University of Delhi, Delhi, India.
University of Delhi, Delhi, India.
National Institutes of Health, Bethesda, Maryland, USA
Immunogenetic and immune factors associated with infectious diseases like leprosy, tuberculosis and HCV-HIV co-infections and autoimmune disorders like Type 1 diabetes, hypoparathyroidism and vitiligo.
Key words : MHC, LMP, TAP, cytokine genes, PTPN22, detoxification genes, Glutathione S transferase genes, NQO1 and VDR genes, melanocyte-keratinocyte network and mesenchymal stem cells
Avinash Kumar, Bhukya Saida, Suraj Varkhande, Anshu Sharma, Jaya Singh, Sukanya Prathipati, Kapoor Chand, Amarnath Prasad
Summary of Research
Immunogenetic bases of differential immune responses in infectious and autoimmune diseases.
Immune responses to the infections differ in different individuals, some people clear the infection, some become immune to further infection and some develop chronic disease. We are interested in studying immunogenetic basis of differential immune responses. Our interests involve an array of genes whose products have a role in the immune response ranging from the Major Histocompatibility Complex (MHC) genes, Low molecular weight proteases (LMP), transporters associated with antigen processing (TAP), Cytotoxic T lymphocyte associated antigen-4 (CTLA-4), cytokine genes, vitamin D receptor genes, PTPN22 to phase II detoxification genes like Glutathione S transferase and NQO1 genes. The products of these genes interact in integrated networks which results in the final outcome of the infection or autoimmunity in terms of manifestations of, or protection from the diseases. We have been involved in molecular immunogenetic studies of infectious diseases like leprosy and tuberculosis, HCV-HIV co-infections and autoimmune diseases like psoriasis, hypoparathyroidism, Type 1 Diabetes and vitiligo.
Identification and attenuation of autreactive T cells in Type 1 diabetes along with replenishing insulin producing stem cells
Type 1 diabetes is an autoimmune disorder where most of the pancreatic beta cells are destroyed before the patients report to the clinic. The only treatment of choice is insulin injections, which does take care of the insulin requirement of the patients but does not really treat the patients. So, we aim to develop a two prong approach where on one hand, we would like to stop autoimmunity by using nano / micro-particle encapsulated peptides. Secondly, we would like to replenish the mice that are lacking the insulin producing beta cells with mesenchymal stem cells (MSCs) that would take care of their natural requirement of insulin. Thus beta cell neogenesis would provide a new therapy along with inhibition of autoimmunity using nano/micro-particle encapsulated peptides. For this purpose, we have encapsulated the peptides (which have earlier shown to inhibit autoimmunity in-vitro) in biodegradable nano/micro particles and are studying their in-vivo efficacy in streptozotocin induced diabetes in Balb/c mice and Non-Obese diabetic (NOD) mice. We are also growing mesenchymal stem cells from bone-marrow of Balb/c mice and studying their efficacy in treatment of diabetes with or without peptide loaded nano-particles. Besides, we are also differentiating MSCs into insulin producing cells using different approaches so that they may be transplanted in diabetic mice to take care of their daily insulin requirement. Successful treatment strategies developed in this way would be helpful in devising ways to treat patients suffering from Type 1 diabetes.
Study of Immunogenetic and autoimmune factors associated with vitiligo
Vitiligo is a depigmenting disorder of the skin caused by selective loss of pigment producing cells called melanocytes. It is the most common pigmentation disorder affecting 0.5-1 % of the world population We are interested in studying the autoimmune and immunogenetic factors associated with predisposition to develop vitiligo and mechanisms of melanocyte destruction and melanin disappearance in vitiligo. We have recently published the largest study on MHC associations in vitiligo. We have studied the molecular signatures of the peptide binding groove of the MHC class-I and II molecules in vitiligo patients and observed significant differences in the key residues involved in peptide binding between the patients and controls suggesting the affinity of auto-antigens being presented by these molecules. We are currently studying the functional implications of the MHC associations in vitiligo. Besides this, other genes involved in antigen processing and presentation, cytokine genes and phase II detoxification genes are also being investigated to understand the intricate networks in which these genes interact to manifest the complex phenotype of vitiligo. We observed significant increase in certain cytokines in the lesional skin and peripheral circulation of the patients. We have also studied the expression of genome-wide micro RNAs (miRNA) in the lesional and non-lesional skin and observed certain miRNAs to be significantly increased in the lesional skin of the patients when compared to their own non-lesional skin. We are now studying the global effect of these cytokines and micro RNAs (that were increased in the lesional skin of vitiligo) on primary melanocyte and keratinocyte cultures to study their role in aetiopathogenesis of vitiligo.
