Clinical and immunologic features of an atypical intracranial mycobacterium avium complex (MAC) infection compared with those of pulmonary MAC infections

Abstract

Members of the Mycobacterium avium complex (MAC) may cause chronic pulmonary infections in otherwise healthy elderly persons but rarely invade parts of the body outside of the lungs in immunocompetent hosts. We present a case of an isolated intracranial MAC infection in an apparently immunocompetent individual and review previous reports. We studied the T-cell and monocyte responses in healthy volunteers, individuals with a pulmonary MAC infection, and one individual with an isolated intracranial MAC infection. Genomic DNA from the individual with the brain MAC infection was studied for gamma interferon (IFN-gamma) receptor mutations. Individuals with localized pulmonary MAC infections showed increased activation of monocytes and enhanced monocyte and T-cell tumor necrosis factor alpha (TNF-alpha) production in response to lipopolysaccharide and MAC antigens but defects in T-cell IFN-gamma secretion. The individual with an intracranial MAC infection showed a lack of monocyte activation and deficiencies in both monocyte and T-cell TNF-alpha production and monocyte interleukin-12 (IL-12) production but had preserved T-cell IFN-gamma production. Mutations or deletions in the IFN-gamma receptor were not detected in the individual with the intracranial MAC infection. Our data suggest that distinct immune defects characterize two different manifestations of MAC infection. A relative defect in IFN-gamma production in response to MAC may predispose an individual to localized but partially controlled lung disease, whereas defects leading to reduced IL-12 and TNF-alpha production may allow the dissemination of MAC. Further studies delineating the potential role of TNF-alpha in limiting the spread of MAC outside the lung are warranted.

FIG. 1.

A contrast-enhanced head computed tomography of index patient revealed a ring enhancing lesion in the left frontal lobe (a). Microscopic examination of the brain biopsy specimen revealed multiple foci of spindle cell pseudotumor formation, consistent with a poorly developed granulomatous response (b). Ziehl-Neelsen stains of the biopsy specimen demonstrate a large number of acid-fast bacilli (c).

FIG. 2.

Production of TNF-α and IL-10 by antigen-stimulated CD14 monocytes. PBMCs from patients with pulmonary MAC infections (n = 3), an intracranial MAC infection (n = 1), and healthy controls (n = 4) were incubated ex vivo with LPS (a) or heat-killed MAC antigen (b) for 6 h in the presence of brefeldin A. The cells were then harvested, stained for CD14, and then permeabilized and stained for cytokines. Intracellular cytokine expression within CD14 gated cells was subsequently measured by flow cytometry, as described in the text. Mean values ± standards deviations are shown. *, P < 0.05 for patients with pulmonary MAC infections compared with the results for the healthy controls; **, P < 0.01 for patients with pulmonary MAC infections compared with the results for the healthy controls.

FIG. 3.

Production of TNF-α, IFN-γ, and IL-10 by antigen-stimulated T cells. T cells from patients with pulmonary MAC infections (n = 3), an intracranial MAC infection (n = 1), and healthy controls (n = 4) were incubated with antibodies to CD3 and CD28 (a) or heat-killed MAC antigen (b and c) for 6 h in the presence of brefeldin A. The cells were harvested and stained, and cytokine expression on gated CD3-positive cells was subsequently measured by flow cytometry, as described in the text. Representative data from the index patient, a healthy volunteer, and an individual with a localized pulmonary MAC infection are shown in panel b. In panel b, the values above the boxes indicate the percentage of CD3 staining cells expressing TNF-α In panels a and c, mean values ± standards deviation are shown. *, P < 0.01 for patients with pulmonary MAC infections compared with the results for the healthy controls; **, P < 0.05 for patients with pulmonary MAC infections compared with the results for the healthy controls.

FIG. 4.

Individuals with localized lung MAC infections may have an IFN-γ secretion defect in response to MAC antigen, and the patient with an intracranial MAC infection displays IL-12 deficiency in response to MAC antigen and LPS. The extracellular production of IFN-γ (a) and IL-12 (b) by MAC antigen-stimulated PBMCs was measured. PBMCs were isolated from patients with pulmonary MAC infections, a patient with an intracranial MAC infection, and healthy controls and were cultured with heat-killed MAC antigen and/or LPS. The cytokine concentrations within the supernatants were measured by enzyme-linked immunosorbent assay. Mean values ± standard deviations are shown.