Common genetic susceptibility loci link PFAPA syndrome, Behçet's disease, and recurrent aphthous stomatitis

Kalpana Manthiram, Silvia Preite, Fatma Dedeoglu, Selcan Demir, Seza Ozen, Kathryn M Edwards, Sivia Lapidus, Alexander E Katz, Genomic Ascertainment Cohort, Henry M Feder Jr, Maranda Lawton, Greg R Licameli, Peter F Wright, Julie Le, Karyl S Barron, Amanda K Ombrello, Beverly Barham, Tina Romeo, Anne Jones, Hemalatha Srinivasalu, Pamela A Mudd, Roberta L DeBiasi, Ahmet Gül, Gary S Marshall, Olcay Y Jones, Settara C Chandrasekharappa, Yuriy Stepanovskiy, Polly J Ferguson, Pamela L Schwartzberg, Elaine F Remmers, Daniel L Kastner, David P Ascher, Leslie G Biesecker, Priscilla Chan, Thomas P Conrads, Jennifer J Johnston, Alexander E Katz, Katie L Lewis, G Larry Maxwell, Justin Paschall, Henoke Shiferaw, Tyra G Wolfsberg, Wendy S W Wong, Suiyuan Zhang, Kalpana Manthiram, Silvia Preite, Fatma Dedeoglu, Selcan Demir, Seza Ozen, Kathryn M Edwards, Sivia Lapidus, Alexander E Katz, Genomic Ascertainment Cohort, Henry M Feder Jr, Maranda Lawton, Greg R Licameli, Peter F Wright, Julie Le, Karyl S Barron, Amanda K Ombrello, Beverly Barham, Tina Romeo, Anne Jones, Hemalatha Srinivasalu, Pamela A Mudd, Roberta L DeBiasi, Ahmet Gül, Gary S Marshall, Olcay Y Jones, Settara C Chandrasekharappa, Yuriy Stepanovskiy, Polly J Ferguson, Pamela L Schwartzberg, Elaine F Remmers, Daniel L Kastner, David P Ascher, Leslie G Biesecker, Priscilla Chan, Thomas P Conrads, Jennifer J Johnston, Alexander E Katz, Katie L Lewis, G Larry Maxwell, Justin Paschall, Henoke Shiferaw, Tyra G Wolfsberg, Wendy S W Wong, Suiyuan Zhang

Abstract

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most common periodic fever syndrome in children. The disease appears to cluster in families, but the pathogenesis is unknown. We queried two European-American cohorts and one Turkish cohort (total n = 231) of individuals with PFAPA for common variants previously associated with two other oropharyngeal ulcerative disorders, Behçet's disease and recurrent aphthous stomatitis. In a metaanalysis, we found that a variant upstream of IL12A (rs17753641) is strongly associated with PFAPA (OR 2.13, P = 6 × 10-9). We demonstrated that monocytes from individuals who are heterozygous or homozygous for this risk allele produce significantly higher levels of IL-12p70 upon IFN-γ and LPS stimulation than those from individuals without the risk allele. We also found that variants near STAT4, IL10, and CCR1-CCR3 were significant susceptibility loci for PFAPA, suggesting that the pathogenesis of PFAPA involves abnormal antigen-presenting cell function and T cell activity and polarization, thereby implicating both innate and adaptive immune responses at the oropharyngeal mucosa. Our results illustrate genetic similarities among recurrent aphthous stomatitis, PFAPA, and Behçet's disease, placing these disorders on a common spectrum, with recurrent aphthous stomatitis on the mild end, Behçet's disease on the severe end, and PFAPA intermediate. We propose naming these disorders Behçet's spectrum disorders to highlight their relationship. HLA alleles may be factors that influence phenotypes along this spectrum as we found new class I and II HLA associations for PFAPA distinct from Behçet's disease and recurrent aphthous stomatitis.

Keywords: Behçet’s disease; PFAPA; aphthous ulcers; periodic fever; tonsillitis.

Conflict of interest statement

Competing interest statement: F.D. is a consultant to Novartis and receives royalties from UpToDate. K.M.E. is on the Data Safety and Monitoring Board for Seqirus, Pfizer, Sanofi, Moderna, and X4 Pharma, and serves as an advisor to Bio-Net and Merck. P.F.W. is on the scientific advisory boards for GlaxoSmithKline, Sanofi-Pasteur, and Meissa Vaccines.

Copyright © 2020 the Author(s). Published by PNAS.

Figures

Fig. 1.
Fig. 1.
Expression of IL-12p70 subunits during PFAPA flares and comparison of IL-12p70 production according to IL12A risk allele. During PFAPA flares, a higher percentage of patient CD14+ monocytes express both subunits of IL-12p70, p35 and p40, compared with nonflare periods and with healthy controls; ex vivo FACS analysis of PBMCs (A). Peripheral blood CD14+ monocytes from adults homozygous and heterozygous for the risk allele near IL12A (rs17753641) secrete more IL-12p70 following priming with IFN-γ and stimulation with LPS than monocytes from individuals without the risk allele; ELISA on supernatant of in vitro-stimulated cells (B). Each dot represents an individual. Mean and SD are plotted. *P < 0.05, **P < 0.005.
Fig. 2.
Fig. 2.
The BSDs include recurrent aphthous stomatitis, PFAPA, and Behçet’s disease. Recurrent aphthous ulcers are on the mild end of the spectrum with relatively weak HLA associations, while Behçet's disease has the most severe disease manifestations and strongest HLA associations, and PFAPA is between the two.

