Jane E. Dalton

BACKGROUND & AIMS: Kupffer cells (KCs), the resident tissue macrophages of the liver, play a crucial role in the clearance of pathogens and other particulate materials that reach the systemic circulation. Recent studies have identified KCs as a yolk sac-derived resident macrophage population that is replenished independently of monocytes in the steady state. Although it is now established that following local tissue injury, bone marrow derived monocytes may infiltrate the tissue and differentiate into macrophages, the extent to which newly differentiated macrophages functionally resemble the KCs they have replaced has not been extensively studied. METHODS: We studied the two populations of KCs using intravital microscopy, morphometric analysis and gene expression profiling. An ion homeostasis gene signature, including genes associated with scavenger receptor function and extracellular matrix deposition, allowed discrimination between these two KC sub-types. RESULTS: Bone marrow derived "KCs" accumulating as a result of genotoxic injury, resemble but are not identical to their yolk sac counterparts. Reflecting the differential expression of scavenger receptors, yolk sac-derived KCs were more effective at accumulating acetylated low density lipoprotein, whereas surprisingly, they were poorer than bone marrow-derived KCs when assessed for uptake of a range of bacterial pathogens. The two KC populations were almost indistinguishable in regard to i) response to lipopolysaccharide challenge, ii) phagocytosis of effete red blood cells and iii) their ability to contain infection and direct granuloma formation against Leishmania donovani, a KC-tropic intracellular parasite. CONCLUSIONS: Bone marrow-derived KCs differentiate locally to resemble yolk sac-derived KC in most but not all respects, with implications for models of infectious diseases, liver injury and bone marrow transplantation. In addition, the gene signature we describe adds to the tools available for distinguishing KC subpopulations based on their ontology. LAY SUMMARY: Liver macrophages play a major role in the control of infections in the liver and in the pathology associated with chronic liver diseases. It was recently shown that liver macrophages can have two different origins, however, the extent to which these populations are functionally distinct remains to be fully addressed. Our study demonstrates that whilst liver macrophages share many features in common, regardless of their origin, some subtle differences in function exist. DATA REPOSITORY: Gene expression data are available from the European Bioinformatics Institute ArrayExpress data repository (accession number E-MTAB-4954).

•Sodium antimony gluconate contributes towards the pathogenesis of PKDL.•UV light plays a pivotal role in the development of PKDL.•Development of PKDL can be viewed as a reinfection or activation of latent Leishmania parasites.•PKDL can be resolved by mounting an effective tissue-specific memory T cell response.•Host genetic factors play a contributory role. 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. 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. The leishmaniases comprise a diverse group of poverty-related neglected tropical diseases that have a major impact on health worldwide. Among the manifestations of leishmaniasis, post kala-azar dermal leishmaniasis (PKDL; see Glossary) caused by the protozoan parasite Leishmania donovani, is possibly the most intriguing clinically and scientifically, as it generally develops as a sequela after apparent successful cure from visceral leishmaniasis (VL; also known as kala-azar) [1Antinori S. et al.Post kala-azar dermal leishmaniasis as an immune reconstitution inflammatory syndrome in a patient with acquired immune deficiency syndrome.Br. J. Dermatol. 2007; 157: 1032-1036Crossref PubMed Scopus (46) Google Scholar, 2Ganguly S. et al.Post kala-azar dermal leishmaniasis – an overview.Int. J. Dermatol. 2010; 49: 921-931Crossref PubMed Scopus (63) Google Scholar]. The clinical presentation of VL and PKDL differ substantially; in VL, patients suffer from prolonged fever, hepatosplenomegaly, weight loss, and anaemia, whereas manifestations of PKDL are limited to macular, papular, or nodular lesions in the skin [2Ganguly S. et al.Post kala-azar dermal leishmaniasis – an overview.Int. J. Dermatol. 2010; 49: 921-931Crossref PubMed Scopus (63) Google Scholar]. PKDL is confined to two geographically distinct zones, namely South Asia (India, Nepal, and Bangladesh) and East Africa, mainly Sudan [2Ganguly S. et al.Post kala-azar dermal leishmaniasis – an overview.Int. J. Dermatol. 