Q. Are the caseating granulomas seen in tuberculosis considered part of innate or adaptive immunity? What’s happening inside them?
A. Caseating granulomas are a part of adaptive immunity. Having said that, innate immune cells (macrophages) are heavily involved. There are several steps in the process of granuloma formation in tuberculosis:
1. Initially, M. tuberculosis infections are unable to be stopped by neutrophils. So, macrophages are called in.
2. Some of the macrophages become activated because of the local production of interferon (primarily IFN-alpha from the macrophages and IFN-beta from lung tissue cells). The IFN-activated macrophages have some limited ability to kill and digest M. tuberculosis organisms.
3. The activated macrophages produce cytokines that draw helper T cells to the area. Since the activated macrophages can have a limited effect on controlling M. tuberculosis and can degrade some of the bacterial cells, they can present the M. tuberculosis antigens on their surface in association with HLA Class II antigens.
4. Helper T cells that recognize M. tuberculosis antigens are activated by the combination of antigen presentation and cytokine production (predominantly, IL-1 and IL-12). The combination of IL-1 and IL-12 activate the helper T cells to become activated Th1 cells.
5. The activated Th1 cells produce IFN-gamma which highly activates macrophages. These highly activated macrophages are able to, in most individuals, kill the M. tuberculosis bacteria.
6. A granuloma forms, with M.tuberculosis in the center, either as free organisms or as macrophage-ingested organisms, depending upon how good the individual’s highly activated macrophages are at killing M. tuberculosis bacteria. The highly activated macrophages are surrounded by activated Th1 cells that keep producing IFN-gamma as the macrophages keep presenting M. tuberculosis antigens. The IFN-gamma in turn keeps the macrophages highly activated, allowing them to continue to kill M. tuberculosis and to continue to present antigens. The Th1 cells are in turn surrounded by additional macrophages that differentiate to become fibroblast-like cells, forming the granuloma.
7. One can view this granuloma as maintaining a balance between the ability of the highly activated macrophages to kill M. tuberculosis organisms as rapidly as they divide and the ability of the M. tuberculosis organisms to kill the macrophages.
If the M. tuberculosis organisms gain the upper hand (perhaps due to immunosuppression that might occur for a variety of reasons), the M. tuberculosis organisms kill the macrophages, causing more and more macrophages to come into the area. The dead and dying macrophages form the caseated material. If the M. tuberculosis organisms replicate sufficiently to break out of the granuloma or prevent the formation of the granuloma in the first place, the activated and highly activated macrophages release their cytokines into the milieu of the lung tissue, rather than into the granuloma. Among the cytokines produced in large amount by highly activated macrophages is tumor necrosis factor (TNF). TNF can kill lung tissue cells, resulting in a kind of accidental “scorched earth” policy. The damage caused results in cavitation in the lung.
- Kristine said No that makes absolute sense! If the likelihood of PE is low, then you do a D-dimer to rule it out (...
- Fatima said As the hemoglobin drops, you need to make more reticulocytes to get up to the normal range of 0.5 –...
- praveen pandey said I read in Harrison 18ed fig 300-3 algorithm. It says we do a d-dimer for low likelihood of PE. For h...
- Md.Abu Jar said thanks a lot my loving teacher….kristine krafts
- sama said Amazing
- vijaya said Thanks
- Sandeep Jain said As always, fantastic explanation! The delay in maturation time with decreasing Hgb is good to know!
- Baraniko Eromanga said Thanks for discussing this, it’s confusing me for long time, now I understand the differences.
- Kristine said Thanks, Raffi. No – the concept of shift reticulocytes is not the same as polychromasia. Polyc...
- Raffi said Thanks for the post. By chance, is the “shift reticulocyte” the same as polychromasia? I...
- vetstudent said u make things a lot of easier! tq
- Kristine said Sure – you just multiply the percentages by the total white blood cell count. For example: the...