Research progress of primary immunodeficiency disease with hyper IgE syndrome / 中华实用儿科临床杂志

The hyper IgE syndrome (HIES) is a rare primary immunodeficiency disorder characterized by atopic dermatitis, recurrent skin and lung infections along with elevated IgE levels.The JOB syndrome due to heterozygous loss-of-function mutations in the signal transduction and transcription activator-3(STAT3) gene is the prototype of HIES.However, several other immunodeficiency disorders with the phenotype of HIES have been identified over the past decade.This study aims to review these disorders and their molecular mechanisms, aiming to improve the understanding of this rare disease.

Observation of efficacy of allogeneic hematopoietic cell transplantation using unrelated cord blood or haploidentical donors in children with primary immunodeficiency diseases / 中华实用儿科临床杂志

Objective:To evaluate the efficacy of allogeneic hematopoietic cell transplantation(allo-HSCT) using unrelated cord blood or haploidentical donors in the treatment of children with primary immunodeficiency diseases (PID).Methods:The clinical data of 60 children with PID admitted to Chinese People′s Liberation Army General Hospital-Sixth Medical Center from April 2014 to October 2019 were retrospectively analyzed, including 56 cases of chronic granulomatous disease, 2 cases of severe combined immunodeficiency disease, 1 case of high-IgM syndrome and 1 case of severe congenital neutropenia.All patients underwent allo-HSCT, including 12 cases receiving the transplantation from unrelated cord blood (UCB group) and 48 cases from haploidentical donors combined with a third party unrelated cord blood (haploid group). Among these patients, there were 59 males and 1 female, with a median age of 3.4 years.All patients received a myeloablative conditioning regimen based on Busulfan.The prophylaxis of acute graft versus host disease (aGVHD) was performed based on Cyclosporine.In the UCB group, the median dose of mononuclear cells and CD 34+ cells was 0.67×10 8/kg and 0.51×10 6/kg recipient body weight, respectively; In the haploid group, bone marrow and peripheral stem cells from haploid donors were infused on day 01 and day 02, respectively.The third party cord blood was infused 4 hours before bone marrow infusion.The median dose of mononuclear cells and CD 34+ cells of bone marrow and peripheral stem cells from haploid donors was 9.97×10 8/kg and 5.12×10 6/kg recipient body weight, respectively.Kaplan-Meier method was used to analyze the overall survival rate. Results:The median day to neutrophil and platelet engraftment was 13.0 days and 23.5 days, respectively.The rate of complete donor chime-rism was shown 30.0 days after transplantation.There was no case with primary engraftment failure, and 1 case with secondary engraftment failure.The incidence of grade Ⅰ-Ⅱ and grade Ⅲ-Ⅳ aGVHD was 43.3% and 15.5%, respectively.The incidence of chronic graft versus host disease with limited skin type was 6.7%, while that with extensive type was 1.1%.The median follow-up period was 818 days.There were 6 death cases, among which, 5 cases died from infection and 1 case died from heart failure.The total mortality related to transplantation was 11.9%.A total of 53 cases survived without diseases.The estimated 5-year failure free survival and overall survival rate was 83.9% and 88.1%, respectively.Conclusion:The efficacy of allo-HSCT in the treatment of children with PID using unrelated cord blood and haploidentical donors is favorable.

Clinical effect of allogeneic hematopoietic stem cell transplantation in children with hyper-IgM syndrome / 中国当代儿科杂志

OBJECTIVES@#To evaluate the clinical effect of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in children with hyper-IgM syndrome (HIGM).@*METHODS@#A retrospective analysis was performed on the medical data of 17 children with HIGM who received allo-HSCT. The Kaplan Meier method was used for the survival analysis of the children with HIGM after allo-HSCT.@*RESULTS@#After allo-HSCT, 16 children were diagnosed with sepsis; 14 tested positive for virus within 100 days after allo-HSCT, among whom 11 were positive for Epstein-Barr virus, 7 were positive for cytomegalovirus, and 2 were positive for JC virus; 9 children were found to have invasive fungal disease. There were 6 children with acute graft-versus-host disease and 3 children with chronic graft-versus-host disease. The median follow-up time was about 2 years, and 3 children died in the early stage after allo-HSCT. The children had an overall survival (OS) rate of 82.35%, an event-free survival (EFS) rate of 70.59%, and a disease-free survival (DFS) rate of 76.47%. The univariate analysis showed that the children receiving HLA-matched allo-HSCT had a significantly higher EFS rate than those receiving HLA-mismatched allo-HSCT (P=0.019) and that the children receiving HLA-matched unrelated allo-HSCT had significantly higher OS, EFS, and DFS rates than those receiving HLA-mismatched unrelated allo-HSCT (P<0.05). Compared with the children with fungal infection after allo-HSCT, the children without fungal infection had significantly higher EFS rate (P=0.02) and DFS rate (P=0.04).@*CONCLUSIONS@#Allo-HSCT is an effective treatment method for children with HIGM. HLA-matched allo-HSCT and active prevention and treatment of fungal infection and opportunistic infection may help to improve the prognosis of such children.

