Abstract
Over the years, the commonly used term to describe juvenile idiopathic arthritis (JIA) has changed. By definition, JIA includes all types of arthritis with no apparent cause, lasting more than 6 weeks, in patients aged less than 16 years at onset. JIA pathogenesis is still poorly understood: the interaction between environmental factors and multiple genes has been proposed as the most relevant working mechanism to the development of JIA. The concept that various microbes that colonize or infect not only the mucosal surfaces, like the oral cavity, but also the airways and gut might trigger autoimmune processes, resulting in chronic arthritides, and JIA was first drafted at the outset of last century. JIA development might be initiated and sustained by the exposure to environmental factors, including infectious agents which affect people at a young age, depending on the underlying genetic predisposition to synovial inflammation. Many data from patients with JIA suggest a scenario in which different external antigens incite multiple antigen-specific pathways, cytotoxic T cell responses, activation of classical complement cascade, and production of proinflammatory cytokines. In this review, emphasis is paid not only to the potential role of parvovirus B19 and Epstein-Barr virus in primis but also to the general involvement of different bacteria as Salmonella spp., Shigella spp., Campylobacter spp., Mycoplasma pneumoniae, Chlamydophila pneumoniae, Bartonella henselae, and Streptococcus pyogenes for the development of immune-mediated arthritides during childhood. No unequivocal evidence favoring or refuting these associations has been clearly proved, and today, the strict definition of JIA etiology remains unknown. The infection can represent a random event in a susceptible individual, or it can be a necessary factor in JIA development, always in combination with a peculiar genetic background. Further studies are needed in order to address the unsolved questions concerning this issue.
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Kwiatkowska B, Maślińska M (2012) Macrolide therapy in chronic inflammatory diseases. Mediators Inflamm 2012:636157
Ravelli A, Martini A (2007) Juvenile idiopathic arthritis. Lancet 369:767–778
Petty RE, Southwood TR, Manners P et al (2004) International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol 31:390–392
Stabile A, Avallone L, Compagnone A, Ansuini V, Bertoni B, Rigante D (2006) Focus on juvenile idiopathic arthritis according to the 2001 revised Edmonton classification from the International League of Associations for Rheumatology: an Italian experience. Eur Rev Med Pharmacol Sci 10:229–234
Martini A (2012) Systemic juvenile idiopathic arthritis. Autoimmun Rev 12:56–59
Manners PJ, Bower C (2002) Worldwide prevalence of juvenile arthritis why does it vary so much? J Rheumatol 29:1520–1530
Prahalad S, Zept AS, Pimentel R et al (2010) Quantification of the familial contribution to juvenile idiopathic arthritis. Arthritis Rheum 62:2525–2529
Saurenmann RK, Rose JB, Tyrrell P et al (2007) Epidemiology of juvenile idiopathic arthritis in a multiethnic cohort: ethnicity as a risk factor. Arthritis Rheum 56:1974–1984
Mauldin J, Cameron HD, Jeanotte D, Solomon G, Jarvis JN (2004) Chronic arthritis in children and adolescents in two Indian health service user populations. BMC Musculoskelet Disord 5:30
Lin YT, Wang CT, Gershwin ME, Chiang BL (2011) The pathogenesis of oligoarticular/polyarticular vs systemic juvenile idiopathic arthritis. Autoimmun Rev 10:482–489
