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Need lung tissue from autopsies for studies of the pathogenesis of adult pulmonary tuberculosis


Robert Hunter May 1, 2012 11:37 AM
Posted in group: TBCohortCollaborators

 

The immediate goals are:

 

Establish scientific collaborations with pathologists who have access to autopsy specimens of lung tissue from people who died of untreated or inadequately treated pulmonary tuberculosis.   I would like to gain access to formalin fixed, paraffin embedded lung tissues from autopsies of people who die of tuberculosis for molecular and immunohistochemical studies. Using new multispectral imaging microscopes with advanced image analysis, it is possible to do precise quantitative studies on human histologic sections.  Such studies could be coordinated with studies on cohorts of patients proposed in this RFA.

 

Background

M. tuberculosis (MTB) produces two major types of infection, primary and postprimary. There are many models and much is known about primary tuberculosis in which the organisms become localized in caseating granulomas that usually resolve with developing immunity.  Postprimary tuberculosis, in contrast, remains poorly understood. It develops in the lungs of immunocompetent young adults with a high level of immunity and is responsible for 80% of all clinical disease and nearly 100% of transmission if infection. A central problem in tuberculosis research, therefore, is to explain why immunity to infection does not enable some adult humans to resolve lung infection and thereby stop development of the disease.

 

Understanding of the pathogenesis of post primary tuberculosis has remained largely beyond the reach of modern science because of misconceptions of its morphologic pathology. It has been a paradigm of contemporary literature that the caseating granuloma is the characteristic lesion of both primary and post primary tuberculosis and that cavities develop by erosion of caseating granulomas into bronchi. We recently reported that this is an apt description of the cavities produced by M. bovis, but not those produced by MTB. We studied of over 100 cases of untreated post primary tuberculosis and reviewed the literature from the preantibiotic era when human tissues were readily available. The conclusion is that post primary tuberculosis develops as an endogenous lipid pneumonia with infection limited to foamy alveolar macrophage in certain parts of the lungs in people with sufficient immunity to heal all caseating granulomas.

 

The lipid pneumonia of post primary tuberculosis may smolder for months before rapidly undergoing caseous necrosis to produce cavities in persons with no caseating granulomas anywhere in their bodies. Caseating granulomas are characteristic of primary tuberculosis and may develop in response to aging caseous pneumonia in post primary disease, but do not significantly contribute to cavity formation.

 

 With the demonstration that post primary tuberculosis begins as an infection of alveolar macrophages in people with sufficient immunity to heal caseating granulomas, key unresolved questions of adult tuberculosis shift away from caseating granulomas to  1) how MTB establish a privileged site within foamy alveolar macrophages in certain areas of the lung while the rest of the body remains highly immune, 2) what causes the pneumonia to undergo sudden necrosis to form cavities and 3) why don’t cavities heal?

 

References:

 

Hunter RL. Pathology of post primary tuberculosis of the lung: An illustrated critical review.   Tuberculosis (Edinb). 2011 Nov;91(6):497-509. Epub 2011 Jul 6.

 

Welsh KJ, Risin SA, Actor JK, Hunter RL. Immunopathology of postprimary tuberculosis: increased T-regulatory cells and DEC-205-positive foamy macrophages in cavitary lesions. Clin Dev Immunol. 2011;2011:307631. Epub 2010 Dec 21..

 

Hunter RL, Jagannath C, Actor JK.  Pathology of postprimary tuberculosis in humans and mice: contradiction of long-held beliefs. Tuberculosis (Edinb). 2007 Jul;87(4):267-78. Epub 2007 Mar 21.