A 34-year-old woman comes to the office for tuberculosis evaluation. The patient was advised to have tuberculosis testing after her father, who is visiting her family from Haiti, was found to have active pulmonary tuberculosis. She has no history of tuberculosis or any other chronic medical conditions and takes no medications. Tuberculin skin testing is performed and results 48 hours later are negative. Eight weeks later, the patient returns for follow-up and says she feels healthy and has had no fever, cough, shortness of breath, or weight loss. Physical examination shows no abnormalities. Repeat tuberculin skin testing reveals significant skin induration around the injection site at 48 hours. Chest radiograph shows no parenchymal opacities, pleural effusion, or enlarged lymph nodes. Which of the following effector cells are primarily responsible for immunologic control of this patient's infection?
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Mycobacterium tuberculosis is transmitted by aerosolized droplets from a patient with active pulmonary tuberculosis. Initially, the pathogen replicates in an unchecked fashion due to virulence factors (eg, cord factor) that allow the bacteria to escape destruction within the phagolysosomes of alveolar macrophages. After a few weeks, antigen-presenting cells in the draining lymphatic system display mycobacterial antigens on major histocompatibility complex class II molecules and release interleukin-12, which differentiates naïve CD4 cells into T-helper subtype-1 (Th1) cells.
Th1 cells migrate to the sites of infection and secrete interferon-gamma, resulting in the activation of macrophages. Activated macrophages are able to form fully mature phagolysosomes to destroy intracellular mycobacteria. They also differentiate into cells (eg, epithelioid, Langhans giant cells) that surround extracellular mycobacteria and form granulomas. Granulomas have an acidic, hypoxic central environment that limits the proliferation of mycobacteria but does not usually eliminate the infection.
Because the cell-mediated response to M tuberculosis takes several weeks to form, recently exposed patients frequently have a negative initial tuberculin skin test (as in this patient). Although most patients with primary tuberculosis have no symptoms and no chest x-ray findings, after several months, a Ranke complex (calcified lower lobe nodule and ipsilateral hilar lymph node) can often be seen on x-ray.
(Choice A) Facultative, intracellular organisms such as M tuberculosis are protected from antibodies and complement when within cells. As a result, elimination of these pathogens does not primarily rely on the humoral immune system (eg, B lymphocytes).
(Choice C) Neutrophils are a crucial immune component for control of most extracellular bacterial infections (eg, Streptococcus pneumoniae). However, macrophages are the more important effector cells for control of M tuberculosis and many other intracellular bacterial infections.
(Choice D) Intracellular organisms that replicate in the cytosol, such as viruses or certain intracellular bacteria (eg, Listeria), are processed by the proteasome and displayed on major histocompatibility complex (MHC) class I molecules. This leads to the activation of CD8 T lymphocytes. M tuberculosis primarily replicates within the phagosome (not the cytosol), leading to display of mycobacterial antigens on MHC class II molecules and the subsequent activation of CD4, rather than CD8, cells.
(Choice E) Natural killer cells are cytotoxic lymphocytes that can recognize damaged or infected cells without requiring MHC activation. They are important for clearing viral infections and for tumor immunosurveillance, but are not the primary effector cell in tuberculosis infection.
Educational objective:
Mycobacterium tuberculosis primarily replicates within the phagosome, leading to display of mycobacterial antigens on major histocompatibility complex class II molecules. This results in the activation of CD4 cells and subsequent control of the infection with macrophages.