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Int J Biol Sci 2022; 18(9):3731-3746. doi:10.7150/ijbs.67587 This issue Cite

Review

The role of YKL-40 in the pathogenesis of autoimmune diseases: a comprehensive review

Kalthoum Tizaoui^1,*, Jae Won Yang^2,*, Keum Hwa Lee³, Ji Hong Kim³, Minseok Kim⁴, Sojung Yoon⁴, Yeonwoo Jung⁴, Joon Beom Park⁴, Kitae An⁴, Hyeok Choi⁴, Donggyu Song⁴, HyunTaek Jung⁴, Seongmin Ahn⁴, Taeho Yuh⁴, Hee Min Choi⁴, Jae Ha Ahn⁴, Younjuong Kim⁴, Sanghyun Jee⁴, Hyeongsun Lee⁴, Soohwa Jin⁴, Jun-Gu Kang⁴, Bohyun Koo⁴, Joo Yeop Lee⁴, Kyoung Min Min⁴, Wonseok Yoo⁴, Hyeong Jun Rhyu⁴, Yeonjung Yoon⁴, Min Ho Lee⁴, Sung Eun Kim⁴, Jimin Hwang⁵, Ai Koyanagi^6,7, Louis Jacob^6,8, Seoyeon Park⁴, Jae Il Shin³ , Lee Smith⁹

1. Laboratory Microorganismes and Active Biomolecules, Sciences Faculty of Tunis, University Tunis El Manar, Tunis, Tunisia.
2. Department of Nephrology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea.
3. Department of Pediatrics, Yonsei University College of Medicine, Seoul, Republic of Korea.
4. Yonsei University College of Medicine, Seoul, Republic of Korea.
5. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, USA.
6. Parc Sanitari Sant Joan de Deu/CIBERSAM, ISCIII, Universitat de Barcelona, Fundacio Sant Joan de Deu, Sant Boi de Llobregat, Barcelona, Spain.
7. ICREA, Pg. Lluis Companys 23, Barcelona, Spain.
8. Faculty of Medicine, University of Versailles Saint-Quentin-en-Yvelines, Montigny-le-Bretonneux, France.
9. The Cambridge Centre for Sport and Exercise Sciences, Anglia Ruskin University, Cambridge, UK.
* These authors contributed equally to this work.

✉ Corresponding author: Jae Il Shin, M.D., Ph.D. Address: 50 Yonsei-ro, Seodaemun-gu, C.P.O. Box 8044, Department of Pediatrics, Yonsei University College of Medicine, Seoul 03722, Republic of Korea. Tel: +82-2-2228-2050; Fax: +82-2-393-9118; E-mail: shinjiac More

Abstract

YKL-40, a chitinase-3-like protein 1 (CHI3L1) or human cartilage glycoprotein 39 (HC gp-39), is expressed and secreted by various cell-types including macrophages, chondrocytes, fibroblast-like synovial cells and vascular smooth muscle cells. Its biological function is not well elucidated, but it is speculated to have some connection with inflammatory reactions and autoimmune diseases. Although having important biological roles in autoimmunity, there were only attempts to elucidate relationships of YKL-40 with a single or couple of diseases in the literature. Therefore, in order to analyze the relationship between YKL-40 and the overall diseases, we reviewed 51 articles that discussed the association of YKL-40 with rheumatoid arthritis, psoriasis, systemic lupus erythematosus, Behçet disease and inflammatory bowel disease. Several studies showed that YKL-40 could be assumed as a marker for disease diagnosis, prognosis, disease activity and severity. It is also shown to be involved in response to disease treatment. However, other studies showed controversial results particularly in the case of Behçet disease activity. Therefore, further studies are needed to elucidate the exact role of YKL-40 in autoimmunity and to investigate its potential in therapeutics.

Keywords: YKL-40, Autoimmune disease, Pathogenesis, Diagnostic marker, Biomarker

1. Introduction

YKL-40 is a 40-kDa heparin-and-chitin binding glycoprotein and also known as chitinase-3-like protein 1 (CHI3L1) [1], a 38-kDa heparin-binding glycoprotein [2] or human cartilage glycoprotein 39 (HC gp-39) [3]. YKL-40, coded by the gene CHI3L1 in chromosome 1q31-q32. [4,5], was first discovered in 1992 in the secretion of human osteoblastic cells in culture [6]. The name YKL-40 was derived from the three N-terminal amino acids - tyrosine (Y), lysine (K), and leucine (L) - present on the secreted form [7]. Although YKL-40 is a member of glycoside 18 family of chitinases [8], it does not have enzymatic properties [5,9,10].

