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Decreased expression of HLA-DQ and HLA-DR on cells of the monocytic lineage in cystic fibrosis

Abstract

We studied HLA class II molecules on blood monocyte subsets, blood dendritic cells, sputum macrophages, and monocyte-derived macrophages at the protein (flow cytometry) and mRNA level (RT-PCR) in adult patients with cystic fibrosis (CF) and healthy control subjects as putative contributors to the CF phenotype. In healthy donors, we found a high average HLA-DQ expression of 4.35 mean specific fluorescence intensity units (ΔMnI) on classical blood monocytes. In F508del homozygous CF patients, the average ΔMnI was low (1.80). Patients were divided into two groups, in which 14 of these patients had HLA-DQ expression above 2 ΔMnI (average 3.25 ΔMnI, CF-DQgroup1) and 36 below (average 1.24 ΔMnI, CF-DQgroup2). Also, the CD16-positive monocyte subset and blood dendritic cells showed much lower levels of HLA-DQ for the CF-DQgroup2 patients compared with healthy controls. In macrophages from sputum and derived from monocytes, in vitro HLA-DQ expression was dramatically decreased to background levels in CF-DQgroup2. MHC class II transcripts were reduced in CF with a sevenfold decrease in HLA-DQβ1 for CF-DQgroup2 patients. Higher levels of the inflammation marker CRP were associated with low HLA-DQ protein expression, and in vitro treatment with the inflammatory molecule lipopolysaccharide reduced HLA-DQ expression. Interferon γ (IFNγ) could overcome this effect in healthy donor cells while, in CF, the IFNγ-induced activation was impaired. Our data demonstrate a pronounced reduction of HLA-DQ expression in CF, which is associated with inflammation and a reduced response to IFNγ.

Key message

• CF patients show a reduced expression of MHCII molecules in monocytes and macrophages.

• HLA-DQ and HLA-DR transcript levels are also reduced in CF patients.

• CF patient C-reactive protein levels correlate with low HLA-DQ expression.

• Reduced expression of MHC class II molecules appears to be linked to inflammation.

• CF patients exhibit an impaired response to IFNgamma.

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References

  1. Rogan MP, Stoltz DA, Hornick DB (2011) Cystic fibrosis transmembrane conductance regulator intracellular processing, trafficking, and opportunities for mutation-specific treatment. Chest 139:1480–1490

    CAS  PubMed  Article  Google Scholar 

  2. Matsui H, Grubb BR, Tarran R, Randell SH, Gatzy JT, Davis CW, Boucher RC (1998) Evidence for periciliary liquid layer depletion, not abnormal ion composition, in the pathogenesis of cystic fibrosis airways disease. Cell 95:1005–1015

    CAS  PubMed  Article  Google Scholar 

  3. Boucher RC (2007) Evidence for airway surface dehydration as the initiating event in CF airway disease. J Intern Med 261:5–16

    CAS  PubMed  Article  Google Scholar 

  4. Boucher RC (2007) Airway surface dehydration in cystic fibrosis: pathogenesis and therapy. Annu Rev Med 58:157–170

    CAS  PubMed  Article  Google Scholar 

  5. Doring G, Gulbins E (2009) Cystic fibrosis and innate immunity: how chloride channel mutations provoke lung disease. Cell Microbiol 11:208–216

    PubMed  Article  Google Scholar 

  6. Matsui H, Wagner VE, Hill DB, Schwab UE, Rogers TD, Button B, Taylor RM 2nd, Superfine R, Rubinstein M, Iglewski BH et al (2006) A physical linkage between cystic fibrosis airway surface dehydration and Pseudomonas aeruginosa biofilms. Proc Natl Acad Sci U S A 103:18131–18136

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  7. Ziegler-Heitbrock L (2007) The CD14+ CD16+ blood monocytes: their role in infection and inflammation. J Leukoc Biol 81:584–592

