CD1c+ dendritic cells can cause rheumatoid arthritis (RA)


Researchers at Trinity are providing fresh insights into joint inflammation in patients with rheumatoid arthritis (RA). The condition currently affects about 1 percent of the world’s population and about 2,000 new cases are diagnosed annually in Ireland.

Patients suffering from RA require lifelong treatment and can experience joint destruction, pain and disability, as well as depression, and social isolation.

While treatments are improving, there is still a very real need to identify new treatment strategies, as unfortunately only one in every four patients will reach full remission.

The Molecular Rheumatology Group at the School of Medicine, led by Professor Ursula Fearon is working to better understand the complex cellular and molecular events that occur directly in the affected joints of patients.

This urgent research will enable a more directed approach to treating this autoimmune disease. Two recently published papers from the group have presented unique insights into joint inflammation in RA.

Through the examination of cells and tissue from the site of inflammation in well-defined patient cohorts, the group aims to understand what drives disease and response and how cells interact with each other to orchestrate the inflammatory response.

Now, two of the groups research fellows, Dr. Mary Canavan and Dr. Achilleas Floudas are examining the cells in ‘the synovium’ which is the primary site of the inflammatory process, which if untreated leads to irreversible damage to the adjacent cartilage and bone. Two cell types involved in the inflammation process are ‘dendritic cells’ and ‘T-cells’ which interact with one another in the joint to drive inflammation.

Dr. Mary Canavan’s findings were recently published in Frontiers in Immunology, and provide unique and previously unexplored insights into the complex role ‘dendritic cells’ may have in joint inflammation in patients with RA. Dendritic cells are a key immune cell in the body, and there are many different subtypes – each with its own unique role.

This was the first study of its kind to examine these cells at the site of inflammation – that is, in the affected joints of the patients – and not just in the peripheral blood.

Dr. Canavan said: “There is no doubt that the activities of these dendritic cells have consequences for neighboring cells in the synovium, such as T cells. Our findings also demonstrated that this CD1c+ dendritic cell population produces large amounts of ‘matrix degrading enzymes’ which can destroy cartilage and bone.

Therefore, this study provides unique and previously unexplored insights into the complex role dendritic cells may have in joint inflammation in patients suffering from rheumatoid arthritis.”

Dr. Achilleas Floudas’s study, recently published in the journal Annals of Rheumatic Diseases, examines the previously unconsidered population of immune (T) cells found in synovial tissue become dysfunctional and exert many negative impacts associated with RA.

Crucially, however – with regard to their potential as prognostic and therapeutic targets – these cells begin to malfunction before the clinical onset of RA. As a result, the scientists hope they may one day serve as “early-warning flares” that may allow medics to detect at-risk individuals and act before RA becomes established.

Dr. Floudas said: “The window for effective therapeutic intervention in rheumatoid arthritis (RA) is limited, and current T cell-specific therapies for treatment are broad and affect all T cells irrespective of their contribution to disease pathogenesis and progression, therefore not differentiating between protective and pathogenic T cell responses.

Additionally, if we can spot the ‘early-warning flares’ set off by specific T cells in the synovial tissue of at-risk individuals, we should be able to extend the window for effective therapeutic intervention.”

Professor Ursula Fearon, professor of molecular rheumatology, said: “We have found that the level of dysfunction observed in these immune cells varies between individual patients and is associated with level of disease activity, thus may also allow the opportunity to monitor disease as well as develop more refined and targeted therapeutic strategies while limiting the side effects and toxicity.

Understanding the role that these specific immune cells play in driving inflammation in the individual patient, has the potential for the development of precision treatments that prevent onset or impact early in disease, thus would have a significant impact for the patient’s quality of life.”

The first study of dendritic cells (DCs) was published in 1973, when Ralph Steinman and Zan Cohn discovered a small group of cells with unique stellate morphology by microscopic studies of glass-adhering mouse splenocytes (1). In the mononuclear phagocyte system (MPS), some MPS cells retain incompletely degraded antigen and present it to T cells, thus activating T cells (2). These so-called antigen-presenting cells (APCs) initiate a response by activating T cells, which subsequently stimulate antibody production from B cells, thus bridging innate immunity and adaptive immunity (3). DCs serve as a bridge between innate immunity and adaptive immunity, and the discovery of DCs is the result of efforts to understand the cellular initiating factors of the adaptive immune response (2).

