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Natural autoimmunity in oligoarticular juvenile idiopathic arthritis

Pediatric Rheumatology volume 21, Article number: 44 (2023) Cite this article

Abstract

Background

Oligoarticular juvenile idiopathic arthritis (oligo-JIA) is considered as an antigen-driven lymphocyte-mediated autoimmune disease. Natural antibodies (NAbs) are pre-immune antibodies produced in the absence of exogenous antigen stimulation, participating in both, innate and adaptive immunity. Considering their major immunoregulatory role in homeostasis and autoimmune pathogenesis, we designed this study to further elucidate their role in oligo-JIA pathogenesis.

Methods

Seventy children with persistent oligo-JIA and 20 healthy matched controls were enrolled in the study. Serum IgM and IgA antibodies against human G-actin, human IgG F(ab΄)2 fragments and the hapten TriNitroPhenol (TNP) as well as the total concentration of serum IgM and IgA were measured by in-house enzyme-immunoassays. Kolmogorov–Smirnov normality test, Kruskal–Wallis H and Mann–Whitney tests were used to assess data distribution, and significant differences of non-parametric data between groups of the study. Backward regression analysis was used to analyze the effect of multiple factors (age, gender, disease activity, anti-nuclear antibody positivity, presence of uveitis) on continuous dependent variables (activities and activity/ concentration ratios of IgM and IgA NAbs).

Results

The ratios of IgA anti-TNP, anti-actin and anti-F(ab΄)2 levels to total serum IgA concentration were found to be significantly increased in patients with oligo-JIA compared to healthy subjects. Significantly elevated levels of IgM anti-TNP antibodies were also found in children with inactive oligo-JIA compared to those of children with active disease and of healthy controls. In the presence of anterior uveitis, IgM anti-TNP levels were significantly higher than in patients without uveitis or in healthy controls. Backward regression analysis revealed that the disease activity and the presence of anterior uveitis independently affect IgM anti-TNP levels.

Conclusuions

Our findings are in accordance with the hypothesis that NAbs contribute to the pathogenesis of autoimmune diseases and provide additional evidence that disturbances in natural autoimmunity may contribute to the as yet unclarified pathogenesis of oligo-JIA.

Background

Natural antibodies (NAbs) are defined as pre-immune antibodies produced spontaneously by distinct progenitors (B-1 cells) in the absence of exogenous antigen stimulation and providing immediate protection against infection while a specific and long-lasting adaptive response is mounting. Unique properties of NAbs setting them apart from antigen-specific antibodies are their broad cross-reactivity with a variety of epitopes expressed on both self and non-self antigens (autopolyreactivity), low affinity and germline structure (lacking non-templated nucleotides and little to no somatic hypermutation) [1]. IgM NAbs account for about 80% of all resting serum IgM and, therefore, are most extensively studied [2]. IgA NAbs represent about 50% of circulating IgA, while IgG and IgE NAbs have been also recognized. Beyond protection against various infections, IgM NAbs play fundamental roles in several diverse processes, including clearance of apoptotic debris, [3] regulation of B cell development [4, 5], selection of the B cell repertoire [6] and regulation of B cell responses [7]. It is believed that these functions of IgM NAbs help to maintain tissue homeostasis preventing, as a result, the development of autoimmune diseases [8, 9].

Oligoarticular juvenile idiopathic arthritis (oligo-JIA), the most common amongst the seven subtypes of JIA defined by the International League of Associations for Rheumatology (ILAR) [10], is classically thought of as an antigen-driven lymphocyte-mediated autoimmune disease [11, 12]. Despite that underlying immune pathways are yet to be elucidated, current evidence suggests that altered peripheral B cell homeostasis could be a factor significantly contributing to its pathogenesis [13, 14]. Changes in the frequency of autoreactive B cell subsets have been demonstrated that are accompanied by changes in the molecular events that control B cell tolerance. Indeed, CD5+ B cells, considered as the human counterparts of the murine NAbs producers B-1a cells [15], are expanded in the peripheral blood of patients with oligo-JIA [16]. Moreover, an expansion in CD24hiCD38hi transitional B cells has been reported in oligo-JIA [17]. Like B-1 cells, a high proportion of these cells express polyreactive B cell receptors (BCRs), as they are still undergoing negative selection [18].

