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Decreased levels of interleukin-12p40 in the serum of patients with Whipple’s disease

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International Journal of Colorectal Disease Aims and scope Submit manuscript

Abstract

Background

An impaired production of interleukin (IL)-12 and T cell interferon-γ (IFN-γ) of in vitro stimulated monocytes has been discussed as a pathogenic factor in Whipple’s disease (WD). It is unclear whether this defect of cellular immunity is translated to the humoral immune system and to serum correlates.

Methods

We analyzed the serum of 40 patients with Whipple’s disease in various degrees of disease activity by sandwich enzyme-linked immunosorbent assay for differences in cytokine and cell adhesion molecule concentrations compared with age- and sex-matched controls.

Results

We observed a highly significant reduction of IL-12p40 levels (patients, 0.18±0.05 ng/ml (mean±SEM); controls, 3.19±0.39 ng/ml; p<0.01) in all stages of disease activity, whereas the concentration of IL-12p70 was comparable with controls. Furthermore, we observed a slight decrease in tumour necrosis factor α (TNF-α) concentrations in the serum of patients (patients, 6.36±0.90 pg/ml; controls, 10.5±1.23 pg/ml; p<0,05). The levels of other cytokines such as IFN-γ, IL-2, IL-13 and transforming growth factor β, as well as soluble cell adhesion molecules lymphocyte function-associated antigen 3 and intercellular adhesion molecule 1, were not significantly different compared with controls. Levels of immunoglobulin G2 (IgG2) measured in the serum of WD patients were below normal in 24 of 29 patients and were even below the 95% confidence interval in 10 patients.

Conclusion

Our data demonstrate a persistent defect of the cellular immune response with decreased serum concentrations of IL-12p40 and TNF-α and decreased IgG2 levels in a large group of WD patients. These data support as in vivo finding the results obtained in previous investigations with stimulated monocytes/lymphocytes. The isolated decrease in IL-12p40 may hint at possible defects in the IL-12/IFN-γ promoter system.

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Abbreviations

ANOVA:

analysis of variance

ELISA:

enzyme-linked immunosorbent assay

ICAM:

intercellular adhesion molecule

ICSBP:

interferon consensus sequence binding protein

IFN-γ:

interferon gamma

IgG2:

immunoglobulin G2

IL:

interleukin

LFA:

lymphocyte function-associated antigen

LPS:

lipopolysaccharide

SD:

standard deviation

TGF-β:

transforming growth factor beta

TNF-α:

tumor necrosis factor alpha

WD:

Whipple’s disease

References

  1. Whipple GH (1907) A hitherto undescribed disease characterized anatomically by deposits of fat and fatty acids in the intestinal and mesenteric lymphatic tissues. Bull Johns Hopkins Hosp 18:382–391

    CAS  Google Scholar 

  2. Singer R (1998) Diagnosis and treatment of Whipple’s disease. Drugs 55:699–704

    CAS  PubMed  Google Scholar 

  3. Dobbins WO III (1987) Whipple’s disease. Charles C. Thomas, Springfield, IL

    Google Scholar 

  4. Marth T (1996) Whipple-Erkrankung. In: Hahn EG, Riemann JF (eds) Klinische Gastroenterologie, 3rd edn. Thieme, Stuttgart, pp 947–951

    Google Scholar 

  5. Fenollar F, Raoult D (2001) Whipple’s disease. Minireview. Clin Diagn Lab Immunol 8:1–8

    CAS  PubMed  Google Scholar 

  6. Marth T, Strober W (1996) Whipple’s disease. Semin Gastrointest Dis 7:41–48

    CAS  PubMed  Google Scholar 

  7. Maiwald M, Relman DA (2001) Whipple’s disease and Tropheryma whippelii: secrets slowly revealed. Clin Infect Dis 32:457–463

    CAS  PubMed  Google Scholar 

  8. Marth T, Raoult D (2003) Whipple’s disease. Lancet 361:239–246

    PubMed  Google Scholar 

  9. Black-Schaffer B (1949) Tinctorial demonstration of a glycoprotein in Whipple’s disease. Proc Soc Exp Biol Med 72:225

    CAS  PubMed  Google Scholar 

  10. Fredricks DN, Relman DA (2001) Localization of Tropheryma whippelii rRNA in tissues from patients with Whipple’s disease. J Infect Dis 183:1229–1237

    CAS  PubMed  Google Scholar 

  11. Trier JS, Phelps PC, Eidelman S et al (1965) Whipple’s disease: light and electron microscopic correlation of jejunal mucosal histology with antibiotic treatment and clinical status. Gastroenterology 48:684–707

