Genetic basis of tuberculosis susceptibility in India.

Tuberculosis is a complex disease resulting from the responses of immunological, genetic and environmental factors to the chronic infectious agent, Mycobacterium tuberculosis. Several genetic factors have been implicated in host disease susceptibility and the prevalence of a disease in a population may be equal to the product of the frequencies of the susceptible alleles present in the population living in an endemic area. The endogamous, sympatrically isolated gene pools, exposed to the highly infectious environmental load of India, is an ideal model to study tuberculosis susceptibility. Our recent studies in this endemic region have reiterated the association of HLA-DRB1*02 and its subtype DRB1*1501 with tuberculosis susceptibility and have identified an IL-10 associated disease susceptibility in HLAnon-DRB1*02, BCG scar negative individuals and a skewed usage of TCR Vb in BCG scar negative, HLA high risk allele carrying individuals. This indicates that there may be several pathways leading to disease. Tuberculosis susceptibility is not thus a one-gene one product manifestation but multifactorial and epistatic influences of various factors finally lead to the disease. We review the factors that has been explored under Indian context in tuberculosis susceptibility.

Diversity And Dynamics Of Populations And Disease Susceptibility.

In an endemic environment, all susceptibles will develop the disease.†South India, like the rest of the country is known for its caste system. The origin, level of inbreeding, endogamy and sympatric isolation amongst the caste system will lead to divergence of their gene pool and Ir (Immune response) genes are no exception to this. These differences may result in differential susceptibility at the population level. The lessons from inbred strains of animals explain this phenomenon and no immunologist or geneticist of today would like to carry out an experiment by mixing up the different strains of a species. In human populations in general, and in Indian caste groups in particular, the population dynamics like migration, miscegenation, social taboos and marriage patterns skew the picture and mask the differences between these populations particularly the prevalence and susceptibility to disease. Most of the research workers are disabled having a limited knowledge and even more limited facilities to do an 'ideal' experimental study in humans. Thus, in any clinical disease or immunological study in humans, a (case), caste, sex, nativity and haplotype (HLA or Ir gene) matched controls may need to be studied to understand the immunogenetic basis of disease susceptibility. The studies hitherto carried out at Madurai have revealed: i) different caste groups possess different haplotypes, some characteristic to a caste whereas others were common to many of them, ii) genetic distance calculated based on allele frequency brought out their affinity to each other; iii) not many Brahmin populations of India, have the same of the gene pool, presumably because of their origin, though they have all adopted the Hindu philosophy and religion, iv) numerically larger and geographically adjacent patrilineal clans of a tribe are genetically closer to each other; v ) a given HLA disease association transcend ethnic barrier (eg. pulmonary tuberculosis, leprosy), due to Ir gene dependant immunogeneric predisposition, vi) a few other HLA disease associations found in some populations or caste groups and not in others (eg. psoriasis) may be due to a linked gene and hitch hike phenomenon. Another new dimension is added to this genetic epidemiology: settlements, population size and the microbial world and infections increase in size as a function of time over the decades, resulting in faster transmission of a disease. The epidemiology is also changing over a period in the same place. As a result the newborn of today are subjected to a newer set of stress and selections than they were a generation ago. The epidemiology is known to affect the thymic education of lymphocytes through MHC, resulting in a different repertoire among children brought up in different environments. This has had great implications in subsequent environmental challenges and infections. Today any problem should be investigated and tackled by a group of open minded, knowledgeable scientists cutting across the barriers of their field of specializations. This is the need of the hour in this country.

Major histocompatibility complex restriction in tuberculosis susceptibility.

