, by monitoring for arthritis
RA pathogenesis is the result of a com- development and joint pathology. They
plex interaction between genetic and discovered that Wnt5a cKO mice were
environmental factors, inducing the resistant to arthritis development, and
aberrant activation of innate and ad- some parameters of inflammation were
Competing interests: none declared. aptative immune system which cause reduced, including the extent of cells

One year in review 2018: pathogenesis of RA / E. Calabresi et al.

infiltration, extra-articular inflamma- notype. NKG2D is a C-type lectin re- Furthermore, Kurowska-Stolarska et
tion, cartilage destruction and osteo- ceptor present on natural killer (NK) al. provided evidence that MicroRNA
clast activity. They results suggest that cells, γδ, CD81 and CD41 T cells. (miR)-34a supplies homoeostatic con-
Wnt5a may play a role in the develop- Upon ligand binding, NKG2D medi- trol of CD1c+ dendritic cells (DCs)
ment of arthritis, by promoting inflam- ates activatory and co-stimulatory sig- activation via regulation of tyrosine
mation and osteoclast fusion (1). nals to NK cells and activated CD41 T kinase receptor AXL, an important in-
It is well known that matrix metallopro- cells, respectively. Their study revealed hibitory DC auto-regulator. They found
teinases (MMPs) are the key enzymes that A allele of NKG2D9 and T allele that this pathway is aberrant in CD1c+
responsible for the joint destruction of NKG2D10 was significantly higher DCs from patients with RA, with up-
and their activity is highly regulated by in patients with deformities, while regulation of miR-34a and lower levels
proinflammatory cytokines. Recently, haplotype analysis revealed that the of AXL compared to DC from healthy
Sotjanovic et al. investigated the im- frequency of haplotype GC-A-G-A-T- donors. In addition, silencing miR-34a
pact of Tumor necrosis factor (TNF)-α C-C was higher in RA patients than in in animal model allowed to reduce the
G-308A polymorphism on MMP-9 lev- controls, suggesting that the NKG2D production of pro-inflammatory cy-
els in blood plasma (BP) and synovial gene polymorphisms may modify the tokines, while miR-34a-deficient mice
fluid (SF) of patients with RA, focusing risk of development and severity of the were resistant to collagen-induced ar-
on their role in the progression of joint disease (4). thritis (CIA), interfering with the inter-
destruction. They were able to reveal Moreover, in order to describe new action of DCs and T cells (7).
that MMP-9 activity in BP and SF was candidate genes for the development In addition to TNF-α, IL-1b and IL-6
significantly higher in RA compared to of RA, Shchetynsky et al. performed other cytokines such as IL-23, IL-17
controls, as well as in SF of patients RNA-sequencing-(RNA-seq)-based and interferon gamma (IFN-γ) also
with erosive compared to non-erosive expression analysis of 377 genes with play crucial roles in the pathogen-
RA. In addition, the presence of TNF- previously verified RA-associated loci esis of RA. A recent meta-analysis
α-308A allele was found to be associ- in blood cells from subgroups of RA pa- described that IL-17 levels were sig-
ated with increased MMP-9 activity in tients. From this analysis they demon- nificantly higher in the RA than in the
SF from patients with early RA and it strated that differences in the expression control groups and that expression of
