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Open Access 01-02-2021 | Cytokines | Original Article

Identification of Critical Transcriptomic Signaling Pathways in Patients with H Syndrome and Rosai-Dorfman Disease

Authors: Samuel Lara-Reyna, James A. Poulter, Elton J.R. Vasconcelos, Mark Kacar, Michael F. McDermott, Reuben Tooze, Rainer Doffinger, Sinisa Savic

Published in: Journal of Clinical Immunology | Issue 2/2021

Abstract

Biallelic mutations in SLC29A3 cause histiocytosis-lymphadenopathy plus syndrome, also known as H syndrome (HS). HS is a complex disorder, with ~ 25% of patients developing autoinflammatory complications consisting of unexplained fevers, persistently elevated inflammatory markers, and unusual lymphadenopathies, with infiltrating CD68⁺, S100⁺, and CD1a⁻ histiocytes, resembling the immunophenotype found in Rosai-Dorfman disease (RDD). We investigated the transcriptomic profiles of monocytes, non-activated (M0), classically activated (M1), and alternatively activated macrophages (M2) in two patients with HS, one without autoinflammatory (HS1) and one with autoinflammatory complications (HS2). RNA sequencing revealed a dysregulated transcriptomic profile in both HS patients compared to healthy controls (HC). HS2, when compared to HS1, had several differentially expressed genes, including genes associated with lymphocytic-histiocytic predominance (e.g. NINL) and chronic immune activation (e.g. B2M). The transcriptomic and cytokine profiles of HS patients were comparable to patients with SAID with high levels of TNF. SERPINA1 gene expression was found to be upregulated in all patients studied. Moreover, higher levels of IFNγ were found in the serum of both HS patients when compared to HC. Gene ontology (GO) enrichment analysis of the DEGs in HS patients revealed the terms “type I IFN,” “IFNγ signaling pathway,” and “immune responses” as the top 3 most significant terms for monocytes. Gene expression analysis of lymph node biopsies from sporadic and H syndrome-associated RDD suggests common underlying pathological process. In conclusion, monocytes and macrophages from both HS patients showed transcriptomic profiles similar to SAIDs and also uniquely upregulated IFNγ signature. These findings may help find better therapeutic options for this rare disorder.

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Bolze A, Abhyankar A, Grant AV, Patel B, Yadav R, Byun M, et al. A mild form of SLC29A3 disorder: a frameshift deletion leads to the paradoxical translation of an otherwise noncoding mRNA splice variant. PLoS One. 2012;7(1):e29708. https://doi.org/10.1371/journal.pone.0029708.CrossRefPubMedPubMedCentral

Molho-Pessach V, Ramot Y, Camille F, Doviner V, Babay S, Luis SJ, et al. H syndrome: the first 79 patients. J Am Acad Dermatol. 2014;70(1):80–8. https://doi.org/10.1016/j.jaad.2013.09.019.CrossRefPubMed

Molho-Pessach V, Lerer I, Abeliovich D, Agha Z, Abu Libdeh A, Broshtilova V, et al. The H syndrome is caused by mutations in the nucleoside transporter hENT3. Am J Hum Genet. 2008;83(4):529–34. https://doi.org/10.1016/j.ajhg.2008.09.013.CrossRefPubMedPubMedCentral

Bloom JL, Lin C, Imundo L, Guthery S, Stepenaskie S, Galambos C, et al. H syndrome: 5 new cases from the United States with novel features and responses to therapy. Pediatr Rheumatol Online J. 2017;15(1):76. https://doi.org/10.1186/s12969-017-0204-y.CrossRefPubMedPubMedCentral

Morgan NV, Morris MR, Cangul H, Gleeson D, Straatman-Iwanowska A, Davies N, et al. Mutations in SLC29A3, encoding an equilibrative nucleoside transporter ENT3, cause a familial histiocytosis syndrome (Faisalabad histiocytosis) and familial Rosai-Dorfman disease. PLoS Genet. 2010;6(2):e1000833. https://doi.org/10.1371/journal.pgen.1000833.CrossRefPubMedPubMedCentral

Melki I, Lambot K, Jonard L, Couloigner V, Quartier P, Neven B, et al. Mutation in the SLC29A3 gene: a new cause of a monogenic, autoinflammatory condition. Pediatrics. 2013;131(4):e1308–13. https://doi.org/10.1542/peds.2012-2255.CrossRefPubMed