Clinical features and diagnostic progress of activated phosphoinositide 3-kinase δ syndrome / 中国综合临床

Activated phosphoinositide 3-kinase δ syndrome(APDS) is an autosomal dominant inherited primary immunodeficiency disease that is caused by mutations in PIK3CD or PIK3R1 genes leading to overactivation of the PI3Kδ signaling pathway, first reported by Angulo et al in 2013. The clinical manifestations of the disease are recurrent respiratory tract infections, benign lymph node hyperplasia, autoimmune diseases, lymphoma and so on. Although most patients develop the disease in childhood, there are also reports of adult onset and asymptomatic patients. In addition, the immunophenotype of activated phosphoinositide 3-kinase δ syndrome is changeable, usually the IgA levels are reduced, the IgM levels can be normal or elevated, and the IgG levels are variable, so it is easy to be misdiagnosed at first diagnosis. There is no unified diagnostic standard at present, and timely genetic testing is required to confirm the diagnosis.

Advances in phenotyping activated phosphoinositide 3-kinase-delta syndrome type 1 and type 2 / 国际儿科学杂志

Activated phosphoinositide 3-kinase-delta syndrome(APDS) is a rare autosomal dominant primary immunodeficiency disease.According to mutation types, APDS is divided into two types, APDS1 and APDS2.APDS1 patients have more susceptibility to develop bronchiectasis, sinusitis, hepatomegaly, splenomegaly, asthma, autoimmune or inflammatory diseases, and are more frequently infected with Streptococcus pneumoniae and Haemophilus influenzae, while APDS2 patients are more prone to get pneumonia, eye infection, and lymphadenopathy, malignancy, neurological and growth retardation.Among the immunological features, the T cell count of APDS1 is significantly low, and APDS2 is more obvious to appear elevated IgM levels.Rapamycin is beneficial for both types of APDS, and Leniolisib is better tolerated in patients with APDS1.This article reviews the differences in pathogenesis, clinical manifestations, immunological characteristics, and treatment between APDS1 and APDS2 to improve the understanding by clinicians.

Analysis of lymphocyte subsets and clinical characteristics in children with abnormal reaction to Bacillus Calmette-Guérin vaccination / 国际儿科学杂志

Objective:To investigate the lymphocyte subsets and clinical characteristics of children with abnormal reaction to Bacillus Calmette-Guérin(BCG)vaccination.Methods:A total of 35 children with BCG disease diagnosed in the Children′s Hospital Affiliated to Xi′an Jiaotong University from January 2013 to December 2019 were enrolled retrospectively.Patients with strong local reaction and lymphadenitis after vaccine injection were selected as the localized group, and with lymphadenitis complicated with distant organ involvement were classified as the disseminated group.The differences in clinical infection indicators, demographic data, lymphocyte subsets and prognosis between the two groups were compared.Results:There are 25 cases in the localized group and 10 cases in the disseminated group, male 20 cases and female 15 cases.Compared with the localized group, the incidence of cough, fever and growth retardation all increased in the disseminated group, with statistical significance(all P<0.05). Lymphocyte ratio[(61.14±18.61)% vs.(39.64±31.45)%], T lymphocytes [CD3 + (×10 6/L): (1 821±487)vs.(1 065±539)], helper/inducible T lymphocytes[CD3 + CD4 + (×10 6/L): (1 058±357)vs.(445±140)], double positive T lymphocytes[CD3 + CD4 + CD8 + (×10 6/L): (24.07±7.17)vs.(14.10±8.89)], CD4 + /CD8 + ratio[CD4 + /CD8 + (%): (1.65±0.73)vs.(1.00±0.25)], natural killer cells[CD16 + CD56 + (×10 6/L): (19.70±2.34)vs.(12.76±7.01)]were lower in the disseminated group than those in the localized group and the differences were significant(all P<0.05). In the disseminated group, 6 cases were diagnosed with immunodeficiency disease and 7 cases died during the follow-up period.All the children in the localized group were cured. Conclusion:Most BCG reaction have a good prognosis, while disseminated children combined with primary immune deficiency have worst prognosis.Early lymphocyte subsets analysis is effective for BCG disease screening.