may be a predictor of rapid radiograph- of ERBB2, TP53 and THOP1 were sim- IL-17A rs2275913, IL-17F rs763780
ic progression of the disease (2). ilar in both treated and non-treated pa- and IL-17A rs3819024 polymorphisms
Several candidate gene variants have tients with RA, suggesting that ERBB2, were significantly more expressed in
been identified by genetic mapping TP53 and THOP1 may represent new RA patients (8). By selecting an Irish
in RA such as VAV1 polymorphism. candidate genes involved in the patho- population, McCarthy et al. studied
VAV1 is a member of a tripartite family genesis of the disease (5). the prevalence of α1 -antitrypsin de-
of guanine nucleotide exchange factors For the same purpose, a gene-based as- ficiency (AATD) in RA, showing that
(GEF) for Rho/Rac GTPases, respon- sociation testing with GATES (Gene- there were no differences in the preva-
sible for bridging extracellular signals based Association Test using Extended lence of heterozygous AATD between
into a number of outcomes, ranging Simes procedure) was performed in RA and healthy groups. On the con-
from tissue remodelling, cell migra- 14,361 RA subjects and 43,923 con- trary they observed a positive associa-
tion, activation and gene expression. trols of European ancestry, using tion between heterozygosity for AATD
This seems to be present exclusively 8,694,488 single-nucleotide polymor- and the production of anti-citrullinated
in haematopoietic cells, acting on the phism (SNPs). They observed that 115 peptide autoantibodies (ACPA) with
downstream pathway of immune recep- genes were significantly associated increased autoantibody titers, assum-
tors. Guerreiro-Cacais et al. showed in with RA by gene-based association ing that AATD may define a distinct
rat model of T-cell-dependent pristane- testing, corresponding to 43 RA risk subset of patients with increased dis-
induced arthritis (PIA) a correlation be- loci and particularly 6 new top gene ease severity (9).
tween VAV1 polimorphism expression hits for each of the following 6 RA risk It is well known that DNA methylation
and the activity of anti-CCP negative loci: RPP14 (for DNASE1L3-ABHD6- is an epigenetic modification relevant
RA. Subsequently, these results were PXK), PXT1 (for ETV7), MIR5708 in RA pathogenesis. Rhead et al. dem-
confirmed by meta-analysis in case- (for TPD52), DDX6 (for CXCR5), onstrated that hypermethylation was
control studies performed in RA patients SUOX (for CDK2), and PCAT29 present in RA PB compared to controls,
from several Caucasian populations, (for LOC145837). A new potential supporting that FLS-representative
suggesting a contribution of VAV1 gene RA risk locus (11q23.3, start position DNA methylation signatures derived
in anti-CCP negative RA (3). 118528941 bp) which contains the from the PB may prove to be valuable
Furthermore, in an Indian population of following 3 genes: TREH-PHLDB1- biomarkers for the risk of RA or for dis-
RA patients, Mariaselvam et al. inves- MIR6716 was also identified, confirm- ease status (10).
tigated the influence of polymorphism ing prior RA risk loci and identifying Some interesting results on novel
of NKG2D receptor on predisposition novel risk genes including non-coding genetic factors regulating organ in-
to and modification of the disease phe- regulatory miRNAs in RA (6). volvement in RA have been recently

