Common variable immunodeficiency disorders(CVID),a heterogeneous group of inborn errors of immunity,is the most common symptomatic primary immunodeficiency disorder.Patients with CVID have highly variable clinical pre...Common variable immunodeficiency disorders(CVID),a heterogeneous group of inborn errors of immunity,is the most common symptomatic primary immunodeficiency disorder.Patients with CVID have highly variable clinical presentation.With the advent of whole genome sequencing and genome wide association studies(GWAS),there has been a remarkable improvement in understanding the genetics of CVID.This has also helped in understanding the pathogenesis of CVID and has drastically improved the management of these patients.A multiomics approach integrating the DNA sequencing along with RNA sequencing,proteomics,epigenetic and metabolomics profile is the need of the hour to unravel specific CVID associated disease pathways and novel therapeutic targets.In this review,we elaborate various techniques that have helped in understanding the genetics of CVID.展开更多
BACKGROUND Cytotoxic T Lymphocyte Antigen-4(CTLA4)deficiency is a genetic defect that causes a common variable immunodeficiency(CVID)clinical phenotype.Several studies have reported an association between CTLA mutatio...BACKGROUND Cytotoxic T Lymphocyte Antigen-4(CTLA4)deficiency is a genetic defect that causes a common variable immunodeficiency(CVID)clinical phenotype.Several studies have reported an association between CTLA mutations or variants and various autoimmune diseases.Targeted therapy models,which have become increasingly popular in recent years,have been successful in treating CTLA4 deficiency.In this article,we discuss the clinical outcomes of abatacept treatment in a patient with CTLA4 and lipopolysaccharide-responsive beige-like anchor(LRBA)variants that was previously diagnosed with CVID.CASE SUMMARY A 25-year-old female patient,who was visibly cachectic,visited our clinic over the course of five years,complaining of diarrhea.The patient was diagnosed with ulcerative colitis in the centers she had visited previously,and various treatments were administered;however,clinical improvement could not be achieved.Severe hypokalemia was detected during an examination.Her serum immunoglobulin levels,CD19+B-cell percentage,and CD4/CD8 ratio were low.An endoscopic examination revealed erosive gastritis,nodular duodenitis,and pancolitis.Histopathological findings supported the presence of immune mediated enteropathy.When the patient was examined carefully,she was diagnosed with CVID,and intravenous immunoglobulin treatment was initiated.Peroral and rectal therapeutic drugs including steroid therapy episodes were administered to treat the immune mediated enteropathy.Strict follow-ups and treatment were performed due to the hypokalemia.After conducting genetic analyses,the CTLA4 and LRBA variants were identified and abatacept treatment was initiated.With targeted therapy,the patient’s clinical and laboratory findings rapidly regressed,and there was an increase in weight.CONCLUSION The heterozygous CTLA4 variant identified in the patient has been previously shown to be associated with various autoimmune diseases.The successful clinical outcome of abatacept treatment in this patient supports the idea that this variant plays a role in the immunopathogenesis of the disease.In the presence of severe disease,abatacept therapy should be considered until further testing can be conducted.展开更多
BACKGROUND Patients with lipopolysaccharide(LPS)-responsive beige-like anchor protein(LRBA)deficiency have a variety of clinical symptoms,but there is no apparent genotype–phenotype correlation,and patients carrying ...BACKGROUND Patients with lipopolysaccharide(LPS)-responsive beige-like anchor protein(LRBA)deficiency have a variety of clinical symptoms,but there is no apparent genotype–phenotype correlation,and patients carrying the same mutations may have different phenotypes.Therefore,it is not easy for doctors to make a decision regarding hematopoietic stem cell transplantation(HSCT)for LRBA-deficient patients.We hypothesized that there may be a protein–phenotype correlation to indicate HSCT for LRBA-deficient patients.AIM To report on three Chinese LRBA-deficient patients and determine the correlation between residual protein expression and disease phenotypes.METHODS Clinical data of three Chinese LRBA-deficient patients were collected,and protein levels were detected by Western blot analysis.In addition,LRBA mutation information of another 83 previously reported patients was summarized.RESULTS All the major clinical findings indicated enteropathy,but patients 1 and 3 presented with more severe symptoms than patient 2.Endoscopy and histology indicated nonspecific colitis for patients 1 and 3 but Crohn's disease-like colitis for patient 