Senniappan S, Hughes M, Shah P, Shah V, Kaski JP, Brogan P, et al. Pigmentary hypertrichosis and non-autoimmune insulin-dependent diabetes mellitus (PHID) syndrome is associated with severe chronic inflammation and cardiomyopathy, and represents a new monogenic autoinflammatory syndrome. J Pediatr Endocrinol Metab. 2013;26(9–10):877–82. https://doi.org/10.1515/jpem-2013-0062.CrossRefPubMed

McDermott MF, Aksentijevich I, Galon J, McDermott EM, Ogunkolade BW, Centola M, et al. Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell. 1999;97(1):133–44. https://doi.org/10.1016/s0092-8674(00)80721-7.CrossRefPubMed

Hsu CL, Lin W, Seshasayee D, Chen YH, Ding X, Lin Z, et al. Equilibrative nucleoside transporter 3 deficiency perturbs lysosome function and macrophage homeostasis. Science. 2012;335(6064):89–92. https://doi.org/10.1126/science.1213682.CrossRefPubMed

10.

Baldwin SA, Yao SY, Hyde RJ, Ng AM, Foppolo S, Barnes K, et al. Functional characterization of novel human and mouse equilibrative nucleoside transporters (hENT3 and mENT3) located in intracellular membranes. J Biol Chem. 2005;280(16):15880–7. https://doi.org/10.1074/jbc.M414337200.CrossRefPubMed

11.

Govindarajan R, Leung GP, Zhou M, Tse CM, Wang J, Unadkat JD. Facilitated mitochondrial import of antiviral and anticancer nucleoside drugs by human equilibrative nucleoside transporter-3. Am J Physiol Gastrointest Liver Physiol. 2009;296(4):G910–22. https://doi.org/10.1152/ajpgi.90672.2008.CrossRefPubMedPubMedCentral

12.

Babraham Bioinformatics - Trim Galore! : https://www.bioinformatics.babraham.ac.uk/projects/trim_galore/ (2020). Accessed.

13.

Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29(1):15–21. https://doi.org/10.1093/bioinformatics/bts635.CrossRefPubMed

14.

Trapnell C, Roberts A, Goff L, Pertea G, Kim D, Kelley DR, et al. Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks. Nat Protoc. 2012;7(3):562–78. https://doi.org/10.1038/nprot.2012.016.CrossRefPubMedPubMedCentral

15.

DAVID Functional Annotation Bioinformatics Microarray Analysis. https://david.ncifcrf.gov/ (2020). Accessed.

16.

Mistry A, Parry D, Matthews B, Laws P, Goodfield M, Savic S. A case of SLC29A3 spectrum disorder-unresponsive to multiple immunomodulatory therapies. J Clin Immunol. 2016;36(5):429–33. https://doi.org/10.1007/s10875-016-0301-6.CrossRefPubMed

17.

McDermott MF, Aganna E, Hitman GA, Ogunkolade BW, Booth DR, Hawkins PN. An autosomal dominant periodic fever associated with AA amyloidosis in a north Indian family maps to distal chromosome 1q. Arthritis Rheum. 2000;43(9):2034–40. https://doi.org/10.1002/1529-0131(200009)43:9<2034::AID-ANR14>3.0.CO;2-J.CrossRefPubMed

18.

Liu H, Lorenzini PA, Zhang F, Xu S, Wong MSM, Zheng J, et al. Alternative splicing analysis in human monocytes and macrophages reveals MBNL1 as major regulator. Nucleic Acids Res. 2018;46(12):6069–86. https://doi.org/10.1093/nar/gky401.CrossRefPubMedPubMedCentral

19.

Goncalves ANA, Lever M, Russo PST, Gomes-Correia B, Urbanski AH, Pollara G, et al. Assessing the impact of sample heterogeneity on transcriptome analysis of human diseases using MDP webtool. Front Genet. 2019;10:971. https://doi.org/10.3389/fgene.2019.00971.CrossRefPubMedPubMedCentral

20.

Canna SW, de Jesus AA, Gouni S, Brooks SR, Marrero B, Liu Y, et al. An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome. Nat Genet. 2014;46(10):1140–6. https://doi.org/10.1038/ng.3089.CrossRefPubMedPubMedCentral

21.

Duncan CJA, Dinnigan E, Theobald R, Grainger A, Skelton AJ, Hussain R, et al. Early-onset autoimmune disease due to a heterozygous loss-of-function mutation in TNFAIP3 (A20). Ann Rheum Dis. 2018;77(5):783–6. https://doi.org/10.1136/annrheumdis-2016-210944.CrossRefPubMed

22.