Oen K, Schroeder M, Jacobson K et al (1998) Juvenile rheumatoid arthritis in a Canadian First Nations (aboriginal) population: onset subtypes and HLA associations. J Rheumatol 25:783–790
Prahalad S, Glass DN (2008) A comprehensive review of the genetics of juvenile idiopathic arthritis. Pediatr Rheumatol Online J 6:11
Prahalad S, O’Brien E, Fraser AM et al (2004) Familial aggregation of juvenile idiopathic arthritis. Arthritis Rheum 50:4022–4027
Berkun Y, Padeh S (2010) Environmental factors and the geoepidemiology of juvenile idiopathic arthritis. Autoimmun Rev 9:A319–A324
Prahalad S (2006) Genetic analysis of juvenile rheumatoid arthritis: approaches to complex traits. Curr Probl Pediatr Adolesc Health Care 36:83–90
Brunner HI, Ivaskova E, Haas JP et al (1993) Class I associations and frequencies of class II HLA-DRB alleles by RFLP analysis in children with rheumatoid-factor-negative juvenile chronic arthritis. Rheumatol Int 13:83–88
Thomson W, Barrett JH, Donn R et al (2002) Juvenile idiopathic arthritis classified by the ILAR criteria: HLA associations in UK patients. Rheumatology (Oxford) 41:1183–1189
Murray KJ, Moroldo MB, Donnelly P et al (1999) Age-specific effects of juvenile rheumatoid arthritis-associated HLA alleles. Arthritis Rheum 42:1843–1853
Ploski R, Vinje O, Ronningen KS et al (1993) HLA class II alleles and heterogeneity of juvenile rheumatoid arthritis. DRB1*0101 may define a novel subset of the disease. Arthritis Rheum 36:465–472
Date Y, Seki N, Kamizono S et al (1999) Identification of a genetic risk factor for systemic juvenile rheumatoid arthritis in the 5′-flanking region of the TNF-alpha gene and HLA genes. Arthritis Rheum 42:2577–2582
Ogilvie EM, Khan A, Hubank M, Kellam P, Woo P (2007) Specific gene expression profiles in systemic juvenile idiopathic arthritis. Arthritis Rheum 56:1954–1965
Murray K, Thompson SD, Glass DN (1997) Pathogenesis of juvenile chronic arthritis: genetic and environmental factors. Arch Dis Child 77:530–534
Thompson SD, Sudman M, Ramos PS et al (2010) The susceptibility loci juvenile idiopathic arthritis shares with other autoimmune diseases extend to PTPN2, COG6, and ANGPT1. Arthritis Rheum 62:3265–3276
Thompson SD, Marion MC, Sudman M et al (2012) Genome-wide association analysis of juvenile idiopathic arthritis identifies a new susceptibility locus at chromosomal region 3q13. Arthritis Rheum 64:2781–2791
Singh S, Bhattad S, Danda D (2014) Genetics of juvenile idiopathic arthritidis. Int J Rheum Dis 17:233–236
Behrens EM, Finkel TH, Bradfield JP et al (2008) Association of the TRAF1-C5 locus on chromosome 9 with juvenile idiopathic arthritis. Arthritis Rheum 58:2206–2207
Hinks A, Barton A, Stephard N et al (2009) Identification of a novel susceptibility locus for juvenile idiopathic arthritis by genome-wide association analysis. Arthritis Rheum 60:258–263
Stelmaszczyk-Emmel A, Jackowska T, Rutkowska-Sak L, Marusak-Banacka M, Wąsik M (2012) Identification, frequency, activation and function of CD4+ CD25(high)FoxP3+ regulatory T cells in children with juvenile idiopathic arthritis. Rheumatol Int 32:1147–1154
Barnes MG, Grom AA, Thompson SD et al (2009) Subtype-specific peripheral blood gene expression profiles in recent-onset juvenile idiopathic arthritis. Arthritis Rheum 60:2102–2112
Kivity S, Agmon-Levin N, Blank M, Shoenfeld Y (2009) Infections and autoimmunity—friends or foes? Trends Immunol 30:409–414