Progress of screening for primary immunodeficiency diseases in neonates / 中国小儿急救医学

Primary immunodeficiency disease (PID) is a disease that seriously affects children′s life and health.Early identification and timely intervention can significantly improve prognosis.Some PIDs appear clinical warning symptoms in neonatal period, which help clinicians to carry out early recognition.However, there are still great challenges in early detection of PIDs.At present, there are PID screening methods based on dried blood spots, including TREC screening for SCID and other T lymphocytopenia diseases, KREC screening for XLA and other B-lymphocytopenia diseases, and multiplex protein profiling screening for complement and phagocyte deficiencies.With the development of gene sequencing, next generation sequencing(NGS) has a good prospect in the application of newborn PID screening.Therefore, it is urgent to establish screening process of Chinese newborn PID.This review elaborated on the progress of newborn PID screening.

Clinical and genetic characteristics and differential diagnosis in children with autosomal dominant hyper-IgE syndrome / 中华实用儿科临床杂志

Objective:To summarize the clinical features of children with autosomal dominant hyper-IgE syndrome (AD-HIES) and the differential diagnosis of hyper-IgE syndrome and allergic diseases as well.Methods:All clinical data, including general information, clinical features, and genetic changes, from 7 children with AD-HIES who were diagnosed in Beijing Children′s Hospital Affiliated to Capital Medical University from April 2016 to June 2020 were analyzed retrospectively.The diagnostic criteria are based on the National Institutes of Health′s (NIH)′s hyper-IgE syndrome score and combined with the results of gene detection, shown as follows: (1) NIH score over 40, with signal transducer and activator of transcription 3 gene ( STAT3) pathogenic mutation; (2) NIH score between 20 and 40, with reported STAT3 pathogenic mutation; (3) NIH score less than 20 points was excluded. Results:There were 3 males and 4 females.The onset age of 7 cases was within 2 months after birth, and the mean age at diagnosis was 3 years old.All seven cases had recurrent skin or lung infections, with 4 cases having skin and lung infections, 1 case of skin abscesses at the BCG vaccination site, and 2 cases without skin infection suffering from recurrent pneumonia.The mean onset age of skin abscess in 5 cases was 1.5 years, and pus culture of 3 cases were Staphylococcus aureus.Four cases developed bullae and 6 cases had lung infections.Four cases had otitis media, and oral thrush was seen in 4 cases.One case of skin and lung infection developed liver abscess and sepsis.Seven cases had eczema, which was disco-vered in the neonatal period for 6 cases.Four cases had the symptoms of eczema for the first visit.Two cases had food allergy, and 1 case had recurrent wheezing within 1 year old.The serum IgE level and blood eosinophil count in 7 children were elevated.All children had heterozygous pathogenic mutations in STAT3.Six patients had de novo mutations.There were 6 different mutation sites.The 4 mutation sites were reported: c.1145G>A, c.1144C>T, and c. 1699A>G were missense mutations, and c. 1139+ 5G>A was splicing mutation.Two mutation sites had not been reported: c.1031A>C was missense mutation, and c. 2050G>T was nonsense mutation.The pathogenic grade of them were likely pathogenic, and the NIH score of 2 cases were above 40 score, which was consistent with the clinical diagnosis of hyper-IgE syndrome. Conclusions:Eczema is a common and early clinical manifestation of hyper-IgE syndrome, along with elevated IgE levels and eosinophil counts that need to be differentiated from allergic diseases.On the contrary, it often had recurrent skin abscesses or pneumonia, which was prone to bullae.The clinical manifestations of young children were atypical, and genetic testing was helpful for early diagnosis.

