Thalidomide as an Effective Treatment in Sideroblastic Anemia, Immunodeficiency, Periodic Fevers, and Developmental Delay (SIFD).

PURPOSE: Sideroblastic anemia, immunodeficiency, periodic fevers, and developmental delay (SIFD) is an autosomal recessive syndrome caused by biallelic loss-of-function variant of tRNA nucleotidyl transferase 1 (TRNT1). Efficacious methods to treat SIFD are lacking. We identified two novel mutations in TRNT1 and an efficacious and novel therapy for SIFD. METHODS: We retrospectively summarized the clinical records of two patients with SIFD from different families and reviewed all published cases of SIFD. RESULTS: Both patients had periodic fever, developmental delay, rash, microcytic anemia, and B cell lymphopenia with infections. Whole-exome sequencing of patient 1 identified a previously unreported homozygous mutation of TRNT1 (c.706G > A/p.Glu236Lys). He received intravenous immunoglobulin (IVIG) replacement and antibiotics, but died at 1 year of age. Gene testing in patient 2 revealed compound heterozygous mutations (c.907C > G/p.Gln303Glu and c.88A > G/p.Met30Val) in TRNT1, the former of which is a novel mutation. Periodic fever was controlled in the first month after adalimumab therapy and IVIG replacement, but recurred in the second month. Adalimumab was discontinued and replaced with thalidomide, which controlled the periodic fever and normalized inflammatory markers effectively. A retrospective analysis of reported cases revealed 69 patients with SIFD carrying 46 mutations. The male: female ratio was 1: 1, and the mean age of onset was 3.0 months. The most common clinical manifestations in patients with SIFD were microcytic anemia (82.6%), hypogammaglobulinemia/B cell lymphopenia (75.4%), periodic fever (66.7%), and developmental delay (60.0%). In addition to the typical tetralogy, SIFD features several heterogeneous symptoms involving multiple systems. Corticosteroids, immunosuppressants, and anakinra have low efficacy, whereas etanercept suppressed fever and improved anemia in reports. Bone-marrow transplantation can be used to treat severe SIFD, but carries a high risk. In total, 28.2% (20/71) of reported patients died, mainly because of multi-organ failure. Biallelic mutations located in exon1-intron5 lead to more severe phenotypes and higher mortality. Furthermore, 15.5% (11/71) patients survived to adulthood. The symptoms could be resolved spontaneously in five patients. CONCLUSIONS: Thalidomide can control the inflammation of SIFD and represents a new treatment for SIFD.

Progressive osseous heteroplasia in a 5-year-old boy with a novel mutation in exon 2 of GNAS: a case presentation and literature review.

BACKGROUND: Progressive osseous heteroplasia (POH) is a rare genetic condition that causes progressive ossification. This usually results from an inactivating mutation of the paternal GNAS gene. Herein, we report a case of POH caused by a novel mutation in exon 2 of the GNAS gene. CASE PRESENTATION: A 5-year-old Chinese boy was referred to our hospital for a growing mass in his right foot. Although laboratory findings were normal, radiographic imaging revealed severe ossification in his right foot and smaller areas of intramuscular ossification in his arms and legs. A de novo mutation (c.175C > T, p.Q59X) in exon 2 of the GNAS gene was identified, prompting a diagnosis of POH. We conducted a systematic literature review to better understand this rare disease. CONCLUSION: We have discovered that a de novo nonsense mutation in exon 2 of GNAS can lead to POH. Our literature review revealed that ankylosis of the extremities is the primary clinical outcome in patients with POH. Unlike other conditions such as fibrodysplasia ossificans progressiva (FOP), patients with POH do not experience respiratory failure. However, much remains to be learned about the relationship between the type of GNAS gene mutation and the resulting POH symptoms. Further research is needed to understand this complex and rare disease. This case adds to our current understanding of POH and will contribute to future studies and treatments.

Novel autoantibodies identified in ACPA-negative rheumatoid arthritis.

