Dendritic cells, TLR recognition and endotoxin tolerance in severe malarial infection
Sujoy Khan, PathLinks Immunology, Scunthorpe General Hospital, England, United Kingdom
28 February 2007
The article by Climent Casals-Pascual and colleagues demonstrates an inverse relationship between two key cytokines, IL-12 and IL-10, in different stages of severe malarial infection and malarial anaemia. Studies on murine models have shown such an inverse relationship at different stages of malaria and the phenomenon of endotoxin tolerance (possibly via dendritic cells) was suggested to explain this observation [1]. Dendritic cells (DCs) are important antigen presenting cells which upregulate MHC-class I and II molecules leading to the production of cytokines which then regulate different phases of the immune response to an infection.
Murine models infected with Plasmodium yoelii have shown that DCs release high levels of IFN- in an IL-12 dependent manner in initial stages of malaria as part of an innate immune response, while later stages of infection are dominated by IL-10 (a potent anti-inflammatory cytokine) [2]. Studies have demonstrated that late stage DCs still retain their potential to activate naïve T cells through expression of costimulatory molecules. This enables DCs to present antigen to T cells resulting in the production of malaria-specific T cells and subsequently protective antibodies, which means DCs are involved in the induction of adaptive immunity.
Recent evidence suggests that Toll-like receptors (TLRs) are involved in the innate immune recognition and responses to Plasmodium. In murine malaria infection, a cytoplasmic adaptor molecule termed as myeloid differentiation factor 88 (MyD88) was shown to be critical for IL-12 induction [3]. Plasmodium falciparum blood-stage parasites can activate human plasmacytoid DCs and murine DCs through MyD88- and TLR9-dependent pathways. The signal recognized by TLR9 and dependent on MyD88 is haemozoin (HZ), a detoxification product of haem molecules persisting in the food vacuoles of Plasmodium parasites. Ingestion of HZ by monocytes increases production of IL-10 and TNF-alpha relative to the production of IL-12, and correlates with the severity of malarial anaemia. Blocking IL-10 with IL-10 neutralizing antibodies, but not TNF-alpha antibodies, restores HZ-induced suppression of IL-12 [4]. It is possible that repeated stimulation of TLR9 by HZ tolerizes and/or blocks the MyD88 signaling pathway or via upregulation of TLR4 by MyD88-independent signaling pathway. High temperature have shown to result in DC-upregulation of TLR4 and cells can be rendered unresponsive to further signaling if repeated stimulation is used via lipopolysaccharide (the ligand for TLR4). Polymorphisms in these highly conserved innate recognition system of molecules are associated with an increase risk of malaria. Common polymorphisms such as TLR4-Asp299Gly and TLR9 T-1486C in P. falciparum infected women increase the risk of low birth weight in term infants by 6-fold, and, TLR4 Asp299Gly polymorphism increase the risk of maternal anemia by 5-fold [5].
The evidence therefore suggests that DC tolerance to TLR signaling leads to downregulation of pro-inflammatory cytokines and endotoxin tolerance and as they retain the potential to activate naïve T cells, they also generate the much-needed adaptive immune response. This may prove to be an important mechanism and knowledge of DC and TLR signalling to maintain the much-needed protection against this evasive protozoan parasite can be exploited in vaccine development.
2.Pouniotis DS, Proudfoot O, Bogdanoska V, Apostolopoulos V, Fifis T, Plebanski M. Dendritic cells induce immunity and long-lasting protection against blood-stage malaria despite an in vitro parasite-induced maturation defect. Infect Immun. 2004; 72: 5331-5339.
3.Adachi K, Tsutsui H, Kashiwamura S, Seki E, Nakano H, Takeuchi O, Takeda K, Okumura K, Van Kaer L, Okamura H, Akira S, Nakanishi K. Plasmodium berghei infection in mice induces liver injury by an IL-12- and toll-like receptor/myeloid differentiation factor 88-dependent mechanism. J Immunol. 2001; 167: 5928-5934.
4.Pichyangkul S, Yongvanitchit K, Kum-arb U, Hemmi H, Akira S, Krieg AM, Heppner DG, Stewart VA, Hasegawa H, Looareesuwan S, Shanks GD, Miller RS. Malaria blood stage parasites activate human plasmacytoid dendritic cells and murine dendritic cells through a Toll-like receptor 9-dependent pathway. J Immunol. 2004; 172: 4926-4933.
5.Mockenhaupt FP, Hamann L, von Gaertner C, Bedu-Addo G, von Kleinsorgen C, Schumann RR, Bienzle U. Common polymorphisms of toll-like receptors 4 and 9 are associated with the clinical manifestation of malaria during pregnancy. J Infect Dis. 2006; 194:184-188.
