Evidence for involvement of Th17 type responses in post kala azar dermal leishmaniasis (PKDL).
BACKGROUND
Post kala-azar dermal leishmaniasis (PKDL), a dermal sequel of visceral leishmaniasis, caused by Leishmania donovani, constitutes an important reservoir for the parasite. Parallel functioning of counter acting immune responses (Th1/Th2) reflects a complex immunological scenario, suggesting the involvement of additional regulatory molecules in the disease pathogenesis.


RESULTS
In the present study, human cytokine/chemokine/receptor specific cDNA array technique was employed to identify modulations in gene expression of host immuno-determinants during PKDL, followed by evaluation of Th17 type responses by analyzing mRNA and protein expression of Th17 markers (IL-23, IL-17, RORγt) and performing functional assays using Leishmania antigen (TSLA) or recombinant (rec)IL-17. Array analysis identified key immuno-regulatory molecules including cytokines (TNF-α, IFN-γ, IL-10, IL-17), chemokines (MCP-1, MIP-1α), apoptotic molecules (FasL, TRAIL, IRF-1) and receptors (CD40, Fas). Up regulation in lesional expression of Th17 markers was observed during PKDL compared to control (IL-17 and IL-23, P = 0.0008; RORγt, P = 0.02). In follow-up samples, chemotherapy significantly down regulated expression of all markers. In addition, lesional expression of IL-17 was confirmed at protein level by Immuno-histochemistry. Further, systemic presence of Th17 responses (IL-17 and IL-23) was observed in plasma samples from PKDL patients. In functional assays, TSLA stimulated the secretion of IL-17 and IL-23 from PBMCs of PKDL patients, while recIL-17 enhanced the production of TNF-α as well as nitric oxide (NO) in PKDL compared to control (TNF-α, P = 0.0002; NO, P = 0.0013). Further, a positive correlation was evident between lesional mRNA expression of IL-17 and TNF-α during PKDL.


CONCLUSIONS
The results highlight key immune modulators in PKDL and provide evidence for the involvement of Th17 type responses in the disease pathogenesis.
National Institute of Pathology (ICMR), Safdarjung Hospital Campus, New Delhi, India.
Gajendra Kumar
GK
Katara
Nasim Akhtar
NA
Ansari
Avninder
A
Singh
V
V
Ramesh
Poonam
P
Salotra
D000293:Adolescent; D000328:Adult; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D007891:Leishmania; D007893:Leishmania donovani / Q000276:immunology* / Q000472:pathogenicity*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology*; D007898:Leishmaniasis, Visceral / Q000276:immunology*; D008297:Male; D046228:Microarray Analysis; D010949:Plasma / Q000737:chemistry; D060888:Real-Time Polymerase Chain Reaction; D058504:Th17 Cells / Q000276:immunology*; D055815:Young Adult
D016207:Cytokines