OBJECTIVES: Lack of effective biomarkers in anti-citrullinated protein antibody (ACPA)-negative rheumatoid arthritis (RA) impedes early diagnosis and treatment. This study aimed to identify novel autoantibodies in RA and verify their diagnostic values in ACPA-negative RA based on protein microarray technology. METHODS: A total of 1011 sera from 559 RA (276 ACPA-positive and 283 ACPA-negative), 239 disease controls (DCs) and 213 healthy controls (HCs) were collected and sampled on two sequential microarrays and ELISA and western blot (WB) detection, for novel autoantibodies discovery, validation and verification, respectively. The high-density protein microarray printed with a broad spectrum of recombinant human proteins was first employed to screen candidate autoantibodies, then focused microarrays composed of candidate autoantigens were used for validation, followed by ELISA and WB to verify the presence of the most promising candidates in ACPA-negative RA. RESULTS: Nine novel autoantibodies were identified by two sequential microarrays with positivity 17.93%-27.59% and specificities >90% in ACPA-negative RA. Among these, anti-PTX3 and anti-DUSP11 autoantibodies presented with the highest sensitivity and were consistently verified by ELISA and WB. Pooling samples of all cohorts, the positivities of anti-PTX3 and anti-DUSP11 in ACPA-negative RA were 27.56% and 31.80%, respectively, similar to those in ACPA-positive RA, and significantly higher than in HCs (4.69% and 2.35%) and DCs (10.04% and 8.49%) (p<0.0001). Combination of anti-PTX3 with anti-DUSP11 significantly increased the diagnostic sensitivity (38.00%) with specificity of 88.72%, regardless of ACPA status. CONCLUSION: Anti-PTX3 and anti-DUSP11 autoantibodies are newly identified biomarkers for diagnosis of ACPA-negative RA.

Expression profile of long noncoding RNAs in children with systemic lupus erythematosus: a microarray analysis.

OBJECTIVES: Long noncoding RNAs (lncRNAs) are reported to play crucial roles in several physiological and biological processes. However, knowledge of lncRNAs in children with systemic lupus erythematosus (cSLE) remains limited. We investigate lncRNA expression profiling of cSLE and explore the potential function of lncRNAs. METHODS: LncRNA and mRNA microarrays were performed to identify changes in lncRNA and mRNA expression between children with SLE and paired healthy children. Quantitative polymerase chain reaction (qPCR) validated these results. A Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed to explore the potential lncRNA function. RESULTS: A comparison between children with SLE and paired healthy children revealed that 1042 lncRNAs and 1162 mRNAs were differentially expressed. By using gene co-expression network analysis, we constructed a complex lncRNA target network consisting of 817 matched lncRNA-mRNA pairs for 309 differentially expressed lncRNAs and 210 differentially expressed mRNAs. The results of further GO and KEGG pathway analyses indicated that lncRNAs were involved mainly in pathways with crucial pathobiological relevance in SLE. CONCLUSIONS: We firstly characterised the expression profiles of lncRNA and mRNA in children with SLE and propose herein their possible roles in the pathogenesis of SLE. These results provide novel insights into the mechanisms of SLE pathogenesis and may serve as diagnostic biomarkers for SLE therapy.

Identification of Novel Biomarkers for Behcet Disease Diagnosis Using Human Proteome Microarray Approach.

