Unraveling the Role of Immune Checkpoints in Leishmaniasis

Silva, Rafael de Freitas e; Stebut, Esther von

doi:10.3389/fimmu.2021.620144

Cited by 22 publications

(11 citation statements)

References 213 publications

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“…Infection by protozoan parasites is associated with the production of immunoglobulin G (IgG) and immunoglobulin M (IgM). 19–21 With helminths there is, in addition, the synthesis of substantial amounts of immunoglobulin E (IgE). 22 …”

Section: Introductionmentioning

confidence: 99%

Metabolomics in infectious diseases and drug discovery

et al. 2021

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Section: Introductionmentioning

confidence: 99%

Metabolomics in infectious diseases and drug discovery

et al. 2021

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“…Infected DC process parasite antigen, migrate to draining lymph nodes and prime T cells [ 2 ]. Release of IL-12 as well as other cytokines from infected DC directs Th1/Tc1 education of parasite-specific T cells [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Cross-reactive, natural IgG recognizing L. major promote parasite internalization by dendritic cells and promote protective immunity

et al. 2021

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In cutaneous leishmaniasis, infection of dendritic cells (DC) is essential for generation of T cell-dependent protective immunity. DC acquires Leishmania major through Fc receptor (FcR)-mediated uptake of complexes comprising antibodies bound to parasites. We now assessed the development of the initial B cell and DC response to the parasite itself and if natural IgG play a role. L. major parasites display large numbers of phospholipids on their surface. Parasites were opsonized with normal mouse serum (NMS), or serum containing anti-phospholipid IgG (PL). We found that L. major bound to PL which significantly enhanced parasite phagocytosis by DC as compared to NMS. Similar results were obtained with cross-reactive human PL antibodies using myeloid primary human DC. In addition, mice infected with PL-opsonized parasites showed significantly improved disease outcome compared to mice infected with NMS-opsonized parasites. Finally, IgMi mice, which produce membrane-bound IgM only and no secreted antibodies, displayed increased susceptibility to infection as compared to wild types. Interestingly, once NMS was administered to IgMi mice, their phenotype was normalized to that of wild types. Upon incubation with IgG-opsonized parasite (IgG derived from infected mice or using PL antibodies), also the IgMi mice were able to show superior immunity. Our findings suggest that “natural” cross-reactive antibodies (e.g., anti-PL Ab) in NMS bind to pathogens to facilitate phagocytosis, which leads to induction of protective immunity via preferential DC infection. Prior L. major-specific B cell-priming does not seem to be absolutely required to facilitate clearance of this important human pathogen in vivo. Key messages We found that anti-phospholipid (anti-PL) antibodies enhance phagocytosis of L. major by DCs. We also found that normal mouse sera have natural antibodies that can imitate PL specific antibodies. Using different genetically modified mice, we found that these antibodies can be IgG, not only IgM.

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“…As such, combining immunotherapy, specifically drugs targeting inhibitory molecules and regulatory cytokines, with drugs routinely used earlier in the process when T cell exhaustion appears could reduce the chances of VL patients acquiring resistance to conventional treatments. Such strategies have been gaining attention from the scientific and medical communities ( 124 , 178 – 180 ). The optimization of treatments combining typical drugs with immunotherapy might help to delay the emergence of resistance and increase the therapeutic lifespan of the respective drugs.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

T Lymphocyte Exhaustion During Human and Experimental Visceral Leishmaniasis

Costa-Madeira¹,

Trindade²,

Almeida³

et al. 2022

Front. Immunol.

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A key point of immunity against protozoan Leishmania parasites is the development of an optimal T cell response, which includes a low apoptotic rate, high proliferative activity and polyfunctionality. During acute infection, antigen-specific T cells recognize the pathogen resulting in pathogen control but not elimination, promoting the development and the maintenance of a population of circulating effector cells that mount rapid response quickly after re-exposure to the parasite. However, in the case of visceral disease, the functionality of specific T cells is lost during chronic infection, resulting in inferior effector functions, poor response to specific restimulation, and suboptimal homeostatic proliferation, a term referred to as T cell exhaustion. Multiple factors, including parasite load, infection duration and host immunity, affect T lymphocyte exhaustion. These factors contribute to antigen persistence by promoting inhibitory receptor expression and sustained production of soluble mediators, influencing suppressive cell function and the release of endogenous molecules into chronically inflamed tissue. Together, these signals encourage several changes, reprogramming cells into a quiescent state, which reflects disease progression to more severe forms, and development of acquired resistance to conventional drugs to treat the disease. These points are discussed in this review.

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Unraveling the Role of Immune Checkpoints in Leishmaniasis

Cited by 22 publications

References 213 publications

Metabolomics in infectious diseases and drug discovery

Metabolomics in infectious diseases and drug discovery

Cross-reactive, natural IgG recognizing L. major promote parasite internalization by dendritic cells and promote protective immunity

T Lymphocyte Exhaustion During Human and Experimental Visceral Leishmaniasis

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