CLINICAL EXAMPLE 2-1

Primary and secondary response to tuberculosis The afferent phase of the primary response begins after the inhalation of live organisms, which proliferate slowly within the lung. Alveolar macrophages ingest the bacteria and transport the organisms to the hilar lymph nodes, where the processing phase begins. Over the next few days, as T and B lymphocytes are primed, the hilar nodes become enlarged because of the increased number of dividing T and B lymphocytes as well as the generalized increased trafficking of other lymphocytes through the nodes. The effector phase begins when the primed T lymphocytes recirculate and enter the infected lung. The T lymphocytes interact with the macrophage-ingested bacteria, and cytokines are released that activate neighboring macrophages to differentiate into epithelioid cells and to fuse into giant cells, eventually forming caseating granulomas. Meanwhile, some of the effector T lymphocytes home to other lymph nodes throughout the body, where they become inactive memory T lymphocytes, trafficking and recirculating throughout the secondary lymphoid tissue.

A secondary response in the skin is the basis of the tuberculin skin test used to diagnose tuberculosis (TB).The afferent phase of the secondary response begins when a purified protein derivative (PPD) reagent (antigens purified from nontuberculous mycobacteria) is injected into the dermis. These antigens are taken up by dermal macrophages.

The secondary processing phase begins when these PPD-stimulated macrophages migrate into the draining lymph node, where they encounter memory T lymphocytes from the previous lung infection. This leads to reactivation of memory T lymphocytes.

The secondary effector phase commences when the reactivated memory T lymphocytes recirculate and home back into the dermis, where they encounter additional antigen and macrophages at the injection site, causing the T lymphocytes to become fully activated and release cytokines. Within 24–72 hours, the cytokines induce infiltration of additional lymphocytes and monocytes as well as fibrin clotting. This process produces the typical indurated dermal lesion of the TB skin test, called the tuberculin form of delayed hypersensitivity (DH). Some individuals, however, are not able to mount a robust DH immune response, explaining the situation of a negative PPD result in the face of active infection (anergy).

A disadvantage of skin testing is the need to examine the injection site 48–72 hours later. The interferon-gamma release assays (IGRAs) eliminate this disadvantage. In this testing method, peripheral blood is collected and exposed to specific M tuberculosis antigens. If a patient has been exposed to TB, circulating T lymphocytes that are TB antigen specific should be present. When exposed to TB antigen, the T cells release interferon gamma (IFN-γ), which can be measured either as the concentration of IFN-γ or as the number of cells releasing IFN-γ.