Behcet disease (BD) is a chronic systemic vasculitis and considered as an autoimmune disease. Although rare, BD can be fatal due to ruptured vascular aneurysms or severe neurological complications. To date, no known biomarker has been reported for this disease, making it difficult to diagnosis in the clinics. To undertake this challenge, we employed the HuProt arrays, each comprised of ∼20,000 unique human proteins, to identify BD-specific autoantibodies using a Two-Phase strategy established previously. In Phase I, we profiled the autoimmunity on the HuProt arrays with 75 serum samples collected from 40 BD patients, 15 diagnosed autoimmune patients who suffer from Takayasu arteritis (TA; n = 5)), ANCA associated vasculitis (AAV; n = 5), and Sjogren's syndrome (SS; n = 5), and 20 healthy subjects, and identified 20 candidate autoantigens that were significantly associated with BD. To validate these candidates, in Phase II we constructed a focused array with these 20 candidate BD-associated antigens, and use it to profile a much larger cohort, comprised of serum samples collected from 130 BD patients, 103 autoimmune patients (i.e. 40TA, 40 AAV and 23 SS), and 110 healthy controls. This allowed us to validate CTDP1 (RNA polymerase II subunit A C-terminal domain phosphatase)as a BD-specific autoantigen. The association of anti-CTDP1 with BD patients was further validated using the traditional Western blotting analysis. In conclusion, anti-CTDP1 antibody serves a novel autoantibody for Behcet disease and is expected to help more accurate clinical diagnosis.

Chemotaxis of Vδ2 T cells to the joints contributes to the pathogenesis of rheumatoid arthritis.

OBJECTIVES: To explore the role of Vδ2 T cells in the pathogenesis of rheumatoid arthritis (RA). METHODS: Sixty-eight patients with RA, 21 patients with osteoarthritis and 21 healthy controls were enrolled in the study. All patients with RA fulfilled the 2010 American College of Rheumatology/European League Against Rheumatism criteria for RA. Peripheral Vδ2T population, chemokine receptor expression and proinflammatory cytokine secretion were quantified by flow cytometry. The infiltration of Vδ2 T cells within the synovium was examined by immunohistochemistry and flow cytometry. The effect of tumour necrosis factor (TNF)-α and interleukin (IL)-6 on Vδ2 T migration was determined by flow cytometry and transwell migration assay. RESULTS: Peripheral Vδ2T cells, but not Vδ1 T cells, were significantly lower in patients with RA, which was negatively correlated with disease activity gauged by Disease Activity Score in 28 joints. Vδ2 T cells from RA accumulated in the synovium and produced high levels of proinflammatory cytokines including interferon-γ and IL-17. Phenotypically, Vδ2 T cells from RA showed elevated chemotaxis potential and expressed high levels of chemokine receptors CCR5 and CXCR3, which was driven by increased serum TNF-α through nuclear factor kappa B signalling. In vivo, TNF-α neutralising therapy dramatically downregulated CCR5 and CXCR3 on Vδ2 T cells and repopulated the peripheral Vδ2 T cells in patients with RA. CONCLUSIONS: High levels of TNF-α promoted CCR5 and CXCR3 expression in Vδ2 T cells from RA, which potentially infiltrated into the synovium and played crucial roles in the pathogenesis of RA. Targeting Vδ2 T cells might be a potential approach for RA.

The predictive value of TNF family for pulmonary tuberculosis: a pooled causal effect analysis of multiple datasets.

Objective: Despite extensive research on the relationship between pulmonary tuberculosis (PTB) and inflammatory factors, more robust causal evidence has yet to emerge. Therefore, this study aims to screen for inflammatory proteins that may contribute to the susceptibility to PTB in different populations and to explain the diversity of inflammatory and immune mechanisms of PTB in different ethnicity. Methods: The inverse variance weighted (IVW) model of a two-sample Mendelian Randomization (MR) study was employed to conduct causal analysis on data from a genome-wide association study (GWAS). This cohort consisting PTB GWAS datasets from two European and two East Asian populations, as well as 91 human inflammatory proteins collected from 14,824 participants. Colocalization analysis aimed to determine whether the input inflammatory protein and PTB shared the same causal single nucleotide polymorphisms (SNPs) variation within the fixed region, thereby enhancing the robustness of the MR Analysis. Meta-analyses were utilized to evaluate the combined causal effects among different datasets. Results: In this study, we observed a significant negative correlation between tumor necrosis factor-beta levels (The alternative we employ is Lymphotoxin-alpha, commonly referred to as LT) (P < 0.05) and tumor necrosis factor receptor superfamily member 9 levels (TNFRSF9) (P < 0.05). These two inflammatory proteins were crucial protective factors against PTB. Additionally, there was a significant positive correlation found between interleukin-20 receptor subunit alpha levels (IL20Ra) (P < 0.05), which may elevate the risk of PTB. Colocalization analysis revealed that there was no overlap in the causal variation between LT and PTB SNPs. A meta-analysis further confirmed the significant combined effect of LT, TNFRSF9, and IL20Ra in East Asian populations (P < 0.05). Conclusions: Levels of specific inflammatory proteins may play a crucial role in triggering an immune response to PTB. Altered levels of LT and TNFRSF9 have the potential to serve as predictive markers for PTB development, necessitating further clinical validation in real-world settings to ascertain the impact of these inflammatory proteins on PTB.