Bearing in mind the above, we designed this study to further elucidate the role of natural autoimmunity in the pathogenesis of oligo-JIA. Correlations between clinical parameters of the disease and NAb levels could also indicate their potential role as prognostic biomarkers in oligo-JIA. For this purpose, we examined levels of IgM and IgA NAbs against three selected antigens, namely TriNitroPhenol (TNP), G-actin and F(ab’)2 fragments, which share informative features associated with NAb recognition and their regulatory functions. More specifically, TNP was used for exogenous recognition, since it is a synthetic molecule to which individuals are not normally exposed [13]. Actin was used as an endogenous target, since it is a vital and abundant cytoskeleton component, largely preserved throughout evolution and a frequent target of NAbs [19, 20]. Last but not least, F(ab’)2 fragments were used as endogenous regulatory target, since Fab-Fab interactions participate in major immunoregulatory mechanisms [21], contributing to the termination of successful antibody responses and/or the control of autoreactive B cells [22, 23].

Methods

Patients enrolled in the study

Seventy (70) patients with persistent oligo-JIA diagnosed according to ILAR criteria, and twenty (20) healthy controls were enrolled in the study (Table 1). Patients with IgA immunodeficiency were excluded. Thirty-nine patients were in active disease and thirty-one with inactive. Active disease was clinically defined according to JADAS (Juvenile arthritis disease activity score assessment) 27 cut off scoring definition. Inactive disease state was defined as the presence of no joints with active arthritis, no systemic manifestations attributable to JIA, no active uveitis, normal levels of acute-phase reactants, a physician’s global assessment of disease activity indicating no disease activity, and duration of morning stiffness lesser or equal to 15 min [24, 25]. The presence or absence of disease activity was corroborated by Power Doppler ultrasonography performed by a pediatric radiologist. The Standardisation of Uveitis Nomenclature (SUN) criteria were used to define the anatomical location and time course of uveitis [26]. A valid analysis of the effect of treatment on NAb levels was not feasible, since the therapeutic modalities and schemes varied widely among patients. The study was approved by the Ethics Committee of the Children’s Hospital “Aghia Sofia”, and informed consent was obtained from the patient’s legal guardians.

Table 1 Patients and controls enrolled in the study
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IgM and IgA antibodies against human skeletal muscle globular actin (G-actin), trinitrophenol-bovine serum albumin (TNP-BSA) conjugate and human IgG F(ab΄)2 fragments were measured in sera using in-house enzyme-linked immunosorbent assays (ELISA). In addition, total concentration for serum IgM and IgA was measured by ELISA. To evaluate the actual NAb-activity we took into consideration the total IgM/IgA concentration, in order to eliminate the possibility that higher NAb activity is due to increased IgM/IgA concentration. Therefore, in cases where significant differences were observed between groups with regard to the total IgM and/or IgA concentration, the ratio of NAb levels to the total IgM and IgA concentrations was used for comparisons instead of NAb levels.

Antigens and antibodies

G-actin, TNP-BSA conjugate and F(ab΄)2 fragments derived from an IVIg preparation (Kiovig) were prepared as previously described [27, 28]. The purity and integrity of the above-mentioned antigens was evaluated by sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE). Antibodies used were unconjugated and alkaline phosphatase conjugated: goat antibodies recognizing human IgM (μ-chain specific) and human IgA (α-chain specific) (Sigma-Aldrich).

Measurement of serum NAbs levels

IgM and IgA NAb activity in patients’ sera were evaluated by in-house ‘indirect’ ELISAs against G-actin, TNP-BSA and F(ab΄)2 fragments immobilized on high-binding, flat-bottomed 96-well MaxiSorp plates (Nunc, Denmark). Briefly, plates were 1) coated with antigens [10 μg/ml of human G-Actin, 10 μg/ml of TNP-BSA and 2 μg/ml of F(ab΄)2 fragments (in carbonate-bicarbonate buffer 0,1 M pH 9,6)], washed up and saturated with 1% BSA (Sigma-Aldrich) in PBS, 2) incubated with patients’ and healthy control sera [diluted (1/25 or 1/50, depending on the Ig isotype) in PBS containing 0.1% Tween and 1% BSA (PBS-T-BSA)] overnight at 4 °C, and washed, 3) incubated with alkaline phosphatase linked secondary antibodies (goat anti-human -μ, and -α chain) (0.5 μg/ml in PBS-T-BSA), for 2 h at 37 °C., and washed,, and 4) incubated with the enzyme’s soluble chromogenic substrate p-nitrophenyl phosphate disodium hexahydrate (pNPP) (Sigma-Aldrich) and optical density (OD) of colored product was measured at 405 nm (620 nm reference) with a TECAN spectrophotometer (TECAN Spark Control Magellan V2.2, Grödig/Salzburg, Austria). The enzyme reaction was stopped when the mean value of three selected positive controls reached OD equal to 1.00 (~ 1 h). As sera were tested in different microplates coated with the same antigen (at the same concentration and coating buffer), three standard control sera (treated as sample sera) were always added in each of the plates used to get normalization. All experiments were run in duplicate.

