Abstract
Research on the pathogenesis of tuberculosis (TB) has been hamstrung for half a century by the paradigm that granulomas are the hallmark of active disease. Human TB, in fact, produces two types of granulomas, neither of which is involved in the development of adult type or post-primary TB. This disease begins as the early lesion; a prolonged subclinical stockpiling of secreted mycobacterial antigens in foamy alveolar macrophages and nearby highly sensitized T cells in preparation for a massive necrotizing hypersensitivity reaction, the Koch Phenomenon, that produces caseous pneumonia that is either coughed out to form cavities or retained to become the focus of post-primary granulomas and fibrocaseous disease. Post-primary TB progresses if the antigens are continuously released and regresses when they are depleted. This revised paradigm is supported by nearly 200 years of research and suggests new approaches and animal models to investigate long standing mysteries of human TB and vaccines that inhibit the early lesion to finally end its transmission.
Highlights
Improved understanding of the pathogenesis of tuberculosis (TB) tops most lists of needs for developing more effective vaccines and therapies [1]
Granulomas are almost universally considered the hallmark of TB and cavities are thought to arise by erosion of granulomas into bronchi. This concept arose from studies in animals in the late 20th century and has no support among investigators who studied the pathology of developing post primary TB (PPTB) [6,7,8,9]
These are the functions of primary TB and PPTB, respectively [7,9,77]
Summary
Improved understanding of the pathogenesis of tuberculosis (TB) tops most lists of needs for developing more effective vaccines and therapies [1]. Granulomas are almost universally considered the hallmark of TB and cavities are thought to arise by erosion of granulomas into bronchi This concept arose from studies in animals in the late 20th century and has no support among investigators who studied the pathology of developing post primary TB (PPTB) [6,7,8,9]. As stated by Robert North, “A central problem in tuberculosis research is to explain why immunity to infection does not enable mice, guinea pigs, rabbits or susceptible humans to resolve lung infection and thereby stop development of the disease” [18]. Using chemotherapy or vaccines to reduce the MTB load in the lungs by 2 logs does not enable immunity to cause the much lower level of infection to resolve [18]
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