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Published on: June 27, 2011
Anti-GM-CSF autoantibodies in patients with cryptococcal meningitis
Lindsey B Rosen1, Alexandra F Freeman, Lauren M Yang
1Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Abstract:
Cryptococcal meningitis has been described in immunocompromised patients, as well as in those for whom no immune defect has been identified. GM-CSF regulates the function of phagocytes and pulmonary alveolar macrophages, critical elements in cryptococcal control. We performed clinical histories, immunological evaluation, and anticytokine autoantibody screening in four current patients with cryptococcal meningitis and identified and tested 103 archived plasma/cerebrospinal fluid samples from patients with cryptococcal meningitis. We assessed the ability of anti-GM-CSF autoantibody-containing plasmas to inhibit GM-CSF signaling. We recognized anti-GM-CSF autoantibodies in an otherwise healthy female with cryptococcal meningitis who later developed pulmonary alveolar proteinosis (PAP). Her diagnosis prompted screening of patients with cryptococcal meningitis for anticytokine autoantibodies. We identified seven HIV-negative patients with cryptococcal meningitis who tested positive for high-titer anti-GM-CSF autoantibodies. Two of the seven later developed evidence of PAP. Plasma from all patients prevented GM-CSF-induced STAT5 phosphorylation and MIP-1α production in normal PBMCs. This effect was limited to their IgG fraction. Anti-GM-CSF autoantibodies are associated with some cases of cryptococcal meningitis in otherwise immunocompetent patients. These cases need not have associated PAP.
Insights
Autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF) were found in immunocompetent patients with cryptococcal meningitis. These autoantibodies can impair GM-CSF signaling, contributing to fungal infections and sometimes pulmonary alveolar proteinosis.
Area of Science:
- Immunology
- Infectious Diseases
Background:
- Cryptococcal meningitis typically affects immunocompromised individuals.
- Granulocyte-macrophage colony-stimulating factor (GM-CSF) is crucial for controlling fungal infections, particularly by pulmonary alveolar macrophages.
Observation:
- A subset of HIV-negative patients with cryptococcal meningitis, who appeared otherwise immunocompetent, were found to have high-titer autoantibodies against GM-CSF.
- One patient initially diagnosed with cryptococcal meningitis later developed pulmonary alveolar proteinosis (PAP), prompting further investigation.
Findings:
- Autoantibodies targeting GM-CSF were identified in seven HIV-negative patients with cryptococcal meningitis.
- These autoantibodies were shown to inhibit GM-CSF signaling pathways, specifically blocking GM-CSF-induced STAT5 phosphorylation and MIP-1α production in peripheral blood mononuclear cells.
- The inhibitory effect was attributed to the IgG fraction of the patients' plasma.
Implications:
- The presence of anti-GM-CSF autoantibodies offers a potential explanation for cryptococcal meningitis in immunocompetent individuals.
- These findings suggest that screening for anti-GM-CSF autoantibodies may be beneficial in diagnosing cryptococcal meningitis in certain patient populations.
- The association highlights a potential link between anti-GM-CSF autoimmunity, cryptococcal infections, and the development of PAP, even in the absence of overt immune defects.
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