Reappraisal of the immunopathogenesis of disseminated leishmaniasis: in situ and systemic immune response

Abstract

Disseminated leishmaniasis (DL) is an emerging form of Leishmania braziliensis infection characterised by multiple cutaneous lesions on different parts of the body and a high rate of mucosal involvement. Systemic production of TNFα and IFNγ in DL patients is lower than in cutaneous leishmaniasis (CL) caused by L. braziliensis, which may account for parasite dissemination due to the decreased ability to control parasite growth. In this study, the systemic and in situ immune response of DL and CL patients was characterised through evaluation of chemokine and cytokine production. In situ evaluation showed similar production of IFNγ, TNFα, IL-10, transforming growth factor-beta (TGFβ), chemokine (C-C motif) ligand 2 (CCL2), CCL3, CCL11 and chemokine (C-X-C motif) ligand 10 (CXCL10) in papular and ulcerative lesions from DL as well as in ulcerated lesions from CL. Serum levels of CXCL9, a chemokine that attracts T-cells, was higher in serum from DL than from CL. These data indicate that a decrease in the type 1 immune response in peripheral blood of DL patients is due to attraction of Leishmania antigen-activated T-cells to the multiple cutaneous lesions. This may account for the absence of or few parasites in the lesions and for the development of ulcers similar to those observed in CL.

Figure 1

A disseminated leishmaniasis patient with intense facial and trunk involvement.

Figure 2

Chemokine production in 21 disseminated leishmaniasis (DL) and 21 cutaneous leishmaniasis (CL) patients: (A) chemokine (C-C motif) ligand 2 (CCL2), macrophage inflammatory protein 1-alpha (MIP-1α/CCL3) and CCL11 production and (B) chemokine (C-X-C motif) ligand 9 (CXCL9) and CXCL10 production in serum were determined as described in Section 2.4. Chemokine levels were measured by ELISA. Symbols refer to data for individual patients and the horizontal bar indicates the median.

Figure 3

Cytokine profiles in 12 disseminated leishmaniasis (DL) and 8 cutaneous leishmaniasis (CL) patients: (A) IFNγ and TNFα and (B) IL-5 and IL-10 production in peripheral blood mononuclear cell (PBMC) supernatants stimulated with Leishmania antigen were determined as described in Section 2.4. Levels of cytokines were measured by ELISA. Data are given as mean (blocks) ± SD (bars).

Figure 4

Tissue expression (% of stained area) of chemokine (C-X-C motif) ligand 10 (CXCL10) in cutaneous leishmaniasis (CL) and disseminated leishmaniasis (DL): biopsy section showing production of CXCL10 in (A) a CL ulcerated lesion, (B) a DL papule and (C) a DL ulcer (final magnification, 200 ×).