176 Clinical and Experimental Rheumatology 2018

One year in review 2018: pathogenesis of RA / E. Calabresi et al.

published. Particularly Oka et al. de- the severity of arthritis in the murine development and atrazine, a commonly
scribed the expression of different model of CIA and induces a dose- used herbicide, as well as toxaphene,
miR profiles in two Japanase popula- dependent NETosis in isolated human an organochlorine insecticide, regard-
tions of RA with or without Interstitial neutrophils (14). less of age, smoking and educational
Lung Disease (ILD). These are small Survivin is an inhibitor of apoptosis that level (19). Ilar et al. found an increased
non-coding RNAs with approximate prevents the activation of caspases and risk of developing RA in electronics
22 nucleotide length and are stably de- a regulator of cell cycle progression by workers, bricklayers, concrete work-
tected in plasma or serum. It is widely aiding formation of the chromosomal ers, material handling operators among
known that they are able to modulate passenger complex. Survivin seems to men and assistant nurse and attendants
the expression of protein-coding genes be involved as a mediator of smoking among women in the Swedish EIRA
at the post-transcription level and play in the pathogenesis of RA as its levels cohort (20).
important roles in cell activation, pro- are higher in the sera of RA smoking
liferation, differentiation or death. The patients compared to non-smokers and Diet
authors found that expression levels in bone marrow (BM) of CIA mice Among the individual components of
of hsa-miR-214-5p and hsa-miR-7-5p treated with nicotine. A further analysis the Alternative Healthy Eating Index
were increased in RA with ILD, iden- of these mice BM showed that nicotine (AHEI-2010), a dietary quality score
tifying for the first time a correlation exposure causes CD8+ T cells to adopt based on the Dietary Guidelines for
between miRs and ILD in RA (11). a non-exhausted phenotype, character- Americans, both moderate alcohol
ised by loss of expression of the pro- consumption and lower red meat in-
Enviromental factors grammed cell death -1 (PD-1) receptor take were found to be most associated
Many environmental factors, such as and induction of IL-7 receptor, associ- with decreased-onset RA risk (21). In
cigarette smoking (CS), occupational ated with loss of tolerance and devel- addition, low sodium intake in RA pa-
and atmospheric agents, have been opment of arthritis (15). Furthermore, tients seems to reduce the expression
proposed as trigger stimuli for the de- Andersson et al. found that smoking is of IL-9 and transforming growth factor
velopment of RA in genetically predis- associated with the expression of all the (TGF)-β, suggesting that a restricted so-
posed individuals. three isoforms of survivin in the sera of dium dietary intake could contribute to
RA patients and with deregulation of dampen the pro-inflammatory response
Cigarette smoking miR processing machinery. The latter (22). In this regard, also short-term low
Among all the environmental factors results in a restricted global expression magnesium intake seems to have pro-
that seem to be involved in the patho- of miR through the reduction of Dicer1 tective effect on arthritis severity in a
genesis of RA, CS in the one with endonuclease levels, necessary for the murine model of arthritis (23).
strongest evidence, predisposing to cleavage of the system loop structure
the generation of citrullinated proteins of pre-miR. Increased levels of Dicer1 Microbiota and infections
especially in subjects carrying deter- and restoration of miR production was A growing number of studies under-
mined SE alleles. achieved by treating human leukocytes scores the association between the
Epidemiological studies have been un- with non-selective inhibition of all the development of RA and periodontitis.
derlining the association between CS three survivin isoforms (16). In this setting Porphyromonas Gingi-
and RA. Recently Svendsen et al. con- valis infection is of particular impor-
firmed in an historical Danish twin co- Occupational and atmospheric agents tance and represents the link between
hort that risk of developing RA is more Recently, some evidences indicate a periodontitis and citrullination since P.
than doubled after 20 years of smoking possible correlation between the de- gingivalis is the only bacterium con-
in both sexes (12). velopment of RA and the exposure to stitutively equipped with the peptidyl
New insights about molecular mecha- occupational and atmospheric agents. arginine deiminase (PAD) enzyme.
nisms and the role of nicotine in the im- High risk of developing ACPA-posi- Schmikler et al. confirmed an associa-
mune process are now available. Meng tive RA was observed among silica- tion between development of RA and
et al. identified a gene-environment exposed smokers in a small Swedish worse oral health conditions, (24) and
interaction between smoking and SNPs cohort (17). Furthermore, Bernatsky the presence of P. Gingivalis in peri-
in the rs6933349 gene influencing the et al. provided evidence that industrial odontal pocket seems associated to RA
DNA methylation level of cg21325723. air pollution emissions and proximity autoantibodies (25).
They found that among current smok- to major industrial emitters are asso- Oral and intraperitoneal inoculation of
ers, minor allele (rs6933349_A) carri- ciated with positivity for ACPA in the Porphyromonas Gingivalis in the CIA
ers had a lower level of methylation at Canadian CARaGENE cohort (18). In murine model (especially after the im-
cg21325723 which seems to be associ- addition, it has been suggested that the munisation process) seems to increase
ated with increased risk of developing exposure to some pesticides may play synovial inflammation and expression
ACPA-positive RA (13). a role in the development of RA among of several synovial protein like enolase
Lee et al. found that exposure to high male farmers. Meyer et al. found a and fibronectin and their citrullinated
systemic level of nicotine exacerbates dose-response association between RA forms (26).

