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.
(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.
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.
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?
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.