References

    1. Marshall G. S., Edwards K. M., Butler J., Lawton A. R., Syndrome of periodic fever, pharyngitis, and aphthous stomatitis. J. Pediatr. 110, 43–46 (1987).
    1. Masters S. L., Simon A., Aksentijevich I., Kastner D. L., Horror autoinflammaticus: The molecular pathophysiology of autoinflammatory disease. Annu. Rev. Immunol. 27, 621–668 (2009).
    1. Wurster V. M., Carlucci J. G., Feder H. M. Jr, Edwards K. M., Long-term follow-up of children with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome. J. Pediatr. 159, 958–964 (2011).
    1. Feder H. M., Salazar J. C., A clinical review of 105 patients with PFAPA (a periodic fever syndrome). Acta Paediatr. 99, 178–184 (2010).
    1. Manthiram K., Nesbitt E., Morgan T., Edwards K. M., Family history in periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome. Pediatrics 138, e20154572 (2016).
    1. Di Gioia S. A., et al. , Analysis of the genetic basis of periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome. Sci. Rep. 5, 10200 (2015).
    1. Remmers E. F., et al. , Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behçet’s disease. Nat. Genet. 42, 698–702 (2010).
    1. Kirino Y., et al. , Genome-wide association analysis identifies new susceptibility loci for Behçet’s disease and epistasis between HLA-B*51 and ERAP1. Nat. Genet. 45, 202–207 (2013).
    1. Takeuchi M., et al. , Dense genotyping of immune-related loci implicates host responses to microbial exposure in Behçet’s disease susceptibility. Nat. Genet. 49, 438–443 (2017).
    1. Mizuki N., et al. , Genome-wide association studies identify IL23R-IL12RB2 and IL10 as Behçet’s disease susceptibility loci. Nat. Genet. 42, 703–706 (2010).
    1. Ombrello M. J., et al. , Behçet disease-associated MHC class I residues implicate antigen binding and regulation of cell-mediated cytotoxicity. Proc. Natl. Acad. Sci. U.S.A. 111, 8867–8872 (2014).
    1. Dudding T. et al. .; 23andMe Research Team , Genome wide analysis for mouth ulcers identifies associations at immune regulatory loci. Nat. Commun. 10, 1052 (2019).
    1. Kelly R. J., Rouquier S., Giorgi D., Lennon G. G., Lowe J. B., Sequence and expression of a candidate for the human Secretor blood group α(1,2)fucosyltransferase gene (FUT2). Homozygosity for an enzyme-inactivating nonsense mutation commonly correlates with the non-secretor phenotype. J. Biol. Chem. 270, 4640–4649 (1995).
    1. McGovern D. P. et al. .; International IBD Genetics Consortium , Fucosyltransferase 2 (FUT2) non-secretor status is associated with Crohn’s disease. Hum. Mol. Genet. 19, 3468–3476 (2010).
    1. de Graaf M., van Beek J., Koopmans M. P., Human norovirus transmission and evolution in a changing world. Nat. Rev. Microbiol. 14, 421–433 (2016).
    1. Cheung M. S., et al. , Periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis syndrome is associated with a CARD8 variant unable to bind the NLRP3 inflammasome. J. Immunol. 198, 2063–2069 (2017).
    1. International HapMap Consortium et al. , A second generation human haplotype map of over 3.1 million SNPs. Nature 449, 851–861 (2007).
    1. International Study Group for Behçet’s Disease , Criteria for diagnosis of Behçet’s disease. Lancet 335, 1078–1080 (1990).
    1. Gourh P., et al. , HLA and autoantibodies define scleroderma subtypes and risk in African and European Americans and suggest a role for molecular mimicry. Proc. Natl. Acad. Sci. U.S.A. 117, 552–562 (2020).
    1. Cantarini L., et al. , PFAPA syndrome and Behçet’s disease: A comparison of two medical entities based on the clinical interviews performed by three different specialists. Clin. Rheumatol. 35, 501–505 (2016).
    1. Scattoni R., et al. , Genital ulcer as a new clinical clue to PFAPA syndrome. Clin. Exp. Dermatol. 40, 286–288 (2015).
    1. Lin C. M., et al. , Genital ulcers as an unusual sign of periodic fever, aphthous stomatitis, pharyngotonsillitis, cervical adenopathy syndrome: A novel symptom? Pediatr. Dermatol. 28, 290–294 (2011).
    1. de Menthon M., Lavalley M. P., Maldini C., Guillevin L., Mahr A., HLA-B51/B5 and the risk of Behçet’s disease: A systematic review and meta-analysis of case-control genetic association studies. Arthritis Rheum. 61, 1287–1296 (2009).