Clinical and Experimental Rheumatology 2018 177

One year in review 2018: pathogenesis of RA / E. Calabresi et al.

An analysis of the citrullinome of gin- tory cells in the pathogenesis of RA, delayed arthritis initiation. According
gival crevicular fluid (GCF) and peri- providing a source for macroscopic to these results, caspase-8 is also im-
odontal tissue, identified an overlap be- and histological data simultaneously. plicated in the maintenance of synovial
tween periodontal citrullinated peptides Using these in-vivo models, the disease tissue-resident macrophages that can
and citrullinated peptides recognised can be macroscopically monitored over limit arthritis, and potentially controls
by autoantibodies in RA. A novel pep- time via scoring systems. For histologi- the endocytic capacity of macrophages
tide was recognised as target of autoan- cal examination, knee sections can be through the enhancement of CD206
tibodies, the cytokeratin 13 (cCK13- used for haematoxylin and eosin stain- expression. This receptor makes mac-
1) which has a direct correlation with ing to visualise cellular infiltration as rophages capable of endocytosing cel-
anti-citrullinated tenascin-c (c-TNC5) well as for tartrate-resistant acid phos- lular debris arising from inflamed and
autoantibodies and antibodies against phatase (TRAP) staining to identify damaged tissue, driving to the control
periodontal pathogen Prevotella Inter- osteoclast-like cells. Flow cytometric of inflammation itself. In both cas-
media (27). Recent studies showed that analysis allow to identify different pase-8 deletion constructs, global dele-
antibody response to Prevotella Copri population of myeloid cells infiltrating tion of RIPK3 abrogates the response
(component of gastrointestinal micro- the synovium such as tissue resident to K/BxN serum transfer-induced ar-
biota) seems to correlate with immune- macrophages, DCs and neutrophils. thritis, potentially trough other mecha-
response to GNAS and FLNA, two Different arthritis models such as CIA, nisms independently of controlling cell
novel HLA-DR presented peptides au- antigen induced arthritis, and Strepto- death (33).
to-antigen identified directly in the syn- coccal cell wall induced arthritis have Additionally to their central function in
ovial tissue and PBMCs of RA patients been exploited to investigate different the pathophysiology of synovial inflam-
(28). An over-expansion of P. Copri aspects of the pathogenesis of arthritis mation, monocytes/macrophages are at
in stool of new onset and chronic RA (32). In this regard, Dominguez et al. the origin of pathological bone erosion
patients was identified, in both group used K/BxN serum transfer-induced in RA. In fact, these cells contribute to
the antibody response was specific for arthritis model, in order to investigate both inflammation and cartilage and
RA (29). With regard to other microor- the impact of caspase-8 in develop- bone destruction through the production
ganisms, recent studies demonstrated a ment and progression of arthritis (33). of degradative enzymes, cytokines and
higher prevalence of anti-Toxoplasma In this model, the arthritis was induced chemokines. In recent years, particular
Gondii IgG antibodies among RA pa- by injection of arthritogenic serum interest has been given to the investiga-
tients (30), and an inverse association from KRN and NOD mice (K/BxN tion of cytokine production in mono-
between high anti-Epstein Barr virus mice), with the development of an in- cytes/macrophages, in order to identify
(EBV) and anti-Parvovirus B19 IgG flammatory state characterised by se- novel possible therapeutic targets. Re-
levels and the risk of developing ACPA vere, spontaneous, symmetric, erosive cently, lactoferrin-containing immuno-
positive RA (31). and chronic arthritis, that resembles complexes seems to be responsible of
the effector stage of RA. Moreover, K/ pro-inflammatory cytokines produc-
Innate immune responses BxN serum transfer-induced arthritis tion by these cells, thereby contribut-
In RA the dysregulation of immune model is mediated by innate immune ing to the pathogenesis of autoimmune
system culminates in chronic inflam- cells and relatively T and B cells-in- diseases such as RA (34). Lactoferrin
mation, leading to progressive joint de- dependent. Caspase-8 is a cysteine-as- (LTF) is a multifunctional iron-binding
struction. Growing interest has recently partic acid protease and acts as initiator glycoprotein of the transferrin family
been given to professional phagocytes of apoptosis and suppressor of necrop- and represents an important first line
and DCs, as emerging critical cell pop- tosis. Previous studies evidenced defense molecule against infection.
ulations in the pathogenesis of RA. In that caspase-8 also maintains death- This protein in known to be a target for
the peripheral blood of RA patients in- independent inflammatory processes, humoral autoimmune reactions in hu-
creased numbers of circulating mono- through a signalling axis that involves mans, with the generation of anti-LTF
cytes have been reported. These cells the suppression of receptor-interacting specific autoantibodies (LTF-Abs) and
are able to infiltrate the joints where serine-threonine kinases (RIPKs). In LTF-containing immune complexes
they differentiate into synovial mac- addition, they observed opposing roles (ICs) (LTF-ICs). LTF-Abs are found in
rophages, that are highly activated in for caspase-8 signalling in lysozyme sera of patients with RA and other auto-
RA patients. Although different studies M-expressing cells and CD11 express- immune diseases such as systemic lupus
provide strong evidences for the impli- ing cells in the joint, utilising two cas- erythematosus (SLE), ulcerative colitis,
cation of macrophages and DCs in the pase-8 deletion constructs. Namely, Crohn’s disease and ANCA-related vas-
pathogenesis of RA, relatively little is caspase-8 in lysozyme M-expressing culitis. Hu et al. reported the effective-
known about the mechanisms behind cells exacerbated the arthritis severity ness of LTF-ICs to induce TNF-α and
their involvement. The use of experi- and hindered the resolution stage of ar- IL-1β production by human monocytes
mental arthritis mouse models can be thritis itself. By contrast, caspase 8 in in vitro. On the contrary, control ICs or
useful to clarify the role of professional CD11-expression cells reduced the se- LTF and LTF-Abs alone were not able
phagocytes, DCs and other inflamma- verity of effector phase of disease and to elicit proinflammatory cytokine pro-

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One year in review 2018: pathogenesis of RA / E. Calabresi et al.