It is expressed and secreted by various kinds of cells such as chondrocytes, fibroblast-like synovial cells, vascular smooth muscle cells, and macrophages. Its exact pathophysiological function and mechanism of action is currently unknown, but it is thought to play a role in inflammation, tissue remodeling, and angiogenesis [11]. It is involved in the activation of the innate immune system, extracellular matrix remodelling, [8,12] and the differentiation of CD14+ monocytes to CD14- and CD16+ macrophages [13]. YKL-40 stimulates the proliferation of human connective tissue cells (fibroblasts, chondrocytes, synovial cells) in a dose-dependent manner [14,15] and also plays important roles in the antigen-induced T-helper 2-response, antigen sensitization and IgE induction as well as activation of innate immune cells [16]. Recent studies have suggested important roles of YKL-40 in various autoimmune diseases. However, these findings have not been reviewed comprehensively. This review will discuss the potential of YKL-40 in the pathogenesis of autoimmune and rheumatic diseases, such as rheumatoid arthritis, psoriasis, systemic lupus erythematosus, Behçet disease, and inflammatory bowel disease. Possible therapeutic strategies by targeting YKL-40 will also be discussed.

2. Rheumatoid arthritis (RA) and YKL-40

Rheumatoid arthritis (RA) is a chronic autoimmune disease principally affecting the synovial joints, causing pain and limitation of motion by the destruction of arthritic cartilage and joint ankylosis. The main aim of RA treatment is to achieve early remission with minimal disease activity. Disease modifying anti-rheumatic drugs (DMARDs) (i.e. sulfasalazine, methotrexate and hydroxychloroquine), glucocorticoids (GC) and biologics such as anti-tumour necrosis factor (TNF)-α inhibitors have been used in the treatment of RA. Disease activity is usually assessed by some indices, such as the 28-joint disease activity score (DAS28) [17] which evaluates the count of tender and swollen joints, inflammation and patient´s assessment of the disease activity.

Although the exact mechanism of joint destruction is still elusive, the presentation of exogenous and autologous antigens by antigen presenting cells (APCs) to T-cells are considered to be an early process of disease, and YKL-40 has been recognized as a potential candidate autoantigen [2,3,4,5,7]. Recently, there have been publications on important roles of YKL-40 in the pathogenesis of RA such as correlations with disease activity of RA and diagnostic or prognostic biomarkers. We will discuss the role of YKL-40 in RA pathogenesis as well as its potential therapeutic target.

A total of 47 articles discussing the association between RA and YKL-40 were identified from PubMed search. There were two review articles: one about the association between YKL-40 and RA [18], and the other about the association between YKL-40, inflammation, and cancer [19]. Twenty-three articles were reviewed in these two review articles [14,15,16,20-40]. From 21 articles newly published after the review, one article was excluded due to multiple confounding variables [41], and another was excluded because it was a phase 1 clinical trial which did not discuss the effect of YKL-40 [42]. We have summarized the key findings of 43 eligible articles (Table 1), 24 of which were included in reviews by Johansen et al. [18] and Kzhyshkowska et al. [19] which have been published thereafter.

2.1 Correlation between YKL-40 and pathogenesis of rheumatoid arthritis

YKL-40 is an important autoantigen in RA immunopathology. Several researches showed locally elevated concentration of YKL-40 in serum and synovial fluid of RA patients, suggesting that YKL-40 plays an important role in RA pathophysiology [43-45]. The immune reaction induced by YKL-40 differs, showing anti-inflammatory phenotypes in healthy people versus proinflammatory phenotypes in half of the RA patients [20]. mRNA for YKL-40 was identified specifically in human articular chondrocytes and liver [21] and overexpressed in the synovium and peripheral blood mononuclear cells (PBMCs) from RA patients [14]. YKL-40 expression is closely related to differentiation of monocytes into macrophages which produce higher levels of YKL-40 in rheumatoid synovium [15]. YKL-40 binds to the HLA-DR4 peptide-binding motif which leads to mononuclear cell proliferation [16,22]. Intracellular HLA-DM also has a crucial role in presenting YKL-40 to CD4+ T cell through “epitope editing” [23]. Moreover, the APCs presenting the immunodominant epitope of YKL-40 mainly appeared at the primary disease sites [24]. One phase 1 study reported that HLA-DR4B1-Org3660l, a peptide derived from YKL-40, inactivated T cell response and induced immune tolerance in RA patients [25]. It also indicates that YKL-40 has an association with RA pathogenesis.