Measurement of serum total IgM and IgA concentration

Human serum total IgM and IgA were measured by in-house ‘sandwich' ELISAs, following standard methodology. Briefly, goat anti-human IgM and IgA antibodies were used for coating (2.5 μg/ml in PBS) of microplates, and BSA (1% in PBS) for post-coating. Sera (diluted 1/4.000 for IgM and 1/15.000 for IgA), were incubated with coated plates, then AP-conjugated secondary anti-μ and anti-α antibodies were added. Dilution and wash buffers, as well as incubation time were as described above in NAbs-ELISA. An 8-point standard curve for IgM and IgA was included in each microplate using a standard control (N/T Protein Control SL/M, Siemens, Germany) (useful range: 500 to 3.9 ng/ml). OD values, reflecting IgM and IgA concentrations, were estimated according to the linear part of the standard curve.

Statistical analysis

Statistical analysis was performed using the IBM SPSS v. 19.0 software. Graphical illustration was made in GraphPad Prism version 6.0.0. Data distribution was assessed with the Kolmogorov–Smirnov normality test. The Kruskal–Wallis H test was used to determine significant differences of non-parametric data between three groups followed by the Mann–Whitney test for two groups mean rank comparisons. Backward regression analysis was used to analyze the effect of multiple factors (age, gender, disease activity, anti-nuclear antibody (ANA) positivity, presence of uveitis) on continuous dependent variables (activities and activity/ concentration ratios of IgM and IgA NAbs). Statistical significance was set at the p < 0.05 level.

Results

IgM and IgA NAbs reactive to TNP, actin, and F(ab’)2 fragments were detected in the sera of oligo-JIA patients and matched healthy controls. All data analyzed in this study are included in supplementary information file 1 (SF1). Total IgA concentration in oligo-JIA patients was significantly lower compared to that of healthy controls (p = 0.001). The ratios of IgA anti-TNP, anti-actin and anti-F(ab΄)2 levels to total IgA concentration were significantly increased in patients with oligo-JIA compared to healthy subjects (p = 0.001, p < 0.001 and p < 0.001, respectively) (Fig. 1).

Fig. 1
figure 1

Measurements on IgA NAbs. Oligo-JIA patients (n = 70) and Healthy controls (n = 20) were measured for a total serum IgA concentration. Ratios of IgA NAb levels to total IgA concentration were estimated and analyzed for b anti-TNP, c anti-actin, and d anti-F(ab’)2 NAbs

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Differences in total serum IgM concentration were not detected among any group of patients or healthy controls. Females were observed to have significantly increased levels of IgM anti-TNP NAbs compared to males (p = 0.001). Significantly elevated levels of IgM anti-TNP NAbs were also found in children with inactive oligo-JIA compared to those of children with active disease (p = 0.025) and healthy controls (p = 0.036). In the presence of anterior uveitis, IgM anti-TNP levels was significantly higher than in patients without uveitis (p = 0.016) or in healthy controls (p = 0.010) (Fig. 2). Backward regression analysis showed significant associations between the IgM anti-TNP and anti-actin levels with anterior uveitis in the oligo-JIA group (p = 0.005/standardized coefficient 0.349 and p = 0.038/standardized coefficient 0.250, respectively). The same regression model identified an impact of both ANA and gender on the reactivity of the IgM isotype to the F(ab’)2 fragments (p = 0.016/standardized coefficient -0.298 and p = 0.028/standardized coefficient 0.272, respectively). No other associations were found among any other of the tested NAb levels or ratios and the parameters of gender and age, disease activity, ANA positivity and presence of anterior uveitis.

