Ann Lab Med.  2019 May;39(3):284-290. 10.3343/alm.2019.39.3.284.

Neopterin Levels and Indoleamine 2,3-Dioxygenase Activity as Biomarkers of Immune System Activation and Childhood Allergic Diseases

• Ãœnüvar S
• Erge D
• Kılıçarslan B
• Gözükara BaÄŸ HG
• Çatal F
• Girgin G
• Baydar T

• KMID: 2431606
• DOI: http://doi.org/10.3343/alm.2019.39.3.284

Abstract

BACKGROUND
Although Th2 immune activation is predominant in allergic diseases, neopterinlevels and indoleamine 2,3-dioxygenase (IDO)-1 activity (kynurenine:tryptophan ratio), which reflect Th1 immune activity, increase with interferon-gamma (IFN-γ) stimulation. We investigated neopterin, tryptophan, and kynurenine levels as biomarkersof the Th1 immune system activation and changes in IDO-1 activityin children with asthma, allergic rhinitis, and atopic dermatitis, as well as the relationship between these biomarkers and the total IgE level, age, and disease severity.
METHODS
We divided 205 children (80 girls and 125 boys, four months to 17 years old) into four groups: controls, patients with asthma, patients with allergic rhinitis, and patients with atopic dermatitis. Peripheral venous blood samples were collected. Neopterin levels were determined by an enzyme immunoassay. Tryptophan and kynurenine levels were analyzed using HPLC. IDO-1 enzyme activity was calculated using tryptophan and kynurenine levels. IgE levels were measured. The Mann-Whitney U test, Kruskal-Wallis test, and Conover post-hoc method were used for statistical analysis.
RESULTS
Neopterin, tryptophan, and kynurenine levels were higher and IgE levels and IDO-1 enzyme activity were lower in patients with asthma and allergic rhinitis than in controls (P < 0.05). Patients with atopic dermatitis showed higher neopterin, tryptophan, and kynurenine levels, higher IDO-1 activity, and lower IgE levels thancontrols (P < 0.05).
CONCLUSIONS
The Th1/Th2 balance is disrupted in children with allergic diseases, concomitant with increased Th1-mediated immune response activation and reduced IgEproduction, which is promoted by Th2-type cytokines.

Keyword

Allergy; Kynurenine; Neopterin; Tryptophan; Atopic dermatitis; Allergic rhinitis; Asthma; Th1 immune response; indoleamine 2,3-dioxygenase activity

MeSH Terms

Asthma
Biomarkers*
Child
Chromatography, High Pressure Liquid
Cytokines
Dermatitis, Atopic
Female
Humans
Hypersensitivity
Immune System*
Immunoenzyme Techniques
Immunoglobulin E
Indoleamine-Pyrrole 2,3,-Dioxygenase*
Interferon-gamma
Kynurenine
Methods
Neopterin*
Rhinitis, Allergic
Tryptophan
Biomarkers
Cytokines
Immunoglobulin E
Indoleamine-Pyrrole 2,3,-Dioxygenase
Interferon-gamma
Kynurenine
Neopterin
Tryptophan

Reference

1. Haanpää L, af Ursin P, Nermes M, Kaljonen A, Isolauri E. Association of allergic diseases with children's life satisfaction: population-based study in Finland. BMJ Open. 2018; 8:e019281.

2. Pawankar R, Canonica GW, et al. World Allergy Organisation (WAO) white book on allergy: update 2013. Milwaukee (WI): World Allergy Organization;2013. p. 1–10.

3. Spergel JM. Atopic march: link to upper airways. Curr Opin Allergy Clin Immunol. 2005; 5:17–21. PMID: 15643339.

4. Bousquet J, Khaltaev N, Cruz AA, Denburg J, Fokkens WJ, Togias A, et al. Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and Aller-Gen). Allergy. 2008; 63:8–160. PMID: 18331513.

