Key terms: damage, mycobacterial, host immune response.
So a suggestion in answering this topic is focussing on the general mycobacterial species which cause TB and going through the mechanism of pathogenesis and conclude whether the host immune response is causative of the damage in the course of the mycobacterial disease. Another way is to begin with the damage/symptoms of TB and discuss how the immune system is responsible. Anyways I have bolded the most important points in addressing the topic. Any suggestions are most welcome :)
Background Information
- Mycobacterium species are rod shaped obligate aerobes
- do not produce exotoxins or endotoxins
- pathogenesis of TB is mainly the result of the host immune response
- Damage is caused by chronic inflammation and survival within the macrophages and presents in two stages: Primary and Secondary TB
Primary Infection
- Transmission, mainly by breathing aerosols or dust particles containing bacilli
- Upon inhalation, bacilli are ingested by resident alveolar macrophages or survive and replicate
- Delayed hypersensitivity – mycobacterial antigens presented to T lymphocytes and initiate antigen specific immune response
- Assembly of macrophages and T cells surrounding the bacilli forms a granuloma or tubercle and contain the infection
- healing with fibrosis with calcification occurs
- however bacilli may not be killed and remain dormant in the tubercles
- maybe become reactivated and known as Secondary TB infection
- Reasons on what precipitates secondary infection is unknown but may include: a slowed development of the delayed hypersensitivity reaction, other infections causing immunosuppression, re-infecton with mycobacteria, malnutrition, stress and hormonal level imbalances and old age
Secondary Infection
- Over time the tubercules may become necrotic
- results in tissue damage and cheesy substance known as caseous material
- Caseous necrosis is unstable and liquefies and discharges into the bronchial tree creating larger lesions
- Thus allows the formation of pulmonary cavities
- cavities provide aerobic conditions where bacilli can replicate and the spread to other parts of the lungs = pneumonia
- Inflammation of the bronchi stimulates increased mucous secretion and the cough reflex
- resulting in coughing up bacilli-containing sputum and blood due to tissue destruction.
Macrophage Involvement
- macrophages can kill intracellular bacilli, intracellular mycobacteria can persist
- immunological imbalance occurs and consists of macrophages killing the bacilli, macrophages being infected and macrophages harbouring and spreading dormant bacilli for periods of time
- processing of killed bacilli leads to continued exhaustion of the immune response
- In immuno-comprimised people the primary infection is not contained due to their incompetent immunity
- bacilli enter systemic system and cause a fatal infection called miliary tuberculosis
- Activated macrophages release the cytokines IL-1 and TNFα
- These cytokines contribute to the symptoms of the disease and mediate fever, weight loss and night sweats
- the release of IL-10also by macrophages suppresses the immune response and may promote disease progression
Conclusion
- Tissue damage is caused by the immune response to mycobacterial species
- two immunological defence mechanisms to control the infection are the antimicrobial action of macrophages and the walling off and containment by fibrosis and calcification
- In absence of cellular immunity and delayed hypersensitivity, caseous necrosis would not develop
- However bacilli would be able to proliferate and invade the blood stream and Milliary TB would eventuate
- In conlusion, the host immune response thus contains the disease at the cost of damage
5 comments:
Myocobacterial infections do NOT just include M.Tuberculae. In fact leprosy is another disease to be considered. Leprosy also slowly progresses throughout the body until the immune system begins to mount an immune response. Curiously 5% of individuals are genetically predisposed to contracting Leprosy. While the pathophysiology is not 100% understood, it is reported that most damage that underlies skin lesions and neural damage is associated with an immune attack.
I found something about another mycobacterium pathogen called "Mycobacterium avium complex" (MAC) in AIDS and other immunocompromised patients.
"The risk of MAC is inversely related to the patient's CD4 count, and increases significantly when the CD4 count decreases below 50 cells/mm³. Other risk factors for acquisition of MAC infection include using an indoor swimming pool, consumption of raw or partially cooked fish or shellfish, bronchoscopy and treatment with granulocyte stimulating factor."