Common variable immune deficiency in adult patients: analysis of 13 cases and literature review / 南方医科大学学报

OBJECTIVE@#To investigate the clinical and immunological characteristics, treatment and prognosis of common variable immune deficiency (CVID) in adult patients.@*METHODS@#We retrospectively analyzed the clinical data of 13 adult patients hospitalized in our hospital for CVID diagnosed according to the criteria in International Consensus Document (2016), and analyzed their clinical manifestations, laboratory test results, imaging findings, pathological examinations and treatments.@*RESULTS@#The mean age of onset was 24.46±16.82 years in these patients, who had a mean age of 32.54±14.86 years at diagnosis with a median diagnostic delay of 5 years (IQR: 2-15 years). The main manifestation of the patients was repeated infections, including repeated respiratory tract infection (10 cases; 76.9%) and repeated diarrhea (3 cases; 23.1%). Three (23.1%) of the patients had autoimmune disease and 10 (76.9%) had chronic pulmonary disease. IgG, IgA and IgM were decreased in all the patients. The proportion of CD4+T cells decreased in 10 patients (76.9%), CD8+T cells increased in 11 patients (84.6%), and CD4/ CD8 decreased in 10 patients (76.9%). Complement C3 decreased in 58.3% (7/12) and C4 decreased in 33.3% (4/12) of the patients. Twelve patients (92.3%) were treated with intravenous infusion of gamma globulin with symptomatic treatments. One patient died due to massive gastrointestinal hemorrhage, and the other patients showed improve ments after the treatments and were discharged.@*CONCLUSIONS@#The clinical manifestations of CVID are diverse, and recurrent respiratory tract infection is the most common manifestation. Decreased IgG often accompanied by lowered IgA and IgM levels is a common finding in laboratory tests. The treatment of CVID currently relies on gamma globulin with symptomatic treatments for the complications.

Mutation of CTLA-4 causes primary immunodeficiency disease: One case report / 中国免疫学杂志

The main biological function of cytotoxic T cell-associated protein 4 (CTLA-4) is to suppress the T cell response and suppress the immune response, and its mutation will cause a series of immune related abnormalities. This case reports a rare case of onset of lymphocytosis, immune hemolysis, repeated infection, and other similar symptoms of autoimmune lymphoproliferative syndrome which caused by CTLA4 Exon2 c. 151 C＞T mutation. Sequencing validation was performed to clarify the source of gene mutation. We review the pathogenesis of CTLA4 and new progress in treatment in this case, and the follow-up treatment for the patient was prospected.

Clinical analysis of 10 cases of severe combined immunodeficiency disease / 中国小儿急救医学

Objective To improve the pediatrician's understanding of severe combined immunodefi-ciency disease (SCID),so as to strengthen the early diagnosis and treatment of SCID. Methods The clinical manifestations,related immunological findings,imaging findings and outcomes of 10 SCID children admitted to our hospital from 2007 to 2018 were retrospectively analyzed. Results The clinical manifestations of primary SCID were frequent infections shortly after birth. There were 8 males and 2 females in this study. The average age of onset was 4. 2 months,and the average age of diagnosis was 6 months. Eight cases of thymus shadow were absent,9 cases of pulmonary CT showed severe pneumonia,and 3 cases of pulmonary fungal infection. Six of 7 children died of infection and the age of death was less than 1 year old. Laboratory exami-nation showed that 10 patients had abnormal cell and humoral immune function;10 cases of CD3 +T cells were <20%,3 cases of CD16 +CD56 +( NK%) >85%,7 cases ≤ 2%. There was an increase in B cell reactivity of 7 cases,but the secretion of immunoglobulin in 5 cases was significantly reduced. Seven cases of IgG<2. 0 g/L,3 cases>2. 0 g/L. Eight cases were confirmed of the primary SCID by genetic testing. Con-clusion The clinical manifestations of SCID are frequent bacterial,viral and fungal infections in a short time after birth. In clinical work,when small infants are repeatedly infected after birth,or multiple sites are serious-ly infected and prolonged,we must think of the possibility of SCID and timely related immune function tests, strive to achieve early diagnosis,timely treatment,and early bone marrow stem cell transplantation.

Diagnosis and treatment of atypical severe combined immunodeficiency disease in 7 children / 临床儿科杂志

Objective To explore the diagnosis and treatment of atypical severe combined immunodeficiency disease (SCID). Methods The clinical data of atypical SCID in 7 children with IL2RG,JAK3,and RAG1 mutations were reviewed and analyzed from September 2012 to June 2017. Results In 7 cases (6 males and 1 female), there were 5 infants, 1 toddler and 1 school-age child. Cases 2, 4, and 6 were classic SCID clinical phenotypes. Cases 1, 3, 5, 7 were atypical SCID clinical phenotypes. Case 6 were diagnosed with Omenn syndrome. Cases 2, 5 were classic SCID immune phenotypes, cases 1, 3, 4, 6, 7 were atypical SCID immune phenotypes, and case 1 had maternal chimera. The next generation sequencing indicated that case 1 had a compound heterozygous JAK3 mutation with c.3097-1G>A/c.946-950GCGGA>ACinsGGT.Cases 2,3,and 4 had IL2RG mutations,with c.865C>T/p.R289X,c.664C>T/R222C,52delG,respectively.Case 5 had JAK3 mutations with c.2150A>G/p.E717G and c.1915-2A>G.Sanger sequencing indicated that case 6 had a RAG1 mutation of complex heterozygosity with c.994C>T/p.R332X and c.1439G>A/p.S480N. Case 7 had homozygous RAG1 mutation with c.2095C>T/p.R699W.Conclusion Under certain conditions,gene mutation can lead to atypical clinical and/or immune phenotypic SCID.

Analysis of clinical phenotype and genetic diagnosis in patients with Omenn syndrome / 临床儿科杂志

Objective To investigate the clinical features and genetic change of Omenn syndrome. Method Clinical data of two sporadic patients with Omenn syndrome and their family members were collected, and next generation sequencing was used to analyze immunodeficiency associated genes. Results Two patients (one boy and one girl) had a history of recurrent infection and skin rash. The level of IgA, IgM and IgG was decreased. Both of them have a lower level of CD8+T lymphocytes and CD19+B lymphocytes, but the number of NK cells increased. Sequencing found a homozygous mutation (c.1211G>A) in RAG1 gene in the girl,and both her father and mother were heterogeneous carrier of this mutation.In the boy,we found novel compound heterozygous mutations,c.830A>G and c.104G>C in RAG2R gene,inherited from his mother and father,respectively. Bioinformatics predicts that these two mutations are likely to be pathogenic. Conclusions The age of Omenn syndrome onset was earlier, with compromised immunological function. Gene detection was helpful for early diagnosis. We found that two novel mutations in RAG2R could cause Omenn syndrome.

Clinical features and genetic characteristics of primary immunodeficiency disease with skin symptoms in 15 children / 临床儿科杂志

Objective To explore the clinical features and genetic characteristics of primary immunodeficiency disease (PIDs) with skin symptoms in children. Methods The clinical data of PIDs with skin symptoms in 15 children from January 2014 to March 2017 were analyzed retrospectively. Results The median age at onset in 15 children was 4 months (neonatal period to 11 years 8 months). All of them showed obvious skin symptoms, including eczema or chilblain rash, pustular psoriasis, skin infections, subcutaneous hemorrhage or skin ecchymosis, ichthyosiform erythroderma, progeroid appearance, or other cutaneous vasculitis. The accompanying manifeslations included recurrent infections, auto inflammation, autoimmunity, growth retardation, or lymphoid proliferation, and impairment of brain, lung, kidney and other important organs. Eosinophil counts were increased in 5 children, IgE levels were elevated in 5 children, and 4 children were abnormal in both indicators. Gene detection showed WAS, RNASEH2C, NLRP12, IL36RN, NRAS, PIK3CD, STAT1, FOXP3, STAT3, DOCK8, TYK2, SPINK5, NBAS or ITGB2 gene mutations, respectively. Two children died from multiple organ dysfunction syndrome, 1 child was lost for follow up, the remaining 12 children survived and were under the individualized treatment. Conclusions A variety of PIDs can have skin symptoms. When accompanied by recurrent infections, auto inflammation, autoimmune, growth retardation, or lymph proliferation, PIDs should be considered, and gene detection is helpful for the diagnosis.