Endogenous processing and major histocompatibility complex (MHC) II-mediated presentation of YKL-40, play major roles in the pathophysiology of RA [46]. Human ex-vivo differentiated DR4+ dendritic cells and macrophages, which were similar to synovial joint APC, were also capable of MHC II-presentation of YKL-40 epitopes [44]. A study using binding assay visualized the constitution of HLA-DR4 (B1*0410)/YKL-40 complex and showed that this can modify antigen-specific, pro-inflammatory responses in HLA-DR4 transgenic mice [45]. Not only inducing T cell proliferation, YKL-40 also activates the FAK/PI3K/Akt pathway, thereby inducing the production of IL-18 in osteoblasts and the inhibition of miR-590-3p. This, in turn, stimulates endothelial progenitor cell (EPC) angiogenesis, subsequently promoting inflammation, a process critical to the pathogenesis of RA [47]. Serum and synovial YKL-40 levels were strongly correlated with the levels of other inflammatory cytokines like IL-1β and TNF-α, suggesting that these molecules together play an important role in RA pathogenesis and disease activity [48]. Moreover, Petersson et al. (2006) also reported that arginine-vasopressin (AVP) and parathyroid hormone-related peptide (PTHrP) stimulated YKL-40 secretion particularly in RA chondrocytes [26,32], while Nielsen et al. suggested the association between the g.-131 (C > G) promoter SNP in the CHI3L1 gene and the serum concentration of YKL-40 [49]. Proposed pathogenic mechanisms of YKL-40 in RA are demonstrated in Figure 1.

2.2 Efficacy of YKL-40 as a biomarker of rheumatoid arthritis

Diagnostic marker

Since the serum and synovial fluid YKL-40 levels in RA patients were higher than those in the healthy controls, YKL-40 seemed to be a useful diagnostic marker for RA [16,27]. In one study which synovial biopsy samples are obtained from 154 patients, presentation of specific YKL-40 peptides in the context of class Ⅱ MHC was a highly specific histopathologic marker with a PPV of >90% for atypical RA patients [50].

However, mere serum or synovial YKL-40 level has a significant limitation to be an effective diagnostic tool since it cannot differentiate RA from other joint inflammatory diseases [28]. Production of YKL-40 might be a just response to an altered tissue environment, since YKL-40 plays a role in cartilage-remodeling process [16]. Moreover, some argued that YKL-40 values have a limited efficacy as a diagnostic marker. Harvey et al. (2000) suggested that serum YKL-40 level does not provide any additional information that would not be attainable by means of conventional biochemical measurements of disease activity like ESR or CRP levels [29]. Sekine et al. (2001) also suggested that it is not a sensitive marker for RA diagnosis as YKL-40 was detected in only 1 of 87 RA patients [30].

In contrast to mere expression of YKL-40, monoclonal antibody 12A staining in the synovial membrane was highly specific for RA. Monoclonal antibody 12A, which acts directly against HLA-DR4/HC gp‐39^263-275 complex, can be a novel immune-pathologic diagnostic tool for RA [24]. Steenbakkers et al. showed that monoclonal antibody 12A has the highest specificity for the complex among 5 monoclonal antibodies that bind to HLA-DR4/HC gp‐39^263-275 complex, and therefore can be used to effectively detect MHC/peptide/TCR complexes in the synovium of RA patients [31]. Also, in review paper by Johansen et al., the author suggested YKL-40 as a potential diagnostic marker of RA because of higher YKL-40 elevation in RA rather than OA compared to healthy people [18]. However, there are few papers about YKL-40 as a diagnosis marker. Therefore, whether YKL-40 can be used to diagnosis in RA should be further studied.

 Figure 1 

Role of YKL-40 in RA pathogenesis. (A) YKL-40 binds to the HLA-DR4, inducing mononuclear cell proliferation through HLA-DM dependent MHC II-mediated presentation of APCs. Intracellular HLA-DM also plays an important role in the presentation of YKL-40 to CD4+ T cells via "epitope editing”. YKL-40 induces mononuclear cell proliferation by binding to the HLA-DR4 peptide binding motif (B) YKL-40 also activates FAK/PI3K/Akt pathway in osteoblast, resulting in IL-18 production and EPC angiogenesis through inhibition of miR-590-3p. This in turn stimulates endothelial progenitor cell (EPC) angiogenesis, promoting inflammation, a process critical in the pathogenesis of RA. Abbreviations: RA: rheumatoid arthritis; HLA: human leukocyte antigen; MHC: major histocompatibility complex; APC: antigen presenting cell; FAK: focal adhesion kinase; PI3K: phosphoinositide 3-kinase; Akt: protein kinase B; IL-18: interleukin-18; EPC: endothelial progenitor cell; miR: microRNA.