Recent research shows that DCs can be classified into major subtypes based on origin and differentiation state. Human DCs are produced through a lymphoid-specific bone marrow haematopoiesis pathway. DC subset differentiation is affected by different specific transcription factors, among which the roles of IRF8 and IRF4 are particularly important (4–7).

Under the regulation of these cellular transcription factors, DCs can differentiate into three main subgroups: plasmacytoid DCs (pDCs), type 1 myeloid/conventional DCs (cDC1s) and type 2 myeloid/conventional DCs (cDC2s) (8). In 2019, Brown et al. further classified cDC2s into cDC2A(T-bet+) and cDC2B(T-bet-) by assessing the expression of T-bet, and they are different from proinflammatory and anti-inflammatory phenotypes in vivo ( 9). In addition, increasing evidence has shown that mature DCs can limit effector T cells and promote the differentiation of regulatory T (Treg) cells to promote the formation of immune tolerance in related diseases (10–12).

Researchers have found that genes encode not only functional products such as proteins but also a variety of unique RNAs (13). Despite a lack of protein-coding regions, Caenorhabditis elegans was found to carry some RNAs with conserved functions required for cell development (14). Owing to advances in sequencing technologies, researchers have found a large number of various non-coding RNAs.

These non-coding RNAs can be divided into several subsets, including microRNAs (miRNAs), circular RNAs (circRNAs), long non-coding RNAs (lncRNAs), tRNA-derived small RNAs (tsRNAs), ribosomal RNAs (rRNAs), and PIWI-interacting RNAs (piRNAs) (14). Some highly conserved RNAs, including miRNAs (15), circRNAs, and lncRNAs, lacking conservation between species (16), account for approximately 60% of the transcriptional output of human cells (17, 18). It is clear that cellular processes and pathways can be regulated though non-coding RNAs in developmental and pathological settings.

Noncoding RNAs play various roles in the regulation of immune cell differentiation and function. Kuiper et al. observed that conditional depletion of Dicer in mouse CD11c+ DCs did not affect the presence of transient resident DCs in lymph nodes or spleen. However, the lack of miRNAs led to a selective loss of these cells in the epidermis, and those cells that did exist lacked the capacity to mature and present antigens (19).

Wang et al. demonstrated that lnc-DCs, exclusively expressed in human conventional DCs (cDCs), decreased DC differentiation and reduced the antigen presentation ability of DCs by increasing the expression of STAT3 (20). Zhang et al. found that the expression of circular malat-1 (circ_malat-1) was attenuated by GDF15, leading to repression of the maturation of DCs (21).

Due to the unique role of DCs in immune diseases, researchers have paid more attention to the regulation of DCs by non-coding RNAs in recent years, considering this an important mechanism for further studying the relevant mechanisms and pathological processes in immune diseases. This review summarizes recent developments in non-coding RNA and DC research related to various autoimmune diseases and transplantation immunity, especially highlighting the immunomodulatory role of miRNAs, circRNAs, and lncRNAs in the processes of immune diseases mediated by DCs (Table 1).

Table 1

The targets and regulatory effect of noncoding RNAs on DCs in autoimmune and immune tolerance-related diseases.

