Broad Area of Research
Immunogenetics of Autoimmune Disorders
Details of Work done so far and significance of the scientific contribution
Role of host gene polymorphisms in Malaria:
Host inflammatory responses to P. falciparum are mainly mediated by glycosylphosphatidylinositol (GPI), a constituent of parasite. TLR2 and to some extent TLR4 on host monocytes/macrophages recognize GPI and produce inflammatory cytokines and nitric oxide etc., which are associated with severe malarial pathogenesis. Variants of innate genes have been associated with improper immune response. In present study we show a significant association between TLR4 (Gly299Gly) and CD14 (CT + TT) polymorphism and increased susceptibility to severe P. falciparum malaria. Combined analysis revealed association of TLR4 (Asp299Asp)/TLR4 (Thr399Ile+Ile399Ile)/CD14 (CT+TT) genotypes with
susceptibility to develop multi-organ dysfunctions (MOD) in human malaria. Further, this combined genotype correlated well with higher plasma levels of TNF-α thus contributing to pathogenesis of severe malaria (Unpublished results).
A 23bp insertion/deletion polymorphism at 5’UTR of TLR2 gene has been reported but its functional relevance is still largely unknown. We show that Ins/del and del/del genotypes display higher surface expression of TLR2 and plasma TNF- α compared to ins/ins. Further, by stimulation with wide range of TLR2 ligands these genotypes (Ins/del and del/del) produce higher levels of pro-inflammatory molecules as compared to ins/ins cases. The del/del genotype is associated with susceptibility to MOD and malarial mortality.
Scrutiny of database revealed that lower primates (Rhesus monkey, Baboon and Marmoset) display ‘del’ mutation while higher primates (Chimpanzee, Gorilla and Orangutan) display ‘ins’ type. Further we analysed DNA of 25 Chimpanzees, 8 Gorillas, 1 Orangutan, 5 Rhesus monkeys and 3 Baboons, suggesting an evolution relationship of this mutation in primates. ‘ins’allele of TLR2 gene could have been selected out in higher primates by malaria during evolution since it offers survival advantage (Unpublished results)
Binding of un-infected RBCs to infected RBCs called rosetting, has been attributed in literature to be a possible pathogenic mechanism for development of severe P. falciparum malaria. we show that blood group “O” is protected from developing severe malaria and mortality and meta-analysis also confirmed the above findings. These observations also explain higher frequency of blood group“O” observed in various malaria endemic areas (1).
Role of host gene polymorphisms in Filariasis:
Lymphatic Filariasis (LF) is a chronic and debilitating tropical disease caused by vector borne nematode parasites display a wide range of clinical manifestations. These heterogeneities of clinical phenotypes have been attributed to environmental factors, parasite genotypes and host genetic factors. Filarial parasites contain Wolbachia an endosymbiotic bacteria, which are essential for worm development and fertility. It has been demonstrated that human TLRs recognize Wolbachia and induce inflammatory responses and it is currently assumed that such responses could be the basis for development of chronic disease manifestations. Our investigation revealed a strong association of TLR4 (Thr399Ile) polymorphism with protection from development of chronic filarial disease. In contrast, TLR2 (23bp ins/del) variant predisposed endemic subjects for development of chronic filariasis (Unpublished results)
Mannose binding lectin (MBL) plays an important role in various infectious diseases – it activates complement and augments opsonization and phagocytosis. We observed higher prevalence of MBL low producer genotypes (LXA/LYB, LYB/LYB and LXB/LXB) in asymptomatic carriers as compared to endemic controls suggesting subjects with low MBL levels possibly are unable to clear microfilariae in circulation (Unpublished results).
Endothelin-1
(ET-1) is a key inflammatory molecule that induces vasoconstriction and activation of endothelial cells. Hydrocele patients displayed higher plasma ET-1 corroborating previous reports. Prevalence of Ala288Ala wild type was significantly associated with higher plasma ET-1 and predisposition to development of hydrocele. Role of TNFRII in human filariasis has been reported in literature. Significant association of TNFRII ‘high’ producer (M196M) polymorphism with susceptibility to development of elephantiasis was observed. In addition, a combined analysis of ET-1 (Ala288Ser) and TNFRII (M196R) polymorphisms revealed their association with one or the other form of chronic disease (2).
Role of Mannose binding lectin in Systemic Lupus Erythematosus:
The innate immune system plays an important role in pathogenesis of SLE. Mannose binding lectin (MBL) is an essential component of innate immunity which recognizes carbohydrate residues on surface of micro-organisms viz. bacteria, viruses, fungi, protozoa and activates complement system through MBL associated serine proteases. We demonstrate MBL as promising biomarker of disease activity (3). Further, show MBL low producer genotypes are associated with predisposition to SLE and autoimmune hemolytic anemia (4).