duction by monocytes. These results mice. The molecule CD11c is constitu- notype which may be involved in the
demonstrated that IC formation be- tively expressed on the cellular surface regulation of inflammatory responses.
tween human LTF and specific IgG in of DCs, that are potent antigen-present- In parallel, TLR-2 activation induced
RA patients is essential to induce mono- ing cells with an essential role in initiat- mitochondrial dysfunction in RA-SF
cytes activation. Furthermore, the au- ing adaptive immune responses. in-vitro system, such as reduction of
thors found that LTF-ICs utilised both CD11b+Gr1dim tolDC-LCs can be mitochondrial membrane potential and
CD32a (FcγRIIa) and membrane-an- classified as a subset of tolDCs, pheno- increase of ROS and 4-hydroxynon-
chored mCD14 (glycophosphotidyl in- typically different from tipical tolDCs, enal (4-HNE), that is a marker of lipid
ositol-anchored CD14 or GPI-anchored expressing high levels of PD-L1 and peroxidation. In previous studies ROS
mCD14) to trigger monocyte activation low levels of CD80. This new subset had been reported as primary source
in an internalization-, Toll-like receptor of tolDCs express high levels of both of mitochondrial mutagenesis and dys-
(TLR)-4- and TLR-9-dependent man- PD-L1 and CD80. The molecular function, since mitochondrial genome
ner. The GPI-anchored mCD14 is a mechanisms of ILD suppression by is highly susceptible to oxidative dam-
surface marker for phagocytic cells that CD11b+Gr1 dim to lDC-LCs are still to age. Meanwhile, the increase in 4HNE,
relies on TLR-4 for signalling following be elucidated (35). in parallel to a decrease in mitochon-
sequester bacterial lipopolysaccharides Another important feature of innate drial membrane potential, is consistent
(LPS) ligation. This element underlines immune cells is the activation of anti- with previous studies showing that lipid
the key role of the CD14/TLR4 com- microbial pro-inflammatory immune peroxidation induces the mitochondrial
plex (major components of the LPS responses through TLRs, which can membrane to become more permeable
signalling machinery) in the signalling initiate different signalling pathways. to protons, dissipating the mitochon-
during monocytes / macrophages acti- These signalling pathways are also im- drial membrane potential. This is a con-
vation. These results support the hypo- plicated in the metabolic switch from sequence of the reaction of ROS with
thesis that LTF-ICs may perpetuate lo- mitochondrial respiration to anaerobic lipids. Taken together, these data sug-
cal inflammation and contribute to the glycolysis, that occurs under hypoxic gest that TLR-2-induced ROS produc-
pathogenesis of autoimmune diseases conditions, even during inflammatory tion can drive mitochondrial mutation,
by triggering activation of infiltrating states. For example, TLR-4, TLR-2 and lipid peroxidation, and damaging of the
monocytes or tissue macrophages in TLR-9 signalling induces an increase in mitochondrial membrane. The damag-
vivo (34). glycolytic rate and glucose consump- ing of mitochondrial membrane can
While synovial macrophages are cru- tion in DCs, while activation of TLR- further induce ROS production, result-
cial in RA pathogenesis, the pathologi- 4, TLR-2 and TLR-6 in macrophages ing in a vicious cycle of mitochondrial
cal role of of DCs is still unclear. Evi- promotes an M1 phenotype, resulting dysfunction, which can drive inflamma-
dences from synovial tissues in RA in- in increase in mitochondrial reactive tion (36).
dicates that DCs contribute to increase oxygen species (ROS) and a depend- Among all cells implicated in the
local infiltration of leukocytes and help ency on glycolysis. pathogenesis of RA, neutrophils exert
initiation of disease by producing cy- Previous studies have shown increased the greatest cytotoxic effects, due to
tokines and presenting autoantigens to mitochondrial DNA mutation frequen- their ability in releasing degradative
autoreactive T cells. Several types of cy and mitochondrial dysfunction in the enzymes and reactive ROS. Neutro-
DCs act as regulators of immune re- RA joints. These effects are associated phils also contribute to the production
sponses, so they are reported as tolero- with oxidative stress state, angiogen- of cytokine and chemokine cascades as-
genic DCs (TolDCs). TolDCs suppress esis processes, pro-inflammatory cy- sociated to inflammatory processes and
autoreactive T cells in the thymus dur- tokines production and activation of the regulating immune responses via cell-
ing central tolerance, limit effector T NLRP3 inflammasome. In this regard, cell interactions.
cells and promote regulatory T cell dif- McGarry et al. demonstrated altera- A particular subpopulation of periph-
ferentiation in the periphery. tions in mitochondrial function in the eral blood mononuclear cells (PBMC),
Interestingly, Sendo et al. identified a RA joint in response to TLR-2 signal- known as low-density granulocytes
new cellular population, CD11b+Gr1dim ling, in parallel with a dysregulation of (LDGs), was firstly identified in the
tolDC-LCs, in the severely inflamed glucose metabolism (36). The authors blood of SLE patients in 1986 and sub-
lungs of SKG mice, an animal model investigated the effect of TLR-2 activa- sequently described as a group of cells
of RA associated to an ILD, induced tion on mitochondrial function and bio- expressing surface markers specific for
through injection of zymosan A (ZyA). energetics in primary RA-FLS, identi- mature neutrophils (CD15 high/CD14low/
The authors demonstrated that GM- fying a link between TLR signalling, CD10+/CD16+) with a gene expressing
CSF, produced by both helper T (Th) ROS and mitochondrial dysfunction in profile characteristic of immature neu-
cells and innate lymphoid cells (ILCs), these cells. The authors demonstrated trophils. During early stage of neutro-
stimulates the differentiation of Mye- that TLR-2 induced random mitochon- phils differentiation, granule protein
loid-derived suppressor cells (MDSCs) drial point mutations in RA synovial genes and cell-cycle checkpoint genes
into CD11b+Gr1dim tolDC-LCs, that tissue and primary RA-FLS, result- are expressed at higher levels, while
serve as suppressor of ILD in SKG ing into mitochondrial mutator phe- expression of genes codifying apoptotic

Clinical and Experimental Rheumatology 2018 179

One year in review 2018: pathogenesis of RA / E. Calabresi et al.

