Cryptococcus gattii Infection as the Major Clinical Manifestation in Patients with Autoantibodies Against Granulocyte-Macrophage Colony-Stimulating Factor.

PURPOSE: Anti-granulocyte-macrophage colony-stimulating factor autoantibodies (anti-GM-CSF Abs) are a predisposing factor for pulmonary alveolar proteinosis (PAP) and Cryptococcus gattii cryptococcosis. This study aimed to investigate clinical manifestations in anti-GM-CSF Ab-positive patients with C. gattii cryptococcosis and analyze the properties of anti-GM-CSF Abs derived from these patients and patients with PAP. METHODS: Thirty-nine patients diagnosed with cryptococcosis (caused by C. neoformans or C. gattii) and 6 with PAP were enrolled in the present study. Clinical information was obtained from medical records. Blood samples were collected for analysis of autoantibody properties. We also explored the National Health Insurance Research Database (NHIRD) of Taiwan to investigate the epidemiology of cryptococcosis and PAP. RESULTS: High titers of neutralizing anti-GM-CSF Abs were identified in 15 patients with cryptococcosis (15/39, 38.5%). Most anti-GM-CSF Ab-positive cryptococcosis cases had central nervous system (CNS) involvement (14/15, 93.3%). Eleven out of 14 (78.6%) anti-GM-CSF Ab-positive CNS cryptococcosis patients were confirmed to be infected with C. gattii, and PAP did not occur synchronously or metachronously in a single patient from our cohort. Exploration of an association between HLA and anti-GM-CSF Ab positivity or differential properties of autoantibodies from cryptococcosis patients and PAP yielded no significant results. CONCLUSION: Anti-GM-CSF Abs can cause two diseases, C. gattii cryptococcosis and PAP, which seldom occur in the same subject. Current biological evidence regarding the properties of anti-GM-CSF Abs cannot provide clues regarding decisive mechanisms. Further analysis, including more extensive cohort studies and investigations into detailed properties, is mandatory to better understand the pathogenesis of anti-GM-CSF Abs.

Pathogenic autoantibodies to IFN-γ act through the impedance of receptor assembly and Fc-mediated response.

Anti-interferon (IFN)-γ autoantibodies (AIGAs) are a pathogenic factor in late-onset immunodeficiency with disseminated mycobacterial and other opportunistic infections. AIGAs block IFN-γ function, but their effects on IFN-γ signaling are unknown. Using a single-cell capture method, we isolated 19 IFN-γ-reactive monoclonal antibodies (mAbs) from patients with AIGAs. All displayed high-affinity (KD < 10-9 M) binding to IFN-γ, but only eight neutralized IFN-γ-STAT1 signaling and HLA-DR expression. Signal blockade and binding affinity were correlated and attributed to somatic hypermutations. Cross-competition assays identified three nonoverlapping binding sites (I-III) for AIGAs on IFN-γ. We found that site I mAb neutralized IFN-γ by blocking its binding to IFN-γR1. Site II and III mAbs bound the receptor-bound IFN-γ on the cell surface, abolishing IFN-γR1-IFN-γR2 heterodimerization and preventing downstream signaling. Site III mAbs mediated antibody-dependent cellular cytotoxicity, probably through antibody-IFN-γ complexes on cells. Pathogenic AIGAs underlie mycobacterial infections by the dual blockade of IFN-γ signaling and by eliminating IFN-γ-responsive cells.

Anti-IFN-γ autoantibodies underlie disseminated Talaromyces marneffei infections.

Talaromyces marneffei causes life-threatening opportunistic infections, mainly in Southeast Asia and South China. T. marneffei mainly infects patients with human immunodeficiency virus (HIV) but also infects individuals without known immunosuppression. Here we investigated the involvement of anti-IFN-γ autoantibodies in severe T. marneffei infections in HIV-negative patients. We enrolled 58 HIV-negative adults with severe T. marneffei infections who were otherwise healthy. We found a high prevalence of neutralizing anti-IFN-γ autoantibodies (94.8%) in this cohort. The presence of anti-IFN-γ autoantibodies was strongly associated with HLA-DRB1*16:02 and -DQB1*05:02 alleles in these patients. We demonstrated that adult-onset acquired immunodeficiency due to autoantibodies against IFN-γ is the major cause of severe T. marneffei infections in HIV-negative patients in regions where this fungus is endemic. The high prevalence of anti-IFN-γ autoantibody-associated HLA class II DRB1*16:02 and DQB1*05:02 alleles may account for severe T. marneffei infections in Southeast Asia. Our findings clarify the pathogenesis of T. marneffei infection and pave the way for developing novel treatments.

A model for predicting risk of serious bacterial infection in febrile infants younger than 3 months of age.

BACKGROUND: The objective of this study was to construct a model for predicting the risk of serious bacterial infection (SBI) in febrile infants. METHODS: A total of 135 febrile infants younger than 3 months of age who met the inclusion criteria were assessed on the following: physical appearance, complete blood count, serum C-reactive protein (CRP), urinalysis, stool smears for white blood cell (WBC) count if diarrhea was apparent, and blood and urine cultures. Chest X-rays were performed if respiratory symptoms were evident. Cerebrospinal fluid was analyzed if central nervous system infection was suspected. RESULTS: Of the 135 infants, 34 were diagnosed with SBI. Data from 99 infants were used to construct a model for predicting SBI by multivariate logistic regression. Sex (male), spun urine WBC count (>or= 10 per high-powered field [400x]) and CRP (>or= 3.6 mg/L) were significantly related to SBI. A probability cut-off of 0.265 was selected, where values below and above the cut-off reflected low and high SBI risk respectively. Data from the remaining 36 infants were used to test model validity. Both sensitivity and specificity were 77.8% for predicting SBI using this model. CONCLUSION: These findings suggest that sex, serum CRP concentration and spun urine WBC count can be used to accurately predict SBI in febrile infants aged less than 3 months of age.

Placental weight and birth characteristics of healthy singleton newborns.

To determine the relationship of placental weight and birth characteristics of healthy Chinese singleton newborns, 552 consecutive singleton near-term and uncomplicated pregnancies were enrolled in a retrospective study from October 2000 to April 2001. Maternal age, infants' gender, gestational age, placental weight (PW), birth weight (BW), birth length (BL), cord length, ponderal index, and appearance of meconium-stained amniotic fluid or a nuchal cord were recorded and analyzed. Our results show that the mean value of BW was 3235 +/- 17 g, birth length was 48.8 +/- 0.1 cm, PW was 646.2 +/- 0.3 g, BW/BL was 66.2 +/- 0.3, BW/PW was 5.1 +/- 0.1, and ponderal index was 2.8 +/- 0.0, respectively. Male neonates had significantly larger BWs (p<0.05) and BLs (p<0.01) than did female neonates. However, there was no significant difference in PW between male and female neonates. PW was positively correlated with BW (r=0.413, p<0.01), BL (r=0.305, p<0.01), BW/BL (r=0.397, p<0.01), and cord length (r=0.264, p<0.01). The PW of studied infants showed no significant difference when grouped by gestational age, maternal age, presence of meconium stained amniotic fluid, or presence of a nuchal cord. Of the studied healthy neonate, 81.9% and 69.4% had no meconium-stained amniotic fluid or nuchal cord, respectively. There were no significant differences in PW or BW/PW between neonates with the presence or absence of meconium-stained amniotic fluid or a nuchal cord. These results indicate that PW has a significant role in fetal growth in terms of weight, body length, and cord length. Furthermore, it has no significant role in the presence of meconium-stained fluid or a nuchal cord in healthy neonates.