Therapy of chronic recurrent vulvovaginal can- didiasis (VVC) caused by Candida glabrata is still rare in comparison to C. albicans infection, but therapy remains more difficult. Combination therapy with topical antif...Therapy of chronic recurrent vulvovaginal can- didiasis (VVC) caused by Candida glabrata is still rare in comparison to C. albicans infection, but therapy remains more difficult. Combination therapy with topical antifungals may improve therapy outcome, but still standard agents as fluconazole or itraconazole often fail. Posaconazole is a new systemic triazole with a wide antifungal spectrum including rare Candida species. Up to now, no clinical trials with posa- conazole in chronic recurrent VVC have been undertaken. Here, first results of the application of a new therapy regimen consisting of oral posaconazole in combination with topical ciclopiroxolamine are presented. 15 patients with chronic recurrent VVC caused by C. glabrata have been treated. 14 of these patients experienced successful therapy, clinical and mycological cure 30 days after begin of therapy has been observed. Long-term results are promising, as in 4 patients clinical and mycologic cure persists for more than 1 year up to now.展开更多
Autosomal Dominant Chronic Mucocutaneous Candidiasis (AD-CMC) is characterized by defective T cell immunity, leading to fungal infections limited to mucosal surfaces. Recently it was discovered that mutations in the c...Autosomal Dominant Chronic Mucocutaneous Candidiasis (AD-CMC) is characterized by defective T cell immunity, leading to fungal infections limited to mucosal surfaces. Recently it was discovered that mutations in the coiled-coil (CC) domain of STAT1 are the cause of AD-CMC. STAT1 deficiency has been implicated in experimental models of oesophageal cancer (EC) and head and neck carcinoma (HNC). Both carcinoma types are prevalent among CMC patients. Consequently, we postulated that the same mutation in the STAT1 gene triggering AD-CMC, could also be involved in oesophageal- or head and neck carcinogenesis. However we failed to identify the c.820C>T mutation in the STAT1 CC domain in 3 cohorts of Dutch Caucasian origin: being 351 EC patients, 325 HNC patients and 309 controls. Although it seems valuable to investigate the relationship between AD-CMC and upper aerodigestive neo- plasms, the c.820C>T mutation in the STAT1 gene does not seem implicated in EC and HNC aetiology.展开更多
目的探讨3例慢性皮肤黏膜念珠菌病伴有自身免疫性疾病的信号传导与转录激活因子1(signal transducer and activator of transcription 1,STAT1)功能获得性突变(gain-of-function,GOF)的临床特征及基因特点。方法选取就诊阜阳市人民医院...目的探讨3例慢性皮肤黏膜念珠菌病伴有自身免疫性疾病的信号传导与转录激活因子1(signal transducer and activator of transcription 1,STAT1)功能获得性突变(gain-of-function,GOF)的临床特征及基因特点。方法选取就诊阜阳市人民医院儿科的3例确诊为STAT1 GOF的患儿,对其临床特征进行分析总结,采集外周血样,运用高通量测序(high-throughput sequencing,NGS)进行基因检测,并同时进行父母的基因组DNA测序。结果3例患者均出现慢性皮肤黏膜念珠菌病、支气管扩张,并且伴有不同类型的自身免疫性疾病,基因检测证实均存在STAT1基因突变,有不同的突变位点,3个突变均属功能获得性突变,而父母基因均正常,为新发错义变异。结论STAT1 GOF新发突变易导致慢性皮肤黏膜念珠菌病合并自身免疫性疾病,并且在病程的不同时期STAT1基因突变可能伴随不同的自身免疫性疾病的表现,需定期观察,完善相关基因检测有助于早期诊断,避免漏诊及误诊。展开更多
Inborn errors of the signal transducer and activator of transcription 1(STAT1)result in four types of immunodeficiency disease with varying degrees of impaired STAT1 function:autosomal recessive(AR)complete STAT1 defi...Inborn errors of the signal transducer and activator of transcription 1(STAT1)result in four types of immunodeficiency disease with varying degrees of impaired STAT1 function:autosomal recessive(AR)complete STAT1 deficiency,AR partial STAT1 deficiency,autosomal dominant(AD)STAT1 deficiency,and AD STAT1 gain-of-function(STAT1-GOF).Of which,the STAT1-GOF mutations promote a clinical syndrome of immune dysregulation characterized by recurrent infections,especially chronic mucocutaneous candidiasis(CMC)and Talaromyces marneffei infection and predisposition to humoral autoimmunity.STAT1-GOF mutations lead to enhanced phosphorylation of STAT1(pSTAT1),delayed dephosphorylation,and impaired nuclear dephosphorylation.As a result,the development of T helper(Th)17 cells is impaired,limiting the production of interleukin(IL)-17,which plays an important role in antifungal immunity.Additionally,mutations can also cause a decrease in the proportion of CD4^(+),CD8^(+),and natural killer(NK)cells.Recent research demonstrated that in the absence of overt infection,STAT-GOF mice can disrupt naïve CD4^(+)T cell homeostasis and promote expansion and differentiation of abnormal T-follicular helper/T-helper 1-like(Tfh/Th1-like)T cells and germinal center-like(GC-like)B cells,and thus reminds us of the complex molecular mechanism of autoimmune disease with/without fungal infection,which may further involve specific clinical treatment including antifungal and anti-autoimmunity therapies.In addition,sex and location of mutation were also associated with the clinical phenotype.Individuals with DNA binding domain(DBD)mutations had a higher prevalence of autoimmunity and aberrant B cell activation.Disrupted CD4^(+)T cell homeostasis occurred sooner and more robustly in females,highlighting the importance of specific treatment to normalize STAT1 expression and restore immune tolerance in patients with STAT1-GOF syndrome.Herein,we provide a comprehensive review of STAT1-GOF aiming to further clarify the regulatory mechanism of cellular and humoral immune deficiency in patients with fungal infection with or without autoimmunity.展开更多
文摘Therapy of chronic recurrent vulvovaginal can- didiasis (VVC) caused by Candida glabrata is still rare in comparison to C. albicans infection, but therapy remains more difficult. Combination therapy with topical antifungals may improve therapy outcome, but still standard agents as fluconazole or itraconazole often fail. Posaconazole is a new systemic triazole with a wide antifungal spectrum including rare Candida species. Up to now, no clinical trials with posa- conazole in chronic recurrent VVC have been undertaken. Here, first results of the application of a new therapy regimen consisting of oral posaconazole in combination with topical ciclopiroxolamine are presented. 15 patients with chronic recurrent VVC caused by C. glabrata have been treated. 14 of these patients experienced successful therapy, clinical and mycological cure 30 days after begin of therapy has been observed. Long-term results are promising, as in 4 patients clinical and mycologic cure persists for more than 1 year up to now.
