Nocardia-Induced Granulocyte Macrophage Colony-Stimulating Factor Is Neutralized by Autoantibodies in Disseminated/Extrapulmonary Nocardiosis

Nocardiosis is an opportunistic infection that generally occurs in immunocompromised patients, especially in those with phagocyte defects that are induced by systemic corticosteroids or seen in chronic granulomatous disease [1]. However, there remain some patients with nocardiosis for whom no defect has been found. Nocardia's proclivity for central nervous system involvement has been long appreciated [2], although the mechanisms underlying this remain obscure. Anticytokine autoantibodies are an emerging cause of adult-onset immunodeficiency [3]. Neutralizing anti–interferon gamma (IFN-γ) autoantibodies have been identified in the context of severe disseminated opportunistic infections [4]; anti–interleukin (IL) 17A, anti–IL-17F, and anti–IL-22 autoantibodies in association with and chronic mucocutaneous candidiasis [5, 6]; anti–IL-6 autoantibodies in the setting of staphylococcal skin infections [7]; and recently, anti–granulocyte macrophage colony-stimulating factor (GM-CSF) autoantibodies in association with Cryptococcus gattii meningitis [8]. Anti–GM-CSF autoantibodies were first recognized as etiologic in most cases of pulmonary alveolar proteinosis (PAP), a rare lung disorder characterized by the accumulation of proteinaceous material within the alveoli [9] due to defective GM-CSF–dependent surfactant clearance by pulmonary macrophages [10]. It is now appreciated that these autoantibodies may also contribute to infection susceptibility in the absence of PAP [8, 11]. Abrogation of GM-CSF signaling, either by gene knockout in mice or neutralizing autoantibodies, impacts other phagocytic activities [12, 13] and increases susceptibility to infection with opportunists typically controlled by phagocytes, such as Nocardia species, Histoplasma, and Cryptococcus [9, 14–16]. These observations implicate a direct role for GM-CSF in host defense against these opportunists. The recognition of anti–GM-CSF autoantibodies in previously healthy patients with cryptococcal meningitis [8] prompted us to evaluate the plasma of healthy, human immunodeficiency virus (HIV)-uninfected and otherwise immunocompetent adults with disseminated/extrapulmonary nocardiosis.