Review
doi: 10.1016/j.pt.201312004.
Epub 2014 Jan 2.
Post kala-azar dermal leishmaniasis: an unresolved mystery
Affiliations
- PMID: 24388776
- PMCID: PMC3919212
- DOI: 10.1016/j.pt.201312004
Item in Clipboard
Review
Post kala-azar dermal leishmaniasis: an unresolved mystery
Debanjan Mukhopadhyay et al.
Trends Parasitol.
2014 Feb.
Display options
Format
Display options
Format
Abstract
Post kala-azar dermal leishmaniasis (PKDL), a cutaneous sequela of visceral leishmaniasis (VL), develops in some patients alongside but more commonly after apparent cure from VL. In view of the pivotal role of PKDL patients in the transmission of VL, here we review clinical, epidemiological, parasitological, and immunological perspectives of this disease, focusing on five hypotheses to explain the development of PKDL: (i) the role of antimonial drugs; (ii) UV-induced skin damage; (iii) reinfection; (iv) organ specific failure of memory T cell responses; and (v) genetic susceptibility of the host. This review will enable researchers and clinicians to explore the unresolved mystery of PKDL and provide a framework for future application of 'omic' approaches for the control and eventual elimination of VL.
Keywords: UV light; antimony; post kala-azar dermal leishmaniasis (PKDL); regulatory T cells; vitamin D.
Copyright © 2014 Elsevier Ltd. All rights reserved.
Figures
Current immunological scenario in Indian PKDL. Patients with Indian PKDL have distinct patterns of immunity in the skin and periphery. In the skin, immunity is regulated by IL-10 and FoxP3 , because despite the enhanced levels of IFN-γ and TNF-α, their respective receptors are downregulated , . Additionally, in the skin, there is an increased presence of Th17 cells and IL-17 . By contrast, peripheral immunity is controlled mostly by CD8+ T cells that are the major sources of IL-10 and are anergic in nature , . Lack of co-stimulation was also evident because decreased CD28 and CD86 was found in circulating CD8+ T cells and CD14+ monocytes, respectively , . Abbreviations: PKDL, post kala-azar dermal leishmaniasis; IL-10, interleukin 10; FoxP3, forkhead box P3; IFN-γ, interferon γ; TNF-α, tumour necrosis factor α; Th, T helper.
Pathogenesis induced by UV light. UV light has a potential role in the pathogenesis of PKDL via enhanced secretion of cis-urocanic acid from keratinocytes and vitamin D3. This translates into a reduced number of E-LCs, which also have an altered morphology . In E-LCs, expression of MHCII, CD80, and CD86 are decreased, and IL-10 is increased , . IL-4 secreted from Th2 cells subsequently activates dDCs to secrete more IL-10, which then induces an increased presence of Tregs, allowing for parasite persistence. Similarly, TGF-β from infected macrophages can activate Tregs, which then produce more TGF-β, facilitating parasite persistence. Another possibility is that raised levels of vitamin D3 polarise macrophages towards an alternatively activated phenotype that along with an enhanced presence of Tregs collectively generates an immunosuppressive milieu. Abbreviations: PKDL, post kala-azar dermal leishmaniasis; dDC, dermal dendritic cell; E-LC, epidermal Langerhans cells; MHC, major histocompatibility complex; IL-4, interleukin 4; IL-10, interleukin 10; Treg, T regulatory cell; TGF-β, tumour growth factor β; Th, T helper.
Failure of organ-specific memory T cell response. Following infection with Leishmania parasites, individuals develop VL, and generally antileishmanial treatment results in lifelong immunity due to the presence of systemic CM and EM T cells. In patients with self-limiting PKDL (e.g., in Sudan), an increased EM T cell response in the skin causes spontaneous resolution. However, in Indian PKDL, a weak skin-specific EM T cell response accounts for its non-self-healing nature. Abbreviations: CM T cells, central memory T cells; EM T cells, effector memory T cells; VL, visceral leishmaniasis; PKDL, post kala-azar dermal leishmaniasis.
Genetic susceptibility of the host. A model indicating the possible interplay of genes that contributes towards host susceptibility in PKDL. SLC11A1 enhances macrophage activation in terms of its antimicrobial activity (e.g., iron sequestration from parasites) . Polymorphisms of SLC11A1 (SLC11A1lo) can render the host susceptible to VL; additionally, in these individuals, a polymorphism in the IFN-γR gene (IFN-γRlo) makes them more susceptible to developing PKDL, owing to the reduced functionality of the IFN-γR gene. Tregs secrete both IL-10 and IFN-γ, but due to the decreased activity of IFN-γR, the immune deactivating properties of IL-10 predominate; conversely, IFN-γRhi individuals are cured of VL and are less prone to develop PKDL. Abbreviations: Mφ, macrophage; SLC11A1, solute carrier family 11A1; IFN-γR, interferon γ receptor; IL-10R, interleukin 10 receptor; Treg, T regulatory cell; VL, visceral leishmaniasis; PKDL, post kala-azar dermal leishmaniasis.
References
-
- Antinori S. Post kala-azar dermal leishmaniasis as an immune reconstitution inflammatory syndrome in a patient with acquired immune deficiency syndrome. Br. J. Dermatol. 2007;157:1032–1036. - PubMed
-
- Ganguly S. Post kala-azar dermal leishmaniasis – an overview. Int. J. Dermatol. 2010;49:921–931. - PubMed
-
- Desjeux P., Ramesh V. In: Kala Azar in South Asia – Current Status and Challenges Ahead. Jha T.K., Noiri E., editors. Springer; 2011. Post kala-azar dermal leishmaniasis: facing the challenge of eliminating kala-azar from South Asia; pp. 111–124.
-
- Zijlstra E.E. Post kala-azar dermal leishmaniasis. Lancet Infect. Dis. 2003;3:87–98. - PubMed
-
- Mondal D., Khan M.G. Recent advances in post kala-azar dermal leishmaniasis. Curr. Opin. Infect. Dis. 2011;24:418–422. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources