Systemic lupus erythematosus is a complex and potentially fatal autoimmune disease, characterized by autoantibody production and multi-organ damage. By a genome-wide association study (320 patients ...and 1,500 controls) and subsequent replication altogether involving a total of 3,300 Asian SLE patients from Hong Kong, Mainland China, and Thailand, as well as 4,200 ethnically and geographically matched controls, genetic variants in ETS1 and WDFY4 were found to be associated with SLE (ETS1: rs1128334, P = 2.33x10(-11), OR = 1.29; WDFY4: rs7097397, P = 8.15x10(-12), OR = 1.30). ETS1 encodes for a transcription factor known to be involved in a wide range of immune functions, including Th17 cell development and terminal differentiation of B lymphocytes. SNP rs1128334 is located in the 3'-UTR of ETS1, and allelic expression analysis from peripheral blood mononuclear cells showed significantly lower expression level from the risk allele. WDFY4 is a conserved protein with unknown function, but is predominantly expressed in primary and secondary immune tissues, and rs7097397 in WDFY4 changes an arginine residue to glutamine (R1816Q) in this protein. Our study also confirmed association of the HLA locus, STAT4, TNFSF4, BLK, BANK1, IRF5, and TNFAIP3 with SLE in Asians. These new genetic findings may help us to gain a better understanding of the disease and the functions of the genes involved.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disease characterized by defective neutrophil killing of microbial pathogens and recurrent infections. We aimed to investigate ...the clinical, genetic features, treatment, and outcomes in patients with CGD.
Pediatric patients diagnosed with CGD from a medical center in Taiwan were enrolled from January 1999 to Oct 2021.
Nine pediatric patients with CGD were enrolled: six X-linked (XL) CGD with CYBB gene mutations, three autosomal recessive (AR) CGD with two NCF1 and one CYBA gene mutations. The median age of onset and age of diagnosis was 0.92 and 2.64 years, respectively. Patients with XL-CGD had a younger age of onset (4.6 months vs. 1.83 years, P = 0.06) and age of diagnosis (1.71 vs. 8.86 years, P = 0.024) than AR-CGD patients. The most common sites of infections were skin and soft tissue abscesses. The most common pathogens were Staphylococcus, Serratia, and Salmonella spp. Prophylactic antibiotics, anti-fungal agents, and interferon-gamma (IFN-γ) were given in 9 (100%), 7 (77.8%), and 8 (88.9%) patients, respectively. The mean duration of IFN-γ usage was 5.15 years. One male patient with XL-CGD was successfully treated with hematopoietic stem cell transplantation at 2.2 years. The mortality rate was 11.1%, and the estimated overall survival at 20 years was 66.7%.
Staphylococcus aureus, Serratia marcescens, and Salmonella infections are important in Taiwanese CGD patients. Patients with XL-CGD have early disease onset. IFN-γ prophylaxis and prophylactic anti-microbial agents might have an effect on alleviating the infection episodes in CGD patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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•The reactogenicity and safety of a liquid PCV-free HRV were assessed.•Adverse event rates were similar for the liquid PCV-free HRV and the lyophilized HRV.•In both groups, about 6% ...of infants reported at least one serious adverse event.•The liquid PCV-free HRV has a favorable safety profile.
The introduction of rotavirus vaccines in national immunization programs has decreased mortality and hospitalizations due to diarrhea. GSK’s live-attenuated, human rotavirus vaccine (HRV) is a 2-dose vaccine for oral administration. Following the detection of porcine circovirus type 1 (PCV-1) in HRV, a PCV-free (no detection of PCV-1 and PCV-2 according to the detection limits of tests used) HRV was developed. The immunogenicity, reactogenicity and safety of a liquid (liq) PCV-free HRV were assessed in two prior studies. The present study aimed to generate additional reactogenicity and safety data.
This phase III, observer-blind, randomized, controlled multi-country study enrolled healthy 6–12-week-old infants. Infants were randomized to receive 2 doses of either the liq PCV-free HRV (N = 677) or the lyophilized (lyo) HRV (N = 674) 1–2 months apart. Solicited adverse events (AEs) were recorded for 8 days after each dose, unsolicited AEs for 31 days and serious AEs (SAEs) from dose 1 until the end of the 6-month safety follow-up.
The occurrence of solicited general AEs was comparable between the liq PCV-free HRV and the lyo HRV groups, with irritability/fussiness being the most frequently reported (74.9% 95% confidence interval: 71.4–78.1 and 72.1% 68.6–75.5). Unsolicited AEs were reported for 29.7% (26.3–33.3) and 30.6% (27.1–34.2) of infants in the liq PCV-free HRV and the lyo HRV group. A total of 39 and 38 infants reported at least one SAE, respectively. The most common SAEs were upper respiratory tract (0.7% and 0.9%) and urinary tract infections (0.9% and 0.6%). One SAE (constipation) in the liq PCV-free HRV group was considered as potentially causally related to vaccination by the investigator. No deaths were reported.
The study showed that the reactogenicity and safety profiles of the liq PCV-free HRV and the lyo HRV are similar.
ClinicalTrials.gov identifier: NCT03954743.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We recently identified ten novel SLE susceptibility loci in Asians and uncovered several additional suggestive loci requiring further validation. This study aimed to replicate five of these ...suggestive loci in a Han Chinese cohort from Hong Kong, followed by meta-analysis (11,656 cases and 23,968 controls) on previously reported Asian and European populations, and to perform bioinformatic analyses on all 82 reported SLE loci to identify shared regulatory signatures. We performed a battery of analyses for these five loci, as well as joint analyses on all 82 SLE loci. All five loci passed genome-wide significance: MYNN (rs10936599, Pmeta = 1.92 × 10-13, OR = 1.14), ATG16L2 (rs11235604, Pmeta = 8.87 × 10 -12, OR = 0.78), CCL22 (rs223881, Pmeta = 5.87 × 10-16, OR = 0.87), ANKS1A (rs2762340, Pmeta = 4.93 × 10-15, OR = 0.87) and RNASEH2C (rs1308020, Pmeta = 2.96 × 10-19, OR = 0.84) and co-located with annotated gene regulatory elements. The novel loci share genetic signatures with other reported SLE loci, including effects on gene expression, transcription factor binding, and epigenetic characteristics. Most (56%) of the correlated (r2 > 0.8) SNPs from the 82 SLE loci were implicated in differential expression (9.81 × 10-198 < P < 5 × 10-3) of cis-genes. Transcription factor binding sites for p53, MEF2A and E2F1 were significantly (P < 0.05) over-represented in SLE loci, consistent with apoptosis playing a critical role in SLE. Enrichment analysis revealed common pathways, gene ontology, protein domains, and cell type-specific expression. In summary, we provide evidence of five novel SLE susceptibility loci. Integrated bioinformatics using all 82 loci revealed that SLE susceptibility loci share many gene regulatory features, suggestive of conserved mechanisms of SLE etiopathogenesis.
BackgroundA novel human rhinovirus (HRV) species, HRV-C, was recently discovered, but its clinical features and epidemiology, compared with HRV-A and HRV-B, remains poorly understood, especially in ...adults MethodsOne thousand two hundred nasopharyngeal aspirate samples obtained from hospitalized children and adults during a 1-year period were subject to reverse-transcriptase polymerase chain reaction to detect HRV. The clinical and molecular epidemiology of the 3 HRV species was analyzed ResultsHRVs were detected in 178 (29.7%) of 600 nasopharyngeal aspirate samples from children and 42 (7%) of 600 nasopharyngeal aspirate samples from adults. HRV-A was most prevalent (n=111), followed by HRV-C (n=91) and HRV-B (n=18). Although upper respiratory tract infection was the most common presentation in children, 8 (62%) of the 13 adults with HRV-C infection had pneumonia, compared with 6 (27%) of the 22 adults with HRV-A infection (P<.05). Wheezing episodes were also more common among individuals with HRV-C (37%) and HRV-A (20%) infection than among those with HRV-B (0%) infection (P<.05). Clinical and molecular data analysis revealed HRV-C as a frequent cause of community and institutionalized outbreaks. A diverse set of HRV-C genotypes was circulating throughout the year, among which a potential distinct subgroup of strains was observed ConclusionHRV-C is associated with pneumonia in adults and outbreaks of respiratory infections requiring hospitalization. A potential novel HRV-C subgroup was identified
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Cryopyrin-associated periodic syndrome (CAPS) comprises a group of disorders characterized by recurrent bouts of systemic inflammation related to overactivation of inflammasome. So far, neither large ...cases of the correlation between genotype and phenotype nor treatment strategies have been clearly stated in China. Here, we studied the clinical and genetic characteristics and their correlation from 30 CAPS patients in China. We identified the pathogenesis for novel mutations by activating
NLRP3
inflammasome for peripheral cells with ATP plus LPS, compared characteristics with other case series, and analyzed treatment outcomes of these patients. The patients harbored 19 substitutions in
NLRP3
, and 8 of them were novel mutations. Among these novel mutations, percentages of severe musculoskeletal, ophthalmologic, and neurological symptoms were higher compared with other case serials. The correlation of phenotypes and their variants seemed different in our cases, such as T350M, S333G/I/R, and F311V (somatic mosaicism). Ten patients received Canakinumab treatment, which proved effective at alleviating musculoskeletal, neurological, auditory, visual manifestations, fever, and rash for 10–20 months follow-up. Patients treated with prednisolone or prednisolone plus thalidomide or methotrexate, tocilizumab, TNF inhibiting agents, and sirolimus achieved only partial remission. Importantly, we firstly identified somatic mosaicism mutation of F311V, which was severe. Our study extended the spectrum of genotype and phenotype and characteristics of their correlations and provided detailed responses to different treatment strategies. These data provide guidance for future diagnosis and management for CAPS.
BackgroundInfluenza virus is a cause of substantial annual morbidity and mortality worldwide. The potential emergence of a new pandemic strain (eg, avian influenza virus) is a major concern. ...Currently available vaccines and anti-influenza drugs have limited effectiveness for influenza virus infections, especially for new pandemic strains. Therefore, there is an acute need to develop alternative strategies for influenza therapy. γδ T cells have potent antiviral activities against different viruses, but no data are available concerning their antiviral activity against influenza viruses MethodsIn this study, we used virus-infected primary human monocyte-derived macrophages (MDMs) to examine the antiviral activity of phosphoantigen isopentenyl pyrophosphate (IPP)–expanded human Vγ9Vδ2 T cells against influenza viruses ResultsVγ9Vδ2 T cells were selectively activated and expanded by IPP from peripheral blood mononuclear cells. IPP-expanded Vγ9Vδ2 T cells efficiently killed MDMs infected with human (H1N1) or avian (H9N2 or H5N1) influenza virus and significantly inhibited viral replication. The cytotoxicity of Vγ9Vδ2 T cells against influenza virus–infected MDMs was dependent on NKG2D activation and was mediated by Fas–Fas ligand and perforin–granzyme B pathways ConclusionOur findings suggest a potentially novel therapeutic approach to seasonal, zoonotic avian, and pandemic influenza—the use of phosphoantigens to activate γδ T cells against influenza virus infections
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Natural killer (NK) cells are indispensable components of both the innate and adaptive immune response. However, their precise roles in the cross-talk between innate and adaptive immunity during ...influenza virus infection remain controversial. By comparing NK cell dynamics and activity under a sub-lethal dose and high dose of influenza virus infection, we showed that influenza virus PR8 directly infected NK cells during natural infection, which was consistent with our previous findings obtained from an in vitro investigation of human NK cells. The impairments in cytotoxicity and IFN-γ production by spleen NK cells following high-dose infection were accompanied by decreased virus-specific killing mediated by cytotoxic T lymphocytes (CTLs). Importantly, the weakened CTL activity could be reversed by adoptive transfer of spleen NK cells harvested from low-dose-infected mice but not healthy donors. Taken together, our data provide direct evidence supporting the contribution of NK cells to antiviral T-cell responses. This study also indicates that a novel NK-targeted immune evasion strategy is used by influenza virus to shrink both innate and adaptive immune responses.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Signal transducer and activator of transcription 3 (
) gain-of-function (GOF) mutations cause early-onset immune dysregulation syndrome, characterized by multi-organ autoimmunity and ...lymphoproliferation. Of them, interstitial lung disease (ILD) usually develops after the involvement of other organs, and the onset time is childhood and beyond rather than infancy. Here, we reported a patient who presented with fatal infancy-onset ILD, finally succumbing to death. Next-generation sequencing identified a novel heterozygous mutation in
(c.989C>G, p.P330R). Functional experiments revealed it was a gain-of-function mutation. Upon interleukin 6 stimulation, this mutation caused a much higher activation of STAT3 than the wild-type control. In addition, the mutation also activated STAT3 under the steady state. The T helper 17 cell level in the patient was significantly higher than that in normal controls, which may contribute to the autoimmune pathology caused by the STAT3
mutation. Apart from Janus kinase (JAK) inhibitors, we also provided experimental evidence of a STAT3 selective inhibitor (Stattic) effectively suppressing the activation of mutant STAT3
. Collectively, our study expanded the clinical spectrum of
GOF syndrome.
GOF mutation appears as a new etiology of ILD and should be considered in patients with early-onset ILDs. In addition to JAK inhibitors, the specific STAT3 inhibitor would be an appealing option for the targeted treatment.
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