Phelan JD, Thompson SD, Glass DN (2006) Susceptibility to JRA/JIA: complementing general autoimmune and arthritis traits. Genes Immun 7:1–10
Mayerl C, Prelog M (2012) Immunosenescence and juvenile idiopathic arthritis. Autoimmun Rev 11:297–300
Bach JF (2005) Infections and autoimmune diseases. J Autoimmun 25(Suppl 1):74–80
Ogrendik M (2013) Antibiotics for the treatment of rheumatoid arthritis. Int J GenMed 7:43–47
Chorba T, Coccia P, Holman RC et al (1986) The role of parvovirus B19 in aplastic crisis and erythema infectiosum (fifth disease). J Infect Dis 154:383–393
Nocton JJ, Miller LC, Tucker LB, Schaller JG (1993) Human parvovirus B19-associated arthritis in children. J Pediatr 122:186–190
Oğuz F, Akdeniz C, Unüvar E, Küçükbasmaci O, Sidal M (2002) Parvovirus B19 in the acute arthropathies and juvenile rheumatoid arthritis. J Paediatr Child Health 38:358–362
Lehmann HW, Knöll A, Küster RM, Modrow S (2003) Frequent infection with a viral pathogen, parvovirus B19, in rheumatic diseases of childhood. Arthritis Rheum 48:1631–1638
Angelini F, Cancrini C, Colavita M et al (2003) Role of parvovirus B19 infection in juvenile chronic arthritis. Is more investigaton needed? Clin Exp Rheumatol 21:684
Lehmann HW, Plentz A, von Landenberg P, Küster RM, Modrow S (2008) Different patterns of disease manifestations of parvovirus B19-associated reactive juvenile arthritis and the induction of antiphospholipid antibodies. Clin Rheumatol 27:333–338
von Landenberg P, Lehmann HW, Knöll A, Dorsch S, Modrow S (2003) Antiphospholipid antibodies in pediatric and adult patients with rheumatic disease are associated with parvovirus B19 infection. Arthritis Rheum 48:1939–1947
Gonzales B, Larranaga C, Leòn O et al (2007) Parvovirus B19 may have a role in the pathogenesis of juvenile idiopathic arthritis. J Rheumatol 34:1336–1340
Weissbrich B, Süss-Fröhlich Y, Girschick HJ (2007) Seroprevalence of parvovirus B19 IgG in children affected by juvenile idiopathic arthritis. Arthritis Res Ther 9:R82
Aghighi Y, Gilani Sh M, Razavi M, Zamani A, Daneshjoo K (2007) Juvenile rheumatoid arthritis in children with Epstein-Barr virus infection. Pak J Biol Sci 10:3638–3643
Massa M, Mazzoli F, Pignatti P et al (2002) Proinflammatory responses to self HLA epitopes are triggered by molecular mimicry to Epstein-Barr virus proteins in oligoarticular juvenile idiopathic arthritis. Arthritis Rheum 46:2721–2729
Kawada J, Ito Y, Torii Y, Kimura H, Iwata N (2013) Remission of juvenile idiopathic arthritis with primary Epstein-Barr virus infection. Rheumatology (Oxford) 52:956–958
Miossec P, Korn T, Kuchroo VK (2009) Interleukin-17 and type 17 helper T cells. N Engl J Med 361:888–898
Tsai YT, Chiang BL, Kao YF, Hsieh KH (1995) Detection of Epstein-Barr virus and cytomegalovirus genome in white blood cells from patients with juvenile rheumatoid arthritis and childhood systemic lupus erythematosus. Int Arch Allergy Immunol 106:235–240
Chantler JK, Tingle AJ, Petty RE (1985) Persistent rubella virus infection associated with chronic arthritis in children. N Engl J Med 313:1117–1123
Frenkel LM, Nielsen K, Garakian A, Jin R, Wolinsky JS, Cherry JD (1996) A search for persistent rubella virus infection in persons with chronic symptoms after rubella and rubella immunization and in patients with juvenile rheumatoid arthritis. Clin Infect Dis 22:287–294
Prelog M, Schwarzenbrunner N, Sailer-Hoeck M et al.. Indications for a disturbed peripheral T-cell homeostasis in juvenile idiopathic arthritis (JIA): absent expansion of CD28 T-cells and no decrease of naive T-cells in cytomegalovirus-positive patients with JIA. J Rheumatol. 35:520–527