文摘Autosomal Dominant Chronic Mucocutaneous Candidiasis (AD-CMC) is characterized by defective T cell immunity, leading to fungal infections limited to mucosal surfaces. Recently it was discovered that mutations in the coiled-coil (CC) domain of STAT1 are the cause of AD-CMC. STAT1 deficiency has been implicated in experimental models of oesophageal cancer (EC) and head and neck carcinoma (HNC). Both carcinoma types are prevalent among CMC patients. Consequently, we postulated that the same mutation in the STAT1 gene triggering AD-CMC, could also be involved in oesophageal- or head and neck carcinogenesis. However we failed to identify the c.820C>T mutation in the STAT1 CC domain in 3 cohorts of Dutch Caucasian origin: being 351 EC patients, 325 HNC patients and 309 controls. Although it seems valuable to investigate the relationship between AD-CMC and upper aerodigestive neo- plasms, the c.820C>T mutation in the STAT1 gene does not seem implicated in EC and HNC aetiology.
文摘目的探讨3例慢性皮肤黏膜念珠菌病伴有自身免疫性疾病的信号传导与转录激活因子1(signal transducer and activator of transcription 1,STAT1)功能获得性突变(gain-of-function,GOF)的临床特征及基因特点。方法选取就诊阜阳市人民医院儿科的3例确诊为STAT1 GOF的患儿,对其临床特征进行分析总结,采集外周血样,运用高通量测序(high-throughput sequencing,NGS)进行基因检测,并同时进行父母的基因组DNA测序。结果3例患者均出现慢性皮肤黏膜念珠菌病、支气管扩张,并且伴有不同类型的自身免疫性疾病,基因检测证实均存在STAT1基因突变,有不同的突变位点,3个突变均属功能获得性突变,而父母基因均正常,为新发错义变异。结论STAT1 GOF新发突变易导致慢性皮肤黏膜念珠菌病合并自身免疫性疾病,并且在病程的不同时期STAT1基因突变可能伴随不同的自身免疫性疾病的表现,需定期观察,完善相关基因检测有助于早期诊断,避免漏诊及误诊。
基金supported in part by the National Science and Technology Major Project(No.2021 YFC2301803)Shenzhen Fund for Guangdong Provincial High-Level Clinical Key Specialties(No.SZGSP011)+2 种基金Science and Technology Program of Shenzhen,China(No.JCYJ 20230807143411023)the clinical research project of Shenzhen Third Peoples Hospital(No.G2022044)the Teaching Quality and Teaching Reform Project of Education Department of Guangdong Province:Experimental Teaching Demonstration Center of Emerging Infectious Diseases(Y01411846).
文摘Inborn errors of the signal transducer and activator of transcription 1(STAT1)result in four types of immunodeficiency disease with varying degrees of impaired STAT1 function:autosomal recessive(AR)complete STAT1 deficiency,AR partial STAT1 deficiency,autosomal dominant(AD)STAT1 deficiency,and AD STAT1 gain-of-function(STAT1-GOF).Of which,the STAT1-GOF mutations promote a clinical syndrome of immune dysregulation characterized by recurrent infections,especially chronic mucocutaneous candidiasis(CMC)and Talaromyces marneffei infection and predisposition to humoral autoimmunity.STAT1-GOF mutations lead to enhanced phosphorylation of STAT1(pSTAT1),delayed dephosphorylation,and impaired nuclear dephosphorylation.As a result,the development of T helper(Th)17 cells is impaired,limiting the production of interleukin(IL)-17,which plays an important role in antifungal immunity.Additionally,mutations can also cause a decrease in the proportion of CD4^(+),CD8^(+),and natural killer(NK)cells.Recent research demonstrated that in the absence of overt infection,STAT-GOF mice can disrupt naïve CD4^(+)T cell homeostasis and promote expansion and differentiation of abnormal T-follicular helper/T-helper 1-like(Tfh/Th1-like)T cells and germinal center-like(GC-like)B cells,and thus reminds us of the complex molecular mechanism of autoimmune disease with/without fungal infection,which may further involve specific clinical treatment including antifungal and anti-autoimmunity therapies.In addition,sex and location of mutation were also associated with the clinical phenotype.Individuals with DNA binding domain(DBD)mutations had a higher prevalence of autoimmunity and aberrant B cell activation.Disrupted CD4^(+)T cell homeostasis occurred sooner and more robustly in females,highlighting the importance of specific treatment to normalize STAT1 expression and restore immune tolerance in patients with STAT1-GOF syndrome.Herein,we provide a comprehensive review of STAT1-GOF aiming to further clarify the regulatory mechanism of cellular and humoral immune deficiency in patients with fungal infection with or without autoimmunity.