    CAS  PubMed  Google Scholar 

  12. Wilson KH, Blitchington R, Frothingham R, Wilson JAP (1991) Phylogeny of the Whipple’s disease-associated bacterium. Lancet II:474

    Google Scholar 

  13. Raoult D, Birg ML, La Scola B, Fournier PE, Enea M, Lepidi H, Roux V, Piette J-C, Vandenesch F, Vital-Durand D, Marrie TJ (2000) Cultivation of the bacillus of Whipple’s disease. N Engl J Med 342:620–625

    CAS  PubMed  Google Scholar 

  14. Raoult D, La Scola B, Lecocq P, Lepidi H, Fournier PE (2001) Culture and immunological detection of Tropheryma whippelii in the duodenum of a patient with Whipple’s disease. JAMA 285:1039–1043

    CAS  PubMed  Google Scholar 

  15. La Scola B, Fenollar F, Fournier PE, Altwegg M, Mallet MN, Raoult D (2001) Description of Tropheryma whipplei gen. nov., sp. nov., the Whipple’s disease bacillus. Int J Syst Evol Microbiol 51:1471–1479

    PubMed  Google Scholar 

  16. Liang Z, La Scola B, Raoult D (2002) Monoclonal antibodies to immunodominant epitope of Tropheryma whipplei. Clin Diagn Lab Immunol 9:156–159

    CAS  PubMed  Google Scholar 

  17. Raoult D, Lepidi H, Harle JR (2001) Tropheryma whippelii circulating in blood monocytes. N Engl J Med 345:548

    CAS  PubMed  Google Scholar 

  18. Relman DA, Schmidt TM, Mac Dermott RP, Falkow S (1992) Identification of the uncultured bacillus of Whipple’s disease. N Engl J Med 327:293–301

    CAS  PubMed  Google Scholar 

  19. Feurle GE, Dörken B, Schöpf E, Lenhard V (1979) HLA-B27 and defects in the T cell system in Whipple’s disease. Eur J Clin Investig 9:385

    CAS  Google Scholar 

  20. Feurle GE (1985) Association of Whipple’s disease with HLA-B27. Lancet 8:1336

    Google Scholar 

  21. Paulley JW (1952) A case of Whipple’s disease (intestinal lipodystrophy). Gastroenterol 22:128

    CAS  Google Scholar 

  22. Maiwald M, Schuhmacher F, Ditton H-J, von Herbay A (1998) Environmental occurrence of the Whipple’s disease bacterium (Tropheryma whippelii). Appl Environ Microbiol 64:760–762

    CAS  PubMed  Google Scholar 

  23. Bjerknes R, Ødegaard S, Bjerkvig R, Børkje B, Lærum OD (1988) Whipple’s disease: demonstration of a persisting monocyte and macrophage dysfunction. Scand J Gastroenterol 23:611–619

    CAS  PubMed  Google Scholar 

  24. Marth T, Roux M, von Herbay A, Meuer SC, Feurle GE (1994) Persistent reduction of complement receptor 3 α-chain expressing mononuclear blood cells and transient inhibitory serum factors in Whipple’s disease. Clin Immunol Immunopathol 72:217–226

    CAS  PubMed  Google Scholar 

  25. Marth T, Neurath M, Cuccherini BA, Strober W (1997) Defects of monocyte interleukin-12 production and humoral immunity in Whipple’s disease. Gastroenterology 113:442–448

    CAS  PubMed  Google Scholar 

  26. Marth T, Kleen N, Stallmach A, Ring S, Aziz S, Schmidt C, Strober W, Zeitz M, Schneider T (2002) Dysregulated peripheral and mucosal Th1/Th2 response in Whipple’s disease. Gastroenterology 123:1468–1477

    CAS  PubMed  Google Scholar 

  27. Schoedon G, Goldenberger D, Forrer R, Gunz A, Dutly F, Hoechli M, Altwegg M, Schaffner A (1997) Deactivation of macrophages with Interleukin-4 is the key to the isolation of Tropheryma whippelii. J Infect Dis 176:672–677

    CAS  PubMed  Google Scholar 

  28. Germann T, Bongartz M, Dlugonska H, Hess H, Schmitt E, Kolbe L, Kolsch E, Podlaski FJ, Gately MK, Rude E (1995) Interleukin-12 profoundly up-regulates the synthesis of antigen-specific complement-fixing IgG2a, IgG2b and IgG3 antibody subclasses in vivo. Eur J Immunol 25:823–829

    CAS  PubMed  Google Scholar 

  29. Janeway CA, Travers P, Walport M, Shlomchik M (2001) Immunobiology: the immune system in health and disease, 5th edn. Garland, London

    Google Scholar 

  30. Hoffmann JC, Dengler TJ, Knolle PA, Albert-Wolf M, Roux M, Wallich R, Meuer SC (1993) A soluble form of the adhesion receptor CD58 (LFA-3) is present in human body fluids. Eur J Immunol 23:3003–3010

    CAS  PubMed  Google Scholar 

  31. Trinchieri G (1994) Interleukin-12: a cytokine produced by antigen-presenting cells with immunoregulatory functions in the generation of T-helper cells type 1 and cytotoxic lymphocytes. Blood 84:4008–4027

    CAS  PubMed  Google Scholar 

  32. Trinchieri G (2003) Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol 3:133–146

    Article  CAS  PubMed  Google Scholar 

  33. Trinchieri G (1997) Cytokines acting on or secreted by macrophages during intracellular infection (IL-10, IL-12, IFN-γ). Curr Opin Immunol 9:17

    CAS  PubMed  Google Scholar 

  34. Hayes MP, Wang J, Norcross MA (1995) Regulation of interleukin-12 expression in human monocytes: selective priming by interferon-γ of lipopolysaccharide-inducible p35 and p40 genes. Blood 86:646

    CAS  PubMed  Google Scholar 

  35. Ma X, Chow JM, Gri G, Carra G, Gerosa F, Wolf SF, Dzialo R, Trinchieri G (1996) The interleukin 12p40 gene promoter is primed by interferon-γ in monocytic cells. J Exp Med 183:147

    CAS  PubMed  Google Scholar 

  36. Wang IM, Contursi C, Masumi A, Ma X, Trinchieri G, Ozato K (2000) An IFN-γ-inducible transcription factor, IFN consensus sequence binding protein (ICSBP), stimulates IL-12p40 expression in macrophages. J Immunol 165:271–279

    CAS  PubMed  Google Scholar 

  37. Altare F, Durandy A, Lammas D, Emile JF, Lamhamedi S, Le Deist F, Drysdale P, Jouanguy E, Doffinger R, Bernaudin F, Jeppsson O, Gollob JA, Meinl E, Segal AW, Fischer A, Kumararatne D, Casanova JL (1998) Impairment of mycobacterial immunity in human interleukin-12 receptor deficiency. Science 280:1432–1435

    CAS  PubMed  Google Scholar 

  38. Picard C, Fieschi C, Altare F, Al-Jumaah S, Al-Hajjar S, Feinberg J, Dupuis S, Soudais C, Al-Mohsen IZ, Genin E, Lammas D, Kumararatne DS, Leclerc T, Rafii A, Frayha H, Murugasu B, Wah LB, Sinniah R, Loubser M, Okamoto E, Al-Ghonaium A, Tufenkeji H, Abel L, Casanova JL (2002) Inherited interleukin-12 deficiency: IL12B genotype and clinical phenotype of 13 patients from six kindreds. Am J Hum Genet 70:336–348

    CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to acknowledge Prof. Dr. Feurle, Neuwied, Germany, for the provision of serum samples of some patients of group 1 (n=3), which have already been included in a therapy study, Studie zur Initialtherapie des Morbus Whipple (SIMW) of WD.

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Author notes

  1. A. Kalt

    Present address: Department of Dermatology, The University of the Saarland, 66421, Homburg/Saar, Germany

Authors and Affiliations

  1. Department of Internal Medicine I, Charité, Campus Benjamin Franklin Hospital, Berlin, Germany

    T. Schneider, J. Hoffmann & M. Zeitz

  2. Department of Gastroenterology, Deutsche Klinik für Diagnostik, Wiesbaden, Germany

    S. Ring

  3. Department of Gastroenterology, Marienhospital, Katholische Kliniken Essen-Nordwest, Essen, Germany

    A. Stallmach

  4. Department of Clinical Microbiology, Mayo Clinic, Rochester, MN, USA

    D. H. Persing

  5. Department of Internal Medicine, St. Josef Hospital, Barlstrasse 42, 56856, Zell/Mosel, Germany

    T. Marth

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  1. A. Kalt
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Correspondence to T. Marth.

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Kalt, A., Schneider, T., Ring, S. et al. Decreased levels of interleukin-12p40 in the serum of patients with Whipple’s disease. Int J Colorectal Dis 21, 114–120 (2006). https://doi.org/10.1007/s00384-005-0778-6

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  • DOI: https://doi.org/10.1007/s00384-005-0778-6

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