DiseaseNon-coding RNAsType of regulationDCs (subsets or sources)Predicted/identified targetsFunctionRefs
SLEmiR574pDCTLR7Promote pDC maturation and secretion of IFN-α, TNF- and IL-6(22)
miR LET7b miR21
miR-361-5p,pDCTLR7Increase IFN-α secretion(23)
miR-128-3p miR-181a-2-3p
miR-155pDCTLR7MHC class II, CD40, CD86 expressions and IFN-α secretion increased(24)
miR-29bpDCTLR9 Mcl-1, Bcl-2Promote pDCs apoptosis(25)
miRNA-150cDCTREM-1inflammation decreased in SLE(26)
miR-142-3pcDCNDIncrease secretion of related cytokines, inhibit Treg, and promote proliferation of CD4+T(27)
RAmiR-34aDCs (CD1c+)AXLPromote DCs activation of T cells(28)
miR-363cDC (CD11C+av+)NDIncrease Th17 cells differentiation(29)
pSSmiR-29apDCNDIncrease pDCs survival(30)
miR-708cDC (CD1c+)TLR3, TLR7/8Increase the secretion of IL-12 and TNF-α(31)
IBDmiR-10acDC (CD11c+)IL-12/IL-23p40Low inflammatory environment in the intestines(32)
MSmiR-233cDC (CD11b+CD11c+)NDInhibit activation of Th17 by decreasing levels of IL-1, IL-6, IL-23(33)
SScmiR-31cDC (CD11c+)NDReduce the number of DC migrations to CNS(34)
miR-618pDCIRF8Reduce the development of pDCs in SSc(35)
Autoimmune myocarditismiR-223-3pTol-DCNLRP3Inhibition of DCs maturation(36)
GVHDmiR-155DCs (BMDC)NDDecrease the migration and inflammatory activation of DC(37)
miR-146aDCs (BMDC, MoDC)JAK-STATUpgrade histopathological GVHD scores(38)
miR-29aDCs (BMDC, MoDC)TLR7 (mouse)promote DC maturation, migration and activation of T cell proliferation(39)
TLR8 (human)
SLElnc-DC (ENST00000604411.1, ENST00000501122.2)DCs(MoDC)NDPositive correlation with SLEDAI Score(40)
Autoimmune myocarditislncRNA NEAT1cDCs (CD80+, CD86+, MHC II+)Sponge miR-3076-3p NLRP3Increase DC induced Tregs and inhibited T cells proliferation(41)
lncRNA MALAT1Tol-DCs (DC-sign+)mir155-5pPromote the formation of Tol-DCs(42)
SLEcircHLA-CDCsmiR-150Promote pDCs maturation(43)
Autoimmune myocarditiscircSnx5cDC (CD80+, CD86+, MHC II+)miR-544Reduce inflammation of EAM by regulating SOCS1, PU.1(44)
circ_Malat-1cDC (CD11c+CD80+, CD86+, MHC II+)GDF15Increase tolerogenic phenotype of DCs
Increase the secretion of IL-12 and TNF-a; Increased IL-12 and TNF-A secretion in DCs.
GDF15, Growth differentiation factor 15; NF-κB, nuclear factor kappa-B. ND, not done; ↑, upregulated; ↓, downregulated.

Plasmacytoid Dendritic Cells (PDCs)
pDCs are a small subset of DCs that share a similar origin, and pDCs express a narrow range of pattern-recognition receptors (PRRs), including Toll-like receptor 7 (TLR7) and TLR9 (45). Under the stimulation of the above receptors and exogenous or endogenous nucleic acids, pDCs can secrete a large amount of type I IFN and other pro-inflammatory cytokines.

The numbers of pDCs in lymphoid tissues and related target organs, as well as the level of peripheral type I IFN, change in autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and psoriasis (46–48). In SLE, differentiation of Exfo B cells into AFCs requires activation of TRL signalling, which requires the involvement of pDCs (49). Some researchers, therefore, maintain that depletion or functional impairment of pDCs may serve as a viable and potentially specific treatment strategy for lupus (50). In addition to acting directly on autoimmune diseases, pDCs can also affect autoimmunity by regulating other immune cells. Nakamoto et al. demonstrated that bone marrow-derived pDCs induce IL-35 production through Treg cells during ConA-induced acute hepatitis, and the level of type I IFN released by pDCs was also increased. Consequently, the role of pDCs in autoimmune diseases cannot be ignored.

Conventional Dendritic Cells (CDCs)
According to the dependence of transcription factors on development, different subtypes of cDC can be divided into cDC1 and cDC2 (51). In the MHC I environment, cDC1s present antigens to immature CD8+ T cells, while in the MHC II environment, cDC2s present more antigens to immature CD4+ T cells (52).

As cells that play a significant role in nonspecific and specific immunity, cDCs are also involved in a variety of autoimmune diseases. The number of cDCs in the peripheral blood of patients with autoimmune diseases (SLE or RA) is related to their localization in the target tissue (53–56). In RA patients, the number of cDCs was found to be increased in synovial fluid and decreased in peripheral blood (57). cDCs appear to express a unique chemokine receptor: CCL6, the CCL20 receptor. CCL20 leads to infiltration of a variety of inflammatory cells, including immature DCs and Th17 effector lymphocytes, and the production of inflammatory cytokines, including TNF-α, IL-1, and IL-17, in inflammatory synovial tissue, which induces recruitment of local cDCs (58, 59). We demonstrated that the role of abnormal autophagy in the immunogenic maturation of cDCs in autoimmune hepatitis should not be ignored, and inhibition of autophagy may be a novel therapeutic strategy for AIH (60).

Tolerogenic Dendritic Cells (Tol-DCs)
DCs can promote the tolerance of autoreactive T cells and induce effector T cell differentiation in specific tissue environments, thus affecting autoimmunity, immune tolerance, or both (61). DCs in this state are called tolerogenic DCs (Tol-DCs). However, whether there is a specific sensitized cell origin in the body or whether the sensitized phenotype of DCs reflects their activation state is still unclear (62).