Betaine and I-LG may have a predictive value for ATB: A causal study in a large European population.

PURPOSE: To analyze the causal relationship between 486 human serum metabolites and the active tuberculosis (ATB) in European population. METHODS: In this study, the causal relationship between human serum metabolites and the ATB was analyzed by integrating the genome-wide association study (GWAS). The 486 human serum metabolites were used as the exposure variable, three different ATB GWAS databases in the European population were set as outcome variables, and single nucleotide polymorphisms were used as instrumental variables for Mendelian Randomization. The inverse variance weighting was estimated causality, the MR-Egger intercept to estimate horizontal pleiotropy, and the combined effects of metabolites were also considered in the meta-analysis. Furthermore, the web-based MetaboAnalyst 6.0 was engaged for enrichment pathway analysis, while R (version 4.3.2) software and Review Manager 5.3 were employed for statistical analysis. RESULTS: A total of 21, 17, and 19 metabolites strongly associated with ATB were found in the three databases after preliminary screening (P < 0.05). The intersecting metabolites across these databases included tryptophan, betaine, 1-linoleoylglycerol (1-monolinolein) (1-LG), 1-eicosatrienoylglycerophosphocholine, and oleoylcarnitine. Among them, betaine (I2 = 24%, P = 0.27) and 1-LG (I2 = 0%, P = 0.62) showed the lowest heterogeneity among the different ATB databases. In addition, the metabolic pathways of phosphatidylethanolamine biosynthesis (P = 0.0068), methionine metabolism (P = 0.0089), betaine metabolism (P = 0.0205) and oxidation of branched-chain fatty acids (P = 0.0309) were also associated with ATB. CONCLUSION: Betaine and 1-LG may be biomarkers or auxiliary diagnostic tools for ATB. They may provide new guidance for medical practice in the early diagnosis and surveillance of ATB. In addition, by interfering with phosphatidylethanolamine biosynthesis, methionine metabolism, betaine metabolism, oxidation of branched-chain fatty acids, and other pathways, it is helpful to develop new anti-tuberculosis drugs and explore the virulence or pathogenesis of ATB at a deeper level, providing an effective reference for future studies.

Panniculitis with late onset enthesitis-related arthritis: a case report.

BACKGROUND: Panniculitis, a type of inflammation of subcutaneous fat, is a relatively uncommon condition that usually presents as inflammatory nodules or plaques, with various proposed etiologic factors. The association between panniculitis and enthesitis-related arthritis has not been described previously. CASE PRESENTATION: Herein, we describe a case of a 11-year-old girl who presented with recurrent fever and painful subcutaneous nodules on her extremities and buttocks. Histological examination of the skin biopsy specimen revealed lobular panniculitis. Despite the use of prednisone and mycophenolate mofetil for several months, the patient experienced a relapse of skin lesions and additional symptoms of peripheral joint swelling and inflammatory lumbar pain. She was diagnosed with enthesitis-related arthritis after confirmation by imaging. The panniculitis demonstrated a sustained response when a tumor necrosis factor alpha inhibitor was used for enthesitis-related arthritis. At 2-year follow-up, her skin lesions and arthritis remained stable. CONCLUSIONS: Although rare, panniculitis can be considered an unusual extra-articular manifestation of enthesitis-related arthritis based on clinical and pathological insights.

The genetic and clinical characteristics and effects of Canakinumab on cryopyrin-associated periodic syndrome: a large pediatric cohort study from China.

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.

[Prevalence of human papillomavirus infection in women in Tibet Autonomous Region of China.].

OBJECTIVE: To determine the prevalence of cervical type-specific human papillomavirus (HPV) infection as well as risk factors associated in Tibet Autonomous Region of China. METHODS: A cluster sampling study was performed in Lasa, Rikaze and Naqu of Tibet. An epidemiological questionnaire was applied and 3036 cervical specimens were obtained for liquid-based cytology and HPV DNA detection. Statistical analysis included Wald Chi-square and stepwise logistic regression model. RESULTS: The overall HPV prevalence of involved 3036 women was 9.19% (279/3036), of which 7.05% (214/3036) of the women were infected by high-risk types (including 14 sorts of types) and 2.14% (65/3036) by low-risk types (including 6 sorts of types). There were no significant differences of HPV prevalence between age groups (P = 0.936), race (P = 0.718) and areas (P = 0.746), respectively. Twenty-one types of HPV were detected, of which HPV16 (1.52%) was the most common type, followed by HPV33 (1.42%), HPV58 (1.22%), HPV52 (1.15%), and HPV31 (1.05%). HPV type distribution was varied by age. Of the 279 HPV infected women, 14.3% (40/279) exhibited multiple HPV infections. Independent risk factors for HPV infection were smoking (P = 0.027), number of sex partners (P = 0.198) and early age of first intercourse (P = 0.237). CONCLUSION: The overall prevalence of HPV infection in Tibet Autonomous Region is lower than that in China or abroad, in which the most common genotype is HPV16 and the independent risk factors for HPV infection included early age of first intercourse, smoking, and number of sex partners.

Microarray expression profile of circular RNAs and mRNAs in children with systemic lupus erythematosus.

BACKGROUND: Recently, it was reported that circular RNAs (circRNAs) play the crucial role in many physiological and biological processes and can be used as biomarkers. However, the information about circRNAs in children with systemic lupus erythematosus (SLE) is limited. The aim of this study is to determine the expression of circRNAs in children with SLE and investigate the significance of circRNA for diagnosing SLE. METHODS: Microarray profile of circRNAs and mRNAs was performed for identifying the changes in expression of circRNAs and mRNAs between children with SLE and healthy children. Quantitative polymerase chain reaction (qPCR) was used to confirm the results. Spearman correlation test was performed to assess the correlation between circRNAs and clinical variables. The receiver operating characteristic (ROC) curve was calculated for evaluating the diagnostic value. RESULTS: A comparison between the children with SLE and healthy children revealed that 348 circRNAs and 1162 mRNAs were expressed differentially. The authors constructed a complex circRNA target network consisting of 307 matched circRNA-mRNA pairs for 124 differentially expressed circRNAs (74 circRNAs were upregulated, and 50 circRNAs were downregulated) and 142 differentially expressed mRNAs (83 mRNAs were upregulated, and 59 mRNAs were downregulated) by using gene co-expression network analysis. The competing for endogenous RNA (ceRNA) network includes 42 differentially expressed circRNAs, 41 differentially expressed mRNAs, and 71 predicted miRNAs. Among these SLE patients, we detected that the hsa_circ_0021372 and hsa_circ_0075699 levels are associated with C3 and C4 levels in children with SLE. The hsa_circ_0057762 level is positively associated with the SLEDAI-2K score. The ROC curves of circRNAs showed that the levels of hsa_circ_0057762 (AUC 0.804, 95% CI 0.607-1.0, P = 0.02) and hsa_circ_0003090 (AUC 0.848, 95% CI 0.688-1.0, P = 0.008) could differentiate the patients with SLE from the healthy controls. CONCLUSIONS: We firstly characterized the expression profiles of circRNA and mRNA in children with SLE and propose herein their possible roles in the pathogenesis of SLE. These results provide novel insight into the mechanisms of SLE pathogenesis, and circRNAs may serve as useful biomarkers for SLE.