molecules, cytokines, chemokines and RA is unclear. Within this group of pro- by anti-CCP are present in the sputum
their receptors are down-regulated. teins, PAD4 contributes to inflamma- of a portion of FDRs and subjects with
Wright et al. investigated the charac- tion in different murine models of RA; early disease, suggesting that the lung
teristics of a subpopulation of LDGs it is also associated to LPS-induced his- may be a site of anti-CCP generation in
from RA patients, in order to determine tone citrullination and NET formation. this population.
if they are functionally different from Meanwhile, PAD2 is important for cit- Increased levels of IgA and IgG anti-
RA neutrophils. Interestingly, these RA rullination in healthy tissues, is present CCP were detected in RA patients (70%)
LDGs expressed elevated level of tran- in NETs and correlates with disease ac- and in FDRs (25%), including a portion
scripts for granule proteins, including tivity in RA. of FDRs who were serum anti-CCP neg-
elastase and myeloperoxidase (MPO), Bawadekar et al. used an experimental ative. In the FDRs, elevations of sputum
and also expressed cell-cycle genes, animal model of RA (TNF-α-induced IgA and IgG anti-CCP were associated
including cyclin-dependent kinase inflammatory arthritis) to identify the with elevated cell counts and NET lev-
(CDK2, CDK4, CDK6), resembling roles of PAD2 and PAD4 in citrullina- els in the sputum. These findings show
an immature phenotype of neutro- tion and NET formation in inflamed that local airway inflammation and NET
phils. In parallel, apoptosis-regulating joints. formation are associated with increased
genes were expressed at lower levels In mice with TNF-α-induced arthritis, ACPAs in the lung, suggesting that NE-
in LDGs, translated into a significantly there was an increased citrullination in Tosis may drive ACPA generation in the
lower rate of apoptosis in this cellular inflamed joints, which persisted in ab- respiratory tract of FDRs who are at an
population with a decreased response sence of PAD4, but not in absence of elevated risk of developing RA.
to TNF-α in-vitro system. In fact, the PAD2 that was not required for NET Moreover, ACPA isotype positivity was
expression of cytokines and cytokines formation. According to these results present in a proportion of FDRs in the
receptors, especially TNF receptors It seems that PAD4 is not crucial for absence of serum ACPA positivity, even
(TNFRs) were lower in RA LDGs com- generation of citrullinated proteins in if the number of FDRs demonstrating
pared with RA neutrophils; providing TNFa-induced arthritis, although It sputum ACPA positivity exceeds the
an explanation for the lack of response may contribute to RA in other ways. number that statistically will develop
to TNF-inhibitors therapy in some RA On the contrary, PAD2 appeared to be classifiable RA. This suggests that lo-
patients. Further studies are required to required for joint citrullination in TNF- cal ACPA formation may be necessary
clarify the contribution of these cells α-induced arthritis, without a major but not sufficient to develop a systemic
in RA pathogenesis and to understand role in NETs formation, suggesting state of the disease (39).
whether LDGs represent mature neu- the presence of other possible main Taken together, these results support
trophils or a different phenotype of neu- sources of citrullinated antigens, such the hypothesis that lung could play an
trophils (37). Additionally to the well- as immune-mediated membranolysis- important role in the early stages of RA
recognised cytotoxic and immunoregu- induced hypercitrullination, potentially development.
latory functions in RA, neutrophils may catalyzed by PAD2 (38). Nonetheless, In addition, they also characterised in
also provide a source of the autoanti- the importance of NETosis is under- the sputum of subjects at risk for RA
gens, contributing to the genesis of au- lined by spread evidences, since this (at-Risk) the reactivity of antibodies to
toimmune processes in this disease. In phenomenon correlates with presence individual citrullinated and non-citrul-
fact, emerging evidence suggests that and levels of ACPA and with systemic linated proteins/peptides as well as as-
RA neutrophils can release neutrophil inflammation. Furthermore, NETosis is sociations with NETosis. The authors,
extracellular traps (NETs) containing enhanced in the peripheral blood and evaluating the individual antibody re-
chromatin associated with granule en- the synovium of patients with RA. sponses in RA subjects and in subjects
zymes, which not only kill extracellu- The generation of ACPAs in early phas- at-Risk for the future development of
lar microorganisms but also provide a es of RA has been recently investigated RA, based on familial or serologic
source of autoantigens. NETs formation in a study performed by Demoruelle risk factors, concluded that sputum
has been identified as a bridge between et al. Emerging data suggests that RA antibody reactivity to particular citrul-
innate and adaptive immune responses related autoimmunity is initiated at a linated and non-citrullinated proteins/
in autoimmunity. An array of cyto- mucosal site and that ACPAs may be peptides is specific for at-risk and RA
plasmic and extracellular citrullinated initially generated at a mucosal surface. subjects. In addition, the levels of spu-
proteins has been described among In order to clarify the role of lung mu- tum antibodies to citrullinated antigens
NET components. They can act as neo- cosa in the early stages of RA related was significantly higher in at-Risk and
epitopes in loss of immune tolerance. autoimmunity and explore ACPAs gen- RA subjects compared to controls.
These citrullinated proteins are gener- eration in the lung, Demoruelle et al. Within the at-risk subjects, the most
ated by PADs, which replace arginine investigated samples of induced spu- prevalent sputum antibody responses
with citrulline residues, within neutro- tum and serum obtained from RA pa- to citrullinated proteins/peptides were
phils. Although PADs are reported to tients and RA-free first-degree relatives directed to cit-fibrinogen, cit-apolipo-
catalyze citrullination in inflammatory (FDRs) (39). Their study provided evi- protein E and cit-fibronectin, even in
conditions, the precise role of PADs in dence that ACPA isotypes as measured serum ACPA negative at-Risk subjects,