The role of Tol-DCs in autoimmunity is characterized by low expression of costimulatory molecules, production of immunomodulatory cytokines, and inhibition of the proliferation of T cells (63). In addition, the important interaction between Tregs and Tol-DCs in the maintenance of peripheral tolerance in mice and humans cannot be ignored (64). Tol-DCs can promote the differentiation of Treg cells through various mechanisms, such as the production of IL-10, IL-27, TGF and other cytokines and the expression of indoleamine 2,3-dioxygenase (IDO), thereby changing the levels of extracellular adenosine triphosphate (ATP) and adenosine (12, 65–68). Furthermore, treatment centred on tol-DCs administration is yielding promising results as an alternative to immune modulators (69). Tolerant dendritic cells inhibited T cell proliferation and delayed the occurrence of GVHD in mice through lactic acid synthesis (70).

MicroRNAs Regulate Dendritic Cell-Mediated Autoimmune and Immune Tolerance-Related Diseases

Some previous studies have shown that miRNAs can act as regulatory molecules to affect the expression of target genes, thereby altering the immune state of the body (71). MiRNAs influence the pathogenesis of a variety of autoimmune and immune tolerance-related diseases by regulating DCs (Figure 1). In terms of treatment, pri-miRNAs may even become innovative drugs for the treatment of immune diseases (72).

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Figure 1
Typical microRNA-mediated pathways in DCs. 1) Activation of TLR7 by the TLR7 agonist R837 resulted in increased miR155 expression, which in turn promoted pDC maturation (elevated MHC class II/CD86 expression) and increased IFN-α secretion. 2) Under the stimulation of extraneous inflammatory factors, TLR7/8/3 was activated, which increased the expression of miR-708/miR-130a, leading to the inhibition of MSK1 and promoting the secretion of IL-12/TNF-α in cDCs. 3) The increased expression of miR-223-3p was followed by inhibition of NLRP3 inflammocytes, thereby promoting the DC tolerance phenotype (decreased EXPRESSION of MHC Class II/CD86/CD80), leading to increased secretion of IL-10/TGF-β and promoting Treg proliferation. 4) Activation of TLR7 by exosome-derived microRNAs through cell membranes can promote pDC maturation and increase IFN-α secretion.

Rheumatoid Arthritis (RA)

RA is a chronic and inflammatory synovitis systemic autoimmune disease and is the most frequent autoimmune polyarthritis, with a lifetime prevalence of 3.6% in women and 1.7% in men (79, 80). Activation of DCs is involved in the pathogenesis of RA. Synovial fluid can contain both conventional CD1c+ and inflammatory CD1c+ cells, and these cells not only prime naive T cells (81) but also stimulate TLR7/8 ligands; in response, cytokines such as TNF are produced, thereby promoting synovial inflammation (82).

Changes in the expression level of miRNAs can affect the abundance of DC surface receptors and thus regulate the maturation of DCs to change the inflammatory state in RA. A study found that CD1c+ DCs continuously expressed high levels of miR-34a, which inhibited the expression of cellular AXL, a tyrosine kinase receptor, thus contributing to the development of experimental arthritis.

This expression of miR-34a may shift DCs towards a mature state, and mature DCs can support autoreactive T cells. Furthermore, in animal studies, compared with wild-type (WT) mice, miR-34a−/− mice had a significantly lower incidence and severity of arthritis (28), which means that miR-34a inhibitors could be a potential treatment for RA.

In addition, miRNAs can also affect helper T cell differentiation by regulating DCs, thus affecting the development of RA. Another study found that CD11C+av+ DCs induced Th17 cell differentiation. A possible mechanism has been proposed: decreased miR-363 expression in DCs from RA patients was shown to upregulate the expression of integrin av, which induced the activation of TGF-β and promoted the differentiation of Th17 cells (29); Th17 cells can exacerbate RA and are directly involved in cartilage and bone destruction (83).

reference link :

More information: Mary Canavan et al, Functionally Mature CD1c+ Dendritic Cells Preferentially Accumulate in the Inflammatory Arthritis Synovium, Frontiers in Immunology (2021). DOI: 10.3389/fimmu.2021.745226

Achilleas Floudas et al, Loss of balance between protective and pro-inflammatory synovial tissue T-cell polyfunctionality predates clinical onset of rheumatoid arthritis, Annals of the Rheumatic Diseases (2021). DOI: 10.1136/annrheumdis-2021-220458


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