Available online at www.annclinlabsci.org 365 Annals of Clinical & Laboratory Science, vol. 44, no. 4, 2014 Pathogenesis of Post Primary Tuberculosis: Immunity and Hypersensitivity in the Development of Cavities Robert L. Hunter1, Jeffrey K. Actor1, Shen-An Hwang1, Vadim Karev2, and Chinnaswamy Jagannath1 1Department of Pathology and Laboratory Medicine, University of Texas-Houston Medical School Houston, Texas, USA, and 2Scientific-Research Institute of Childhood Diseases of the Federal Medical and Biological Agency, Saint Petersburg, Russia Abstract. M. Tuberculosis (MTB) is an obligate human parasite even though humans are more resistant than any of the animals used for study. It is a human parasite because only humans develop post primary tuberculosis (TB) in their lungs that mediates transmission of infection to new hosts. The extreme paucity of human lung tissue with post primary TB has forced scientists to study animal models and human tissues that do not have the disease. Consequently, the unique features of post primary TB remain largely unknown and misconceptions are widely accepted. This manuscript presents a revised pathogenesis of post primary TB based on studies of lung tissues of thousands of patients by multiple authors and related literature. Pri- mary TB stimulates systemic immunity that kills organisms and heals granulomas resulting in both protec- tion from disseminated TB and resistance to new infection. Post primary TB, in contrast, requires systemic immunity that it subverts to produce local susceptibility in the apex of the lung. It begins in the part of lung with the lowest ventilation, perfusion and movement and then proceeds to paralyze alveolar macrophages, block the exits and suppress inflammation to further isolate the area with post obstructive pneumonia. This ovpr ides a safe place for a small number of MTB to drive prolonged accumulation of host lipids and mycobacterial antigens in an otherwise immune person. After many months, the affected lung suddenly undergoes caseation necrosis with vanishingly few MTB. The necrotic tissue fragments to produce a cavity or hardens to develop fibrocaseous disease. Evidence suggests that this is triggered by a hypersensitivity reac- tion against cord factor and then progresses as the Koch phenomenon against many antigens. MTB grow in perfusion only in dead tissue or on a cavity wall. We anticipate that a more accurate understanding of the pathogenesis of post primary TB will facilitate focusing modern technologies to produce rapid advances in understanding and combating TB. Keywords: Pulmonary tuberculosis, Mycobacterium tuberculosis, Pathogenesis, Pathology, Cavity and Lung Introduction Immunity to TB is different from that of any other infection. The enigma of MTB is that it is an obli- Tuberculosis (TB) remains an urgent global health gate human parasite even though humans are more problem with approximately 9 million new cases resistant than any of the animals used for study. It is and 1.4 million deaths each year [1]. A very large a human parasite because only humans develop number of people are latently infected with post primary disease in their lungs [2,3]. Post pri- Mycobacterium tuberculosis (MTB) and at risk of mary TB produces cavities that support prolifera- developing disease in coming decades. The dual tion of vast numbers of MTB in an otherwise im- pandemic of TB and HIV/AIDS and the emer- mune host. Transmission is accomplished by gence of increasingly drug-resistant strains severely coughing MTB into the environment. aggravate the problem and hamper control efforts. While much progress has been made in under- Address correspondence to Robert L Hunter MD, PhD; Professor; standing granulomas produced by animals, little or Department of Pathology and Laboratory Medicine, MSB 2.034, University of Texas-Houston Medical School, 6431 Fannin Street, no progress has been made in understanding the Houston, TX 77030; phone: 713 500 5301; fax: 713 500 0730; e-mail: [email protected] peculiarities of post primary TB that occur only in humans [4]. Unanswered questions include: What 0091-7370/14/0400-365. © 2014 by the Association of Clinical Scientists, Inc. 366 Annals of Clinical & Laboratory Science, vol. 44, no. 4, 2014 is the nature of immunity that protects 95% of followed by discharge of infected necrotic material people from disease? Why does recovery from post into the airways. Recognizing that this is an apt de- primary TB make people more susceptible to new scription of the disease produced by M. bovis, post primary infections, but not to other types of Medlar examined thousands of tubercles looking TB? [5,6]. Why does it occur only in the lung? for evidence of a similar pathogenesis in humans. What is the role of hypersensitivity? He found none [12]. Once formed, all human MTB granulomas remained small. Recent research has served to deepen the mystery. Unlike HIV that modifies its antigens to evade im- In the pre antibiotic era, multiple investigators, mune responses, MTB keeps its antigens remark- each of