- Goswami R, Singh A, Gupta N, Consortium IGV, Rani R. (2012). Presence of strong association of the Major Histocompatibility Complex (MHC) Class I allele HLA-A*26:01 with idiopathic hypoparathyroidism. Journal of Clinical Endocrinology and Metabolism. First Published ahead of print June 20, 2012 as doi:10.1210/jc.2012-1328
- Singh A, Sharma P, Kar HK, Sharma VK, Tembhre MK, Gupta S, Laddha NC, Dwivedi M, Begum R; The Indian Genome Variation Consortium, Gokhale RS, Rani R. (2012). HLA alleles and amino acid signatures of the peptide binding pockets of HLA molecules in Vitiligo. Journal of Investigative Dermatology. Jan;132(1):124-134; http://dx.doi.org/10.1038/jid.2011.240.
- Natrajan VT, Singh A, Kumar AA, Sharma P, Kar HK, Marrot L, Meunier JR, Natarajan K, Rani R and Gokhale RS. (2010). Transcriptional Upregulation of Nrf2-dependent Phase II Detoxification Genes in the Involved Epidermis of Vitiligo VulgarisJournal of Investigative Dermatology.130: 2781-2789; doi:10.1038/jid.2010.201.
- Rani R, Singh A, Israni N, Singh A, Sharma P, Kar HK. (2009). Role of polymorphic Protein tyrosine phosphatase non-receptor type 22 (PTPN22) in leprosy. Journal of Investigative Dermatology. 129: 2726-2728.
- Israni N, Goswami R, Kumar A, Rani R. (2009). Interaction of vitamin D receptor with HLA-DRB1*0301 in Type 1 diabetes patients from North India. PLoS One. 4(12): e8023. doi:10.1371/journal.pone.0008023I .
- Spierings E, Hendriks M, Absi L, Canossi A, Chhaya S, Crowley J, Dolstra H, Eliaou JF, Ellis T, Enczmann J, Fasano ME, Gervais T, Gorodezky C, Kircher B, Laurin D, Leffell MS, Loiseau P, Malkki M, Markiewicz M, Martinetti M, Maruya E, Mehra N, Oguz F, Oudshoorn M, Pereira N, Rani R, Sergeant R, Thomson J, Tran TH, Turpeinen H, Yang KL, Zunec R, Carrington M, Knijff PD, Goulmy E*. (2007). Phenotype Frequencies of Autosomal Minor Histocompatibility Antigens Display Significant Differences among Populations. PLoS Genet 3(6): e103 doi:10.1371/journal.pgen.0030103.
- Imran M, Laddha NC, Dwivedi M, Shoaib, Singh J, Rani R, Gokhale RS, Sharma VK, Marfatia YS and Begum R. (2012). Interleukin-4 genetic variants correlate with its transcript and protein levels in vitiligo. British Journal of Dermatology 2012, 167:314-323.
- Chaduvula M, Murtaza A, Misra N, Shankar Narayan NP, Ramesh V, Prasad HK, Rani R, Chinnadurai RK, and Nath I. (2011). Peptides of Lsr2 of Mycobacterium leprae show hierarchical responses in lymphoproliferative assays with selective recognition by anergic lepromatous leprosy patients. Infection and Immunity, 5 December 2011 (Infect. Immun. doi:10.1128/IAI.05384-11).
- Kumar R, Goswami R, Agarwal S, Israni N, Singh S. K., Rani R. (2007). Association and interaction of the TNF-alpha gene with other pro and anti-inflammatory cytokine genes and HLA genes in type 1 diabetes patients from North India. Tissue Antigens doi:10.1111/j.1399-0039.2007.00817.x, 2007
- Bharati K, Rani R, Vrati S. (2009). Evaluation of Japanese Encephalitis virus DNA Vaccine candidates in Rhesus Monkey ( Macaca mulatta). Vaccine 27: 10-16.