Immunoregulatory and effector activities in human cutaneous and mucosal Leishmaniasis: Understanding mechanisms of pathology

Abstract

Individuals infected with Leishmania braziliensis may develop the relatively benign localized cutaneous (CL) form or the mucosal (ML) form of the disease, which represents a more severe and mutilating variation. Interaction between parasite and host cells, as well as the genetic background of the host, are important determinants of the immune response, which is critical in determining disease outcome. Our studies over the years have been designed to determine the immunoregulatory and effector functions that culminate in the formation of lesions in CL and ML disease and how these host response factors may be better understood for design of novel therapies and prophylaxis. By studying the immune response from CL and ML patients in both the peripheral blood and in situ, we have learned much concerning the dynamics of the host–pathogen interaction that leads to the development of CL and ML. We used multiparameter flow cytometry to study the immunoregulatory profiles of the peripheral blood leukocytes, as well as laser scanning confocal microscopy to examine in situ several aspects of the local response, including the intensity of the inflammatory infiltrate, the cellular composition, inflammatory and anti-inflammatory cytokine expression, and the expression of the effector cytotoxic molecule, granzyme A, in lesions from CL and ML patients. Moreover, the application of correlative analysis between these immunological parameters has helped shed light on disease progression in CL and ML. These findings are reviewed within the context of understanding cellular and molecular mechanisms associated with the development of pathology in these diseases through a comparative analysis of the clinical forms, CL and ML, as well as of studies derived from peripheral blood and lesions.

Leishmaniasis in Yemen: a clinicoepidemiological study of leishmaniasis in central Yemen

“…In this study, individuals aged ≤17 years were classified as children. The differentiation between CL and MCL was based on clinical findings; lesions that involved mucous membranes of the eyelids, nose, or mouth with any degree of inflammation were considered to represent MCL …”

Mucosal Leishmaniasis: An Underestimated Presentation of a Neglected Disease

“…Similarly, profound genetic differences have been reported between L . braziliensis strains causing CL and ML [33]. Interestingly, it has been hypothesized that some Leishmania strains (particularly L .…”

“…In ML, CD4+ T cells are the major source of cytokines; production of anti-inflammatory molecules from monocytes is reduced and either CD8+ T cells or natural killer cells contribute to tissue destruction in late stages. Symptomatic patients have lower IFN- γ and higher IL-10 levels than asymptomatic ML patients, that is, patients potentially exposed to Leishmania infection since they come from endemic areas with epidemiological evidence of parasite transmission [33]. Furthermore, it has been proved that ML develops in the presence of insufficient or misled immune response in CL early stages [36].…”

“…Furthermore, it has been proved that ML develops in the presence of insufficient or misled immune response in CL early stages [36]. Nevertheless, current experimental evidences show that ML is associated with uncontrolled and self-feeding inflammation [33]. Unfortunately, there is a lack of experimental models for ML caused by Leishmania species other than L. braziliensis complex.…”

Immunoregulation in human American leishmaniasis: balancing pathology and protection

“…Once an adaptive cellular immune response develops following the presentation of classic peptide antigens by MHC class I for CD8+ T cells, MHC class II for CD4+ T cells and CD1‐presented lipid antigens to DN T cells and invariant NK T cells (iNK T cells), the balance between control of the pathogen and pathology development is amplified . The initial expansion of T cell subpopulations with distinct functional potentials begins in earnest within the draining lymph nodes following the initial infection (Figure ).…”