Pacheco-Tena C, Alvarado De La Barrera C, López-Vidal Y et al (2001) Bacterial DNA in synovial fluid cells of patients with juvenile onset spondyloarthropathies. Rheumatology (Oxford) 40:920–927
Saxena N, Misra R, Aggarwal A (2006) Is the enthesitis-related arthritis subtype of juvenile idiopathic arthritis a form of chronic reactive arthritis? Rheumatology (Oxford) 45:1029–1032
Singh YP, Singh AK, Aggarwal A, Misra R (2011) Evidence of cellular immune response to outer membrane protein of Salmonella typhimurium in patients with enthesitis-related arthritis subtype of juvenile idiopathic arthritis. J Rheumatol 38:161–166
Taylor-Robinson D, Thomas B, Rooney M (1988) Association of Chlamydia pneumoniae with chronic juvenile arthritis. Eur J Clin Microbiol Infect Dis 17:211–212
Altun S, Kasapcopur O, Aslan M et al (2004) Is there any relationship between Chlamydophila pneumoniae infection and juvenile idiopathic arthritis? J Med Microbiol 53(Pt 8):787–790
Tsukahara M, Tsuneoka H, Tateishi H, Fujita K, Uchida M (2001) Bartonella infection associated with systemic juvenile idiopathic arthritis. Clin Infect Dis 32:E22–E23
Postepski J, Opoka-Winiarska V, Kozioł-Montewka M, Korobowicz A, Tuszkiewicz-Misztal E (2003) Role of Mycoplasma pneumoniae infection in aetiopathogenesis of juvenile idiopathic arthritis. Med Wieku Rozwoj 7:271–277
Riise OR, Lee A, Cvancarova M et al (2008) Recent-onset childhood arthritis: association with Streptococcus pyogenes in a population-based study. Rheumatology (Oxford) 47:1006–1011
Barash J, Goldzweig O (2007) Possible role of streptococcal infection in flares of juvenile idiopathic arthritis. Arthritis Rheum 57:877–880
Mikuls TR, Thiele GM, Deane KD et al (2012) Porphyromonas gingivalis and disease-related autoantibodies in individuals at increased risk of rheumatoid arthritis. Arthritis Rheum 64:3522–3530
Del Boccio M, Pennelli A, Toniato E et al (2013) Enigmatic question of early reactive arthritis disclosed after researches of mycoplasmas, Chlamydia trachomatis and enteropathogens following the holistic vision of human being. J Biol Regul Homeost Agents 27:1039–1052
Morris D, Inman RD (2012) Reactive arthritis: developments and challenges in diagnosis and treatment. Curr Rheumatol Rep 14:390–394
Alam J, Kim YC, Choi Y (2014) Potential role of bacterial infection in autoimmune diseases: a new aspect of molecular mimicry. Immune Netw 14:7–13
Bach JF (2005) Infections and autoimmune diseases. J Autoimmun 25 (Suppl., 74–80):
Rook GA (2010) 99th Dahlem conference on infection, inflammation and chronic inflammatory disorders: darwinian medicine and the ‘hygiene’ or ‘old friends’ hypothesis. Clin Exp Immunol 160:70–79
Ngoi SM, Sylvester FA, Vella AT (2011) The role of microbial byproducts in protection against immunological disorders and the hygiene hypothesis. Discov Med 12:405–412
Pontes-de-Carvalho L, Mengel J, Figueiredo CA, Social Changes, Asthma and Allergy in Latin America (SCAALA)’s Study Group, Alcântara-Neves NM (2013) Antigen mimicry between infectious agents and self or environmental antigens may lead to long-term regulation of inflammation. Front Immunol 4:314
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Rigante, D., Bosco, A. & Esposito, S. The Etiology of Juvenile Idiopathic Arthritis. Clinic Rev Allerg Immunol 49, 253–261 (2015). https://doi.org/10.1007/s12016-014-8460-9
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DOI: https://doi.org/10.1007/s12016-014-8460-9