Fig. 2
figure 2

Measurements on IgM anti-TNP NAb levels. a Differences between oligo-JIA patients with active disease (n = 39) versus those with inactive disease (n = 31) and Healthy controls (n = 20). b Differences between oligo-JIA patients with uveitis (n = 18) against those without uveitis (n = 52) and Healthy controls (n = 20)

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Discussion

This is the first study on the role of NAbs in the context of persistent oligo-JIA. Significant changes in NAb concentration, repertoire and isotypes have been reported in many systemic and organ-specific autoimmune diseases while increasing evidence suggests that NAbs may interfere or even suppress autoimmune diseases and secondary events [29,30,31,32].

Because of the vast variety of antigens that are potential targets of NAbs, a combination of a minimum number of autoantibodies that reflects the state of the natural autoimmunity in humans is difficult to define [33]. Researchers have focused on different antigens, initially as a means to explore and classify the variety of the target antigens recognized by NAbs and then focused on some, due to their link with pathological conditions. We have selected three antigens, namely TNP, G-actin and F(ab’)2 fragments, as representative target antigens for the estimation of the natural autoimmunity status as: anti-TNP antibodies have been proposed as a surrogate measure for the estimation of serum polyreactivity, which is the key characteristic of NAbs; [34, 35] anti-actin antibodies have been found in sera taken from cord blood and healthy children but their implication in several diseases have been also reported in adult individuals; [18, 19, 36] studies on anti-F(ab’)2 autoantibodies in a variety of diseases, including autoimmune disorders, such as SLE, multiple sclerosis, nephritis, and others, support the experimental evidence regarding their immunoregulatory function [37,38,39].

In our study, significant differences in IgA concentrations were observed among oligo-JIA patients and healthy controls. Moreover, besides the differences in IgA concentration, patients with oligo-JIA presented higher levels of serum IgA NAbs against all the three antigens studied than those observed in age-matched healthy controls. Differences in the levels of IgA NAbs between oligo-JIA and controls observed in our study may reflect disturbances of the gut microbiome characterizing this subtype of JIA [40]. During the last decade, several studies uncover intestinal dysbiosis as a factor contributing to the pathogenesis of JIA subtypes, including oligo-JIA [41]. On the other side, systematically produced and locally secreted IgA NAbs seem to play a critical, despite incompletely understood [42], role in the gut microbiome homeostasis [43].

No differences in total IgM concentration were observed among oligo-JIA patients and healthy controls. Οn the contrary, significant differences in the levels of NAbs against TNP were found among oligo-JIA patients. Disease activity as well as anterior uveitis were proved as independent factors affecting serum levels of IgM anti-TNP NAbs. Indeed, IgM anti-TNP NAb levels in patients with inactive disease and/or anterior uveitis were higher than those of patients with active disease and/or without uveitis, the latter presenting levels similar to those of healthy controls.

Our finding that patients with active disease present with lower IgM NAb levels than those with inactive is in accordance with their contribution to the pathogenesis of autoimmune diseases [44, 45]. Several lines of evidence indicate the pivotal role of NAbs in the pathogenesis of autoimmune diseases [44, 45]. Mouse models of SLE have reduced levels of natural IgM [46, 47] with an increase in the B-1 cell subset and IgG autoantibodies [48, 49]. This reduction in natural IgM levels is associated with loss of the protective role of IgM NAbs, resulting in autoimmune diseases. In addition, in humans as well as in mice, deficiency in IgM increases an individual’s susceptibility for autoimmune diseases [50], while autoreactive IgM levels are greatly elevated in various autoimmune diseases, such as SLE, rheumatoid arthritis, and autoimmune liver diseases [3, 51, 52].

More interesting, however, is our result that the presence anterior uveitis affects independently the levels of circulating IgM NAbs. Similarly, previous studies have shown that in addition to ANA, serum anti-histone-3 antibodies and serum antibodies against ocular antigens are also associated with an increased risk of uveitis [53, 54]. This result signifies the possible involvement of natural autoimmunity in the as yet unclarified pathogenesis of this specific uveitis entity. Overall, the decrease observed in IgM NAb levels in active oligo-JIA patients and the increase of IgM NAb levels observed in uveitis patients may conceal informative features dependently on the systemic and/or the organ-specific form of autoimmunity that needs to be further investigated.

In our study, ANA positivity and gender independently affected IgM anti-F(ab’)2 levels, possibly indicating an imbalance in the idiotypic network resulting from the increase of ANA specificities as also previously found in patients with SLE [55, 56]. Additionally, an increase in anti-TNP IgM reactivity was observed in female subjects. These sex differences in IgM NAbs could be attributed to the fact that nutritional or other environmental exposures may vary by sex with potential long-term implications for immune-mediated disease as it has also been suggested by others [57].