So if an individual is immunocompromised... how are they supposed to mount an immune response?... Especially if the CD4 (T-helper cell population) count is down. CD4 populations play a critical role in the activation of CD8 T cells and B-cell populations...
A brief divergence to understand where CD4 cells may fit in a typical immune response to mycobacteria.
Following our knowledge from immunology - the specific IgE immunoglobulins are produced by the B cells and bind to the Fc(e) receptors that line the plasma membrane of Mast cells. When a specific antigen is detected --> mast cell degranulation, inflammation, all cells of the immune system come to the party.
So it IS possible that the mycobacterium avium complex diseases cause damage, and resulting in death directly whether it be by production of an unknown toxin, or through invasive mechanisms, or even through the facilitation of a new disease.
If that not be the case then... then death resulting from M.avium can still be attributed to inflammation. inflammation may still proceed in immuno compromised individuals with low CD4 count. This is an example of the immune systems built in redundancy!
So i don't know how much of a point that makes... I'd like to hear your comments...
Hi Matty, Thank you for the comprehensive run-down of disease pathology of TB, especially.
Just for reference (and to elaborate on what matthew hinted at), please be aware of the many mycobacteria out there, some ones I've glanced over are:
Mycobacterium tuberculosis
Mycobacterium bovis
Mycobacterium africanum
Mycobacterium canetti
Mycobacterium microti
please note, i believe only some cause human disease (but check!)... summoning the ones that don't cause disease will not answer the question properly.
from what i read, and looking at your post above, if we were to answer this question with a simple yes/no.. the answer most people would write is 'yes', i guess. "most damage" is inadvertently caused our immune responses.
i would argue with such things like it would not be in mycobacterium's best interest to 'kill' its human host in a rapid manner... I would really like to know for most people with inadequate antibiotic treatment (if it was adequate, the disease would be 'entirely eliminated', says wiki), would they die from TB eventually? (or would the latent TB enable alternative and more prevalent causes of death?)
also, i'd maybe mention it has 'evolved' into quite a sweet spot... where our initial human defense/immune mechanisms although trying its absolute hardest will ultimately fail in the end... the only way to defeat it is to introduce antibiotics, and even that, it is so adept in resistance.
we can mention that it's basically evolved and been with us for thousands (and more) years...
one question that links to my first question (do TB-infected people basically ALL succumb to death by TB, or maybe something else, esp if its latent for a long time)... is how do people die from TB in the end?
Do the lung lesions make them cough out blood to death?
Are their lungs filled with tubercles, making breathing less and less?
http://answers.yahoo.com/question/index?qid=20080708160152AAakNm8
Ahh hey boris; I took a look at the discussion on yahoo7 forums and it doesn't seem all that feasible that coughing up blood is the real reason why people suffering from mycobacterial disease is the main reason they die. What I have read is that people suffering from a massive mycobacterial outbreak (even when immunocompromised) die from the resulting systemic inflammation. The histamine release around the body can cause all sorts of problems for the cardiovascular system --> shock and the pathogenesis of many other problems including renal failure ect...
Leprosy, caused by the obligate pathogen Mycobacterium leprae, has a wide spectrum of presentation. At one end of the spectrum is the contained tuberculoid form. At the other end of the spectrum is the aggressive lepromatous form. In between the two is the borderline form, which is a hybrid of the two extremes.
Sufferers of the contained tuberculoid form of leprosy display Delayed Type Hypersensitivity to Mycobacterium leprae, and test positive with a lepromin PPD skin test. There is extensive formation of granulomas, with high levels of inflammation and low numbers of infecting bacteria.
Sufferers of the aggressive lepromatous form most often do not display a DTH reaction to Mycobacterium leprae, and test negative with a lepromin skin test. They have an anergy reaction to Mycobacterium leprae, i.e. they do not display a CMI (T cell) reaction. The reason for this anergy reaction is that M leprae has been successful in suppressing the infected hosts T cell population. No granulomas are formed, there are low levels of inflammation, and high numbers of infecting bacteria. These bacteria go on to cause extensive tissue damage, including loss of extremities (fingers, toes, nose, etc).
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