Correlation with disease activity

There may be various criteria for determining disease activity, such as DAS28, inflammation, radiological score (Larsen score), functional disability, erosion which means joint destruction, and clinical course. In order to explain the relationship between YKL-40 and disease activity, it is necessary to explain whether or not there is a significant relationship with YKL-40 level in each criterion. In addition, whether or not YKL-40 is a marker of disease activity also depends on whether it is a baseline value or a value that reflects treatment response. In fact, Table 1 summarizes many studies explaining the relationship between YKL-40 by distinguishing the baseline state from the treatment response state.

The association between YKL-40 and RA disease activity have been studied primarily via the measurement of YKL-40 levels in the serum (sYKL-40). sYKL-40 levels are increased significantly in RA patients compared to healthy controls [16,32-33], inactive RA groups [16], or in inactive patients who developed active RA [34]. YKL-40 levels have also been studied in the synovium, which have shown an increase of YKL-40 levels in the synovial fluid [35] or an increase in the number of YKL-40 positive cells in the synovial membrane [27]. Correlations have been found between disease activity and sYKL-40 levels in RA patients [27,36], and even between disease activity and the immune response to YKL-40 levels in vitro [37].

In one study, sYKL-40 level was positively correlated with radiological scores used to assess joint destruction, but not with joint pain or swelling [32]. Similarly, YKL-40 expression in the synovial tissue was reported to have correlation with joint destruction [14].

Only one paper was an in vitro experiment [51]. The other papers were in vivo experiments [43,50,52-57]. One of the seven papers evaluated the correlation between sYKL-40, cf-PWV and IMT-C as well as DAS28 [54]. Also, one of the seven papers evaluated sYKL-40 and synovial thickening and vascularization scores [55]. In the early phase of GPI-induced arthritic mice study, high sYKL-40 was detected [51]. In two randomized controlled trial (RCT) studies, sYKL-40 level had a positive correlation with early rheumatoid arthritis (ERA) disease activity [52,53]. In a cross-sectional study including 42 ERA patients and 35 healthy patients, sYKL-40 levels were highly correlated with DAS28 [54]. Another study including 51 ERA patients and 21 polyarthritis (PA) patients, increased YKL-40 in serum was observed only in RA patients [56]. In one study where 25 Danish RA patients got repeated measurement of various serum markers during treatment, YKL-40 serum was significantly elevated in RA patients [43]. In one study, the MBDA score where twelve markers including serum YKL-40 are combined was significantly correlated with RA disease activity [50]. Interestingly, a study evaluating arterial stiffness by cf-PWV and IMT-C by carotid ultrasonography [54] showed that sYKL-40 was highly correlated with cf-PWC and IMT-C as well as DAS28. These results suggest the possibility of early detection of atherosclerosis using sYKL-40 [54]. Correlation between YKL-40 level and synovial thickening and vascularization score was observed in one study [55]. Therefore, YKL-40 serum could be used as a disease activity marker of RA.

Seven papers are available for evaluating sYKL-40 level during RA treatment [34,35,38,43,53,56,58]. sYKL-40 levels decreased with RA treatment in several studies [34,35,38,43,53,58]. However, there were also conflicting results [58]. Administration of intra-articular glucocorticoids, DMARD therapy, and prolonged TNF-alpha neutralization led to a significant decline in sYKL-40 levels in RA patients [34,35,38]. DMARD therapy in combination with prednisolone was reported to be more effective than DMARD therapy alone when the decrease in sYKL-40 levels was compared between the two treatment groups after 1, 7, 14, and 30 days [34]. Specifically, in one RCT study where 99 ERA patients received DMARD therapy for 26 weeks, sYKL-40 levels decreased with DMARD [53,58]. In a 1-year pilot study where 20 RA patients received infliximab and concomitant methotrexate therapy for 52 weeks, sYKL-40 levels decreased after infliximab therapy [58]. In one study including 25 Danish RA patients, sYKL-40 significantly decreased after anti-TNF-α agents [43]. However, in another study, sYKL-40 level was decreased only in patients who achieved remission, but not in all of RA patients [56]. Therefore, sYKL-40 could be used to evaluate treatment response.

