Anti–GM-CSF Autoantibodies in Patients with Cryptococcal Meningitis

Abstract

Background 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. Methods We performed clinical histories, immunological evaluation, and anticytokine autoantibody screening in 4 current patients with cryptococcal meningitis, and identified and tested 103 archived plasma/CSF samples from patients with cryptococcal meningitis. We assessed the ability of anti-GM-CSF autoantibody containing plasmas to inhibit GM-CSF signaling. Results We recognized anti-GM-CSF autoantibodies in an otherwise healthy female with cryptococcal meningitis who later developed pulmonary alveolar proteinosis. Her diagnosis prompted screening of patients with cryptococcal meningitis for anticytokine autoantibodies. We identified 7 HIV uninfected patients with cryptococcal meningitis who tested positive for high-titer anti-GM-CSF autoantibodies. Two of the 7 later developed evidence of PAP. Plasma from all patients prevented GM-CSF-induced STAT-5 phosphorylation and MIP-1α production in normal PBMC. This effect was limited to their IgG fraction. Conclusions Anti-GM-CSF autoantibodies are associated with some cases of cryptococcal meningitis in otherwise immunocompetent patients. These cases need not have associated pulmonary alveolar proteinosis.

Immunity against fungi

“…Some of these disorders respond clinically to mechanism-based immunotherapy with IFN-γ or IFN-α (142). Similarly, neutralizing IFN-γ and GM-CSF autoantibodies can underlie adult-onset acquired immunodeficiency characterized by endemic dimorphic fungal (143) and CNS cryptococcal disease (144). Patients with alveolar proteinosis due to impaired GM-CSF signaling develop aspergillosis (145), consistent with murine studies (146).…”

The Tumor Antigen Cyclin B1 Hosts Multiple CD4 T Cell Epitopes Differently Recognized by Pre-Existing Naive and Memory Cells in Both Healthy and Cancer Donors

“…7 (30, 31). As mentioned by Vella et al (30), the tumor Ag MUC-1 could also be the target of Abs in noncancer patients that could have been elicited by infection (56), as formally observed for GM-CSF autoantibodies (57). We cannot completely exclude a link between the anti-CCNB1 humoral response and the memory CCNB1-specific CD4 T cells that we detected in the short-term T cell assays, but there was no correlation between T and B cell responses.…”

Cryptococcus gattii Infections

“…Patients with C. gattii infection may have subtle defects in immune function (276,279). Marr et al reported IgG2 antibody deficiency in one such patient (280).…”

“…In another PNG study, neither leukocyte antigen class I nor class II phenotypes were associated with C. gattii infection, although there was a trend toward increased susceptibility in patients carrying the human leukocyte antigen B*5601 (275). Recently, high levels of certain anticytokine antibodies (e.g., anti-granulocyte-macrophage colony-stimulating factor [GM-CSF] antibodies) were associated with cryptococcosis in HIV-negative patients (276). These antibodies predispose individuals to opportunistic infections by impairing innate immunity and may be especially relevant among HIV-negative patients in Asia (277,278).…”