| MYCOBACTERIAL DISEASE |
Questionnaire Protocol-Mycobacterial Disease Study Participating Labs Circular 7, Aug, 00- UPDATE Circular 6 Circular 5, Jan, 00 Circular 4, Nov, 99 |
Narinder Mehra, Chair GENERAL: It is proposed to include Mycobacterial diseases as a satellite study in the disease component of the forthcoming 13th IHWC. The goal of this study would be to ascertain contributions of HLA linked and non HLA linked candidate genes in governing susceptibility and/ or immune responsiveness to mycobacterial infections. The study would primarily highlight interesting findings in the field of leprosy and tuberculosis including HIV associated tuberculosis. Well defined patients, their families and ethnic controls will be analysed in this mission through the worldwide collaborative effort. There would be mutual understanding that the DNA samples will only be used for studies described in the aims of the 13th IHWC with free exchange of technologies among participating laboratories. This would help overcome problems relating to inadequate facilities and expertise, if anywhere.  OVERVIEW (2) AIMS: The mycobacterial disease component of the 13th IHWC has been planned with the specific aims as enlisted below with an emphasis on genetic influences and immunological correlates. It is proposed to study:
This collaborative effort would help overcome apparent inconsistencies that may arise between different populations and would have potential relevance in designing molecular therapeutic strategies. OVERVIEW (3) INTRODUCTION: The Mycobacteria with fast erupting multidrug resistant forms continue to pose a major health menace in the form of leprosy and TB at an alarming magnitude. Several lines of evidence highlight the genetic basis of risk to develop mycobacterial diseases. These include racial discrimation, familial clustering, animal studies, concordance rates in MZ twins and association studies with HLA and non HLA genes. The HLA-DR2 (DRB1*1501 and DRB1*1502) have been strongly associated especially with the more severe forms of mycobacterial diseases viz. Lepromatous leprosy (LL) and multi drug resistant (MDR) pulmonary TB. These studies have narrowed down the difference of relevance to the level of a single amino acid at positions 13, 70 and 71 of the DRB chain. Similarly studies on the family of Nramp proteins have presented single amino acid differences as one of the deterimental clues to protection versus risk. The influence of HLA-DR polymorphism on the type of immune response elicited (cytokine response) highlights the importance of immune response genes (HLA) on the immunopathogenesis of mycobacterial diseases. It is therefore proposed to conduct sequence analysis of the positively or negatively associated allelomorphs especially HLA class II to identify the critical amino acid residues involved at the interface of MHC-peptide binding pockets. It shall be appreciated if efforts can be made to delineate and further correlate HLA class II amino acid sequences with the cytokine levels or T cell subsets in these diseases. This shall reveal the involvement of HLA class II alleles in governing immune response and disease manifestation. OVERVIEW (4) TIME SCHEDULE Submission of the questionnaire-- 31st Aug, 1999 Collection and storage of DNA samples for HLA Typing-- 15th Dec, 1999 Collection of cells for Intracellular staining of cytokines and cell surface marker phenotypings by Flow cytometry.(optional)-- 15th Dec, 1999 Complete typing for HLA class I, II alleles and other genetic markers(NRAMP1)-- 31st Oct, 2000 Submission of data to central laboratory for analysis-- 31st Dec, 2000 Compilation and interpretation of data, identification of interesting alleles or haplotypes, comparison of sequences for particular associations, statistical evaluation and analysis-- 15th March, 2001. |