whom had studied over 1000 cases of adult ably constant with even less variation than essential TB, reported that MTB spread through bronchi to structural genes [7]. Why does TB need exactly produce tuberculous pneumonia that underwent these epitopes? Failure to answer these questions caseation and then cavitation [9-14]. Rich reported has frustrated leaders in the field who increasingly “It has been found by all who have studied early believe that TB can never be eliminated without a pulmonary lesions that they represent areas of case- vaccine that prevents transmission of infection [8]. ous pneumonia rather than nodular tubercles.” Lack of understanding of the immunology and [10]. There was much speculation as to what seeded pathogenesis of late stage TB is widely regarded as the pneumonia [15]. Rich believed that small erod- the major impediment to vaccine development. ed granulomas released MTB into bronchi. One can neither rationally design nor test vaccine However, it was universally recognized that devel- candidates without knowledge of the type of im- oping post primary TB was a pneumonic, not a munity needed for protection. granulomatous process. Since human lung tissue with developing cavitary Interest in TB declined with the introduction of an- TB has seldom been available since the introduc- tibiotics in the 1950s. It resumed with resurgence tion of antibiotics in the 1940’s, researchers have of the disease in the 1980’s with a new generation been forced to rely on animal models. Unfortunately, of investigators armed with new technologies and nearly all animals eventually die of primary infec- animal models. The rabbit infected with M. bovis tion that most humans clear in weeks. Consequently, was the only common laboratory animal in which research on animals is producing a detailed under- chronic fibrosing TB with cavities could be readily standing of the early phases of TB. However, with- produced [15]. However, the lesions and life cycle out human tissues for reference, modern science of M. bovis are different from those of MTB. M. has not been able to develop models or studies to bovis must be transmitted to new hosts during the approach the late stages of infection that account lifetime of a cow, not the 10-30 years of MTB in for 80% of clinical disease and nearly 100% of people. M. bovis does not produce post primary TB transmission to new hosts. [3,16]. It remains a particularly aggressive form of primary TB with widespread development of case- The pathology of pulmonary TB has a long history. ating granulomas that erode into surfaces of the Two distinct types of pathology, ‘productive’ and pharynx, bronchi, pleura, GI, urinary tracks and ‘exudative’, were recognized by Laennec in 1821 mammary glands to discharge organisms [17]. The and confirmed by virtually all investigators through differences between lesions produced by MTB and the mid 20th century [9-14]. In modern terms ‘pro- M. bovis were forgotten [3]. As a consequence, the ductive’ refers to nodular tubercles or granulomas concept that the caseating granuloma is the charac- and ‘exudative’ refers to pneumonia. Multiple at- teristic lesion of both primary and post primary TB tempts to explain the pathogenesis of these process- became the bed rock paradigm that has guided TB es were published in the late 19th and early 20th research throughout the rise of cellular immunolo- centuries. Some investigators proposed the mecha- gy, molecular microbiology and genetics. This pa- nism that is widely accepted today, that cavities de- per challenges that paradigm. velop by erosion of granulomas into bronchi Pathogenesis of Post Primary Tuberculosis 367 Figure 1. Characteristics of primary and post pri- mary TB [3, 21]. A. X-ray of primary TB as a discrete round lesion in an upper lobe of lung. B. Cluster of caseating gran- ulomas of primary TB that were mistaken for cancer and resected (H&E 3x). C. Caseating granuloma of miliary TB composed primarily of macrophages and lym- phocytes with central ca- seous necrosis (H&E 40x). D. X-ray of acute post primary TB showing diffuse infiltrate of tuber- culous pneumonia in an upper lobe. E. Section of lung with caseous pneu- monia and developing cavities. No active granu- lomas were present any place in this persons body (H&E 3x). F. Endogenous lipid pneumonia of early post primary TB. The in- fection is confined to al- veolar spaces and has very few AFB(H&E 100x). Reproduced in part from Hunter et al [21] Our investigations in this area were initiated by the search for histologic slides of untreated pulmonary chance observation that injections of cord factor TB. Once we located slides so that we could see (trehalose 6, 6’-dimycolate (TDM)) into sensitized what the earlier investigators had described, the mice produced caseating granulomas [18]. This was pieces began falling together. Post primary TB be- a surprise since the literature had stated or decades gins as an endogenous lipid pneumonia, not as a that mice are a poor model of human TB because caseating granuloma, Figure 1 [21].