IL-18 skews the invariant NKT-cell population via autoreactive activation in atopic eczema.
Atopic eczema (AE) is a chronic relapsing inflammatory skin disease where the commensal yeast Malassezia can act as a microbial trigger factor. Malassezia activates human DC to produce IL-18, an innate cytokine that is elevated in serum of AE patients; however, the precise role of IL-18 in human AE etiology is unknown. Herein, we investigated the effect of IL-18 on the human invariant NKT (iNKT) cell compartment in AE. We found that IL-18 was a potent activator of human iNKT-cells and promoted a pro-inflammatory CD1d-dependent response, even in the absence of exogenous ligands. Chronic activation via IL-18 on the other hand was inhibitory and skewed the iNKT-cell pool by selectively suppressing CD4(+) iNKT-cells. This was mimicked in AE patients where the proportion of CD4(+) iNKT-cells was reduced in peripheral blood and coincided with elevated plasma levels of IL-18. Furthermore, a reduced CD4(+) iNKT-cell pool was associated with elevated IgE levels in plasma, and the plasma levels of IL-18 correlated with both total IgE and disease severity in the AE patients. Based on these findings, we propose that IL-18-mediated activation and subsequent dysregulation of the CD1d-restricted iNKT-cells plays a role in the pathogenesis of human AE.
Lind
Sara M
SM
Clinical Allergy Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
Kuylenstierna
Carlotta
C
Moll
Markus
M
D Jordö
Emilie
E
Winqvist
Ola
O
Lundeberg
Lena
L
Karlsson
Maria A
MA
T Linder
Maria
M
Johansson
Catharina
C
Scheynius
Annika
A
Sandberg
Johan K
JK
Karlsson
Mikael C I
MC
D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000908:Antibodies, Fungal / Q000097:blood; D055610:Antigens, CD1d / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D003876:Dermatitis, Atopic / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood; D007371:Interferon-gamma / Q000378:metabolism; D020382:Interleukin-18 / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D008290:Malassezia / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D055611:Natural Killer T-Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D017471:Receptors, Interferon / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D055815:Young Adult; D000096743:Interferon gamma Receptor
D000908:Antibodies, Fungal; D055610:Antigens, CD1d; D007073:Immunoglobulin E; D007371:Interferon-gamma; D020382:Interleukin-18; D016328:NF-kappa B; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor