The Upf1 protein restricts EV-A71 viral replication.

Enterovirus A71 (EV-A71) is transmitted through the respiratory tract, gastrointestinal system, and fecal-oral routes. The main symptoms caused by EV-A71 are hand, foot, and mouth disease (HFMD) or vesicular sore throat. Upf1 (Up-frameshift protein 1) was reported to degrade mRNA containing early stop codons, known as nonsense-mediated decay (NMD). Upf1 is also involved in the NMD mechanism as a host factor detrimental to viral replication. In this study, we dissected the potential roles of Upf1 in the EV-A71-infected cells. Upf1 was virulently down-regulated in three different EV-A71-infected cells, RD, Hela, and 293T, implying that Upf1 is a host protein unfavorable for EV-A71 replication. Knockdown of Upf1 protein resulted in increased viral RNA expression and production of progeny virus, and conversely, overexpression of Upf1 protein resulted in decreased viral RNA expression and production of progeny virus. Importantly, we observed increased RNA levels of asparagine synthetase (ASNS), one of the indicator substrates for the NMD mechanism, which indirectly suggests that EV-A71 infection of cells suppresses NMD activity in the host. The results shown in this study are useful for subsequent analysis of the relationship between the NMD/Upf1 mechanism and other picornaviruses, which may lead to the development of anti-picornavirus drugs.

Risk factors of Omicron variant associated acute encephalitis/encephalopathy in children.

BACKGROUND: Outbreak of Omicron BA.2 in Taiwan led to an increased number of acute encephalitis/encephalopathy cases in children and several fatal cases drew public attention. In pre-Omicron period, pediatric cases of COVID-19-associated acute encephalitis have been reported and during Omicron epidemic, febrile convulsions, encephalitis were mentioned more frequently. The outcome of patients with neurological complications was worse. However, few studies investigated the risk factors, pathophysiology and prognosis of COVID-19-associated encephalitis/encephalopathy. Here, we describe the presentation of pediatric cases of COVID-19-associated acute encephalitis/encephalopathy and explore the associated risk factors. METHODS: Pediatric patients with confirmed SARS-CoV-2 infections were prospectively enrolled at admission at Chang Gung Memorial Hospital between April and August 2022. Patients were categorized into groups of acute encephalitis/encephalopathy, febrile convulsions or mild disease. Demographic descriptions, clinical manifestations and laboratory data were collected. RESULTS: Of 288 acute COVID-19 patients, there were 38 (13.2%) acute encephalitis/encephalopathy, 40 (13.9%) febrile convulsions, and 210 (72.9%) mild disease. Among acute encephalitis/encephalopathy group, the mean age was 68.3 ± 45.0 months. The common neurological symptoms were lethargy (65.8%), seizures (52.6%), and impaired consciousness (34.2%). Over 3 years old (adjusted odds ratio [aOR]: 7.57, p < 0.001), absolute neutrophil count ≥3150/µL (aOR: 5.46, p = 0.008), and procalcitonin ≥0.5 ng/mL (aOR: 4.32, p = 0.021) were independent factors for acute encephalitis/encephalopathy. CONCLUSIONS: Most cases of COVID-19-associated acute encephalitis/encephalopathy showed no evidence of direct viral invasion but associations with older age, increased peripheral neutrophil, and serum procalcitonin. These findings may imply the neutrophil-mediated systemic inflammatory response plays an important role on central nerve system, leading to cerebral dysfunction.

Autoantibodies against type I IFNs in patients with critical influenza pneumonia.

Autoantibodies neutralizing type I interferons (IFNs) can underlie critical COVID-19 pneumonia and yellow fever vaccine disease. We report here on 13 patients harboring autoantibodies neutralizing IFN-α2 alone (five patients) or with IFN-ω (eight patients) from a cohort of 279 patients (4.7%) aged 6-73 yr with critical influenza pneumonia. Nine and four patients had antibodies neutralizing high and low concentrations, respectively, of IFN-α2, and six and two patients had antibodies neutralizing high and low concentrations, respectively, of IFN-ω. The patients' autoantibodies increased influenza A virus replication in both A549 cells and reconstituted human airway epithelia. The prevalence of these antibodies was significantly higher than that in the general population for patients <70 yr of age (5.7 vs. 1.1%, P = 2.2 × 10-5), but not >70 yr of age (3.1 vs. 4.4%, P = 0.68). The risk of critical influenza was highest in patients with antibodies neutralizing high concentrations of both IFN-α2 and IFN-ω (OR = 11.7, P = 1.3 × 10-5), especially those <70 yr old (OR = 139.9, P = 3.1 × 10-10). We also identified 10 patients in additional influenza patient cohorts. Autoantibodies neutralizing type I IFNs account for ∼5% of cases of life-threatening influenza pneumonia in patients <70 yr old.

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.

Measurements of Anti-SARS-CoV-2 Antibody Levels after Vaccination Using a SH-SAW Biosensor.

To prevent the COVID-19 pandemic that threatens human health, vaccination has become a useful and necessary tool in the response to the pandemic. The vaccine not only induces antibodies in the body, but may also cause adverse effects such as fatigue, muscle pain, blood clots, and myocarditis, especially in patients with chronic disease. To reduce unnecessary vaccinations, it is becoming increasingly important to monitor the amount of anti-SARS-CoV-2 S protein antibodies prior to vaccination. A novel SH-SAW biosensor, coated with SARS-CoV-2 spike protein, can help quantify the amount of anti-SARS-CoV-2 S protein antibodies with 5 µL of finger blood within 40 s. The LoD of the spike-protein-coated SAW biosensor was determined to be 41.91 BAU/mL, and the cut-off point was determined to be 50 BAU/mL (Youden's J statistic = 0.94733). By using the SH-SAW biosensor, we found that the total anti-SARS-CoV-2 S protein antibody concentrations spiked 10−14 days after the first vaccination (p = 0.0002) and 7−9 days after the second vaccination (p = 0.0116). Furthermore, mRNA vaccines, such as Moderna or BNT, could achieve higher concentrations of total anti-SARS-CoV-2 S protein antibodies compared with adenovirus vaccine, AZ (p < 0.0001). SH-SAW sensors in vitro diagnostic systems are a simple and powerful technology to investigate the local prevalence of COVID-19.

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.

Recommendations and guidelines for the treatment of infections due to multidrug resistant organisms.

Antimicrobial drug resistance is one of the major threats to global health. It has made common infections increasingly difficult or impossible to treat, and leads to higher medical costs, prolonged hospital stays and increased mortality. Infection rates due to multidrug-resistant organisms (MDRO) are increasing globally. Active agents against MDRO are limited despite an increased in the availability of novel antibiotics in recent years. This guideline aims to assist clinicians in the management of infections due to MDRO. The 2019 Guidelines Recommendations for Evidence-based Antimicrobial agents use in Taiwan (GREAT) working group, comprising of infectious disease specialists from 14 medical centers in Taiwan, reviewed current evidences and drafted recommendations for the treatment of infections due to MDRO. A nationwide expert panel reviewed the recommendations during a consensus meeting in Aug 2020, and the guideline was endorsed by the Infectious Diseases Society of Taiwan (IDST). This guideline includes recommendations for selecting antimicrobial therapy for infections caused by carbapenem-resistant Acinetobacter baumannii, carbapenem-resistant Pseudomonas aeruginosa, carbapenem-resistant Enterobacterales, and vancomycin-resistant Enterococcus. The guideline takes into consideration the local epidemiology, and includes antimicrobial agents that may not yet be available in Taiwan. It is intended to serve as a clinical guide and not to supersede the clinical judgment of physicians in the management of individual patients.

Life-Threatening Enterovirus 71 Encephalitis in Unrelated Children with Autosomal Dominant TLR3 Deficiency.

PURPOSE: Enterovirus A71 (EV71) causes a broad spectrum of childhood diseases, ranging from asymptomatic infection or self-limited hand-foot-and-mouth disease (HFMD) to life-threatening encephalitis. The molecular mechanisms underlying these different clinical presentations remain unknown. We hypothesized that EV71 encephalitis in children might reflect an intrinsic host single-gene defect of antiviral immunity. We searched for mutations in the toll-like receptor 3 (TLR3) gene. Such mutations have already been identified in children with herpes simplex virus encephalitis (HSE). METHODS: We sequenced TLR3 and assessed the impact of the mutations identified. We tested dermal fibroblasts from a patient with EV71 encephalitis and a TLR3 mutation and other patients with known genetic defects of TLR3 or related genes, assessing the response of these cells to TLR3 agonist poly(I:C) stimulation and EV71 infection. RESULTS: Three children with EV71 encephalitis were heterozygous for rare mutations-TLR3 W769X, E211K, and R867Q-all of which were shown to affect TLR3 function. Furthermore, fibroblasts from the patient heterozygous for the W769X mutation displayed an impaired, but not abolished, response to poly(I:C). We found that TLR3-deficient and TLR3-heterozygous W769X fibroblasts were highly susceptible to EV71 infection. CONCLUSIONS: Autosomal dominant TLR3 deficiency may underlie severe EV71 infection with encephalitis. Human TLR3 immunity is essential to protect the central nervous system against HSV-1 and EV71. Children with severe EV71 infections, such as encephalitis in particular, should be tested for inborn errors of TLR3 immunity.

A potent antibody-secreting B cell response to Mycoplasma pneumoniae in children with pneumonia.

BACKGROUND: Mycoplasma pneumoniae is a major pathogen for community-acquired pneumonia and frequently causes outbreaks in children. M. pneumoniae-specific antibody response is detected upon acute infection and the serology is widely used in the clinical setting. Nevertheless, the cellular basis for antigen-specific antibody response to acute M. pneumoniae infection is largely undetermined in children. METHODS: Hospitalized children with community-acquired pneumonia were enrolled and the infection with M. pneumoniae was confirmed with positive PCR result and negative findings for other pathogens. The M. pneumoniae P1-specific antibody-secreting B cell (ASC) response was examined with the ex vivo enzyme-linked immunosorbent spot assay and the relationships between the ASC frequency and serological level and clinical parameters within M. pneumoniae patients were studied. RESULTS: A robust M. pneumoniae P1-specific ASC response was detected in the peripheral blood among M. pneumoniae-positive patients. By contrast, no M. pneumoniae-specific ASCs were detected among M. pneumoniae-negative patients. The IgM-secreting B cells are the predominant class and account for over 60% of total circulating M. pneumoniae-specific ASCs in the acute phase of illness. The M. pneumoniae P1-specific ASC frequency significantly correlated with the fever duration, and the IgG ASC frequency significantly correlated with serological titer among patients. CONCLUSION: A rapid and potent elicitation of peripheral M. pneumoniae-specific ASC response to acute infection provides the cellular basis of antigen-specific humoral response and indicates the potential of cell-based diagnostic tool for acute M. pneumoniae infection. Our findings warrant further investigations into functional and molecular aspects of antibody immunity to M. pneumoniae.

Investigation of a cluster of Bacillus cereus bacteremia in neonatal care units.

BACKGROUND: Bacillus cereus is a well-known pathogen for self-limited foodborne illness, and rarely an opportunistic pathogen associated with invasive infections among immunocompromised patients. Nosocomial outbreaks have been rarely reported. METHODS: Between August and November 2019, four preterm neonates in neonatal care units of a medical center developed late-onset B. cereus bacteremia. An investigation was carried out. Forty-eight environmental specimens were obtained from these neonatal units, skin surface and environmental objects of Patient 4 for the detection of this organism 19 days after the onset of illness of Patient 4. B. cereus isolates from Patient 4, five unrelated patients and environmental objects if identified were further characterized by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). RESULTS: All four infants survived after vancomycin-containing treatment. Patient 4 developed diffuse cerebritis, brain abscess with severe neurologic sequelae. Of the 48 environmental samplings, 26 specimens showed positive for B. cereus, with one major clone (sequence type 365) accounting for 73%. The isolate from Patient 4 (ST427) was identical to one isolate collected from environmental objects in the same unit. After extensive cleaning of the environment and re-institution of the sterilization procedure of hospital linens, which was ceased since two months before the outbreak, no more cases was identified in these units for at least one year. CONCLUSIONS: We documented a cluster of B. cereus bacteremia involving four preterm infants, which might be associated with cessation of the procedure for linen sterilization and was successfully controlled by re-institution of this procedure.

A Novel Rapid Test to Detect Anti-SARS-CoV-2 N Protein IgG Based on Shear Horizontal Surface Acoustic Wave (SH-SAW).