    CAS  PubMed  Article  Google Scholar 

  8. Ziegler-Heitbrock L, Ancuta P, Crowe S, Dalod M, Grau V, Hart DN, Leenen PJ, Liu YJ, MacPherson G, Randolph GJ et al (2010) Nomenclature of monocytes and dendritic cells in blood. Blood 116:e74–e80

    CAS  PubMed  Article  Google Scholar 

  9. Wright AK, Rao S, Range S, Eder C, Hofer TP, Frankenberger M, Kobzik L, Brightling C, Grigg J, Ziegler-Heitbrock L (2009) Pivotal advance: expansion of small sputum macrophages in CF: failure to express MARCO and mannose receptors. J Leukoc Biol 86:479–489

    CAS  PubMed  Article  Google Scholar 

  10. Germain RN, Margulies DH (1993) The biochemistry and cell biology of antigen processing and presentation. Annu Rev Immunol 11:403–450

    CAS  PubMed  Article  Google Scholar 

  11. da Silva SA, Mazini PS, Reis PG, Sell AM, Tsuneto LT, Peixoto PR, Visentainer JE (2009) HLA-DR and HLA-DQ alleles in patients from the south of Brazil: markers for leprosy susceptibility and resistance. BMC Infect Dis 9:134

    PubMed Central  PubMed  Article  Google Scholar 

  12. Aron Y, Polla BS, Bienvenu T, Dall'ava J, Dusser D, Hubert D (1999) HLA class II polymorphism in cystic fibrosis. A possible modifier of pulmonary phenotype. Am J Respir Crit Care Med 159:1464–1468

    CAS  PubMed  Article  Google Scholar 

  13. Eder C, Frankenberger M, Stanzel F, Seidel A, Schramm KW, Ziegler-Heitbrock L, Hofer TP (2009) Ultrafine carbon particles down-regulate CYP1B1 expression in human monocytes. Part Fibre Toxicol 6:27

    PubMed Central  PubMed  Article  Google Scholar 

  14. Frankenberger M, Eder C, Hofer TP, Heimbeck I, Skokann K, Kassner G, Weber N, Moller W, Ziegler-Heitbrock L (2011) Chemokine expression by small sputum macrophages in COPD. Mol Med 17:762–770

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  15. Dayyani F, Belge KU, Frankenberger M, Mack M, Berki T, Ziegler-Heitbrock L (2003) Mechanism of glucocorticoid-induced depletion of human CD14 + CD16+ monocytes. J Leukoc Biol 74:33–39

    CAS  PubMed  Article  Google Scholar 

  16. Volk HD, Reinke P, Krausch D, Zuckermann H, Asadullah K, Muller JM, Docke WD, Kox WJ (1996) Monocyte deactivation—rationale for a new therapeutic strategy in sepsis. Intensive Care Med 22(Suppl 4):S474–S481

    PubMed  Article  Google Scholar 

  17. Laki J, Laki I, Nemeth K, Ujhelyi R, Bede O, Endreffy E, Bolbas K, Gyurkovits K, Csiszer E, Solyom E et al (2006) The 8.1 ancestral MHC haplotype is associated with delayed onset of colonization in cystic fibrosis. Int Immunol 18:1585–1590

    CAS  PubMed  Article  Google Scholar 

  18. Wolk K, Kunz S, Crompton NE, Volk HD, Sabat R (2003) Multiple mechanisms of reduced major histocompatibility complex class II expression in endotoxin tolerance. J Biol Chem 278:18030–18036

    CAS  PubMed  Article  Google Scholar 

  19. Kim OY, Monsel A, Bertrand M, Coriat P, Cavaillon JM, Adib-Conquy M (2010) Differential down-regulation of HLA-DR on monocyte subpopulations during systemic inflammation. Crit Care 14:R61

    PubMed Central  PubMed  Article  Google Scholar 

  20. Hampton TH, Stanton BA (2010) A novel approach to analyze gene expression data demonstrates that the DeltaF508 mutation in CFTR downregulates the antigen presentation pathway. Am J Physiol Lung Cell Mol Physiol 298:L473–L482

