Mycobacterium tuberculosis is an intracellular pathogen; it grows inside the vesicles of (mostly) macrophages and dendritic cells (DCs). These bacteria are protected from the effects of antibodies and cytotoxic T cells. They cannot be destroyed as they escape acidification in the vesicles due to presence of mycolic acid in their cell walls. Thus, in order to destroy these and other intracellular bacteria, macrophages, T and NK cells are involved. A TH1 cell recognizes the bacterial peptide on infected macrophage when it comes in contact with it, these events trigger off secretion of Interferon (IFN) gamma by T cells, and this activates the macrophage which then destroys the bacteria. NK cells are infected with intracellular bacteria and produce IFN which is important for successful removal of the infection.
Cytokines that are important in immunity to intracellular bacteria
IFN-gamma is a critical cytokine produced by NK and T cells, it is involved in defense against intracellular bacteria like Listeria monocytogenes, and especially mycobacteria. The production of IFN-gamma by activated NK and T cells is regulated by several cytokines like IL-23 but IL-12 is the major cytokine involved, it is secreted by activated macrophages and DCs. They also secrete TNF gamma, also has a host defense. The IL-12 heterodimer (p35 and p40) that is secreted binds to its receptor that is expressed on NK and T cells. This activates STAT4 which triggers the secretion of IFN-gamma by NK and T cells. IFN-gamma in turn binds to its receptor present on macrophages and DCs, the signalling chain of the receptor phosphorylates STAT1, which translocates as a homodimer to the nucleus binds to DNA to activate gene transcription.
In the case of a 6 year old who has developed a reaction due to administration of BCG vaccine which is an anti-tuberculosis vaccine, the site of injection shows the formation of an ulcer, enlarged lymph nodes and the spread of BCG to her lungs and other organs this is known as disseminated BCGosis. It has also been observed that the child does not suffer from problems with other infections, all these symptoms point out to Mendelian susceptibility to mycobacterium diseases (MSMD). This syndrome is thought to arise due to impaired immunity to poorly virulent mycobacteria like bacillus Calmette-Guerin (BCG) and other environmental non-tuberculous mycobacteria. MSMD shows a high level of heterogeneity (that is mutations at different loci on the same gene or on different genes cause the same disease). There are 6 MSMD causing genes, 1 is X-linked and 5 are autosomal genes. Inherited disorders of the IL-12-IFN gamma axis are responsible for this condition. In case of this infant girl, impaired immune function can be the result of mutation in any of the genes. A very detailed and comprehensive analysis needs to be carried out in order to determine the exact cause of MSMD in case of this baby girl. But it can be stated that since the child is suffering from this disorder she may have a functional defect in either of her (macrophages, DCs, NK and T) cells. There have been many other case studies like this relating to the immune response against intracellular bacteria.
Diagnosis of complete IFN gamma R deficiency is necessary; this can be carried out by determining the serum IFN gamma levels using ELISA. A high IFN gamma level indicates complete deficiency of IFN gamma R while low or undetectable levels suggest IL-12, IL-12R, partial IFNR or undetermined defects. IL-12 p40 deficiency can be diagnosed using ELISA, with low levels of IL-12 p40, IL-12 p70 and IFN gamma being secreted by stimulated peripheral blood mononuclear cells. Deficiency of IL-12R beta1 leads to production of low levels of IFN gamma thus the IL-12R beta1 chain on activated T cells cannot be analysed using FACS. Further studies like gene sequencing are necessary to confirm the diagnosis.
To determine whether translocation of STAT1 into the nucleus has taken place, electrophoretic mobility shift assay. Flow cytometry can be used to detect intracellular phosphorylated STAT1.
Patients having complete deficiency in of IFN gamma R do not respond to IFN gamma even at high concentrations (105 IU/mL) and cells of patients having partial deficiency, respond to high but not low concentrations of IFN gamma. More specific and sensitive assays are necessary to determine the exact cause of the disease in each patient.
The antibiotic treatment given to individuals is based on the sensitivity of mycobacterial species. Also a history of BCG vaccination is important, and the unvaccinated children should be considered affected by non-tuberculous mycobacteria. Along with antimycobacterial therapy other measures like drainage of pus in case of lung infections and nutritional care is also important.
Splenectomy and surgical resection of lymph nodes may be necessary in some cases.
IFN gamma therapy
Patients having defects in IL-12, IL-12R and (partial) IFN gamma R usually show a good response to antibiotic treatment, in case of those individuals who do not respond well, they can be given additional IFN gamma therapy.
Bone marrow transplantation (BMT)
BMT can be used, because IFN gamma treatment is not effective in the absence of specific receptors. But it has proved quite difficult in several cases.
Gene therapy can be developed for treating 'complete IFN gamma deficiencies', but extensive research in this area is necessary.
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