Wang N, Liang H, Zen K. Molecular mechanisms that influence the macrophage m1-m2 polarization balance. Front Immunol. 2014;5:614. https://doi.org/10.3389/fimmu.2014.00614.CrossRefPubMedPubMedCentral

23.

Ma WT, Gao F, Gu K, Chen DK. The role of monocytes and macrophages in autoimmune diseases: a comprehensive review. Front Immunol. 2019;10:1140. https://doi.org/10.3389/fimmu.2019.01140.CrossRefPubMedPubMedCentral

24.

Hauser MA, Legler DF. Common and biased signaling pathways of the chemokine receptor CCR7 elicited by its ligands CCL19 and CCL21 in leukocytes. J Leukoc Biol. 2016;99(6):869–82. https://doi.org/10.1189/jlb.2MR0815-380R.CrossRefPubMed

25.

Sokulsky LA, Garcia-Netto K, Nguyen TH, Girkin JLN, Collison A, Mattes J, et al. A critical role for the CXCL3/CXCL5/CXCR2 neutrophilic chemotactic axis in the regulation of type 2 responses in a model of rhinoviral-induced asthma exacerbation. J Immunol. 2020;205:2468–78. https://doi.org/10.4049/jimmunol.1901350.CrossRefPubMed

26.

Cook AD, Lee MC, Saleh R, Khiew HW, Christensen AD, Achuthan A, et al. TNF and granulocyte macrophage-colony stimulating factor interdependence mediates inflammation via CCL17. JCI Insight. 2018;3(6):e99249. https://doi.org/10.1172/jci.insight.99249.CrossRefPubMedCentral

27.

Franze E, Caruso R, Stolfi C, Sarra M, Cupi ML, Ascolani M, et al. High expression of the “A Disintegrin And Metalloprotease” 19 (ADAM19), a sheddase for TNF-alpha in the mucosa of patients with inflammatory bowel diseases. Inflamm Bowel Dis. 2013;19(3):501–11. https://doi.org/10.1097/MIB.0b013e31828028e8.CrossRefPubMed

28.

Aass KR, Kastnes MH, Standal T. Molecular interactions and functions of IL-32. J Leukoc Biol. 2020. https://doi.org/10.1002/JLB.3MR0620-550R.

29.

Margalit A, Sheikhet HM, Carmi Y, Berko D, Tzehoval E, Eisenbach L, et al. Induction of antitumor immunity by CTL epitopes genetically linked to membrane-anchored beta2-microglobulin. J Immunol. 2006;176(1):217–24. https://doi.org/10.4049/jimmunol.176.1.217.CrossRefPubMed

30.

Wakabayashi K, Inokuma S, Matsubara E, Onishi K, Asashima H, Nakachi S, et al. Serum beta2-microglobulin level is a useful indicator of disease activity and hemophagocytic syndrome complication in systemic lupus erythematosus and adult-onset Still’s disease. Clin Rheumatol. 2013;32(7):999–1005. https://doi.org/10.1007/s10067-013-2220-8.CrossRefPubMed

31.

Yoo C, Yoon DH, Suh C. Serum beta-2 microglobulin in malignant lymphomas: an old but powerful prognostic factor. Blood Res. 2014;49(3):148–53. https://doi.org/10.5045/br.2014.49.3.148.CrossRefPubMedPubMedCentral

32.

Seo S, Hong JY, Yoon S, Yoo C, Park JH, Lee JB, et al. Prognostic significance of serum beta-2 microglobulin in patients with diffuse large B-cell lymphoma in the rituximab era. Oncotarget. 2016;7(47):76934–43. https://doi.org/10.18632/oncotarget.12734.CrossRefPubMedPubMedCentral

33.

Duffles Amarante GB, Zotin MC, Rocha E, Delgado AG, Leite M Jr, Gomes CP. Renal tubular dysfunction in patients with primary Sjogren syndrome. Clin Nephrol. 2014;81(3):185–91. https://doi.org/10.5414/CN108142.CrossRefPubMed

34.

Ohashi K. Pathogenesis of beta2-microglobulin amyloidosis. Pathol Int. 2001;51(1):1–10. https://doi.org/10.1046/j.1440-1827.2001.01156.x.CrossRefPubMed

35.

Shi C, Zhu Y, Su Y, Chung LW, Cheng T. Beta2-microglobulin: emerging as a promising cancer therapeutic target. Drug Discov Today. 2009;14(1–2):25–30. https://doi.org/10.1016/j.drudis.2008.11.001.CrossRefPubMed

36.