180 Clinical and Experimental Rheumatology 2018

One year in review 2018: pathogenesis of RA / E. Calabresi et al.

suggesting that these proteins may rep- It is well known that RA is characterised of the disease. By contrast, the absence
resent the earliest antigen targets of by a chronic inflammation, as a result of of IL-9, in genetically deficient mice,
antibodies generated in the lung. On the inability to resolve an immune re- impaired ILC2 proliferation and Treg,
the other hand, within RA subjects, sponse. The physiological pathways in- leading to persistent synovitis and ex-
the most prevalent sputum antibodies volved in the resolution of arthritis are cessive degradation of cartilage and
to citrullinated proteins/peptides were still incompletely understood, but the bone (40).
directed to cit-filaggrin, cit-histone detection of immune components that
2A, cit-histone 2B, cit-fibrinogen, cit- control the resolution process may be The adaptive immune system
fibronectin and cit-clusterin. key to novel therapies. In recent years, The adaptive immune system is a lead-
In the serum of preclinical and early there has been growing interest in the ing actor in the development of RA and
RA subjects, antibodies to non-citrul- biology of newly discovered immune the imbalance of effector (eff) and regu-
linated/native proteins have been de- cells, ILCs, since they are considered latory (reg) lymphocytes is a hallmark
tected in addition to anti-citrullinated crucial mediators of tissue remodeling of disease pathogenesis. The disruptive
antibodies, suggesting that autoimmun- and repair. ILCs are the counterpart of effects of T helper (h) 17 cells in RA
ity may be initially directed to native Th lymphocytes and can orchestrate have been further supported over the
proteins, subsequently to citrullinated inflammation, innate and adaptive re- last year by studies demonstrating the
epitopes through epitope spreading. sponses. For example, they can closely association of IL-17 and intra-articular
Demoruelle et al. sought to explore an- interact with stromal cells, leading to IgA secretion (41), the capability of
tibody reactivity to both citrullinated their up-regulation of adhesion mol- Th17 cells to trigger specific B lympho-
and non-citrullinated antigens during ecules and production of chemokines. cyte clones to produce autoantibodies
different phases of RA development. These cells are also capable of secreting in the preclinical RA phase (42), the
They identified antibodies with both a different mediators in adult lymphoid key role of IL-21 in orchestrating bone
citrullinated and non-citrullinated an- tissues. In particular, ILC2, the counter- damage together with TNF-α (43) and
tigen counterpart, but certain antigens part of Th2 cells, have been reported to the IL-17-induced mitochondrial dys-
appeared to induce a more citrullinat- be crucial in tissue repair through the function in FLS (44). Data from animal
ed specific reactivity. Particularly, the function of cytokines and soluble me- models unmasked novel mechanisms
most citrullinated specific sputum anti- diators. Rauber et al. found that ILC2 leading to a modulation of T cell sub-
bodies in at-risk subjects were directed induce the resolution of inflammation sets such as the anti-inflammatory ef-
to fibrinogen, vimentin and the peptides in RA via the production of IL-9, which fects of IL-38 on Th17 cells (45) or the
fibrinogen A and apolipoprotein A1. has been identified as a master molecule lack of involvement of CTLA-4 in im-
Meanwhile, a high level of cit-speci- in regulating resolution of arthritis and mune priming in CIA (46). In the field
ficity in RA patients was demonstrated preventing the chronicisation of arthri- of Th17 cells, interesting data from Lin
for the proteins fibrinogen, histone 2A, tis itself (40). et al. demonstrate that YY1, a “Yin
histone 2B and vimentin and the pep- The authors investigated the function of Yang” transcription factor involved in
tides histone 2A/a-2 and fibrinogen A. IL-9 in the context of antigen-induced cancer development and progression,
A correlation between sputum levels arthritis, finding that ILC2 are the ma- is able to enhance IL-6 production and
of NET complexes and several sputum jor source of IL-9 during the resolution in consequence Th17 cell commitment
antibodies to citrullinated and non-cit- phase of arthritis and play a pivotal role in CIA mice (47). Conversely, over-
rullinated proteins/peptides in at-Risk in the promotion of regulatory T cells expression/stimulation of programmed
subjects has been reported. The sputum (Treg) with the suppressive activity. cell death 5 (PDCD5), sialic acid-
NET levels were significantly associ- In fact, stimulation of ILC2 with IL-9 binding Ig-like lectin-9 (Siglec-9) or
ated with antibodies to cit-fibrinogen, induced an up-regulation of the Treg- leukocyte-associated Ig-like receptor-1
cit-apolipoprotein A1 and fibrinogen receptor-associated ligands GITRL and (LAIR-1) restores the Treg/Teff ratio by
A, which had also demonstrated high ICOSL, which are known to increase the increase of Treg cells and the reduc-
sputum citrullinated-specificity in at- the suppressive capacity of Treg. This tion of Th1 and Th17 cells in the same
Risk subjects. In the case of antibodies observation is in line with previous re- experimental RA model (48–50).
to histone and vimentin peptides, spu- ports that ILC2 produced IL-9 acts in Semaphorin 7A is a powerful inducer
tum NET levels significantly correlated an autocrine loop to promote ILC pro- of Th1 and Th17 cells (51), while Gal-
only with the citrullinated counterparts. liferation. The described cellular path- phaq-containing G protein, a member
Interestingly these two citrullinated- way effectively reduced tissue damage, of Gq/11 class, is a strong enhancer of
proteins have been identified in the with preservation of cartilage integrity, Th1 cells in experimental model (52).
protein cargo of NETs induced in RA and decreased bone erosions, translated Oncostatin, a cytokine belonging to the
patients’ neutrophils (39). Similarly to into accelerated resolution of arthritis. IL-6 family which action is still un-
the initiation of inflammation, there is Supporting these evidences, high num- clear, demonstrated to be anti-inflam-
a growing appreciation that the resolu- bers of ILC2 expressing IL-9 are de- matory in CIA by hampering Th17 cell
tion of inflammation is an intricate and tectable in the joints and in the circula- commitment through the modulation of
active process. tion of RA patients in remission phase SOCS3, STAT3, and STAT5 (53). As