2010; 49: 921-931Crossref PubMed Scopus (63) Google Scholar, 3Desjeux P. Ramesh V. Post kala-azar dermal leishmaniasis: facing the challenge of eliminating kala-azar from South Asia.in: Jha T.K. Noiri E. Kala Azar in South Asia – Current Status and Challenges Ahead. Springer, 2011: 111-124Crossref Scopus (12) Google Scholar]. In the South Asian variant, polymorphic lesions (coexistence of macules/patches along with papulonodules) are prevalent, whereas the or nodular from PKDL is it is a that a by a to or to the are that PKDL plays a pivotal role in the transmission of VL. the of PKDL for VL, by transmission with PKDL have et al.Post kala-azar dermal PubMed Scopus Google Scholar, in post kala-azar dermal PubMed Scopus Google Scholar, et of post kala-azar dermal leishmaniasis in a in 2010; PubMed Scopus Google Scholar, S. Post kala-azar dermal leishmaniasis in a PubMed Scopus Google Scholar, et of a of post kala-azar dermal leishmaniasis patients in J. PubMed Scopus Google a from group a S. et and a role for T in post kala-azar dermal Dermatol. 2010; PubMed Scopus Google Scholar]. The of PKDL in South Asia and Sudan also as in the are more whereas in the are more et al.Post kala-azar dermal PubMed Scopus Google Scholar]. from to cure from VL and of that PKDL the of VL and can after the This is by an in it that the of PKDL a from in to in et of post kala-azar dermal leishmaniasis in a in 2010; PubMed Scopus Google Scholar]. In the of VL in and a in from the the of PKDL in see a in In South transmission of VL is whereas in it is and patients with PKDL are the of VL in et of in the of kala-azar on the of PKDL in J. Google Scholar]. of PKDL be an of the VL elimination in South Asia that to the of VL to a or by the of this a of the of PKDL is have the and of and of the immune in PKDL [2Ganguly S. et al.Post kala-azar dermal leishmaniasis – an overview.Int. J. Dermatol. 2010; 49: 921-931Crossref PubMed Scopus (63) Google Scholar, et al.Post kala-azar dermal PubMed Scopus Google Scholar, in Post kala-azar dermal PubMed Google Scholar, V. Post kala-azar dermal J. Dermatol. PubMed Scopus Google Scholar, P. Challenges in the of post kala-azar dermal J. Google Scholar, V. of post kala-azar dermal J. Dermatol. PubMed Scopus Google Scholar]. the of PKDL is limited to explain factors the of the parasite to and as In the we review to be in the development of of immune of PKDL are the of the and South Asian PKDL from is to the [2Ganguly S. et al.Post kala-azar dermal leishmaniasis – an overview.Int. J. Dermatol. 2010; 49: 921-931Crossref PubMed Scopus (63) Google Scholar]. In of the cure from VL and development of the immune the of immune after cure from VL. from PKDL patients and by Leishmania and more whereas from T et of post kala-azar dermal leishmaniasis and PubMed Scopus Google Scholar]. South Asian PKDL is more to the cure from VL and T in lesions and et in post kala-azar dermal J. Dermatol. PubMed Scopus Google Scholar, S. et of and are of post kala-azar dermal PubMed Scopus (63) Google Scholar]. also play an role in the of South Asian as by of and S. et and a role for T in post kala-azar dermal Dermatol. 2010; PubMed Scopus Google Scholar, et and with parasite in of post dermal leishmaniasis PubMed Scopus Google Scholar]. In to immune T and of in S. et and a role for T in post kala-azar dermal Dermatol. 2010; PubMed Scopus Google Scholar, S. et of and are of post kala-azar dermal PubMed Scopus (63) Google Scholar]. the of known as or on that an in et the in post kala-azar dermal PubMed Scopus Google Scholar]. of PKDL in South Asian and PKDL with of and the of and the of and in patients with PKDL in and after et and are the major immunological with post dermal PubMed Scopus Google Scholar, et for of and in pathogenesis of post kala-azar dermal PubMed Scopus Google Scholar]. in the variant, a genetic in et and and susceptibility to post kala-azar dermal leishmaniasis in 2007; PubMed Scopus Google Scholar]. In of from as a and a for development of after cure from VL et al.Post kala-azar dermal PubMed Scopus Google Scholar]. the of plays a contributory role for immune of and in lesions and and et for of in post dermal leishmaniasis PubMed Scopus (46) Google Scholar]. immunological that PKDL is a disease, but in of the immune in patients with The immune of PKDL are the of the and South Asian PKDL from is to the [2Ganguly S. et al.Post kala-azar dermal leishmaniasis – an overview.Int. J. Dermatol. 2010; 49: 921-931Crossref PubMed Scopus (63) Google Scholar]. In of the cure from VL and development of the immune the of immune after cure from VL. from PKDL patients and by Leishmania and more whereas from T et of post kala-azar dermal leishmaniasis and PubMed Scopus Google Scholar]. South Asian PKDL is more to the cure from VL and T in lesions and et in post kala-azar dermal J. Dermatol. PubMed Scopus Google Scholar, S. et of and are of post kala-azar dermal PubMed Scopus (63) Google Scholar]. also play an role in the of South Asian as by of and S. et and a role for T in post kala-azar dermal Dermatol. 