5. Novak N, Bieber T. Allergic and nonallergic forms of atopic diseases. J Allergy Clin Immunol. 2003; 112:252–262. PMID: 12897728.

6. Brandt EB, Sivaprasad U. Th2 cytokines and atopic dermatitis. J Clin Cell Immunol. 2011; 2:110. PMID: 21994899.

7. von Bubnoff D, Fimmers R, Bogdanow M, Matz H, Koch S, Bieber T. Asymptomatic atopy is associated with increased indoleamine 2,3-dioxygenase activity and interleukin-10 production during seasonal allergen exposure. Clin Exp Allergy. 2004; 34:1056–1063. PMID: 15248850.

8. Braido F. Failure in asthma control: reasons and consequences. Scientifica (Cairo). 2013; 2013:549252. PMID: 24455432.

9. Selroos O, Kupczyk M, Kuna P, Łacwik P, Bousquet J, Brennan D, et al. National and regional asthma programmes in Europe. Eur Respir Rev. 2015; 24:474–483. PMID: 26324809.

10. Malhotra K, Baltrus P, Zhang S, McRoy L, Immergluck LC, Rust G. Geographic and racial variation in asthma prevalence and emergency department use among Medicaid-enrolled children in 14 southern states. J Asthma. 2014; 51:913–921. PMID: 24915006.

11. Ledochowski M, Murr C, Widner B, Fuchs D. Inverse relationship between neopterin and immunoglobulin E. Clin Immunol. 2001; 98:104–108. PMID: 11141332.

12. Ciprandi G, De Amici M, Tosca M, Fuchs D. Tryptophan metabolism in allergic rhinitis: the effect of pollen allergen exposure. Hum Immunol. 2010; 71:911–915. PMID: 20540982.

13. Platten M, von Knebel Doeberitz N, Oezen I, Wick W, Ochs K. Cancer immunotherapy by targeting IDO1/TDO and their downstream effectors. Front Immunol. 2015; 5:673. PMID: 25628622.

14. Badawy AA. Kynurenine pathway of tryptophan metabolism: Regulatory and functional aspects. Int J Tryptophan Res. 2017; 10:1178646917691938. PMID: 28469468.

15. Favennec M, Hennart B, Caiazzo R, Leloire A, Yengo L, Verbanck M, et al. The kynurenine pathway is activated in human obesity and shifted toward kynurenine monooxygenase activation. Obesity (Silver Spring). 2015; 23:2066–2074. PMID: 26347385.

16. Luukkainen A, Karjalainen J, Honkanen T, Lehtonen M, Paavonen T, Toppila-Salmi S. Indoleamine 2,3-dioxygenase expression in patients with allergic rhinitis: a case-control study. Clin Transl Allergy. 2011; 1:17. PMID: 22410120.

17. Mota Pinto A, Todo Bom A, Vale Pereira S, Alves V, Santos Rosa M. Elevated neopterin levels in non-allergic asthma. Pathophysiology. 2007; 14:35–39. PMID: 17113763.

18. Global initiative for asthma GINA Report: Global strategy for asthma management and prevention. Updated on Feb 2018. https://ginasthma.org/gina-reports/.

19. Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol (Stockh). 1980; 92:44–47.

20. Widner B, Werner ER, Schennach H, Wachter H, Fuchs D. Simultaneous measurement of serum tryptophan and kynurenine by HPLC. Clin Chem. 1997; 43:2424–2426. PMID: 9439467.

21. Laich A, Neurauter G, Widner B, Fuchs D. More rapid method for simultaneous measurement of tryptophan and kynurenine by HPLC. Clin Chem. 2002; 48:579–581. PMID: 11861457.

22. Gostner JM, Becker K, Kofler H, Strasser B, Fuchs D. Tryptophan metabolism in allergic disorders. Int Arch Allergy Immunol. 2016; 169:203–215. PMID: 27161289.

23. Kositz C, Schroecksnadel K, Grander G, Schennach H, Kofler H, Fuchs D. High serum tryptophan concentration in pollinosis patients is associated with unresponsiveness to pollen extract therapy. Int Arch Allergy Immunol. 2008; 147:35–40. PMID: 18446051.

24. Ciprandi G, Fuchs D. Tryptophan metabolic pathway, airway nitric oxide, and allergy. Ann Allergy Asthma Immunol. 2017; 119:395–396. PMID: 29150065.

25. Fuchs D, Stahl-Hennig C, Gruber A, Murr C, Hunsmann G, Wachter H. Neopterin--its clinical use in urinalysis. Kidney Int Suppl. 1994; 47:S8–S11. PMID: 7869677.

26. Eisenhut M. Neopterin in diagnosis and monitoring of infectious diseases. J Biomark. 2013; 2013:196432. PMID: 26317013.

27. Shirai R, Sato K, Yamashita T, Yamaguchi M, Okano T, Watanabe-Kominato K, et al. Neopterin counters vascular inflammation and atherosclerosis. J Am Heart Assoc. 2018; 7:e007359. PMID: 29420219.

28. Pompili M, Lionetto L, Curto M, Forte A, Erbuto D, Montebovi F, et al. Tryptophan and kynurenine metabolites: are they related to depression? Neuropsychobiology. 2019; 77:23–28. PMID: 30110684.

29. Zuo H, Ueland PM, Ulvik A, Eussen SJ, Vollset SE, Nygård O, et al. Plasma biomarkers of inflammation, the kynurenine pathway, and risks of all-cause, cancer, and cardiovascular disease mortality: The Hordaland Health Study. Am J Epidemiol. 2016; 183:249–258. PMID: 26823439.

30. Russo S, Kema IP, Fokkema MR, Boon JC, Willemse PH, et al. Tryptophan as a link between psychopathology and somatic states. Psychosom Med. 2003; 65:665–671. PMID: 12883120.

31. Kurz K, Schroecksnadel S, Weiss G, Fuchs D. Association between increased tryptophan degradation and depression in cancer patients. Curr Opin Clin Nutr Metab Care. 2011; 14:49–56. PMID: 21076293.

32. Capuron L, Geisler S, Kurz K, Leblhuber F, Sperner-Unterweger B, Fuchs D. Activated immune system and inflammation in healthy ageing: relevance for tryptophan and neopterin metabolism. Curr Pharm Des. 2014; 20:6048–6057. PMID: 24641220.

33. Sucher R, Kurz K, Weiss G, Margreiter R, Fuchs D, Brandacher G. IDO-mediated tryptophan degradation in the pathogenesis of malignant tumor disease. Int J Tryptophan Res. 2010; 3:113–120. PMID: 22084593.

34. Luukkainen A, Karjalainen J, Honkanen T, Lehtonen M, Paavonen T, Toppila-Salmi S. Indoleamine 2,3-dioxygenase expression in patients with allergic rhinitis: a case-control study. Clin Transl Allergy. 2011; 1:17. PMID: 22410120.

35. Champe PC, Harvey RA. Biochemistry, Lippincott's illustrated reviews. J.B. Lippincott Publishers Company;1994. p. 457–472.

36. Ciprandi G, De Amici M, Tosca M, Fuchs D. Tryptophan metabolism in allergic rhinitis: the effect of pollen allergen exposure. Hum Immunol. 2010; 71:911–915. PMID: 20540982.

37. Girgin G, Baydar T, Fuchs D, Sahin G, Özmert E, Yurdakök K. Evaluation of serum and urinary levels of some pteridine pathway components in healthy Turkish children. Pteridines. 2013; 23:90–95.

38. Luukkainen A, Karjalainen J, Hurme M, Paavonen T, Huhtala H, Toppila-Salmi S. Relationships of indoleamine 2,3-dioxygenase activity and cofactors with asthma and nasal polyps. Am J Rhinol Allergy. 2014; 28:e5–e10. PMID: 24717869.