Gene mutations and clinical phenotypes in 15 Chinese children with cryopyrin-associated periodic syndrome (CAPS).

The aim of our study is to explore the features of clinical manifestations and genetic mutations in Chinese CAPS patients. Fifteen confirmed patients with CAPS were enrolled. The onset time ranges from 2 days after birth to 6 years and 1 month. Recurrent urticaria rash (93.3%) with fever (100%) were two dominant characteristics of these patients that were presented as either acute or chronic process. Systemic involvements were found in all patients except for one with only rash and fever. The top three symptoms were fever (100%), rash (93.3%) and myalgia (76%). Other clinical manifestations include arthritis (11 cases), lung involvement (seven cases), optical dysfunction (seven cases), nerve deafness (six cases), nervous system involvement (five cases), hepatomegaly, splenomegaly and lymphadenectasis (five cases). Also, four patients had heart involvement and one patient suffered kidney involvement. The laboratory inflammation index such as leukocyte counts, platelet counts, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum amyloid A (SAA) and fibrinogen (FIB) increased significantly at initial stage, but decreased after therapy. As for gene mutation detection, Twelve out of 15 patients were confirmed with mutation in NLRP3, including 11 mutant site: c1789A

Quercetin Mediates ß-Catenin in Pancreatic Cancer Stem-Like Cells.

OBJECTIVE: The aim of this study is to explore how quercetin interacts with pancreatic cancer stem-like cells and the mechanism underlying the effective quercetin-mediated suppression. METHODS: A model of pancreatic cancer stem-like cells was generated by using a sphere formation culture system. A comparative analysis was performed between the parent cells and pancreatic cancer stem-like cells with a related treatment strategy focusing on cancer stem cell (CSC) properties and drug-resistance-related mechanisms in vitro. RESULTS: Our data show that pancreatic cancer stem-like cells have greater resistance to gemcitabine and stronger CSC properties compared with the parent cells. In contrast to the pancreatic cancer stem-like cells, overexpression of ß-catenin was observed in the parent cells. Quercetin suppressed proliferation, invasion and self-renewal capacity, and CSC surface markers expression, with alterations of ß-catenin in pancreatic cancer stem-like cells. The combination of quercetin and gemcitabine can reduce tumor growth and decrease drug resistance in pancreatic cancer. CONCLUSIONS: ß-Catenin plays an important role in maintenance and progression of pancreatic cancer. Targeting ß-catenin using quercetin combined with gemcitabine may be a treatment strategy to improve prognosis in patients with pancreatic cancer.

Hyperactivation and in situ recruitment of inflammatory Vδ2 T cells contributes to disease pathogenesis in systemic lupus erythematosus.

In this study, we measured the proportion of peripheral Vδ2 T cells as well as the status and chemokine receptor expression profiles in SLE patients and healthy control (HC). In addition, Vδ2 T cell infiltration in the kidneys of patients with lupus nephritis was examined. The results showed that the percentage of peripheral Vδ2 T cells in new-onset SLE was decreased, and negatively correlated with the SLE Disease Activity Index score and the severity of proteinuria. These cells had a decreased apoptosis but an increased proliferation, and they showed increased accumulation in SLE kidneys. Moreover, IL-21 production and CD40L, CCR4, CCR7, CCR8, CXCR1 and CX3CR1 expression in Vδ2 T cells from SLE patients was significantly higher than from HC (p < 0.05), and these factors were downregulated in association with the repopulation of peripheral Vδ2 T cells in patients who were in remission (p < 0.05). In addition, anti-TCR Vδ2 antibodies activation significantly upregulated these chemokine receptors on Vδ2 T cells from HC, and this effect was blocked by inhibitors of PLC-γ1, MAPK/Erk, and PI3K signaling pathways. Our findings demonstrate that the distribution and function status of Vδ2 T cells from SLE patients are abnormal, and these aberrations may contribute to disease pathogenesis.