Immunoregulatory mechanisms and CD4−CD8− (double negative) T cell subpopulations in human cutaneous leishmaniasis: A balancing act between protection and pathology (2023)

Citation Excerpt :

Generally, the disease susceptibility in uncontrolled or non-healed infections has been related to Th2 proliferation and production of IL-4, IL-5 and IL-10. In contrast, healing responses and resistance to infection have been associated with expansion of IFN-γ-producing Th1 cells [18–21]. T-cell responses in individuals with mild infection involve a mixture of Th1 and Th2, whereas patients with exacerbating disease show an absence of Th1 response to specific Leishmania antigens.

The objective of the present study was to compare the host's immune responses between unresponsive and responsive patients with anthroponotic cutaneous leishmaniasis (ACL) treated by meglumine antimoniate.

A case-control study was carried out in an endemic focus in Iran. Blood samples were taken from patients and peripheral blood mononuclear cells (PBMCs) were isolated. Two wells were considered for each isolate of unresponsive and responsive patients; one was exposed to L. tropica (Lt-stimulated cells) and the other remained non-exposed (non-stimulated cells). After 24 h of incubation, whole RNA was extracted from each sample. Real-time quantitative PCR was carried out to confirm the differences in expression levels of IL-12 P40, IFN-γ, IL-1β, IL-4 and IL-10 among isolates. Data were analyzed and P < 0.05 was considered to be statistically significant.

In our study, Lt-stimulated cells and non-stimulated cells in unresponsive groups demonstrated significantly lower expression levels of IL-1β, IL-12 P40 and IFN-γ genes and higher expression levels of IL-4 and IL-10 genes, compared to Lt-stimulated cells and non-stimulated cells in responsive groups. There was a negative correlation between IL-12 P40 with IL-10 and IL-1β with IL-10 in ACL Lt-stimulated cells in unresponsive group, while a positive correlation between IL-12 P40 with IL-1β and IL-12 P40 with IFN-γ in ACL Lt-stimulated cells in responsive group.

Probably, different immune responses caused by various factors play a major role in the pathogenesis and development of unresponsiveness in ACL patients. The profile and timing of cytokine production correlated well with the treatment outcome of Leishmania infection.

Citation Excerpt :

Subsequently, patients develop various clinical conditions such as splenomegaly, pancytopenia, anemia, and disseminated hemorrhages (Murray et al., 2005). Two distinct lineages of T-cells, namely CD4 + Th1 andCD4 + Th17, are responsible for the controlled and programmed immune response mediated against Leishmania and supported by various cytokines (such as interleukin-2 [IL-2], interferon-γ[IFN-γ], IL-6, and the tumor necrosis factor [TNF]), and chemokine(such as CXCL8 [also known as IL-8], CXCL10 [also known as IP-10], CXCL1, and CXCL6; Bhattacharya and Ali, 2013; Sanjabi et al., 2009; Gollob et al., 2008). The Th1 group of CD4+ T cells counters Leishmania infection within macrophages in an infected spleen and liver through support from IL-12, IL-2, IFN-γ, etc.

Citation Excerpt :

In humans, the spectrum of the disease may vary from subclinical infection to manifestations such as localized, disseminated or diffuse cutaneous lesions, or even the involvement of the nasal mucosa, pharynx and larynx. In all these possibilities, the expansion of T helper cells exerts a fundamental influence (Gollob et al., 2008). Classically, a Th1 profile is responsible for producing interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), which activates the inducible nitric-oxide synthase (iNOS) to catalyze NO secretion by macrophages, eliminating the parasite.

Citation Excerpt :

Recently, different subsets of T lymphocytes gained focus on parasitic diseases, especially the double negative (DN) T cells, which express neither CD4 nor CD8, including αβ DN T cells, γδ DN T cells, NK T cells (D'Acquisto and Crompton, 2011). In cases of human cutaneous leishmaniasis, elevated numbers of circulating αβ DN T cells are described, associated with elevated production of IFN-γ and TNF-α and high levels of the activation markers CD69 and CD56 (Antonelli et al., 2006; Gollob et al., 2008). Further, the association between NK T cells and immune response during VL has already been studied in the liver of mice infected with L. donovani (Amprey et al., 2004).

Citation Excerpt :

According to the authors, susceptibility to the mucocutaneous form of disease may be directly associated with regulatory polymorphisms affecting TNF-α production. Besides the benefits of Th1 response, Gollob et al. [32] suggest that IL-10 production may be critical for the disease control. Thus, it is postulated that IL-10 levels presented by the patients in this study regulate the production of proinflammatory cytokines, consequently leading to the clinical resolution of the disease.

We investigated the pathophysiological changes in mice lacking α₂-antiplasmin (α₂-AP) and plasminogen activator inhibitor type-1 (PAI-1) genes, and elucidated the involvement of these inhibitors for fibrinolysis in immune response.

The pathophysiological changes induced by a lack of both α₂-AP and PAI-1 were investigated using double knockout (KO) mice. The lung, liver, kidney and spleen tissues from α₂-AP/PAI-1-double KO mice were compared with those from wild-type (WT) mice. Furthermore, the bone marrow cells from α₂-AP/PAI-1-double KO mice were transplanted into 10-Gy X ray irradiated WT mice, and then the effects of the transplantation were studied.