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  21. Knight RA, Kollnberger S, Madden B, Yacoub M, Hodson ME (1997) Defective antigen presentation by lavage cells from terminal patients with cystic fibrosis. Clin Exp Immunol 107:542–547

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  22. del Fresno C, Garcia-Rio F, Gomez-Pina V, Soares-Schanoski A, Fernandez-Ruiz I, Jurado T, Kajiji T, Shu C, Marin E, Gutierrez del Arroyo A et al (2009) Potent phagocytic activity with impaired antigen presentation identifying lipopolysaccharide-tolerant human monocytes: demonstration in isolated monocytes from cystic fibrosis patients. J Immunol 182:6494–6507

    PubMed  Article  Google Scholar 

  23. del Campo R, Martinez E, del Fresno C, Alenda R, Gomez-Pina V, Fernandez-Ruiz I, Siliceo M, Jurado T, Toledano V, Arnalich F et al (2011) Translocated LPS might cause endotoxin tolerance in circulating monocytes of cystic fibrosis patients. PLoS One 6:e29577

    PubMed Central  PubMed  Article  Google Scholar 

  24. Di A, Brown ME, Deriy LV, Li C, Szeto FL, Chen Y, Huang P, Tong J, Naren AP, Bindokas V et al (2006) CFTR regulates phagosome acidification in macrophages and alters bactericidal activity. Nat Cell Biol 8:933–944

    CAS  PubMed  Article  Google Scholar 

  25. Pier GB (2000) Role of the cystic fibrosis transmembrane conductance regulator in innate immunity to Pseudomonas aeruginosa infections. Proc Natl Acad Sci U S A 97:8822–8828

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  26. Aron Y, Polla BS, Bienvenu T, Dall'ava J, Dusser D, Hubert D (1999) HLA class II polymorphism in cystic fibrosis. A possible modifier of pulmonary phenotype. Am J Respir Crit Care Med 159:1464–1468

    CAS  PubMed  Article  Google Scholar 

  27. Rozmahel R, Wilschanski M, Matin A, Plyte S, Oliver M, Auerbach W, Moore A, Forstner J, Durie P, Nadeau J et al (1996) Modulation of disease severity in cystic fibrosis transmembrane conductance regulator deficient mice by a secondary genetic factor. Nat Genet 12:280–287

    CAS  PubMed  Article  Google Scholar 

  28. Caversaccio M, Bonel HM, Carter R, Williams AP, Gadola SD (2008) TAP deficiency syndrome: chronic rhinosinusitis and conductive hearing loss. Eur Arch Otorhinolaryngol 265:1289–1292

    PubMed  Article  Google Scholar 

  29. Zimmer J, Andres E, Donato L, Hanau D, Hentges F, de la Salle H (2005) Clinical and immunological aspects of HLA class I deficiency. QJM 98:719–727

    CAS  PubMed  Article  Google Scholar 

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Acknowledgments

We thank Karl Staples, Clinical & Experimental Sciences, University of Southampton, UK, for his valuable support on cDNA microarray analysis. Furthermore, we thank Kerstin Skokann for excellent technical assistance.

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The authors declare that they have no conflict of interest related to the publication of this manuscript.

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Correspondence to Thomas P. Hofer.

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Hofer, T.P., Frankenberger, M., Heimbeck, I. et al. Decreased expression of HLA-DQ and HLA-DR on cells of the monocytic lineage in cystic fibrosis. J Mol Med 92, 1293–1304 (2014). https://doi.org/10.1007/s00109-014-1200-z

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  • DOI: https://doi.org/10.1007/s00109-014-1200-z

Keywords

  • Cystic fibrosis
  • HLA-DQ
  • HLA-DR
  • Inflammation
  • Monocytes, macrophages and dendritic cells