References
1. Panda AK, Panda SK, Sahu AN, Tripathy R, Ravindran B, Das BK. 2011. Association of ABO blood group with severe falciparum malaria in adults: case control study and meta-analysis. Malar J 10: 309
2. Panda AK, Sahoo PK, Kerketta AS, Kar SK, Ravindran B, Satapathy AK. 2011. Human lymphatic filariasis: genetic polymorphism of endothelin-1 and tumor necrosis factor receptor II correlates with development of chronic disease. J Infect Dis 204: 315-22
3. Panda AK, Parida JR, Tripathy R, Pattanaik SS, Ravindran B, Das BK. 2012. Mannose binding lectin: a biomarker of SLE disease activity. Arthritis Research and Therapy Accepted
4. Panda AK, Parida JR, Tripathy R, Pattanaik SS, Ravindran B, Das BK. 2012. Low producer MBL genotypes are associated with susceptibility to systemic lupus erythematosus in Odisha, India. Hum Immunol
Role of host gene polymorphisms in Malaria:
Host inflammatory responses to P. falciparum are mainly mediated by glycosylphosphatidylinositol (GPI), a constituent of parasite. TLR2 and to some extent TLR4 on host monocytes/macrophages recognize GPI and produce inflammatory cytokines and nitric oxide etc., which are associated with severe malarial pathogenesis. Variants of innate genes have been associated with improper immune response. In present study we show a significant association between TLR4 (Gly299Gly) and CD14 (CT + TT) polymorphism and increased susceptibility to severe P. falciparum malaria. Combined analysis revealed association of TLR4 (Asp299Asp)/TLR4 (Thr399Ile+Ile399Ile)/CD14 (CT+TT) genotypes with
susceptibility to develop multi-organ dysfunctions (MOD) in human malaria. Further, this combined genotype correlated well with higher plasma levels of TNF-α thus contributing to pathogenesis of severe malaria (Unpublished results).
A 23bp insertion/deletion polymorphism at 5’UTR of TLR2 gene has been reported but its functional relevance is still largely unknown. We show that Ins/del and del/del genotypes display higher surface expression of TLR2 and plasma TNF- α compared to ins/ins. Further, by stimulation with wide range of TLR2 ligands these genotypes (Ins/del and del/del) produce higher levels of pro-inflammatory molecules as compared to ins/ins cases. The del/del genotype is associated with susceptibility to MOD and malarial mortality.
Scrutiny of database revealed that lower primates (Rhesus monkey, Baboon and Marmoset) display ‘del’ mutation while higher primates (Chimpanzee, Gorilla and Orangutan) display ‘ins’ type. Further we analysed DNA of 25 Chimpanzees, 8 Gorillas, 1 Orangutan, 5 Rhesus monkeys and 3 Baboons, suggesting an evolution relationship of this mutation in primates. ‘ins’allele of TLR2 gene could have been selected out in higher primates by malaria during evolution since it offers survival advantage (Unpublished results)
Binding of un-infected RBCs to infected RBCs called rosetting, has been attributed in literature to be a possible pathogenic mechanism for development of severe P. falciparum malaria. we show that blood group “O” is protected from developing severe malaria and mortality and meta-analysis also confirmed the above findings. These observations also explain higher frequency of blood group“O” observed in various malaria endemic areas (1).
Role of host gene polymorphisms in Filariasis:
Lymphatic Filariasis (LF) is a chronic and debilitating tropical disease caused by vector borne nematode parasites display a wide range of clinical manifestations. These heterogeneities of clinical phenotypes have been attributed to environmental factors, parasite genotypes and host genetic factors. Filarial parasites contain Wolbachia an endosymbiotic bacteria, which are essential for worm development and fertility. It has been demonstrated that human TLRs recognize Wolbachia and induce inflammatory responses and it is currently assumed that such responses could be the basis for development of chronic disease manifestations. Our investigation revealed a strong association of TLR4 (Thr399Ile) polymorphism with protection from development of chronic filarial disease. In contrast, TLR2 (23bp ins/del) variant predisposed endemic subjects for development of chronic filariasis (Unpublished results)
Mannose binding lectin (MBL) plays an important role in various infectious diseases – it activates complement and augments opsonization and phagocytosis. We observed higher prevalence of MBL low producer genotypes (LXA/LYB, LYB/LYB and LXB/LXB) in asymptomatic carriers as compared to endemic controls suggesting subjects with low MBL levels possibly are unable to clear microfilariae in circulation (Unpublished results).
Endothelin-1
(ET-1) is a key inflammatory molecule that induces vasoconstriction and activation of endothelial cells. Hydrocele patients displayed higher plasma ET-1 corroborating previous reports. Prevalence of Ala288Ala wild type was significantly associated with higher plasma ET-1 and predisposition to development of hydrocele. Role of TNFRII in human filariasis has been reported in literature. Significant association of TNFRII ‘high’ producer (M196M) polymorphism with susceptibility to development of elephantiasis was observed. In addition, a combined analysis of ET-1 (Ala288Ser) and TNFRII (M196R) polymorphisms revealed their association with one or the other form of chronic disease (2).
Role of Mannose binding lectin in Systemic Lupus Erythematosus:
The innate immune system plays an important role in pathogenesis of SLE. Mannose binding lectin (MBL) is an essential component of innate immunity which recognizes carbohydrate residues on surface of micro-organisms viz. bacteria, viruses, fungi, protozoa and activates complement system through MBL associated serine proteases. We demonstrate MBL as promising biomarker of disease activity (3). Further, show MBL low producer genotypes are associated with predisposition to SLE and autoimmune hemolytic anemia (4).
References
1. Panda AK, Panda SK, Sahu AN, Tripathy R, Ravindran B, Das BK. 2011. Association of ABO blood group with severe falciparum malaria in adults: case control study and meta-analysis. Malar J 10: 309
2. Panda AK, Sahoo PK, Kerketta AS, Kar SK, Ravindran B, Satapathy AK. 2011. Human lymphatic filariasis: genetic polymorphism of endothelin-1 and tumor necrosis factor receptor II correlates with development of chronic disease. J Infect Dis 204: 315-22
3. Panda AK, Parida JR, Tripathy R, Pattanaik SS, Ravindran B, Das BK. 2012. Mannose binding lectin: a biomarker of SLE disease activity. Arthritis Research and Therapy Accepted
4. Panda AK, Parida JR, Tripathy R, Pattanaik SS, Ravindran B, Das BK. 2012. Low producer MBL genotypes are associated with susceptibility to systemic lupus erythematosus in Odisha, India. Hum Immunol