Correlation with long-term prognosis

One study showed that sYKL-40 levels have a correlation with RA progression (assessed by the Larsen score and the extent of bone erosions) [32], while other studies suggested no association between sYKL-40 and RA progression [36,39]. Four papers using YKL-40 as a marker are available for long-term prognosis of RA. The others evaluated YKL-40 as a long-term prognosis marker in RA patients [52,58,59]. Four papers had a consensus that sYKL-40 seemed to be not a long-term prognosis marker and to be not associated with radiographic progression in RA [18,52,58,59]. In one cohort study where 238 RA patients are followed for 10 years, sYKL-40 level didn't show any correlation in 5- and 10-years radiographic progression [59]. In 1-year pilot study where 20 RA patients got infliximab and concomitant methotrexate therapy for 52 weeks, YKL-40 did not show correlation with radiographic joint destruction [58]. Also, in two investigatory-initiated RCTs on naïve ERA patients, YKL-40 was not useful in predicting patient's prognosis in radiographic or clinical aspects [52]. Therefore, YKL-40 did not seem to be a long-term prognosis marker, nor was it associated with radiographic progression in RA.

1.3 Effect of YKL-40 suppression in rheumatoid arthritis

Three papers evaluating YKL-40 suppression are available for RA treatment [51,60,61]. Injecting YKL-40 in an early phase of GPI-induced arthritis mice caused decreased antigen-specific T cell proliferation and cytokine production [51]. By using surgical procedures, a study investigated the relationship between and intra-nasal YKL40 injection in lymph nodes and tolerance induction in mice [61]. They concluded that lymph nodes that drain the nasal mucosa is crucial in tolerance induction in mouse model AG (OVA) [61,67]. This showed the possibility of injecting YKL-40 as RA treatment [51,61]. However, in a phase II, double-blinded RCT study where RA patients received internal YKL-40 therapy, there was no significant change in DAS28 compared to placebo group [60]. Therefore, other strategies including changes in way to convey YKL-40 or combination of other immune regulators should be studied.

3. Psoriasis and YKL-40

Psoriasis is an immune-mediated systemic inflammatory disease, characterized by erythematous, well-demarcated plaques with silvery scale [62]. Psoriasis could be classified into five different types: plaque, guttate, inverse, pustular, and erythrodermic psoriasis. Plaque psoriasis, also referred as psoriasis vulgaris, is the most prevalent type. Pustular psoriasis and erythrodermic psoriasis are rare but can be life-threatening. There are diverse comorbidities related to psoriasis, including psoriatic arthritis, cardiovascular disease, lymphoma and Crohn's disease [63]. Psoriasis has high prevalence and demonstrates chronic progress without a definite cure, making it more challenging to deal with. Through PubMed search, a total of 11 studies were found to discuss the relationship between psoriasis and YKL-40 (chitinase-3-like protein 1, CHI3L1, human cartilage glycoprotein-39) (Table 2) [64-74]. Most of them showed a positive association between psoriasis and YKL-40 [64-72], while 2 studies reported negative or no association [73,74].

3.1 Positive correlation between psoriasis and YKL-40

Multiple biomarkers have been used for the diagnosis of psoriatic diseases. Increase in white blood cell count, C-reactive protein (CRP), and several cytokines such as IFN-γ were found in patients with psoriasis; however, these markers alone lack sensitivity and specificity for evaluating the severity of disease [75]. Several studies recently showed the possibility of YKL-40 as a new diagnostic marker for psoriasis and its possible correlation with disease severity. Imai Y et al. first observed the elevation of YKL-40 in patients with psoriasis vulgaris compared with control group, and the difference was more obvious in patients with generalized pustular psoriasis, a more severe inflammatory form of psoriasis [64]. sYKL-40 level was also suggested to show positive relationship with the severity of skin lesions in patients with psoriatic arthritis, a type of arthritis that occurs in psoriasis patients [65]. Ahmed S et al. stated that sYKL-40 level might be used for evaluating disease activity and angiogenesis in patients with psoriasis [66]. YKL-40 could also be helpful for diagnosing and monitoring patients with psoriatic arthritis as an inflammatory marker [67, 68]. Salomon et al. stated that an increased YKL-40 level reflects the presence of systemic inflammation rather than cutaneous lesions [67] and found its correlation with the severity of psoriatic arthritis, which was scored with 28-joint Disease Activity Score (DAS-28) in the study [68]. There were conflicting findings regarding YKL-40's legitimacy in evaluating treatment response. Baran A et al. stated that YKL-40 might be interpreted as a marker of psoriasis, but not for evaluating metabolic condition or efficacy of treatment [69]. However, decreased sYKL-40 level after narrow-band ultraviolet B phototherapy was observed in psoriasis vulgaris patients [70].