More than one mechanism may contribute to disease susceptibility in tuberculosis, viz., major histocompatability complex (MHC) restriction phenomenon, spectrum of immune reactivity/cytokine profile and epidemiology induced anergy. Experiments from our laboratories revealed that (i) human leucocyte antigen D-related allele 2 (HLA DR2) predispose for a more severe form of pulmonary tuberculosis encoding a high responder status, (ii) spectrum of immune reactivity to mycobacteria is 'innate', and it is demonstrable in healthy individuals from endemic area, (iii) there is no correlation between the purified protein derivative (PPD) response and peptide responses, (iv) once a person is high responder to P16 and P38 derived peptides (6/22), he/she (whether a patient or control) is a high responder for a wide range of mycobacterial peptides and (v)majority of the T-cell clones generated in vitro, to peptide 16·3 (amino acids 21-40) of 16 kA a mycobacterial antigen, in an HLA DR2 positive healthy individual is HLA DR restricted, permissive and of Th1 phenotype. The results suggested that MHC class II restriction play a role in peptide recognition and the immune response. Nonetheless the outcome and specificity of the immune reactivity and the resultant disease pathogenesis may depend on the promiscuity of peptide recognition and cytokine profiles.

HLA and Disease Susceptibility in Tamil Nadu, S. India.

Result on HLA polymorphism in the populations of Tamil Nadu, South India are analysed for HLA association with various diseases like pulmonary tuberculosis, leprosy, psoriasis, rheumatoid arthritis, iridocyclitis and Eale's disearse. These studies revealed: i) association of psoriasis with HLA B17 and DR7 is highly significant in Vellala related group and this is attributed to founder effect-hitch hiking of a disease producing gene linked to these alleles, as the population migrated, ii) different castes differ from one another in their HLA allelic and haplotype polymorphism, iii) HLA DR2 predispose for more severe from of pulmonary tuberculosis which transcends ethnic barrier, the susceptibility presumably being due to a generalized MHC dependent immunogenetic and pathological mechanism, iv) HLA B27 and DR4 are associated with iridocyclitis, rheumatoid arthritis and low back pain; the susceptibility may be a HLA dependent molecular mimicry process, v) HLA alleles DR2 and DR4 predispose for severe forms of the respective diseases, though not for initial susceptibility.

Prevalence of sickle cells in Irula, Kurumba, Paniya & Mullukurumba tribes of Nilgiris (Tamil Nadu, India).

A total of 1377 tribals, comprising Irulas (536), Paniyas (196), Kurumbas (87), Mullukrurumbas (156) and Soligas (402), living in the Nilgiris, Tamil Nadu, India were studied for sickle cell trait between 1981-85. Patients attending various tribal clinics at Arayure, Kozhikarai, Kothagiri and Biligiri Rengan hills for various ailments were screened at random by solubility test and by acetate paper electrophoresis, if required. HbAS carrier frequency was 30-37.8 per cent in all the tribals studied except Kurumbas (19.5%). The frequency of carriers were more (37.8%) on the western part of Nilgiris (Nedungode, Kappala and adjoining regions) than the eastern part (30%). Further, the prevalence of carriers was higher (47-49%) in the 10-19 yr age group amongst Paniyas and Mullukurumbas living in the western part of Nilgiris. An episodic, epidemic of malaria so rampant during the early part of this century in the western parts of Nilgiris might have eliminated many children with HbAA and hence the higher frequency of HbAS in this particular age group.

Frequency of HLA antibodies in south India.

Sera from 4088 pregnant women (649 antenatal bleeding and 3439 post-partum bleeding) living in Madurai, were collected and screened for anti-HLA. Α, Β and DR antibodies. 696 of them were screened for anti-HLA DR antibodies. Ten per cent (65/649) of antenatal sera and 13·4% of post-partum sera (463/3439) were positive for HLA A and Β antibodies: nonetheless the percentage of monospecific sera were almost the same in both. Screening for HLA DR antibodies were carried out using platelet absorption in test tray technique: seventy three of 696 (10·5%) were positive. The incidence of anti-HLA A, B antibodies correlates to the allelic frequencies in the population. Thus in India, collection and screening post-partum haemorrhage is the simplest and cost effective method of acquiring polyclonal sera for routine laboratory and diagnostic use.