Knoell DL, Ralston DR, Coulter KR, Wewers MD. Alpha 1-antitrypsin and protease complexation is induced by lipopolysaccharide, interleukin-1beta, and tumor necrosis factor-alpha in monocytes. Am J Respir Crit Care Med. 1998;157(1):246–55. https://doi.org/10.1164/ajrccm.157.1.9702033.CrossRefPubMed

37.

Janciauskiene S, Larsson S, Larsson P, Virtala R, Jansson L, Stevens T. Inhibition of lipopolysaccharide-mediated human monocyte activation, in vitro, by alpha1-antitrypsin. Biochem Biophys Res Commun. 2004;321(3):592–600. https://doi.org/10.1016/j.bbrc.2004.06.123.CrossRefPubMed

38.

Bergin DA, Reeves EP, Meleady P, Henry M, McElvaney OJ, Carroll TP, et al. alpha-1 antitrypsin regulates human neutrophil chemotaxis induced by soluble immune complexes and IL-8. J Clin Invest. 2010;120(12):4236–50. https://doi.org/10.1172/JCI41196.CrossRefPubMedPubMedCentral

39.

Janciauskiene S, Wrenger S, Immenschuh S, Olejnicka B, Greulich T, Welte T, et al. The multifaceted effects of alpha1-antitrypsin on neutrophil functions. Front Pharmacol. 2018;9:341. https://doi.org/10.3389/fphar.2018.00341.CrossRefPubMedPubMedCentral

40.

Keskinen P, Ronni T, Matikainen S, Lehtonen A, Julkunen I. Regulation of HLA class I and II expression by interferons and influenza A virus in human peripheral blood mononuclear cells. Immunology. 1997;91(3):421–9. https://doi.org/10.1046/j.1365-2567.1997.00258.x.CrossRefPubMedPubMedCentral

41.

Pujol-Borrell R, Todd I, Doshi M, Bottazzo GF, Sutton R, Gray D, et al. HLA class II induction in human islet cells by interferon-gamma plus tumour necrosis factor or lymphotoxin. Nature. 1987;326(6110):304–6. https://doi.org/10.1038/326304a0.CrossRefPubMed

42.

Matsuzawa T, Kim BH, Shenoy AR, Kamitani S, Miyake M, Macmicking JD. IFN-gamma elicits macrophage autophagy via the p38 MAPK signaling pathway. J Immunol. 2012;189(2):813–8. https://doi.org/10.4049/jimmunol.1102041.CrossRefPubMed

43.

Rodero M, Crow Y. Type I interferon-mediated monogenic autoinflammation: the type I interferonopathies, a conceptual overview. J Exp Med. 2016;213(12):2527–38. https://doi.org/10.1084/jem.20161596.CrossRefPubMedPubMedCentral

44.

Crow Y. Type I interferonopathies: a novel set of inborn errors of immunity. Ann N Y Acad Sci. 2011;1238:91–8. https://doi.org/10.1111/j.1749-6632.2011.06220.x.CrossRefPubMed

45.

Manthiram K, Zhou Q, Aksentijevich I, Kastner DL. The monogenic autoinflammatory diseases define new pathways in human innate immunity and inflammation. Nat Immunol. 2017;18(8):832–42. https://doi.org/10.1038/ni.3777.CrossRefPubMed

46.

Savic S, Caseley EA, McDermott MF. Moving towards a systems-based classification of innate immune-mediated diseases. Nat Rev Rheumatol. 2020;16(4):222–37. https://doi.org/10.1038/s41584-020-0377-5.CrossRefPubMed

47.

Lounder DT, Bin Q, de Min C, Jordan MB. Treatment of refractory hemophagocytic lymphohistiocytosis with emapalumab despite severe concurrent infections. Blood Adv. 2019;3(1):47–50. https://doi.org/10.1182/bloodadvances.2018025858.CrossRefPubMedPubMedCentral

48.

Vallurupalli M, Berliner N. Emapalumab for the treatment of relapsed/refractory hemophagocytic lymphohistiocytosis. Blood. 2019;134(21):1783–6. https://doi.org/10.1182/blood.2019002289.CrossRefPubMedPubMedCentral

49.

Locatelli F, Jordan MB, Allen C, Cesaro S, Rizzari C, Rao A, et al. Emapalumab in children with primary hemophagocytic lymphohistiocytosis. N Engl J Med. 2020;382(19):1811–22. https://doi.org/10.1056/NEJMoa1911326.CrossRefPubMed

50.

Diamond EL, Durham BH, Ulaner GA, Drill E, Buthorn J, Ki M, et al. Efficacy of MEK inhibition in patients with histiocytic neoplasms. Nature. 2019;567(7749):521–4. https://doi.org/10.1038/s41586-019-1012-y.CrossRefPubMedPubMedCentral

51.