Furthermore, sYKL-40 level is also related to vascular defects in psoriasis patients. YKL-40 level is positively correlated with carotid intima-media thickness and defective aortic elasticity in patients with psoriasis [71]. According to Erfan G et al, YKL-40 might be associated with endothelial dysfunction in psoriasis and could be applied for managing cardiovascular diseases in high-risk psoriasis patients [72].

3.2 Negative or no correlation between psoriasis and YKL-40

There are two studies that show negative or none correlation between psoriasis and YKL-40. Ataseven et al. reported that the YKL-40 levels of psoriasis group are not significantly different from the levels of healthy controls [73]. Jensen et al. revealed that there is no correlation between YKL-40 and psoriasis severity [74]. However in psoriatic arthritis group, which is a type of arthritis that occurs in psoriasis patients, YKL-40 level had association with disease severity and treatment response [74].

4. Systemic lupus erythematosus (SLE) and YKL-40

SLE is an autoimmune disease that involves multiple organs including the skin, kidney, brain, and joints [76]. Majority of patients are women of childbearing age, which accounts for 90% of total SLE patients [77]. There are several classic markers that have been used to estimate disease activity in SLE patients, such as anti-dsDNA titer and measurements of C3, C4, CH50 [78]. A total of 3 associations between SLE and YKL-40 were identified from a PubMed search (Table 3) [36,79,80].

Two studies which compared YKL-40 levels between SLE patients and healthy controls showed concordant findings. Vos et al. first revealed that SLE patients have higher YKL-40 levels than healthy controls [36]. However, YKL-40 levels in SLE patients were lower compared to RA patients and did not correlate with disease activity [36]. Wcisło et al. also showed that average plasma levels of YKL-40 is about twice higher in the SLE group than in controls [79]. Likewise, YKL-40 had no correlation with disease activity or the severity of joint involvement [80]. There was an in vitro study that showed reduced reactivity of T cells from SLE patients in response to YKL-40 [80]. Vos et al. incubated T-cells in the settings of five types of YKL-40 and compared its growth rate between different disease entities including SLE [80]. They studied the responses of T-cells to YKL-40 in patients with various inflammatory conditions [80] and found that T-cells from RA patients showed a proliferative response to YKL-40 [80]. In contrast, T-cells from SLE patients showed low response to YKL-40 [80].

5. Behcet's disease (BD) and YKL-40

BD is a systemic inflammatory disorder with recurrent oral ulcers, genital ulcers, eye lesions, and skin lesions [81]. It can also involve joints, central nervous system, gastrointestinal tract, and large vessels [81]. Although the pathogenesis of BD is not fully known, neutrophilic hyperactivity and overproduction of pro-inflammatory cytokines and reactive oxygen species (ROS) are considered to be major mechanism of the disease [81,82,83]. PubMed search identified two studies describing the association between BD and YKL-40 (Table 4) [84,85].

Seo et al. first reported the correlation between BD and YKL-40 [84]. By comparing sYKL-40 levels of control group and inactive/active BD patients, they revealed that YKL-40 was significantly higher in BD patients [84]. In addition, patients in the active BD group showed an elevation in sYKL-40 levels compared with inactive BD patients [84]. Since YKL-40 levels showed a positive correlation with disease activity, they proposed YKL-40 as an alternative marker to monitor disease activity in BD patients [84]. Bilen et al. also reported YKL-40 elevation in BD patients [85]. However, this study failed to show the association between YKL-40 levels and disease activity, which is inconsistent with the previous study [85]. Therefore, further research is required to clarify the correlation between YKL-40 and BD activity.

6. Inflammatory bowel disease (IBD) and YKL-40

A total of 14 associations between inflammatory bowel disease and YKL-40 were identified from a PubMed search (Table 5) [83-96].

