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• The human immune system
• Infection of the body by bacteria
• The inflammatory response
• Immune evasion by bacteria
• Kochs Postulates
• Bacteria
• Normal flora of the human body
• How are bacteria identified?
• Mycobacteria
• Immune reactions to mycobacteria
• Treatment mycobacteria with antibiotics
• Pathology of mycobacterial diseases

Immune reactions to mycobacteria.

Not all people or animals react in the same way to infection with mycobacteria. Instead, they display a whole spectrum of symptoms. The extreme ends of this spectrum are referred to as the "polar manifestations" of mycobacterioses. At one extreme, some infected people display only a Cell Mediated Immunity (CMI) reaction to the infecting mycobacterium and do not display a humoral reaction. This end of the spectrum is the contained form of mycobacterioses. At the other end of the spectrum, infected people display only a humoral reaction and do not display a CMI reaction. This end of the spectrum is the aggressive form of mycobacterioses.

Most people infected with mycobacteria do not display either of the extreme forms mentioned above, but display symptoms that are somewhere in between the two extremes. The position in the spectrum is determined by the strength of their CMI reaction to the infecting mycobacteria. Some mycobacteria are capable of interfering with the immune system of the infected host. For example, they may produce a toxin that interferes with the action of certain T cells, thus suppressing an appropriate T cell reaction to the infection.

The contained form.

Some mycobacteria, when they infect the human body, evade the defenses of the immune system by hiding inside macrophages. The normal function of macrophages is to ingest and destroy bacteria. But although macrophages are able to ingest mycobacteria, they are not always successful at destroying them. The mechanism by which mycobacteria evade destruction inside macrophages is unknown.

When macrophages fail to destroy the mycobacteria, the human immune systems next line of defense is to form granulomas around the infected macrophages. Layers of two different types of T cells surround the infected macrophage, sealing it inside a barrier from which it cannot escape. This barrier is known as a granuloma. Since the infecting mycobacteria is "contained" inside the granuloma, this form of mycobacterial disease is known as the contained form. Contained mycobacterial disease is typified by low numbers of infecting mycobacteria and high levels of inflammation.

T cells, which confer Cell Mediated Immunity (CMI), are responsible for the formation of these granulomas, hence the contained form of mycobacterial disease is a result of a CMI reaction. As mentioned above, some mycobacteria, notable M leprae (which causes leprosy) is capable of interfering with the T cell population of the infected host.

Individuals can be tested for a CMI reaction to mycobacteria by the means of a PPD skin test. PPD stands for Purified Protein Derivative. The subject mycobacteria are killed, using heat or ultrasound. The PPD for every mycobacterium is different. The PPD for M tuberculosis is called tuberculin, that for M leprae is called lepromin or leprosin, etc. In the test, the PPD of the mycobacterium to be tested is injected under the skin of the patient. The site of injection is then checked one or two days later. If the skin around the injection site is inflamed, or has formed a granuloma, then this shows that the patient is either currently infected or has previously been infected with the mycobacterium. Because the reaction only shows up after a day or two, this type of reaction is called Delayed Type Hypersensitivity (DTH). Failure to display a DTH reaction, as tested with a PPD skin test, is known as an anergy reaction.

The aggressive form.

If the CMI reaction fails and the infecting mycobacteria are not contained inside granulomas, the infected person is then reliant upon the humoral immunity reaction, which is conferred by B cells. B cells can only act upon infecting bacteria if they are extracellular (i.e. outside cells) and thus are ineffective against mycobacteria that are inside hiding inside macrophages.

If both the CMI (T cell) and humoral (B cell) reactions of an individual are unable to control the infecting mycobacteria, then that individual is defenseless against the mycobacteria, and the population of mycobacteria will grow unchecked, potentially causing extensive damage to the infected hosts body. This form of mycobacteriosis is categorised as the aggressive form. Aggressive mycobacterial disease is typified by high numbers of infecting mycobacteria and little or no inflammation.

Leprosy.

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).

Paratuberculosis.

Paratuberculosis in animals can have a dual presentation, with animals displaying a clinical spectrum ranging from the contained to the aggressive forms. See the reference "Description and classification of different types of lesion associated with natural paratuberculosis infection in sheep", which describes this clinical spectrum of presentations in sheep. Paratuberculosis also has a dual-presentation in cattle:- "Immunology: resistance to paratuberculosis".

Tuberculosis.

Tuberculosis, caused by the obligate pathogen Mycobacterium tuberculosis, is an another mycobacterial disease with a contained/aggressive spectrum of presentation.

• Sufferers of the contained form of tuberculosis display Delayed Type Hypersensitivity to Mycobacterium tuberculosis, and test positive with a tuberculin skin test. There is extensive formation of granulomas, with high levels of inflammation and low numbers of infecting bacteria.
• Sufferers of the aggressive form of tuberculosis do not display a DTH reaction to Mycobacterium, and test negative with a tuberculin skin test. No granulomas are formed, there are low levels of inflammation, and high numbers of infecting bacteria. These high degree of infection, if untreated, will almost certainly end in the death of the infected individual.

  M tuberculosis is not known to interfere with the T cell population of the infected host. Therefore, sufferers of the aggressive form of tuberculosis are usually people who are immunocompromised, i.e. their immune systems have been suppressed in some way. The people who most often suffer from the aggressive form of tuberculosis are individuals infected with HIV (Human Immunodeficiency Virus). HIV suppresses the T cell population in AIDS patients, who are then unable to mount a CMI reaction to Mycobacterium tuberculosis.

  See the references "Mycobacterium tuberculosis infection in AIDS" and "Disseminated tuberculosis in the AIDS era" for evidence of the existence of the aggressive form of tuberculosis.

Buruli Ulcers.

Buruli Ulcers, named after a region of Uganda that suffered an epidemic of this disease, are caused by the opportunistic pathogen, Mycobacterium ulcerans. The Purified Protein Derivative of Mycobacterium ulcerans is known as burulin.

With buruli ulcers, most patients experience both the contained and aggressive forms. After initial infection with Mycobacterium ulcerans, most patients do not mount a CMI reaction, and the mycobacterium grows uncontrolled, causing extensive tissue damage. The patient does not display display Delayed Type Hypersensitivity to Mycobacterium ulcerans, i.e. has an anergy reaction, and will test negative with a burulin skin test.

For some unknown reason, this anergy reaction eventually ends, and the patient then mounts a CMI reaction, which contains the infection through the formation of granulomas. The patient will then test positive with a burulin skin test.

Mycobacterium ulcerans is unique among mycobacteria, in that it produces a toxin that causes tissue death. No other mycobacterium is known to produce toxins. This toxin may be responsible for suppressing the T cell reaction of the infected host, thus leading to the aggressive form of disease in the initial stages.

Anergy reactions.

The aggressive form of mycobacterial disease, and indeed many other bacterial diseases, is caused by a failure of the CMI response of the host. There are many possible reasons for this failure. To see some of the possible reasons, see the page "Anergy to Mycobacterium paratuberculosis".