T helper (h)1/Th2 and : paradox rather than paradigm

Alexander, James; Bryson, Karen

doi:10.1016/j.imlet.2005.01.009

Cited by 203 publications

(161 citation statements)

References 76 publications

(79 reference statements)

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“…The Th1/Th2 paradigm to intracellular infection is largely based on investigations using L. major and the roles of IL-12 and IL-4 in driving Th1 and Th2 cell development for resistance and susceptibility respectively are well established [26]. Since previous studies correlated high levels of IL-4 with increased arginase activities and increased parasite burden in L. majorinfected BALB/c mice [16], we aimed to study the status of host arginase in L. donovani-infected mice and the cellular mechanism underlying its modulation.…”

Section: Discussionmentioning

confidence: 99%

“…A report also suggests that arginase is involved in L. infantum parasite survival in the host and the failure to control the progression of splenic infection in mice may be related to the actions of IL-10 attenuating the cytotoxic response via NO downregulation [25]. Pathogenesis and failure to check the proliferation of the intracellular parasites in leishmaniasis has been ascribed to polarized Th2 response [25], but the precise mechanism resulting in the inability to control disease progression is not very well documented.The Th1/Th2 paradigm to intracellular infection is largely based on investigations using L. major and the roles of IL-12 and IL-4 in driving Th1 and Th2 cell development for resistance and susceptibility respectively are well established [26]. Since previous studies correlated high levels of IL-4 with increased arginase activities and increased parasite burden in L. majorinfected BALB/c mice [16], we aimed to study the status of host arginase in L. donovani-infected mice and the cellular mechanism underlying its modulation.…”

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confidence: 99%

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Expression of IL‐10‐triggered STAT3‐dependent IL‐4Rα is required for induction of arginase 1 in visceral leishmaniasis

et al. 2011

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Although enhanced macrophage-specific arginase activity is directly related to increased parasite burden in cutaneous leishmaniasis (CL), the regulation and precise role of arginase in the disease outcome of visceral leishmaniasis (VL) has yet to be explored. As in CL, BALB/c mice infected with Leishmania donovani showed increased levels of arginase in acute infection. Arginase 1 is the major isoform associated with infection and while the IL-4-induced arginase pathway is operative in CL, IL-10 plays a crucial role in modulating arginase activity in VL, although a synergism with IL-4 is required. IL-10, in combination with IL-4, regulated both in vivo and ex vivo arginase 1 induction in a STAT6 and C/EBPbdependent fashion. Further investigation toward the cause of such synergism suggests that induction of a STAT3-dependent IL-10-mediated cascade in VL triggers the expression and surface localization of the IL-4 receptor alpha (IL-4Ra) which, in turn, enhances IL-4 responsiveness toward STAT6 and C/EBPb-dependent signaling for arginase 1. This could also offer a mechanistic explanation for the fact that, in spite of the low level of IL-4 in VL, enhanced IL-4-Ra expression by IL-10 might markedly amplify IL-4-mediated arginase 1 signaling and provide a possible mechanism for synergistic induction of arginase 1.Keywords: Arginase 1 . IL-4 . IL-10 . IL-4 receptor a . Visceral leishmaniasis IntroductionArginase is classically considered as a rate-limiting enzyme of the urea cycle in liver, but has been found to be present in a number of organs and tissues where the urea cycle is not operative. To date, two distinct isoforms of arginase have been identified in mammals. They are encoded by different genes differing in their cellular localization as well as their mode of regulation: type 1 arginase, a cytosolic enzyme expressed at high levels in liver, and type 2 arginase, a mitochondrial enzyme found in several tissues in addition to liver [1]. A growing body of evidence suggests that arginase induction is correlated with parasite-specific immunosuppression of host, thereby facilitating pathogen survival and growth inside the hostile environment of phagocytic cells. Macrophages were found to upregulate arginase 1 expression upon activation by Th2 cytokines and shown to have a detrimental role in parasite infection by limiting the Th1-dependent parasite clearance [2]. Interestingly, cAMP and TGFb are known to induce arginase 1 induction in macrophages [3]. In Chagas disease, induction of the arginase pathway could be used by Trypanosoma cruzi to spread inside host [4]. Arginase activity was triggered in macrophages from mice infected with the helminth Schistosoma mansoni and was associated with an increase in concentration of circulating L-ornithine-derived polyamines [5]. Intracellular pathogens like Salmonella enterica and Mycobacterium tuberculosis also utilize host arginase for their own 992survival within the macrophages [6,7]. Moreover, in bacteria like Helicobacter pyroli, arginase plays a major role in its surv...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Expression of IL‐10‐triggered STAT3‐dependent IL‐4Rα is required for induction of arginase 1 in visceral leishmaniasis