6.1 Correlation between YKL-40 and disease activity in inflammatory bowel disease

A link between YKL-40 and the activity of IBD lies on the process of fibrosis and inflammation during the natural course of IBD [86]. Ten papers reported increased levels of YKL-40 associated with the severity of the disease [86-95]. In both Crohn's disease and ulcerative colitis, the sYKL-40 levels were significantly correlated with C-reactive protein level and disease activity [86]. In Crohn's disease, sYKL-40 level was shown higher in patients with intestinal strictures than in those without intestinal strictures [87]. Vind et al. found that sYKL-40 level is increased in 40-50% of ulcerative colitis and Crohn's disease patients with active disease, and the level was also increased in 30% of patients with Crohn's disease which is clinically inactive [88]. Ytting H et al. reported a case where s YKL-40 level is increased as an appearance of Sweet's syndrome in a patient previously diagnosed with ulcerative colitis, sYKL-40 level acted as a marker of disease activity of Sweet's syndrome [89]. Increased sYKL-40 level was also discovered as the marker for demonstrating articular involvement in inflammatory bowel disease [90]. Punzi L et al. discovered a similar result showing sYKL-40 level was only increased in IBD patient with arthritis, IBD patients without arthritis showed no difference from healthy controls [94]. Among the peptides derived from YKL-40, the human cartilage glycoprotein-39 ^263-275 level was increased in IBD [91]. The fecal YKL-40 level was found to be a marker to assess endoscopic ulceration level in IBD [89]. The fecal sYKL-40 level was also correlated with the severity and disease activity in IBD [93]. In Crohn's disease, sYKL-40 is an autoantigenic target, IgA and secretory IgA antibodies against sYKL-40 level can serve as a marker facilitating the serological diagnosis [95].

6.2 Correlation between YKL-40 and development of cancer in inflammatory bowel disease

The YKL-40 expression in colonic epithelial cells is a biomarker for neoplastic changes in IBD [95]. In a mouse model, the YKL-40 induced cell proliferation and survival while involving down-regulation of the pro-apoptotic S100A9 protein, which promoted tumorigenic changes in the colon and led tumor cells survive and proliferate [97]. In another mouse model, colonic epithelial cells with high levels of YKL-40 expression exhibited malignant transformation in vivo when exposed to azoxymethane, a well-known colonic carcinogen [98]. Higher expression of the YKL-40 was found in the distal colon compared to the proximal colon in mice, resulting in higher chances of tumorigenesis in the distal colon [99].

7. YKL-40 as biomarker of other human diseases with autoimmune mechanism

The serum YKL-40 levels were higher in the multiple sclerosis (MS) group than in control, and which levels in the patients with relapsing remitting multiple sclerosis (RRMS) were correlated with the patients' expanded disability status scale (EDSS) scores and ages. No relationships were determined between the serum YKL-40 levels and the other variables. The findings from this study suggested that YKL-40 may be a useful marker for the inflammatory process of MS [100]. Serum levels of YKL-40 were significantly higher in 40 female patients with systemic sclerosis compared to 14 healthy female controls. In contrast, miR-214 expression in plasma from SSc patients was significantly downregulated compared to controls which shows that the binding of YKL-40 and miR-214 is involved in the mechanism of inflammation and fibrosis [101]. YKL-40 was higher in the poorly controlled symptom and exacerbation group and in patients with non-atopic asthma compared with stable asthma. YKL-40 appears to increase in proportion to the degree of inflammation in diseases with an immune mechanism [102]. Compared to neurological controls, increased YKL-40 levels were detected in sCJD and Alzheimer's disease (AD) but not in vascular dementia (VaD) or in dementia with Lewy bodies (DLB)/Parkinson's disease dementia (PDD). Further, two independent patient cohorts were used to validate the increased CSF YKL-40 levels in Creutzfeldt-Jakob disease (sCJD). YKL-40 is a disease-specific marker of neuroinflammation showing its highest levels in prion diseases [103].

8. Concluding remarks and future perspectives

The biological function of YKL-40 glycoprotein, also known as chitinase-3-like protein 1 (CHI3L1) [1] or human cartilage glycoprotein 39 (HC gp-39) [3], is not that clear, but it is speculated to have some connection with inflammatory reactions and autoimmune diseases [9,11]. We reviewed 51 articles that discussed the association of YKL-40 with RA, Psoriasis, SLE, BD and IBD. Results highlight the value of YKL-40 as biomarker of autoimmunity and rheumatic diseases.