Ye C, Brand D, Zheng S. Targeting IL-2: an unexpected effect in treating immunological diseases. Signal Transduction Targeted Ther. 2018;3:2. https://doi.org/10.1038/s41392-017-0002-5.CrossRef

52.

Abbas A, Trotta E, Simeonov DR, Marson A, Bluestone J. Revisiting IL-2: biology and therapeutic prospects. Sci Immunol. 2018;3(25):eaat1482. https://doi.org/10.1126/sciimmunol.aat1482.CrossRefPubMed

53.

Panelli M, White R, Foster M, Martin B, Wang E, Smith K, et al. Forecasting the cytokine storm following systemic interleukin (IL)-2 administration. J Transl Med. 2004;2(1):17. https://doi.org/10.1186/1479-5876-2-17.CrossRefPubMedPubMedCentral

54.

Molofsky A, Nussbaum J, Liang H, Van Dyken S, Chen GL, Mohapatra A, et al. Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages. J Exp Med. 2013;210(3):535–49. https://doi.org/10.1084/jem.20121964.CrossRefPubMedPubMedCentral

55.

Van Gool F, Molofsky A, Morar M, Rosenzwajg M, Liang H, Klatzmann D, et al. Interleukin-5-producing group 2 innate lymphoid cells control eosinophilia induced by interleukin-2 therapy. Blood. 2014;124(24):3572–6. https://doi.org/10.1182/blood-2014-07-587493.CrossRefPubMedPubMedCentral

56.

Ozen S, Kuemmerle-Deschner JB, Cimaz R, Livneh A, Quartier P, Kone-Paut I, et al. International retrospective chart review of treatment patterns in severe familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, and mevalonate kinase deficiency/hyperimmunoglobulinemia D syndrome. Arthritis Care Res. 2017;69(4):578–86. https://doi.org/10.1002/acr.23120.CrossRef

57.

Kuemmerle-Deschner JB, Gautam R, George AT, Raza S, Lomax KG, Hur P. Systematic literature review of efficacy/effectiveness and safety of current therapies for the treatment of cryopyrin-associated periodic syndrome, hyperimmunoglobulin D syndrome and tumour necrosis factor receptor-associated periodic syndrome. RMD Open. 2020;6(2):e001227. https://doi.org/10.1136/rmdopen-2020-001227.CrossRefPubMedPubMedCentral

58.

Goyal G, Ravindran A, Young JR, Shah MV, Bennani NN, Patnaik MM, et al. Clinicopathological features, treatment approaches, and outcomes in Rosai-Dorfman disease. Haematologica. 2020;105(2):348–57. https://doi.org/10.3324/haematol.2019.219626.CrossRefPubMedPubMedCentral

59.

Passlick B, Flieger D, Ziegler-Heitbrock H. Identification and characterization of a novel monocyte subpopulation in human peripheral blood. Blood. 1989;74(7):2527–34.CrossRefPubMed

60.

Ziegler-Heitbrock L, Ancuta P, Crowe S, Dalod M, Grau V, Hart D, et al. Nomenclature of monocytes and dendritic cells in blood. Blood. 2010;116(16):e74–80. https://doi.org/10.1182/blood-2010-02-258558.CrossRefPubMed

61.

Ziegler-Heitbrock L. Blood monocytes and their subsets: established features and open questions. Front Immunol. 2015;6:423. https://doi.org/10.3389/fimmu.2015.00423.CrossRefPubMedPubMedCentral

62.

Cagdas D, Surucu N, Tan C, Kayaoglu B, Ozgul RK, Akkaya-Ulum YZ, et al. Autoinflammation in addition to combined immunodeficiency: SLC29A3 gene defect. Mol Immunol. 2020;121:28–37. https://doi.org/10.1016/j.molimm.2020.02.014.CrossRefPubMed

Title: Identification of Critical Transcriptomic Signaling Pathways in Patients with H Syndrome and Rosai-Dorfman Disease
Authors: Samuel Lara-Reyna
James A. Poulter
Elton J.R. Vasconcelos
Mark Kacar
Michael F. McDermott
Reuben Tooze
Rainer Doffinger
Sinisa Savic
Publication date: 01-02-2021
Publisher: Springer US
Keyword: Cytokines
Published in: Journal of Clinical Immunology / Issue 2/2021
Print ISSN: 0271-9142
Electronic ISSN: 1573-2592
DOI: https://doi.org/10.1007/s10875-020-00932-1

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