et al. 2011

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“…+ and CD8 + T cells, and regulatory T (Treg) cells, are involved in the control of leishmaniasis (5)(6)(7). These studies have also indicated that a fine balance between effector and regulatory immune responses may be required for the efficient control of Leishmania without extensive collateral tissue damage (8).…”

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confidence: 99%

IL2RA Genetic Variants Reduce IL-2–Dependent Responses and Aggravate Human Cutaneous Leishmaniasis

Oliveira

Dessein

Romano

et al. 2015

The Journal of Immunology

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The outcome of Leishmania infections varies substantially, depending on the host and the parasite strain; infection may be asymptomatic or cause mild or severe skin ulcers (cutaneous leishmaniasis [CL]), limited or disseminated lesions, or lethal visceral disease. We previously reported an association between IL-2R mutations and susceptibility to visceral leishmaniasis in children infected with Leishmania donovani. In the present study, we evaluated the possible role of IL-2 signaling in human CL. We first showed that the transcripts of several genes of the IL-2 pathway were abundant in skin lesions caused by Leishmania braziliensis. We then carried out a genetic analysis, focusing on major genes of the IL-2 pathway. We used a family-based approach and found that polymorphisms of several genes appeared to be associated with CL in a Brazilian population. Moreover, two polymorphisms of the IL2RA gene were significantly and independently associated with CL. We confirmed this result in a second Brazilian sample (also exposed to L. braziliensis) and in Iranians infected with Leishmania tropica: IL2RA rs10905669 T (Pcombined = 6 × 10−7) and IL2RA rs706778 T (Pcombined = 2 × 10−9) were associated with greater susceptibility to lesion development. These alleles were also correlated with a poor IFN-γ response and poor FOXP3+ regulatory T cell activation. Thus, IL-2 plays a crucial role in protection against the cutaneous ulcers caused by Leishmania, and the IL-2 pathway is a potential target for strategies aiming to control Leishmania-related diseases.

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“…The explanation for this difference between visceral leishmaniasis cases with the classical versus asymptomatic forms may lie in the type of host cellular immune response 27 . Another hypothesis is that genetic factors are involved in development of the clinical disease.…”

Section: Discussionmentioning

confidence: 99%

Asymptomatic infection in family contacts of patients with human visceral leishmaniasis in Três Lagoas, Mato Grosso do Sul State, Brazil

et al. 2008

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The Brazilian city of Três Lagoas, Mato Grosso do Sul State, has experienced an urban outbreak of visceral leishmaniasis since 2000. In 2002, due to the increase in the number of cases, 46 families with cases of visceral leishmaniasis were studied to verify the prevalence of asymptomatic infection in household contacts. Indirect immunofluorescence and ELISA showed a 36.4% positive infection rate. There were no cases of symptomatic disease among these contacts. There was no statistically significant difference in gender or age. Median age was 21 years, and the 10-19-year age bracket was the most heavily affected (23%). As for family characteristics, no differences were observed in schooling or family income; most families (58.7%) owned their homes, which were built of masonry (97.8%) and had adequate infrastructure. All the families reported what were probably phlebotomine sand flies in the peridomicile. In conclusion, asymptomatic visceral leishmaniasis infection is frequent and occurs in both males and females, regardless of age.

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T helper (h)1/Th2 and : paradox rather than paradigm

Cited by 203 publications

References 76 publications

Expression of IL‐10‐triggered STAT3‐dependent IL‐4Rα is required for induction of arginase 1 in visceral leishmaniasis

Expression of IL‐10‐triggered STAT3‐dependent IL‐4Rα is required for induction of arginase 1 in visceral leishmaniasis

IL2RA Genetic Variants Reduce IL-2–Dependent Responses and Aggravate Human Cutaneous Leishmaniasis

Asymptomatic infection in family contacts of patients with human visceral leishmaniasis in Três Lagoas, Mato Grosso do Sul State, Brazil

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