Since the Coronavirus disease 2019 (COVID-19) pandemic outbreak, many methods have been used to detect antigens or antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including viral culture, nucleic acid test, and immunoassay. The shear-horizontal surface acoustic wave (SH-SAW) biosensor is a novel pathogen detection platform with the advantages of high sensitivity and short detection time. The objective of this study is to develop a SH-SAW biosensor to detect the anti-SARS-CoV-2 nucleocapsid antibody. The rabbit sera collected from rabbits on different days after SARS-CoV-2 N protein injection were evaluated by SH-SAW biosensor and enzyme-linked immunosorbent assay (ELISA). The results showed that the SH-SAW biosensor achieved a high correlation coefficient (R = 0.9997) with different concentrations (34.375-1100 ng/mL) of the "spike-in" anti-N protein antibodies. Compared to ELISA, the SH-SAW biosensor has better sensitivity and can detect anti-N protein IgG signals earlier than ELISA on day 6 (p < 0.05). Overall, in this study, we demonstrated that the SH-SAW biosensor is a promising platform for rapid in vitro diagnostic (IVD) testing, especially for antigen or antibody testing.

Distribution of lymphadenopathy in patients with Kikuchi disease.

BACKGROUND: Cervical lymphadenopathy is among the cardinal manifestations of Kikuchi disease (KD). The incidences and locations of extra-cervical lymph nodes (LNs) involvement in KD have not been comprehensively reported. METHODS: From 2003 to 2016, 60 patients with pathologically confirmed KD and with computed tomography and/or whole-body inflammation scans at diagnosis were retrospectively identified. The locations, sizes and characteristics of all affected LNs were analyzed by extensive review of the image studies. The clinical and laboratory parameters were abstracted from medical records and the associations with extra-cervical LNs involvement were identified. RESULTS: Female accounted for 35 (58.3%) patients and the median age of all patients was 21.3 years (ranges, 3-64 years). Of 59 patients with evaluable neck images, 42 (71.2%) and 16 (27.1%) patients presented with unilateral and bilateral nodal involvement, respectively, with the most common locations at level II, III and IV by Som's classification. The largest LNs appeared most commonly in level II. The incidences of extra-cervical lymphadenopathy in abdomen, pelvis, inguina, axilla and mediastinum with available images were respectively 52.9% (9/17), 47.1% (8/17), 41.2% (7/17), 30.6% (11/36) and 14.3% (8/56). When compared to cases with solitary cervical lymphadenopathy, the cases with extra-cervical lymphadenopathy had significantly greater incidences of bilateral cervical lymphadenopathy (P = .0379) and leukopenia (P = .0173). CONCLUSION: Unilateral cervical lymphadenopathy was the most frequent form of LNs involvement of KD. Extra-cervical lymphadenopathy was not uncommon and was associated with the appearance of bilateral distribution of cervical LNs and leukopenia.

Clinical characteristics of echovirus 11 and coxsackievirus B5 infections in Taiwanese children requiring hospitalization.

BACKGROUND: Severe illness can occur in young children infected with certain types of enteroviruses including echovirus 11 (Echo11) and coxsackievirus B5 (CoxB5). The manifestations and outcomes of Echo11 and CoxB5 diseases across all ages of children remained not comprehensively characterized in Taiwan. METHODS: Culture-confirmed Echo11 (60 patients) or CoxB5 (65 patients) infections were identified in a hospital from 2010 to 2018. The demographics, clinical presentations, laboratory data and outcomes were abstracted and compared between the two viruses infections. RESULTS: Echo11 and CoxB5 was respectively identified in 7 (77.8%) and 2 (22.2%) of 9 calendar years. The median age of all patients was 15 months (range, 1 day-14.5 years). For infants ≤3 months old, Echo11 (23 cases) was associated with higher incidence of aseptic meningitis (35% versus 0%, P = 0.003), and a lower rate of upper respiratory tract infections (URI) (22% versus 65%, P = 0.004) compared to CoxB5 (20 cases) infections. For patients >3 months old, URI was the cardinal diagnosis (60%) for both viruses. Aseptic meningitis was also more commonly identified in elder children with Echo11 infections (27% versus 11%), though with marginal significance (P = 0.07). Acute liver failure was identified in four young infants with Echo11 infections including one neonate dying of severe sepsis and myocarditis. All patients with CoxB5 infections recovered uneventfully. CONCLUSION: Aseptic meningitis, sepsis-like illness and acute liver failure were more commonly identified in children with Echo11 than those with CoxB5 infections, suggesting greater neurological tropism and virulence toward Echo11.