Dendritic cells, TLR recognition and endotoxin tolerance in severe malarial infection
28 February 2007
The article by Climent Casals-Pascual and colleagues demonstrates an inverse relationship between two key cytokines, IL-12 and IL-10, in different stages of severe malarial infection and malarial anaemia. Studies on murine models have shown such an inverse relationship at different stages of malaria and the phenomenon of endotoxin tolerance (possibly via dendritic cells) was suggested to explain this observation [1]. Dendritic cells (DCs) are important antigen presenting cells which upregulate MHC-class I and II molecules leading to the production of cytokines which then regulate different phases of the immune response to an infection.
Murine models infected with Plasmodium yoelii have shown that DCs release high levels of IFN- in an IL-12 dependent manner in initial stages of malaria as part of an innate immune response, while later stages of infection are dominated by IL-10 (a potent anti-inflammatory cytokine) [2]. Studies have demonstrated that late stage DCs still retain their potential to activate naïve T cells through expression of costimulatory molecules. This enables DCs to present antigen to T cells resulting in the production of malaria-specific T cells and subsequently protective antibodies, which means DCs are involved in the induction of adaptive immunity.
Recent evidence suggests that Toll-like receptors (TLRs) are involved in the innate immune recognition and responses to Plasmodium. In murine malaria infection, a cytoplasmic adaptor molecule termed as myeloid differentiation factor 88 (MyD88) was shown to be critical for IL-12 induction [3]. Plasmodium falciparum blood-stage parasites can activate human plasmacytoid DCs and murine DCs through MyD88- and TLR9-dependent pathways. The signal recognized by TLR9 and dependent on MyD88 is haemozoin (HZ), a detoxification product of haem molecules persisting in the food vacuoles of Plasmodium parasites. Ingestion of HZ by monocytes increases production of IL-10 and TNF-alpha relative to the production of IL-12, and correlates with the severity of malarial anaemia. Blocking IL-10 with IL-10 neutralizing antibodies, but not TNF-alpha antibodies, restores HZ-induced suppression of IL-12 [4]. It is possible that repeated stimulation of TLR9 by HZ tolerizes and/or blocks the MyD88 signaling pathway or via upregulation of TLR4 by MyD88-independent signaling pathway. High temperature have shown to result in DC-upregulation of TLR4 and cells can be rendered unresponsive to further signaling if repeated stimulation is used via lipopolysaccharide (the ligand for TLR4). Polymorphisms in these highly conserved innate recognition system of molecules are associated with an increase risk of malaria. Common polymorphisms such as TLR4-Asp299Gly and TLR9 T-1486C in P. falciparum infected women increase the risk of low birth weight in term infants by 6-fold, and, TLR4 Asp299Gly polymorphism increase the risk of maternal anemia by 5-fold [5].
The evidence therefore suggests that DC tolerance to TLR signaling leads to downregulation of pro-inflammatory cytokines and endotoxin tolerance and as they retain the potential to activate naïve T cells, they also generate the much-needed adaptive immune response. This may prove to be an important mechanism and knowledge of DC and TLR signalling to maintain the much-needed protection against this evasive protozoan parasite can be exploited in vaccine development.
References:
1.Boutlis CS, Yeo TW, Anstey NM. Malaria tolerance--for whom the cell tolls? Trends Parasitol. 2006; 22: 371-377.
2.Pouniotis DS, Proudfoot O, Bogdanoska V, Apostolopoulos V, Fifis T, Plebanski M. Dendritic cells induce immunity and long-lasting protection against blood-stage malaria despite an in vitro parasite-induced maturation defect. Infect Immun. 2004; 72: 5331-5339.
3.Adachi K, Tsutsui H, Kashiwamura S, Seki E, Nakano H, Takeuchi O, Takeda K, Okumura K, Van Kaer L, Okamura H, Akira S, Nakanishi K. Plasmodium berghei infection in mice induces liver injury by an IL-12- and toll-like receptor/myeloid differentiation factor 88-dependent mechanism. J Immunol. 2001; 167: 5928-5934.
4.Pichyangkul S, Yongvanitchit K, Kum-arb U, Hemmi H, Akira S, Krieg AM, Heppner DG, Stewart VA, Hasegawa H, Looareesuwan S, Shanks GD, Miller RS. Malaria blood stage parasites activate human plasmacytoid dendritic cells and murine dendritic cells through a Toll-like receptor 9-dependent pathway. J Immunol. 2004; 172: 4926-4933.
5.Mockenhaupt FP, Hamann L, von Gaertner C, Bedu-Addo G, von Kleinsorgen C, Schumann RR, Bienzle U. Common polymorphisms of toll-like receptors 4 and 9 are associated with the clinical manifestation of malaria during pregnancy. J Infect Dis. 2006; 194:184-188.
Competing interests
None