Despite the limitations of the study in regard to the number of male controls and the effect of treatment, our results provide additional evidence that disturbances in natural autoimmunity may contribute to the as yet unclarified pathogenesis of oligo-JIA. It has been also shown that the three measured NAbs represent a panel satisfactorily describing the state of natural autoimmunity. Moreover, their independent association with disease activity and the presence of anterior uveitis indicates that it is worthy to be studied in appropriately designed epidemiological studies (including newly diagnosed treatment naïve patients, patients stratified according to therapeutic modalities used, etc.) in order to elucidate their possible use as prognostic biomarkers.

Conclusions

  • Disturbances in natural autoimmunity may contribute to the pathogenesis of oligo-JIA.

  • Independent association of certain NAbs with disease activity and the presence of anterior uveitis indicates that they're worthy to be studied as possible prognostic biomarkers.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

JIA:

juvenile idiopathic arthritis

oligo-JIA:

oligoarticular idiopathic arthritis

ANA:

anti-nuclear antibodies

NAbs:

natural antibodies

TNP:

trinitrophenol

OD:

optical density

ELISA:

enzyme-linked immunosorbent assay

References

  1. Holodick NE, Rodríguez-Zhurbenko N, Hernández AM. Defining natural antibodies. Front Immunol. 2017;8:872.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Baumgarth N, Herman OC, Jager GC, Brown L, Herzenberg LA. Innate and acquired humoral immunities to influenza virus are mediated by distinct arms of the immune system. Proc Natl Acad Sci USA. 1999;96:2250–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Gronwall C, Vas J, Silverman GJ. Protective roles of natural IgM antibodies. Front Immunol. 2012;3:66.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Nguyen TT, Elsner RA, Baumgarth N. Natural IgM prevents autoimmunity by enforcing B cell central tolerance induction. J Immunol. 2015;194:1489–502.

    Article  CAS  PubMed  Google Scholar 

  5. Nguyen TT, Klasener K, Zurn C, Castillo PA, Brust-Mascher I, Imai DM, et al. The IgM receptor FcmuR limits tonic BCR signaling by regulating expression of the IgM BCR. Nat Immunol. 2017;18:321–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Freitas AA, Viale AC, Sundblad A, Heusser C, Coutinho A. Normal serum immunoglobulins participate in the selection of peripheral B-cell repertoires. Proc Natl Acad Sci USA. 1991;88:5640–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Boes M, Esau C, Fischer MB, Schmidt T, Carroll M, Chen J. Enhanced B-1 cell development, but impaired IgG antibody responses in mice deficient in secreted IgM. J Immunol. 1998;160:4776–87.

    Article  CAS  PubMed  Google Scholar 

  8. Nguyen TT, Baumgarth N. Natural IgM and the development of B cell-mediated autoimmune diseases. Crit Rev Immunol. 2016;36:163–77.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Notley CA, Brown MA, Wright GP, Ehrenstein MR. Natural IgM is required for suppression of inflammatory arthritis by apoptotic cells. J Immunol. 2011;186:4967–72.

    Article  CAS  PubMed  Google Scholar 

  10. Petty RE, Southwood TR, Manners P, Baum J, Glass DN, Goldenberg J, et al. International League of associations for rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol. 2004;31:390–2.

    PubMed  Google Scholar 

  11. Giancane G, Alongi A, Ravelli A. Update on the pathogenesis and treatment of juvenile idiopathic arthritis. Curr Opin Rheumatol. 2017;29:523–9.

    Article  CAS  PubMed  Google Scholar 

  12. Leong JY, Guan YJ, Albani S, Arkachaisri T. Recent advances in our understanding of the pathogenesis of juvenile idiopathic arthritis and their potential clinical implications. Expert Rev Clin Immunol. 2018;14:933–44.

    Article  CAS  PubMed  Google Scholar 

  13. Corcione A, Ferlito F, Gattorno M, Gregorio A, Pistorio A, Gastaldi R, Gambini C, Martini A, Traggiai E, Pistoia V. Phenotypic and functional characterization of switch memory B cells from patients with oligoarticular juvenile idiopathic arthritis. Arthritis Res Ther. 2009;11(5):R150.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Wouters CH, Ceuppens JL, Stevens EA. Different circulating lymphocyte profiles in patients with different subtypes of juvenile idiopathic arthritis. Clin Exp Rheumatol. 2002;20(2):239–48.