Gene diagnostic method for primary immunodeficiency disease based on targeted panel sequencing / 上海交通大学学报（医学版）

Objective · To design and build a high-throughput sequencing approach based on targeted panel sequencing (TPS) using for the primary immunodeficiency disease (PID) diagnosis. Methods · By reviewing the literature and querying the relevant databases to determine the known diseasecausing genes of PID, capture probes using for the TPS were designed and customized for all exons and flanking sequences of these genes. A child suspected with PID was diagnosed by the customized TPS. Results · The PID sequencing panel contains a total of 100 known pathogenic genes. The sequencing data of the patient has 16414298 reads. The average coverage depth is 157 X, 98.35% of the target region sequencing depth is greater than 20 X, and 99.97% of the target region sequencing depth is greater than 1 X. Finally, a heterozygous nonsense mutation was found in the exon 2 of the CXCR4 gene (c.1000C>T, p.Arg334*) in the child. The results of Sanger sequencing confirmed the variation in the child and showed that his parents were wildtype at the corresponding sites, indicating the mutation is de novo. Conclusion · This study established a high-throughput sequencing diagnostic approach for PID, with which a case of WHIM syndrome was successfully diagnosed.

Treatment of umbilical cord blood transplantation in pediatric rare diseases / 中华实用儿科临床杂志

Rare diseases are very rare,but usually have severe symptoms.Some rare diseases are life-threatening.Most rare diseases cannot be cured.A very small part of these diseases can be cured by hematopoietic stem cell transplantation (HSCT).Umbilical cord blood transplantation(UCBT) is more suitable for children for the weak T cell immunity,the lower request for human leukocyte antigen (HLA) identity type and the lower incidence of graft versus host disease(GVHD).This article reviewed the published data in the treatment of UCBT in primary immunodeficiency disease,inherited metabolic disease,inflammatory bowel disease and bone marrow failure syndrome,in order to improve the level of rare disease treatment by HSCT,especially for UCBT.

Progress of diagnosis and treatment for Wiskott-Aldrich syndrome / 中华实用儿科临床杂志

Wiskott-Aldrich syndrome (WAS) is due to the mutation of the WAS gene on the X chromosome,which has both features of primary immunodeficiency disease (PID) and congenital hereditary hematopoietic disease.Although the clinical manifestations of classic WAS were more obvious,the related gene (WAS) and its protein product (WASP) have the value of diagnosis,but due to the low incidence,and there were significant differences in the severity of clinical symptoms of the patients,so WAS is easily misdiagnosed.This article through collecting and analyzing the recent years of research progress of literature data and the clinical reports,and combined with the author＇s previous experience in the diagnosis and treatment,to induct the main points of diagnosis and treatment for WAS.

Vaccine immunization in children with primary immunodeficiency diseases / 中华实用儿科临床杂志

Primary immunodeficiency diseases (PID)are a heterogeneous group of congenital and genetically determined conditions caused by one or more defects of innate and/or adaptive immunity,which are a common retarding factor of vaccines immunization.The infections,however,play a major role in the final prognosis of most PID.The immune response after the vaccine injection may be impaired in some PID cases,even no protection is evoked.Moreover,some disease caused by the live vaccine virus or bacteria strains could occur after immunization.The contents of this paper is to introduce the consensus of the vaccine immunization based on the category of PID,immunization of the contacts and other concerns.

Establishment of Chinese patient online database and registry system for primary immunodeficiency diseases / 中华实用儿科临床杂志

Primary immunodeficiency disease (PID) are rare diseases caused by inherent defects of the immune system,the main clinical manifestations are increased susceptibility to infections,autoimmune diseases and malignancies.For such rare diseases,it's essential to establish national patient online database for collaborative studies.By using hypertext preprocessor (PHP) and MySQL,the database and registration system are successfully set up,and itcould complete inquiries for the information saving,export,query,retrieval,backup etc.This database includes patient's information on the diagnosis,clinical manifestations,laboratory examinations,treatments.Through communication and information-sharing between multiple centers,it creates a basis for nationwide research on PID.

STAT1 mutations associated with primary immunodeficiency diseases / 国际儿科学杂志

STAT1 plays a central role in multiple intracellular signal transduction pathways.STAT1 gene mutations have led to four types primary immunodeficiency disease,including.autosomal recessive (AR) complete STAT1 deficiency,AR partial STAT1 deficiency,autosomal dominant (AD) STAT1 deficiency,and AD gain of STAT1 activity.The first three diseases due principally to the impairment of IFN-γ-mediated and/or IFN-α/β-mediated immunity.Different from common primary immunodeficiency diseases,AD gain of STAT1 function probably due to an enhancement of IFN-a/b-mediated immunity.This article reviews the pathogenesis,clinical manifestations,diagnosis and treatments of inborn errors of human STAT1 immunity.