Type I immune responses play an essential role in the control of mycobacterial infections. Mutations in the genes involved in the type I cytokine pathway were found in patients with Mendelian... Show moreType I immune responses play an essential role in the control of mycobacterial infections. Mutations in the genes involved in the type I cytokine pathway were found in patients with Mendelian susceptibility to mycobacterial diseases. These patients are highly susceptible to infections with non-tuberculous mycobacteria (NTM), which are usually poorly pathogenic. The first part of this thesis focuses on the relation between the genotype and phenotype in the cause of an impaired immunity leading to the susceptibility to NTM infections. The role of genetic factors in the control of infections with more virulent tuberculous mycobacteria is less evident. The second part of this thesis focuses on putative non-genetic causes of an impaired immunity in the control of tuberculous mycobacterial diseases. In tuberculosis patients type I immune responses regulated by interferon-_ are also repressed. Virally induced interferons, other than interferon-_, may be involved in this repression, thereby influencing the immunopathogenesis of tuberculosis. Show less
Tuberculosis (TB) is an infectious disease, caused by Mycobacterium tuberculosis. MTB infection does not necessarily progress to TB. Only 5-10% of exposed individuals develop clinical signs and... Show moreTuberculosis (TB) is an infectious disease, caused by Mycobacterium tuberculosis. MTB infection does not necessarily progress to TB. Only 5-10% of exposed individuals develop clinical signs and symptoms of TB. Given the impact of mycobacterial exposure and the immunoregulatory consequences for host immunity, it is important to study the integrity and the regulation of immune responses and their downstream signaling pathways in TB endemic areas. Indonesia is a highly TB-burdened country and ranks third globally in TB cases. This thesis, consisting of six studies, explored variation in host immune responses to TB and their genetic background, and variation in clinical presentation. (1) MTB-specific stimulation of IFN-_ production as well as IFN-_ receptor signaling was significantly down-regulated during active TB, correlated with disease severity and __activity. (2) Concentrations of plasma granulysin of active TB patients were found to be low during acute disease. (3) Several genetic markers have been identified to affect susceptibility to TB (IL12B, IL12RB1, IFNG and IFNGR1) and (4) TLR8, DC-SIGN, complement component and scavenger receptor. (5) NRAMP polymorphisms were, however, not associated with susceptibility to TB. (6) TB with concomitant type2 DM presented more symptoms; screening fasting blood glucose in TB patients is clinically important. Show less