In the first place, we found 21 articles discussing associations between RA and YKL-40. Two pathogenesis of RA related to YKL-40 are unknown; acting as an autoantigen or an inducing factor of IL-18 expression [44-47]. There were two articles including a review article on using YKL-40 as a diagnostic marker of RA [18, 50]. Both showed the possibility of YKL-40 as diagnostic marker of RA, and one of them demonstrated the presentation of specific YKL-40 peptides in the context of MHC-II [50]. As a result, YKL-40 could be assumed as a diagnostic marker of RA, but further studies are needed. There were nine articles investigating the correlation of RA disease activity with YKL-40 [18,43,52-57], all of which demonstrated a correlation between YKL-40 level and disease activity of RA. Furthermore, one of the papers that used cf-PWV and IMT-C as disease activity indices presented the potentiality of YKL-40 as an early detection marker of atherosclerosis in RA patients [54]. Including a review article, there were five articles on evaluating s YKL-40 level during RA treatment [18,43,53,56,58]. They revealed YKL-40 levels decreased after therapy by DMARD, infliximab or anti-TNF-alpha agents. Notably, in one of those studies, YKL-40 level was decreased only in patients that achieved remission, but not in all RA patients [56]. As follows, YKL-40 could be used to evaluate treatment response. We could find four articles examining the availability of YKL-40 as long-term prognosis of RA, including a review article [18,52,68,59]. But there was no evidence at all that sYKL-40 level is associated with radiographic progression and long-term prognosis. Lastly, three papers are available for RA treatment using YKL-40 suppression [51,60,61]. This protocol had some controversy, so further studies are warranted.

There were 11 studies on relation between psoriasis and YKL-40. Five of them imply YKL-40 could be used for evaluating disease activity because YKL-40 level is elevated in a more severe form of inflammation than in a less severe form or in controls and in systemic inflammation rather than in cutaneous lesions [64-68], though Jensen et al. argued that there is no correlation [73]. Furthermore, there were two articles which demonstrate YKL-40 level is also related to vascular defects in psoriasis patients [72]. Two of them investigated YKL-40's legitimacy in evaluating treatment response, but their results were inconsistent. There were two studies showing no correlation of sYKL-40 level with presence of disease and psoriasis severity [74]. However, in the psoriatic arthritis group, YKL-40 level had an association with disease severity and treatment response [74].

Two studies which compared YKL-40 levels between SLE patients and healthy controls showed concordant findings [36,79]. They revealed that SLE patients had higher YKL-40 levels than healthy controls [79], but YKL-40 level had no correlation with disease activity or the severity of joint involvement [79]. There was an in vitro study that showed reduced reactivity of T cells from SLE patients in response to YKL-40 [80].

Two studies describing the association between BD and YKL-40 were identified [84,85]. Two studies revealed that YKL-40 was significantly higher in BD patients [82]. But it was controversial whether YKL-40 level is related to BD activity [84,85].

Ten papers reported increased level of YKL-40 associated with the severity of IBD [86-95]. Also, in the papers, YKL-40 level is increased in active disease, patients with Sweet's syndrome, or those with articular involvement [86-90,94]. Not only sYKL-40 level, but also HC gp-39 ^263-275 level, fecal YKL-40 level, IgA and secretory IgA level against sYKL-40 seemed to have potential to be used as markers [91-93,95]. In addition, the YKL-40 expression in colonic epithelial cells could be a biomarker for neoplastic changes in IBD [96]. YKL-40 down-regulate the pro-apoptotic S100A9 protein, which promoted tumorigenic changes in colon and led tumor cells survive and proliferate [97]. Higher expression of YKL-40 in colonic epithelial cells led to higher chances of tumorigenesis [98,99].

9. Conclusion

In conclusion, this systemic review indicates that YKL-40 is a very promising molecule as a biomarker of RA both in diagnostic and therapeutic aspects. Further studies on YKL-40 for autoimmune diseases as Psoriasis, SLE, BD, IBD and other diseases with immune mechanism are essential to fully elucidate its clinical significance and utility.

Consent for publication

All the authors checked and gave their approval of this version to be published.

Funding

No financial support was provided for research conduct and/or preparation of the article.

Author contributions

All authors made substantial contributions to all of the following; (1) conception and design of the study, data acquisition, or analysis and interpretation of data; (2) drafting or critical revision of the article for intellectual content; and (3) final approval of version to be submitted.

Competing Interests

The authors have declared that no competing interest exists.

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Author contact

Corresponding author: Jae Il Shin, M.D., Ph.D. Address: 50 Yonsei-ro, Seodaemun-gu, C.P.O. Box 8044, Department of Pediatrics, Yonsei University College of Medicine, Seoul 03722, Republic of Korea. Tel: +82-2-2228-2050; Fax: +82-2-393-9118; E-mail: shinjiac

Received 2021-9-29
Accepted 2022-2-8
Published 2022-5-21

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