2010; PubMed Scopus Google Scholar, et and with parasite in of post dermal leishmaniasis PubMed Scopus Google Scholar]. 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Post kala-azar dermal leishmaniasis in a PubMed Scopus Google that the development of of of patients with PKDL of VL, to and that et of a of post kala-azar dermal leishmaniasis patients in J. PubMed Scopus Google Scholar]. is that can and is for the of a and for a prolonged for for the of VL for is also that in skin of the of in the for the development of are on the of PKDL in VL patients with more to the in antimony is a of and to patients with VL in S. et for visceral J. PubMed Scopus Google Scholar]. et that for the of VL development of whereas in with of PKDL et of in the of kala-azar on the of PKDL in J. Google Scholar]. and a of have to PKDL et of post kala-azar dermal leishmaniasis in visceral J. 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HIV-1 infection may initiate to an HLA-associated response designated diffuse infiltrative lymphocytosis syndrome, characterized by increased numbers of circulating CD8 T cells that infiltrate salivary glands, lungs, gastrointestinal tract, and kidneys. Since this response could either be an antigenically driven process induced by HIV-1 or a lymphoproliferation of cells with neoplastic or unusual features, we sought to define the phenotype of the cellular populations, the nature of tissue derangement, and the tissue localization of virus in diffuse infiltrative lymphocytosis syndrome. Circulating CD8 T cells were greatly increased while CD4 T cell numbers remained in the range found in asymptomatic seropositive persons. The majority of CD8 and CD4 T cells in both blood and tissues had the memory phenotype of CD29+ (beta 1 integrin) and CD11a+/CD18 (beta 2 integrin) expression, but lacked markers of recent activation. A proportion of the circulating CD8 T cells also expressed CD57 (Leu 7) but not other markers of natural killer cells. HIV-encoded proteins were identified in tissue macrophages located in periacinar areas of the salivary glands. CD54 (intercellular adhesion molecule-1), a ligand for the CD11a integrin, was strongly expressed on postcapillary venule endothelium within lymphoid foci, and HLA-DR molecules were found on limited regions of ductular epithelium adjacent to lymphoid aggregates. These findings suggest that (a) the visceral lymphocytic infiltration in diffuse infiltrative lymphocytosis syndrome is an antigen-driven, and MHC-determined, host immune response to an element associated with HIV-1 infection, and (b) that the specific adhesive molecule interactions mediating the cellular influx, as well as the subsequent tissue damage, reflect altered patterns of gene expression in tissues undergoing an immune response.

The high level of functional diversity and plasticity in monocytes/macrophages has been defined within in vitro systems as M1 (classically activated), M2 (alternatively activated) and deactivated macrophages, of which the latter two subtypes are associated with suppression of cell mediated immunity, that confers susceptibility to intracellular infection. Although the Leishmania parasite modulates macrophage functions to ensure its survival, what remains an unanswered yet pertinent question is whether these macrophages are deactivated or alternatively activated. This study aimed to characterize the functional plasticity and polarization of monocytes/macrophages and delineate their importance in the immunopathogenesis of Post kala-azar dermal leishmaniasis (PKDL), a chronic dermatosis of human leishmaniasis. Monocytes from PKDL patients showed a decreased expression of TLR-2/4, along with an attenuated generation of reactive oxidative/nitrosative species. At disease presentation, an increased mRNA expression of classical M2 markers CD206, ARG1 and PPARG in monocytes and lesional macrophages indicated M2 polarization of macrophages which was corroborated by increased expression of CD206 and arginase-1. Furthermore, altered vitamin D signaling was a key feature in PKDL, as disease presentation was associated with raised plasma levels of monohydroxylated vitamin D3 and vitamin D3- associated genes, features of M2 polarization. Taken together, in PKDL, monocyte/macrophage subsets appear to be alternatively activated, a phenotype that might sustain disease chronicity. Importantly, repolarization of these monocytes to M1 by antileishmanial drugs suggests that switching from M2 to M1 phenotype might represent a therapeutic opportunity, worthy of future pharmacological consideration.