    CAS  PubMed  Google Scholar 

  15. Lee J, Kuchen S, Fischer R, Chang S, Lipsky PE. Identification and characterization of a human CD5+ pre-naive B cell population. J Immunol. 2009;182:4116–26.

    Article  CAS  PubMed  Google Scholar 

  16. Wouters CH, Ceuppens JL, Stevens EA. Different circulating lymphocyte profiles in patients with different subtypes of juvenile idiopathic arthritis. Clin Exp Rheumatol. 2002;20:239–48.

    CAS  PubMed  Google Scholar 

  17. Corcione A, Ferlito F, Gattorno M, Gregorio A, Pistorio A, Gastaldi R, et al. Phenotypic and functional characterization of switch memory B cells from patients with oligoarticular juvenile idiopathic arthritis. Arthritis Res Ther. 2009;11:R150.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Sims GP, Ettinger R, Shirota Y, Yarboro CH, Illei GG, Lipsky PE. Identification and characterization of circulating human transitional B cells. Blood. 2005;105:4390–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Dighiero G, Guilbert B, Fermand JP, Lymberi P, Danon F, Avrameas S. Thirty-six human monoclonal immunoglobulins with antibody activity against cytoskeleton proteins, thyroglobulin and native DNA: Immunological studies and clinical correlations. Blood. 1983;62:264–70.

    Article  CAS  PubMed  Google Scholar 

  20. Zamanou A, Samiotaki M, Panayotou G, Margaritis L, Lymberi P. Fine specificity and subclass of IgG anti-actin autoantibodies differ in health and disease. J Autoimmun. 2003;20:333–44.

    Article  CAS  PubMed  Google Scholar 

  21. Brezski RJ, Knight DM, Jordan RE. The origins, specificity, and potential biological relevance of human anti-IgG hinge autoantibodies. ScientificWorldJournal. 2011;11:1153–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Welschof M, Terness P, Kipriyanov SM, Stanescu D, Breitling F, Dörsam H, et al. The antigen-binding domain of a human IgG-anti-F(ab’)2 autoantibody. Proc Natl Acad Sci USA. 1997;94:1902–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Terness P, Navolan D, Dufter C, Welschof M, Opelz G. Immunosuppressive anti-immunoglobulin autoantibodies: specificity, gene structure and function in health and disease. Cell Mol Biol. 2002;48:271–8.

    CAS  PubMed  Google Scholar 

  24. Consolaro A, Ruperto N, Bazso A, Pistorio A, Magni-Manzoni S, Filocamo G, et al. Development and validation of a composite disease activity score for juvenile idiopathic arthritis. Arthritis Rheum. 2009;61(5):658–66.

    Article  PubMed  Google Scholar 

  25. Consolaro A, Ravelli A. Defining criteria for disease activity states in juvenile idiopathic arthritis. Rheumatology. 2016;55(4):595–6.

    Article  PubMed  Google Scholar 

  26. Clarke SL, Sen ES, Ramanan AV. Juvenile idiopathic arthritis-associated uveitis. Pediatr Rheumatol Online J. 2016;14(1):27.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Dighiero G, Lymberi P, Holmberg D, Lundquist I, Coutinho A, Avrameas S. High frequency of natural autoantibodies in normal newborn mice. J Immunol. 1985;134:765–71.

    Article  CAS  PubMed  Google Scholar 

  28. Sali AD, Karakasiliotis I, Evangelidou M, Avrameas S, Lymberi P. Immunological evidence and regulatory potential for cell-penetrating antibodies in intravenous immunoglobulin. Clin Transl Immunol. 2015;4: e42.

    Article  Google Scholar 

  29. Nagele EP, Han M, Acharya NK, DeMarshall C, Kosciuk MC, Nagele RG. Natural IgG autoantibodies are abundant and ubiquitous in human sera, and their number is influenced by age, gender, and disease. PLoS ONE. 2013;8(4): e60726.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Nguyen TT, Baumgarth N. Natural IgM and the development of b cell-mediated autoimmune diseases. Crit Rev Immunol. 2016;36(2):163–77.

    Article  PubMed  PubMed Central  Google Scholar 

  31. McMahon M, Skaggs B. Autoimmunity: Do IgM antibodies protect against atherosclerosis in SLE? Nat Rev Rheumatol. 2016;12(8):442–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Jiang C, Zhao ML, Scearce RM, Diaz M. Activation-induced deaminase-deficient MRL/lpr mice secrete high levels of protective antibodies against lupus nephritis. Arthritis Rheum. 2011;63(4):1086–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lymberi P, Zannikou M, Hatzioannou A. Natural Autoantibodies in Health and Disease. In Comprehensive Pharmacology. Vol. 5. Elsevier. 2022. p. 342–68. https://doi.org/10.1016/B978-0-12-820472-6.00197-3.

  34. Ragimbeau J, Avrameas S. Single lipopolysaccharide-reactive B cells in the non-immune mouse spleen cell population secrete natural multispecific autoantibodies. Scand J Immunol. 1987;26:29–35.

    Article  CAS  PubMed  Google Scholar 

  35. Zhang H, Chen F, Zhao F, Meng C-M. Structural and electronic properties of 2,4,6-trinitrophenol (TNP). J Mol Struct: THEOCHEM. 2008;857:33–7.

    Article  CAS  Google Scholar 

  36. Mouthon L, Haury M, Lacroix-Desmazes S, Barreau C, Coutinho A, Kazatchkine MD. Analysis of the normal human IgG antibody repertoire. Evidence that IgG autoantibodies of healthy adults recognize a limited and conserved set of protein antigens in homologous tissues. J Immunol. 1995;154:5769–78.

    Article  CAS  PubMed  Google Scholar 

  37. Silvestris F, Bankhurst AD, Searles RP, Williams RC Jr. Studies of anti-F(ab’)2 antibodies and possible immunologic control mechanisms in systemic lupus erythematosus. Arthritis Rheum. 1984;27(12):1387–96.

    Article  CAS  PubMed  Google Scholar 

  38. Terness P, Opelz G. Natural anti-immunoglobulin autoantibodies: irrelevant by-products or immunoregulatory molecules? Int Arch Allergy Immunol. 1998;115(4):270–7.

    Article  CAS  PubMed  Google Scholar 

  39. Hahn BH. Suppression of autoimmune diseases with anti-idiotypic antibodies: murine lupus nephritis as a model. Springer Semin Immunopathol. 1984;7(1):25–34.

    Article  CAS  PubMed  Google Scholar 

  40. Arvonen M, Vänni P, Sarangi AN, Tejesvi MV, Vähäsalo P, Aggarwal A, Stoll ML. Microbial orchestra in juvenile idiopathic arthritis: Sounds of disarray? Immunol Rev. 2020;294:9–26.

    Article  CAS  PubMed  Google Scholar 

  41. Ricciuto A, Sherman PM, Laxer RM. Gut microbiota in chronic inflammatory disorders: a focus on pediatric inflammatory bowel diseases and juvenile idiopathic arthritis. Clin Immunol. 2020;215: 108415.

    Article  CAS  PubMed  Google Scholar 

  42. Panda S, Ding JL. Natural antibodies bridge innate and adaptive immunity. J Immunol. 2015;194:13–20.

    Article  CAS  PubMed  Google Scholar 

  43. Pabst O. New concepts in the generation and functions of IgA. Nat Rev Immunol. 2012;12:821–32.

    Article  CAS  PubMed  Google Scholar 

  44. Avrameas S, Selmi C. Natural autoantibodies in the physiology and pathophysiology of the immune system. J Autoimmun. 2013;41:46–9.

    Article  CAS  PubMed  Google Scholar 

  45. Avrameas S, Alexopoulos H, Moutsopoulos HM. Natural autoantibodies: An undersugn hero of the immune system and autoimmune disorders - A point of view. Front Immunol. 2018;9:1320.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Senaldi G, Ireland R, Bellingham AJ, Vergani D, Veerapan K, Wang F. IgM reduction in systemic lupus erythematosus. Arthritis Rheum. 1988;31:1213.

    Article  CAS  PubMed  Google Scholar 

  47. Gunti S, Kampylafka EI, Tzioufas AG, Notkins AL. Polyreactive antibodies in the circulation of patients with systemic lupus erythematosus. Lupus. 2015;24:1567–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Boes M, Schmidt T, Linkemann K, Beaudette BC, Marshak-Rothstein A, Chen J. Accelerated development of IgG autoantibodies and autoimmune disease in the absence of secreted IgM. Proc Natl Acad Sci USA. 2000;97:1184–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ehrenstein MR, Cook HT, Neuberger MS. Deficiency in serum immunoglobulin (Ig)M predisposes to development of IgG autoantibodies. J Exp Med. 2000;191:1253–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Goldstein MF, Goldstein AL, Dunsky EH, Dvorin DJ, Belecanech GA, Shamir K. Selective IgM immunodeficiency: retrospective analysis of 36 adult patients with review of the literature. Ann Allergy Asthma Immunol. 2006;97:717–30.

    Article  CAS  PubMed  Google Scholar 

  51. Witte T. IgM antibodies against dsDNA in SLE. Clin Rev Allergy Immunol. 2008;34:345–7.

    Article  CAS  PubMed  Google Scholar 

  52. Washington MK. Autoimmune liver disease: overlap and outliers. Modern Pathol. 2007;20(Suppl 1):S15-30.

    Article  CAS  Google Scholar 

  53. Mahmud SA, Binstadt BA. Autoantibodies in the pathogenesis, diagnosis, and prognosis of juvenile idiopathic arthritis. Front Immunol. 2019;14(9):3168.

    Article  Google Scholar 

  54. Busch M, Wefelmeyer KL, Walscheid K, Rothaus K, Bauer D, Deeg CA, Degroote RL, Ackermann D, König S, Thanos S, Kasper M, Heiligenhaus A. Identification of ocular autoantigens associated with juvenile idiopathic arthritis-associated uveitis. Front Immunol. 2019;6(10):1793.

    Article  Google Scholar 

  55. Williams RC Jr, Malone CC, Cimbalnik K, Presley MA, Roux KH, Strelets L, Silvestris F. Cross-reactivity of human IgG anti-F(ab’)2 antibody with DNA and other nuclear antigens. Arthritis Rheum. 1997;40(1):109–23.

    Article  CAS  PubMed  Google Scholar 

  56. Silvestris F, Searles RP, Bankhurst AD, Williams RC. Family distribution of anti-F(ab’)2 antibodies in relatives of patients with systemic lupus erythematosus. Clin Exp Immunol. 1985;60(2):329–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Moradi A, Amin RM, Thorne JE. The role of gender in juvenile idiopathic arthritis-associated uveitis. J Ophthalmol. 2014;2014: 461078.

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Pediatric Rheumatology Unit, First Department of Pediatrics, School of Medicine, University of Athens, Children’s Hospital “Aghia Sofia”, Thivon & Papadiamadopoulou, 11525, Athens, Greece

    Elena Tsitsami & Maria Tsinti

  2. Immunology Laboratory, Immunology Department, Hellenic Pasteur Institute, 127, Vasilissis Sofias Avenue, 11521, Athens, Greece

    Ioannis Sarrigeorgiou & Peggy Lymberi

  3. Faculty of Nursing, School of Health Sciences, University of Thessaly, 41500, Geopolis, Larissa, Greece

    Erasmia C. Rouka

  4. Department of Physiology, Faculty of Medicine, School of Health Sciences, University of Thessaly, BIOPOLIS, 41500, Geopolis, Larissa, Greece

    Sotirios G. Zarogiannis

Authors
  1. Elena Tsitsami
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  2. Ioannis Sarrigeorgiou
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  3. Maria Tsinti
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  4. Erasmia C. Rouka
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  5. Sotirios G. Zarogiannis
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  6. Peggy Lymberi
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Contributions

ET wrote the original article; IS performed the ELISA experiments and was a major contributor in writing the manuscript; MT conducted the sample collection and patient data. ECR performed the statistical analysis; SGZ took over the graphs, and was a major contributor in revising the manuscript; PL supervised the experimental procedures and was a major contributor in editing and revising the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Peggy Lymberi.

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Ethics approval and consent to participate

The study was approved by the Ethics Committee of the Children’s Hospital “Aghia Sofia”, and informed consent was obtained from the patient’s legal guardians.

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The authors declare that they have no competing interests.

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Supplementary Information

Additional file 1: Supplementary information file 1.

Demographic, clinical, and laboratory characteristics of all studyAQ participants.

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Tsitsami, E., Sarrigeorgiou, I., Tsinti, M. et al. Natural autoimmunity in oligoarticular juvenile idiopathic arthritis. Pediatr Rheumatol 21, 44 (2023). https://doi.org/10.1186/s12969-023-00823-w

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  • DOI: https://doi.org/10.1186/s12969-023-00823-w

Keywords

Pediatric Rheumatology

ISSN: 1546-0096