Detection of norovirus and rotavirus among inpatients with acute gastroenteritis in a medical center in northern Taiwan, 2013-2018.

BACKGROUND: Norovirus (NoV) and rotavirus (RV) are among the most common causes of acute gastroenteritis (AGE) of all ages worldwide. There have been scanty reports of the epidemiology data of NoV AGE from clinical virologic laboratory. METHODS: All stool specimens sent to the virologic laboratory in a medical center in Taiwan for detection of both NoV (by reverse transcription-polymerase chain reaction) and RV (by enzyme immunoassay) from 2013 to 2018 were included for analysis. RESULTS: A total of 15,991 specimens, annually ranging from 2430 in 2017-2915 in 2013, were included. 48.0% and 73.1% of the specimens were obtained from children aged < two years and < five years, respectively. Overall, the positive rate was 13.8% for NoV and 13.2% for RV. Yearly positive rate of NoV ranged from 11.1% to 17.4%. The positive rate in 2018 (17.4%) was significantly higher than that in other study years. NoV positive rate was higher in cold season from January (28.3%), February (23.1%), to March (17.9%) while lower in warm seasons from May to September (less than 10%). By age, NoV positive rate was highest in aged 1-4 years (17.3%) and decreased with age. The yearly positive rate of RV showed a significantly steady decrease from 15.6% in 2013 to 9.1% in 2018 (p < 0.001 by trend analysis). CONCLUSIONS: In northern Taiwan, NoV, surpassing RV, accounted for one of seven inpatients with AGE during 2013-2018. NoV activity peaked in cold season and children aged <5 years were more commonly encountered.

Molecular epidemiology and clinical features of rhinovirus infections among hospitalized patients in a medical center in Taiwan.

BACKGROUND: Human rhinovirus (HRV) can cause severe illnesses in hospitalized patients. However, there are no studies regarding the prevalence of HRV infection, particularly the recently identified HRV-C, in hospitalized patients reported from Taiwan. METHODS: Respiratory specimens collected from 487 hospitalized patients in designated wards between 2013 and 2014 in a medical center in northern Taiwan were retrospectively detected for HRV. Positive specimens were further determined for genotyping. Medical charts of the HRV-positive patients were reviewed retrospectively. RESULTS: Totally, 76 patients (15.6%) were HRV positive, of which 60 were pediatric patients. HRV-A was identified in 41 (54%) patients, HRV-B in 6 patients (7.9%) and HRV-C in 29 patients (38%). A total of 47 different genotypes were identified. HRV infections were predominant during fall and winter seasons. 21.1% were affected by HRV alone and 78.9% were found to be co-infected with other microorganisms. The detection rate of HRV in children (18.6%) was significantly higher than in adults (9.6%). Compared with pediatric patients, adult patients were significantly associated with underlying disease, Pneumocystis jirovesii pneumonia co-infection, a diagnosis of pneumonia, fatal outcome, hospital acquisition of HRV, antibiotics administration and requiring intensive care, while pediatric patients were significantly associated with viral co-infection. CONCLUSIONS: HRV was a common cause of respiratory tract infection in Taiwan, particularly in pediatric patients. Eighty percent of HRV-infected inpatients had other microorganisms co-infection. Adult patients were more likely to be associated with a severe respiratory disease entity.

Disseminated Cryptococcosis Due to Anti-Granulocyte-Macrophage Colony-Stimulating Factor Autoantibodies in the Absence of Pulmonary Alveolar Proteinosis.

INTRODUCTION: Autoantibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF) can cause acquired pulmonary alveolar proteinosis (PAP). Cases of acquired PAP susceptible to typical respiratory pathogens and opportunistic infections have been reported. Anti-GM-CSF autoantibodies have been reported in a few patients with cryptococcal meningitis. This study evaluated the presence of neutralizing anti-GM-CSF autoantibodies in patients without known congenital or acquired immunodeficiency with severe pulmonary or extrapulmonary cryptococcal infection but without PAP. METHODS: We took a clinical history and performed an immunologic evaluation and screening of anti-cytokine autoantibodies in patients with cryptococcal meningitis. The impact of autoantibodies to GM-CSF on immune function was assessed by intracellular staining of GM-CSF-induced STAT5 phosphorylation and MIP-1α production in normal peripheral blood mononuclear cells incubated with plasma from patients or normal control subjects. RESULTS: Neutralizing anti-GM-CSF autoantibodies were identified in four patients with disseminated cryptococcosis, none of whom exhibited PAP. Plasma from patients blocked GM-CSF signaling and inhibited STAT5 phosphorylation and production of MIP-1α. One patient died of disseminated cryptococcosis involving the central nervous system, which was associated with defective GM-CSF activity. CONCLUSIONS: Anti-GM-CSF autoantibodies increase susceptibility to cryptococcal infection in adults without PAP. Cryptococcal central nervous system infection associated with anti-GM-CSF autoantibodies could result in neurological sequelae or be life-threatening. Therefore, timely detection of neutralizing anti-GM-CSF autoantibodies and development of an effective therapy are necessary to prevent deterioration of cryptococcal infection in these patients.

Identification of a major epitope by anti-interferon-γ autoantibodies in patients with mycobacterial disease.

The binding of autoantibodies (autoAbs) to interferon (IFN)-γ in people with mycobacterial diseases has become an emerging medical concern. Many patients display specific human leukocyte antigen (HLA) class II haplotypes, which suggests that a common T cell-dependent and B cell-dependent mechanism might underlie the production of specific anti-IFN-γ autoAbs. We show here that these autoAbs target a major epitope (amino acids 121-131, designated position (P)121-131) in a region crucial for IFN-γ receptor (IFN-γR) activation to impair IFN-γ-mediated activities. The amino acid sequence of this epitope is highly homologous to a stretch in the Noc2 protein of Aspergillus spp., which was cross-reactive with autoAbs from patients. Rats immunized with Aspergillus Noc2 developed antibodies that reacted with human IFN-γ. We generated an epitope-erased variant of IFN-γ (EE-IFN-γ), in which the major neutralizing epitope region was altered. The binding affinity of anti-IFN-γ autoAbs for EE-IFN-γ was reduced by about 40%, as compared to that for IFN-γ1-131. Moreover, EE-IFN-γ activated the IFN-γR downstream signaling pathway ex vivo, irrespectively of anti-IFN-γ autoAbs. In conclusion, we identified a common, crucial B cell epitope that bound to anti-IFN-γ autoAbs in patients, and we propose a molecular-mimicry model for autoAb development. In addition, treatment with EE-IFN-γ might be worth investigating in patients producing anti-IFN-γ autoAbs.

Clinical manifestations, course, and outcome of patients with neutralizing anti-interferon-γ autoantibodies and disseminated nontuberculous mycobacterial infections.

Neutralizing anti-interferon-γ autoantibody (nAIGA)-associated immunodeficiency is an emerging medical issue worldwide. In the present study, we describe and discuss the clinical features and outcomes of patients with nAIGAs and disseminated infections by nontuberculous mycobacteria (dNTM).We thoroughly reviewed the medical records of all patients. Microorganisms and nAIGAs were identified using previously described methods with modifications. All data were calculated and analyzed using SPSS software.Among 46 adult patients with dNTM infections, we identified 45 cases (97.8%) with nAIGAs. The average patient age was 58.6 years, and there was no sex predominance. Cervical lymphadenitis (81.8%) was the most common clinical manifestation. Endocrine disorder was the leading comorbidity (7 cases). Malignancies were found in 4 patients, and all of the malignancies originated from the T-cell/macrophage lineage. More than half of the identifiable isolates were slow-growing NTMs. Twenty-eight (62.2%) and 18 (40.0%) patients had a history of zoster and salmonellosis, respectively. A high proportion of patients with recurrent episodes of NTM infection or a history of zoster and dNTM infection had initial nAIGA titers ≥10 dilution (P < 0.05). Twenty-seven patients (60.0%) required long-term antimycobacterial therapy and had at least 1 episode of recurrent NTM disease. No mortality was related to dNTM infection.In Taiwan, nAIGAs are a recently recognized mechanism of dNTM infection. Long term of antibiotic treatment and adherence to medical advice are necessary to improve the clinical outcome of patients with nAIGAs.