A 44-year-old man with a chronic cough and progressive weight loss comes to the emergency department. He has lost 5 kg (11 lb) over the past 3 months. The patient recently emigrated from Southeast Asia. Temperature is 37.4 C (99.3 F), blood pressure is 113/70 mm Hg, pulse is 78/min, and respirations are 18/min. Chest x-ray reveals an apical left lung infiltrate. Sputum Gram stain and cultures are negative. However, culture of a lung biopsy specimen grows acid-fast bacilli. Microscopy of the lung specimen is shown below.
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Which of the following processes is most likely to contribute to formation of the finding indicated by the arrow?
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This patient from Southeast Asia has weight loss, cough, and an apical infiltrate with acid-fast bacilli, raising strong suspicion for pulmonary tuberculosis. Mycobacterium tuberculosis is transmitted to the lungs via aerosolized droplets. It initially replicates in an unchecked fashion within the alveoli and alveolar macrophages due to virulence factors (eg, cord factor) that prevent macrophage-mediated destruction. After a few weeks, infected macrophages in the draining lymphatic system display mycobacterial antigens on major histocompatibility complex (MHC) class II molecules, leading to the stimulation of CD4 T lymphocytes.
Stimulated CD4 cells release interferon-gamma that activates macrophages, greatly increasing their ability to kill phagocytized organisms. Activated macrophages can also differentiate into epithelioid histiocytes and coalesce into multinucleated Langhans giant cells that wall off mycobacteria within granulomas. The center of the granuloma is acidic and hypoxic, which causes it to appear acellular, necrotic, and "cheese-like" (caseating). Granulomas typically limit mycobacterial proliferation but do not fully eliminate the infection.
Although Langhans giant cells are an important component of the immunologic response to pulmonary tuberculosis, they are a nonspecific finding that may also be present in other chronic infectious or inflammatory conditions (eg, sarcoidosis, Crohn disease).
(Choice A) Some intracellular bacterial pathogens (eg, Listeria, Rickettsia) have virulence factors that allow them to escape the phagosome and replicate within the cytosol. These pathogens are primarily processed by the proteasome (rather than the lysosome), leading to the display of bacterial protein fragments on MHC class I molecules. MHC class I molecules stimulate cytotoxic T cells (CD8 lymphocytes). In contrast, phagocytosed bacteria that remain within the phagosome (eg, M tuberculosis) are broken down by the lysosome and displayed on MHC class II molecules, which activate CD4, not CD8, cells.
(Choice B) Epstein-Barr virus attacks B lymphocytes and leads to long-term, latent infection that is typically asymptomatic but can occasionally lead to B-lymphocyte malignant transformation. Although malignant transformation can cause large, atypical cells, acid-fast bacilli would not be seen on culture.
(Choice C) Fibroblast proliferation and collagen production contribute to caseating granuloma formation but do not cause macrophage activation, which is necessary for the formation of multinucleated Langhans giant cells.
(Choice D) Neutrophils (polymorphonuclear cells) have multilobed nuclei that would be visible at this magnification. Neutrophils play a major role in early inflammation and elimination of extracellular bacterial pathogens (eg, Staphylococcus aureus). However, they are not the primary effector cell in the elimination of facultative intracellular pathogens such as M tuberculosis.
Educational objective:
Mycobacterium tuberculosis triggers CD4 T lymphocytes to release interferon-gamma, which leads to macrophage activation (improves intracellular killing ability) and differentiation into epithelioid histiocytes. These cells, along with horseshoe-shaped, multinucleated Langhans giant cells (fused, activated macrophages) are a key component of granuloma formation.