Plasma IgE levels in the α₂-AP/PAI-1-double KO mice increased with age and exceeded 1000ng/mL after 6months of age. The plasma cells that produced IgE were detected in perivascular assembled lymphocytes. In the α₂-AP/PAI-1-double KO mice, perivascular lymphocyte infiltration was observed in the lung, liver, and kidneys and peribronchial lymphocyte infiltration was present in the lung. When the bone marrow cells from α₂-AP/PAI-1-double KO mice were transplanted into 10-Gy X ray irradiated WT mice, the phenotypes of the recipients were similar to those of α₂-AP/PAI-1-double KO mice.

The simultaneous expression of both the α₂-AP and PAI-1 genes contributes to the maintenance of immunological functions that are related to IgE. Moreover, it is suggested that both α₂-AP and PAI-1 are involved in the recruitment of lymphocytes in the peripheral tissues.

TGF-β1 (transforming growth factor beta 1) is a negative regulator of lymphocytes, inhibiting proliferation and switching on the apoptotic program in normal lymphoid cells. Lymphoma cells often lose their sensitivity to proapoptotic/anti-proliferative regulators such as TGF-β1. Rapamycin can influence both mTOR (mammalian target of rapamycin) and TGF-β signaling, and through these pathways it is able to enhance TGF-β induced anti-proliferative and apoptotic responses. In the present work we investigated the effect of rapamycin and TGF-β1 combination on cell growth and on TGF-β and mTOR signalling events in lymphoma cells.

Rapamycin, an inhibitor of mTORC1 (mTOR complex 1) did not elicit apoptosis in lymphoma cells; however, the combination of rapamycin with exogenous TGF-β1 induced apoptosis and restored TGF-β1 dependent apoptotic machinery in several lymphoma cell lines with reduced TGF-β sensitivity in vitro. In parallel, the phosphorylation of p70 ribosomal S6 kinase (p70S6K) and ribosomal S6 protein, targets of mTORC1, was completely eliminated. Knockdown of Smad signalling by Smad4 siRNA had no influence on apoptosis induced by the rapamycin+TGF-β1, suggesting that this effect is independent of Smad signalling. However, apoptosis induction was dependent on early protein phosphatase 2A (PP2A) activity, and in part on caspases. Rapamycin+TGF-β1 induced apoptosis was not completely eliminated by a caspase inhibitor.

These results suggest that high mTOR activity contributes to TGF-β resistance and lowering mTORC1 kinase activity may provide a tool in high grade B-cell lymphoma therapy by restoring the sensitivity to normally available regulators such as TGF-β1.

In Ethiopia, visceral leishmaniasis (VL) is a growing public health threat. Among the key challenges in VL control in Ethiopia is lack of an effective test of cure. The recommended test of cure is parasite detection. As sterile cure is not expected with the current widely used drugs, the value of parasite detection as test of cure is questionable. Moreover, the sampling is invasive, requires a well-equipped facility and highly skilled personnel, which are all hardly found in endemic set-ups.

Our aim was to assess the value of sCD40L, MMP9 and IL-10 serum levels as signature biomarkers of clinical cure in VL cases from Ethiopia.

A total of 45 VL cases before and after treatment and 30 endemic healthy controls were included in the study. Sandwich ELISA was used to measure serum levels of sCD40L, MMP9 and IL-10.

The mean sCD40L, MMP9 and IL-10 serum levels changed significantly at clinical cure. At individual case level sCD40L and MMP9 showed an increasing trend. Yet, the degree of increase in serum level of MMP9 seems to be affected by nutritional status of the individual VL case. The mean IL-10 serum level was significantly reduced at clinical cure. As seen on case by case basis, all demonstrated a declining trend except that two VL cases had a high IL10 level at clinical cure.

Our result is suggestive of the possibility of developing a signature biomarker to monitor VL treatment in Ethiopia using one or a combination of parameters.

Japanese encephalitis is considered as a secondary legal infectious disease in Korea and is transmitted by mosquitoes in the summer season. The purpose of this study was to predict the ratio of Culex tritaeniorhynchus to all the species of mosquitoes present in the study regions.

From 1999 to 2012, black light traps were installed in 10 regions in Korea (Busan, Gyeonggi, Gangwon, Chungbuk, Chungnam, Jeonbuk, Jeonnam, Gyeongbuk, Gyeongnam, and Jeju) to capture mosquitoes for identification and classification under a dissecting microscope. The number of mosquitoes captured/week was used to calculate its daily occurrence (mosquitoes/trap/night). To predict the characteristics of the mosquito population, an autoregressive model of order p (AR(p)) was used to execute the out-of-sample prediction and the in-sample estimation after presumption.

Compared with the out-of-sample method, the sample-weighted regression method's case was relatively superior for prediction, and this method predicted a decrease in the frequency of Cx. tritaeniorhynchus for 2013. However, the actual frequency of this species showed an increase in frequency. By contrast, the frequency rate of all the mosquitoes including Cx. tritaeniorhynchus gradually decreased.

The number of patients with Japanese encephalitis has been strongly associated with the occurrence and density of vector mosquitoes, and the importance of this infectious disease has been highlighted since 2010. The 2013 prediction indicated an increase after an initial decrease, although the ratio of the two mosquito species decreased. The increase in vector density may be due to changes in temperature and the environment. Thus, continuous prevalence prediction is warranted.