Anti-Granulocyte-Macrophage Colony-Stimulating Factor Autoantibodies Are a Risk Factor for Central Nervous System Infection by Cryptococcus gattii in Otherwise Immunocompetent Patients
Authors: Saijo Tomomi , Chen Jianghan , Chen Sharon C.-A. , Rosen Lindsey B. , Yi Jin , Sorrell Tania C. , Bennett John E. , Holland Steven M. , Browne Sarah K. , Kwon-Chung Kyung J. 
Published: March 2014

Cryptococcosis is caused by eitherCryptococcus neoformansorC. gattii. While cryptococcal meningoencephalitis is caused mostly byC. neoformansin immunocompromised patients, the risk factors remain unclear for patients with no known immune defect. Recently, anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies were detected in the plasma of seven “immunocompetent” cryptococcosis patients, and the cryptococcal strains from these patients were reported asC. neoformans(three strains),C. gattii(one strain), andCryptococcus(three strains not identified to the species level). We identified all three strains that had not been identified to the species level asC. gattii. Notably, the three strains that were reported asC. neoformansbut were unavailable for species confirmation originated from Sothern California and Thailand whereC. gattiiis endemic. Most clinical laboratories designateC. neoformanswithout distinguishing between the two species; hence, these three strains could have beenC. gattii. SinceC. gattiiinfects more immunocompetent patients thanC. neoformans, we pursued the possibility that this antibody may be more prevalent in patients infected withC. gattiithan in those infected withC. neoformans. We screened the plasma of 20 healthy controls and 30 “immunocompetent” patients with cryptococcal meningoencephalitis from China and Australia (multiple ethnicities). Anti-GM-CSF autoantibodies were detected only in the plasma of seven patients infected byC. gattiiand one healthy volunteer and in none infected byC. neoformans. While plasma from theseC. gattiipatients completely prevented GM-CSF-induced p-STAT5 in normal human peripheral blood mononuclear cells (PBMCs), plasma from one healthy volunteer positive for anti-GM-CSF autoantibodies caused only partial blockage. Our results suggest that anti-GM-CSF autoantibodies may predispose otherwise immunocompetent individuals to meningoencephalitis caused byC. gattiibut not necessarily to that caused byC. neoformans.

IMPORTANCECryptococcal meningoencephalitis is the most serious central nervous system (CNS) infection caused byCryptococcus neoformansorC. gattii.Cryptococcusprimarily infects immunocopromised patients but is also sporadically encountered in otherwise “immunocompetent” patients with no known risk. In a recent study, anti-GM-CSF autoantibodies were detected in the plasma of seven otherwise immunocompetent patients with cryptococcal meningoencephalitis. Four of seven (57%) cryptococcal isolates from these patients were identified asC. gattii, while three strains were unavailable for species confirmation. We collected plasma from 30 otherwise healthy patients with CNS cryptococcosis in China and Australia (multiethnic) and analyzed the samples for the presence of anti-GM-CSF autoantibodies. The results suggest that anti-GM-CSF autoantibodies are a risk factor for CNS infection byC. gattiibut notC. neoformans. GM-CSF may have a specific role in host defense againstC. gattii, thereby elevating the importance of determining the level of anti-GM-CSF autoantibodies which can impact clinical management.