    1. Tait Wojno E. D., Hunter C. A., Stumhofer J. S., The immunobiology of the interleukin-12 family: Room for discovery. Immunity 50, 851–870 (2019).
    1. Collison L. W., et al. , IL-35-mediated induction of a potent regulatory T cell population. Nat. Immunol. 11, 1093–1101 (2010).
    1. Collison L. W., et al. , The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 450, 566–569 (2007).
    1. Wang R. X., et al. , Interleukin-35 induces regulatory B cells that suppress autoimmune disease. Nat. Med. 20, 633–641 (2014).
    1. Shen P., et al. , IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases. Nature 507, 366–370 (2014).
    1. Dixon K. O., van der Kooij S. W., Vignali D. A., van Kooten C., Human tolerogenic dendritic cells produce IL-35 in the absence of other IL-12 family members. Eur. J. Immunol. 45, 1736–1747 (2015).
    1. Watford W. T., et al. , Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4. Immunol. Rev. 202, 139–156 (2004).
    1. Nakano H., et al. , GWAS-identified CCR1 and IL10 loci contribute to M1 macrophage-predominant inflammation in Behçet’s disease. Arthritis Res. Ther. 20, 124 (2018).
    1. Ishigaki K., et al. , Polygenic burdens on cell-specific pathways underlie the risk of rheumatoid arthritis. Nat. Genet. 49, 1120–1125 (2017).
    1. Stojanov S., et al. , Cytokine profile in PFAPA syndrome suggests continuous inflammation and reduced anti-inflammatory response. Eur. Cytokine Netw. 17, 90–97 (2006).
    1. Stojanov S., et al. , Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) is a disorder of innate immunity and Th1 activation responsive to IL-1 blockade. Proc. Natl. Acad. Sci. U.S.A. 108, 7148–7153 (2011).
    1. Kolly L., et al. , Periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome is linked to dysregulated monocyte IL-1β production. J. Allergy Clin. Immunol. 131, 1635–1643 (2013).
    1. Yamazaki T., et al. , Markedly elevated CD64 expressions on neutrophils and monocytes are useful for diagnosis of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome during flares. Clin. Rheumatol. 33, 677–683 (2014).
    1. Dytrych P., et al. , Polyclonal, newly derived T cells with low expression of inhibitory molecule PD-1 in tonsils define the phenotype of lymphocytes in children with Periodic Fever, Aphtous Stomatitis, Pharyngitis and Adenitis (PFAPA) syndrome. Mol. Immunol. 65, 139–147 (2015). Erratum in: Mol. Immunol.66, 428 (2015).
    1. Borra R. C., et al. , The Th1/Th2 immune-type response of the recurrent aphthous ulceration analyzed by cDNA microarray. J. Oral Pathol. Med. 33, 140–146 (2004).
    1. Shimizu J., et al. , Excessive CD4+ T cells co-expressing interleukin-17 and interferon-γ in patients with Behçet’s disease. Clin. Exp. Immunol. 168, 68–74 (2012).
    1. Ozyurt K., et al. , Serum Th1, Th2 and Th17 cytokine profiles and alpha-enolase levels in recurrent aphthous stomatitis. J. Oral Pathol. Med. 43, 691–695 (2014).
    1. Lewkowicz N., Lewkowicz P., Banasik M., Kurnatowska A., Tchórzewski H., Predominance of Type 1 cytokines and decreased number of CD4(+)CD25(+high) T regulatory cells in peripheral blood of patients with recurrent aphthous ulcerations. Immunol. Lett. 99, 57–62 (2005).
    1. Geri G., et al. , Critical role of IL-21 in modulating TH17 and regulatory T cells in Behçet disease. J. Allergy Clin. Immunol. 128, 655–664 (2011).
    1. Buño I. J., Huff J. C., Weston W. L., Cook D. T., Brice S. L., Elevated levels of interferon gamma, tumor necrosis factor alpha, interleukins 2, 4, and 5, but not interleukin 10, are present in recurrent aphthous stomatitis. Arch. Dermatol. 134, 827–831 (1998).
    1. Hatemi G., et al. , Apremilast for Behçet’s syndrome—A phase 2, placebo-controlled study. N. Engl. J. Med. 372, 1510–1518 (2015).
    1. Hatemi G., et al. , Trial of apremilast for oral ulcers in Behçet’s syndrome. N. Engl. J. Med. 381, 1918–1928 (2019).
    1. Kolios A. G. A., et al. , Apremilast in treatment-refractory recurrent aphthous stomatitis. N. Engl. J. Med. 381, 1975–1977 (2019).
    1. Schafer P. H., et al. , Apremilast is a selective PDE4 inhibitor with regulatory effects on innate immunity. Cell. Signal. 26, 2016–2029 (2014).
    1. Schafer P. H., et al. , Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis. Br. J. Pharmacol. 159, 842–855 (2010).

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