The balancing act: Immunology of leishmaniosis

Abstract

Immune control of Leishmania infantum, the causative agent of most canine leishmaniosis (CanL), requires a balancing act between inflammatory and regulatory responses. This balance is specifically between the proinflammatory T helper 1 type (Th1) CD4+ T cells that are responsible for controlling parasite replication and T regulatory 1 cells which mediate an immunosuppressive, regulatory, response needed to dampen overabundant inflammation but if predominant, result in CanL progression. How this delicate immune cell interaction occurs in the dog will be highlighted in this review, focusing on the progressive changes observed within myeloid lineage cells (predominantly macrophages), B cells and T cells. After exposure to parasites, macrophages should become activated, eliminating L. infantum through release of reactive oxygen species. Unfortunately, multiple parasite and host factors can prevent macrophage activation allowing parasites to persist within them. T cells balance between a productive T_H1 type CD4+ response capable of producing IFN-γ which aids macrophage activation versus T cell exhaustion which reduces T cell proliferation, IFN-γ production and allows parasite expansion within macrophages. Neutrophils and Th17 cells add to the inflammatory state, aiding in parasite removal, but also leading to pathology. A regulatory B cell population increases IL-10 production and down regulates the T_H1 response allowing parasite growth. All of these immune challenges affect the balance between progression to clinical disease and maintaining sub-clinical disease. Vaccines and immunotherapies targeted at recovering or maintaining T and B cell function can be important factors in mending the immune balance required to survive CanL.

Keywords: Dogs; Immunology; Leishmaniosis; Macrophages; Neutrophils; T cells.

Figure 1.. Sub-clinical leishmaniosis.

Early after infection neutrophils arrive and phagocytose parasites leading to parasite destruction via reactive oxygen species. Th17 cells produce IL-17. During this state there is increased macrophage production of IL-12 promoting CD4+ T cell proliferation and IFN-γ production, by both CD4+ T cells and neutrophils. This pro-inflammatory state results in activated macrophages producing reactive oxygen species and reduced parasite replication. Antigen presentation, here via B cells through the B cell receptor, increases T-cell proliferation while B cell antigen recognition results in B cell clonal expansion and secretion of Leishmania-specific antibodies. Surface expression of PD-1 on T cells and PDL-1 receptor on B cells and macrophages remains at low levels. Surface expression of IgD on B cells present at steady-state levels.

Figure 2.. Clinical leishmaniosis.

After months to years of prolonged parasite survival within neutrophils that are unable to undergo apoptosis, these cells promote inactivated, infected macrophages. Th17 cells produce IL-17 recruiting more neutrophils and macrophages to the site of infection. There is decreased macrophage production of IL-12 leading to decreased CD4+ T cell proliferation and IFN-γ production. This results in reduced production of reactive oxygen species and parasite replication. Increased surface expression of IgD results in increased expression of IL-10 by B cells and induces IgD^lo B cells to produce IL-10 further inhibiting macrophage activation and TH1 cell proliferation. During clinical CanL there is increased production non-specific IgG antibodies leading to immune complexes and pathology. Chronic exposure to Leishmania antigen leads to T cell exhaustion characterized by significant increased surface expression of PD-1. PDL-1 receptor on B cells and macrophages is significantly increased.