Clinical and Experimental Rheumatology 2018 181

One year in review 2018: pathogenesis of RA / E. Calabresi et al.

far as B lymphocytes are concerned, of follicular helper T cells. These pecu- that B10 cells, that in normal condi-
new insights into the mechanism of liar T lymphocytes have been defined tions counteract chronic inflammation,
tolerance breaking and autoantibody peripheral helper T cells (61). abnormally produce RANKL in RA and
production have been provided by Dek- The effects of prostaglandin E2 (PGE2) therefore are involved in the develop-
ker et al. who investigated the response on Treg cells have been described for ment of bone erosion. Interestingly,
of autoreactive B cells against proteins the first time. PGE2 is able to profound- such phenotype is closely correlated
that underwent post-traslational modi- ly affect Treg cells in many ways in- with the severity of the disease, being
fications and observed that not only cluding the down-regulation of FoxP3, less prevalent in patients undergoing
self, but also foreign anti-carbamylated CTLA-4 and glucocorticoid-induced remission (67).
proteins can trigger an aberrant autoim- tumour necrosis factor receptor-related
mune response against self carbamyl- protein (GITR) and the inhibition of IL- Conclusion
ated proteins (54). 10 release (62). During the last year, relevant findings
Over the last year, several papers pro- Another intriguing aspect that has been in the field of RA pathogenesis have
vided evidences about novel modula- investigated is T cell recruitment at RA been described. In particular, new in-
tors of the T lymphocyte subsets also target sites. Wen-Xiu et al. identified a sights come from studies on the innate
in the human counterpart. Cell-to-cell peculiar T cell subset, Vδ2 T cells, that and adaptive immune system, including
contact is a key event allowing cross- express chemokine receptors CCR5 and cells, soluble mediators, adhesion mol-
talk and cognate interaction of im- CXCR3, produce pro-inflammatory cy- ecules and intracellular pathways. Phe-
mune cells. Yang et al. demonstrated tokines and accumulate in RA synovial notypes and functions of T and B lym-
that Th17 cell differentiation requires membrane upon TNF stimulation. Of phocytes have been better characterised
cell-to-cell contact via CD147 with interest, treatment with TNF inhibitors and novel roles of the newly discovered
activated monocytes (55), while Mori strongly down-regulated the expression innate lymphoid cells (ILC) has been
et al. demonstrated that this differen- of these chemokine receptors hence proposed. Future studies will be needed
tiation, as well as the commitment into interfering with the migration of Vδ2 to better understand the mechanisms
Th1 cells, can also be induced by cell- cells (63). Another study, provided the underlying RA, in order to develop
to-cell contact of FLS and naïve T lym- first evidence of an in-vitro chemotac- novel and more specific disease-modi-
phocytes via adhesion molecules (56). tic activity of the insulin growth factor fying therapies.
Interestingly, while in normal condi- binding protein 6 (IGFBP6) on RA T
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