Immunology of tuberculosis Introduction It

Immunology of tuberculosis

Introduction : * It is estimated ﻣﻘﺪﺭ that almost 2 billion people worldwide are infected with M. tuberculosis. * T. B. is an example of an infection in which protective immunity & pathologic hypersensitivity coexist ﺍﻟﻤﻨﺎﻋﻪ ﺍﻟﻤﻔﺮﻃﻪ ﺗﻮﺟﺪ ﻣﻊ ﺍﻻﺻﺎﺑﻪ ﺍﻟﺒﻜﺘﻴﺮﻳﻪ ﻣﻤﺎ ﻳﺴﺒﺐ ﻣﺸﺎﻛﻞ ﺯﻳﺎﺩﻩ , and the lesions ﺍﻟﺘﻘﺮﺣﺎﺕ are caused mainly by the host response ﺍﺳﺘﺠﺎﺑﻪ ﺍﻟﻌﺎﺋﻞ ) ﻣﻨﺎﻋﻪ ﺍﻟﺸﺨﺺ ( ﺍﻟﻤﺼﺎﺏ

* The incidence ﺣﺪﻭﺙ ﺍﻟﻤﺮﺽ has recently been increasing due to : * emergence ﻭﻇﻬﻮﺭ of antibiotic resistant strains ﺍﺟﻨﺎﺱ ﻣﻘﺎﻭﻣﻪ ﻟﻠﻤﻀﺎﺩﺍﺕ * Increased incidence of immunodeficiency caused by HIV infections * immunosuppressive therapy

mode of transmission : ﻃﺮﻳﻘﻪ ﺍﻻﻧﺘﻘﺎﻝ infection is acquired by inhalation of M. tuberculosis in aerosols ﺭﺫﺍﺫ and dust ( airborne transmission ﻛﺎﺋﻨﺎﺕ ﻣﺤﻤﻮﻟﻪ ) ﺑﺎﻟﻬﻮﺍﺀ

infected people cough up large numbers of mycobacteria into the environment the organisms have waxy outer coats therefore can withstand drying and survive for long periods in air and house dust.

airborne transmission by inhalation of droplets from a cough or sneeze.

Primary infection ( : ﺍﻻﺻﺎﺑﻪ ﺍﻻﻭﻟﻰ ) ﺍﻭﻝ ﻣﺮﻩ ( i. e. infections in individuals for the first time ). organisms are inhaled from air or dust. engulfed by alveolar macrophages. ( non- resident ﺍﻟﻐﻴﺮ ﻣﻘﻴﻤﻪ ﺑﺎﻟﺮﺋﻪ macrophages are also attracted ) macrophages ingest the pathogens and carry them via the lymphatics to the local (hilar )ﻧﻮﻉ ﻣﻦ ﺍﻟﻌﻘﺪﺍﻟﻠﻤﻔﺎﻭﻳﻪ ﺑﺎﻟﺮﺋﻪ lymph nodes

Mycobacterium tuberculosis stimulate macrophages by binding Toll-like receptors. - these receptors recognize mycobacterial lipoproteins and polysaccharides this stimulate phagocytosis. secretion of cytokines

Mycobacteria persist ﺗﺪﻭﻡ inside macrophages : - waxy coat block the effect of phagocyte enzymes -they also secrete catalase which prevent the effects of the respiratory burst - macrophages seal off ﺗﺤﺒﺴﻬﺎ ﻭﺗﻤﻨﻌﻬﺎ ﻣﻦ ﺍﻟﺨﺮﻭﺝ mycobacteria inside phagososmes

Mycobacterial peptides presented by macrophages elicit ﻳﺴﺒﺐ strong T helper (TH 1) response activated T-cells secrete cytokines ﺍﻟﻠﻲ ﻓﻲ ﺍﻟﻤﺮﺑﻌﺎﺕ ﻟﻠﻘﺮﺍﺀﻩ ﻓﻘﻂ ﻏﻴﺮ ﻣﻄﻠﻮﺑﻪ tumor necrosis factor interferon-gamma (TNF) (IFN) ﻣﻦ ﺍﻟﻘﺎﻣﻮﺱ A protein that is produced in the presence of an endotoxin, especially by monocytes and macrophages, is able to attack and destroy tumor cells, and exacerbates chronic inflammatory diseases. IFN-γ A 21 -25 k. D glycoprotein lymphokine encoded on chromosome 12 q and produced by activated T and NK cells; IFN-γ is antiviral, regulates class II MHC antigen expression, Fc receptors and immunoglobulin production and class switching, activates monocyte cytotoxicity and enhances NK cell activity

By 6 -8 weeks after infection : Macrophages localize in the draining ﺟﺎﻓﻪ lymph nodes CD 4 T-cells become activated and secrete IFN-gamma ( CD 8 T-cells become activated later ) ( IFN ) activate (infected) macrophages (to enhance their ability to kill phagocytosed bacilli) because it is hard to kill them mycobacteria are sealed ﻣﻐﻠﻖ ﻋﻠﻴﻬﺎ in phagososmes

activated T-cells and activated macrophages secrete tumor necrosis factor (TNF). TNF play a role in: 1. local inflammation 2. further macrophage activation The resulting T-cell reaction (CMI) is adequate to control bacterial spread ( bacilli are contained within tubercles – small granulomas )

DTH reactions : (delayed type hypersensitivity reactions) DTH reactions may occur as : 1. collateral ﺛﺎﻧﻮﻱ damage during a protective response to a microbe 2. DTH may be entirely pathologic as in certain autoimmune diseases

DTH reactions in tuberculosis : Chronic DTH reactions develop when the TH 1 response to mycobacteria activates macrophages but fails to eradicate ﻳﺒﻴﺪ – ﻳﻘﻀﻲ ﻋﻠﻰ phagocytosed microbes this will lead to: granulomatous inflammation which is a form of DTH reactions to the bacilli

In chronic DTH reactions macrophages undergo changes in response to cytokines : they develop increased cytoplasm. and become epithelioid cells they fuse to form multinucleated giant cells these cells surround the ingested bacilli to form part of the granuloma

Tuberculous granuloma.

Granulomas may undergo central necrosis (caseous necrosis) Necrosis result from macrophage products (lysosomal enzymes & reactive oxygen radicals) necrosis serve to eliminate infected macrophages and provide an anoxic ﻧﺎﻗﺼﻪ ﺍﻻﻛﺴﺠﻴﻦ environment in which bacilli cannot divide (even the tissue injury may serve a protective function)

outcome of primary infection depend on immune state of the individual. 1. complete healing 2. progressive infection 3. excessive response to primary infection 4. post primary (reactivation)

outcome of primary infection : In most patients ( 90%), primary infection heal to to leave a small visible scar on radiograph (mycobacteria remain alive inside macrophages) this is called : the Ghon (or primary) complex

The Gohn complex consist of : The lung lesions (tubercles –small granulomas) plus the enlarged lymph nodes tubercles may heal become fibrotic or calcified and persist ﺗﺪﻭﻡ as such for a lifetime show up on chest x- ray as radio-opaque nodules

In individuals with impaired immunity : mild immunodeficiency lead to reactivation, usually in the apices of the lung severe immunodeficiency leads to more widespread infection beyond the lungs

In patients with excessive TNF production , lesions can break down leading to open T. B. In a small proportion of young patients, widespread primary T. B. occur. may present as : 1 - miliary T. B : ﻣﻦ ﺍﻟﻘﺎﻣﻮﺱ Miliary tuberculosis. Tuberculosis TB that has disseminated throughout the body, especially the lungs; the minute, millet seed-sized lesions ﻫﺬﺍ ﺍﻟﻨﻮﻉ ﻳﻨﺘﺸﺮ ﺣﻮﻝ ﺍﻟﺠﺴﻢ 2 - ( or) tuberculous meningitis

Outcome of primary infection : - 5% progressive infection - 90 % remain asymptomatic - 5% reactivation

Reactivation of dormant ﻛﺎﻣﻦ mycobacteria is usually a consequence of impaired immune function resulting from : 1. malnutrition. ﻧﻘﺺ ﺗﻐﺬﻳﻪ 2. infection (e. g. AIDS ). 3. chemotherapy for treatment of tumors. 4. corticosteroids ﺍﺳﻢ ﻫﺮﻣﻮﻥ for treatment of inflammatory disease.

Test for immunity against T. B. (Delayed hypersensitivity skin test. ) The delayed hypersensitivity skin test asses immunologic memory to mycobacteria (T-cell recall response) The test is known as : Tuberculin test, or (Mantoux) The test is carried out with Intradermal ﺗﺤﺖ ﺍﻟﺠﻠﺪ injection of PPD. (purified protein derivative )ﺍﻟﻤﺸﺘﻖ ﺍﻟﺒﺮﻭﺗﻴﻨﻲ ﺍﻟﻤﻨﻘﻰ

The tuberculin test : - Toll-like receptors on dermal macrophages recognize mycobacteria and secrete : TNF & Chemokines. - Dendritic cells (loaded with mycobacterial antigen) migrate from site of injection to draining lymph nodes & activate primed T-cells

Activated T-cells subsequently migrate to injection site and interact with activated macrophages. The cytokines released produce : erythema ﺣﻤﺮﻩ and induration at the site. - positive test may be due to : - BCG vaccination ﺍﺳﻢ ﻟﻘﺎﺡ ﺍﻟﺘﻲ ﺑﻲ - recent exposure to T. B. - negative test may suggest immunodeficiency (secondary to HIV)

Tuberculin test : after intradermal injection of PPD measure diameter of induration after 48 hours

ﺍﻻﺧﺘﺒﺎﺭ ﺍﻟﺜﺎﻧﻲ Blood test for T. B. exposure. The blood test measures interferon – gamma secreted in response to mycobacterial antigen - mycobacterial peptides are added to the patients blood which is then incubated for 12 hours - the amount of (IFN) produced is then measured by ELISA test

Prevention : 1. immunoprophylaxis ﻭﻗﺎﻳﻪ ﻣﻨﺎﻋﻴﻪ ﺗﺴﻤﻰ vaccination ﺗﻄﻌﻴﻢ 2. chemoprophylaxis anti- tuberculous drugs ﺍﺩﻭﻳﻪ ﻣﻀﺎﺩﻩ

Immunoprophylaxis : B. C. G. Vaccine ( Bacillus Calmette Guerin ). A live attenuated non-virulent strain of M. bovis - BCG has been used effectively in situations where tuberculosis is prevalent - Immunization does not prevent infection but allow the body to react quickly to limit proliferation of the organism

* In areas of low prevalence immunization has largely been replaced by chemoprophylaxis * After BCG vaccination the skin test cannot be used as an effective monitor of exposure to M. tuberculosis.