2.Compound heterozygous mutations in LRBA were found in patient 1,and homozygous mutations in LRBA were found in patient 2 and patient 3.Only patient 2 responded well to traditional immunosuppressive treatment.Residual expression of the LRBA protein in patients 1 and 3 was very low,but in patient 2,a more than 0.5-fold in expression of the LRBA protein was found compared to that in the control.After HSCT,patient 1 had increased LRBA protein expression.We summarized the genetic information of 86 patients,and the mutations in patients 1 and 3 were novel mutations.CONCLUSION We described three Chinese LRBA-deficient patients,two of whom carried novel mutations.These patients had no genotype-phenotype correlations,but their residual LRBA protein expression might be associated with disease outcome and could be an indicator for HSCT.展开更多
文摘Common variable immunodeficiency disorders(CVID),a heterogeneous group of inborn errors of immunity,is the most common symptomatic primary immunodeficiency disorder.Patients with CVID have highly variable clinical presentation.With the advent of whole genome sequencing and genome wide association studies(GWAS),there has been a remarkable improvement in understanding the genetics of CVID.This has also helped in understanding the pathogenesis of CVID and has drastically improved the management of these patients.A multiomics approach integrating the DNA sequencing along with RNA sequencing,proteomics,epigenetic and metabolomics profile is the need of the hour to unravel specific CVID associated disease pathways and novel therapeutic targets.In this review,we elaborate various techniques that have helped in understanding the genetics of CVID.
文摘BACKGROUND Cytotoxic T Lymphocyte Antigen-4(CTLA4)deficiency is a genetic defect that causes a common variable immunodeficiency(CVID)clinical phenotype.Several studies have reported an association between CTLA mutations or variants and various autoimmune diseases.Targeted therapy models,which have become increasingly popular in recent years,have been successful in treating CTLA4 deficiency.In this article,we discuss the clinical outcomes of abatacept treatment in a patient with CTLA4 and lipopolysaccharide-responsive beige-like anchor(LRBA)variants that was previously diagnosed with CVID.CASE SUMMARY A 25-year-old female patient,who was visibly cachectic,visited our clinic over the course of five years,complaining of diarrhea.The patient was diagnosed with ulcerative colitis in the centers she had visited previously,and various treatments were administered;however,clinical improvement could not be achieved.Severe hypokalemia was detected during an examination.Her serum immunoglobulin levels,CD19+B-cell percentage,and CD4/CD8 ratio were low.An endoscopic examination revealed erosive gastritis,nodular duodenitis,and pancolitis.Histopathological findings supported the presence of immune mediated enteropathy.When the patient was examined carefully,she was diagnosed with CVID,and intravenous immunoglobulin treatment was initiated.Peroral and rectal therapeutic drugs including steroid therapy episodes were administered to treat the immune mediated enteropathy.Strict follow-ups and treatment were performed due to the hypokalemia.After conducting genetic analyses,the CTLA4 and LRBA variants were identified and abatacept treatment was initiated.With targeted therapy,the patient’s clinical and laboratory findings rapidly regressed,and there was an increase in weight.CONCLUSION The heterozygous CTLA4 variant identified in the patient has been previously shown to be associated with various autoimmune diseases.The successful clinical outcome of abatacept treatment in this patient supports the idea that this variant plays a role in the immunopathogenesis of the disease.In the presence of severe disease,abatacept therapy should be considered until further testing can be conducted.
文摘BACKGROUND Patients with lipopolysaccharide(LPS)-responsive beige-like anchor protein(LRBA)deficiency have a variety of clinical symptoms,but there is no apparent genotype–phenotype correlation,and patients carrying the same mutations may have different phenotypes.Therefore,it is not easy for doctors to make a decision regarding hematopoietic stem cell transplantation(HSCT)for LRBA-deficient patients.We hypothesized that there may be a protein–phenotype correlation to indicate HSCT for LRBA-deficient patients.AIM To report on three Chinese LRBA-deficient patients and determine the correlation between residual protein expression and disease phenotypes.METHODS Clinical data of three Chinese LRBA-deficient patients were collected,and protein levels were detected by Western blot analysis.In addition,LRBA mutation information of another 83 previously reported patients was summarized.RESULTS All the major clinical findings indicated enteropathy,but patients 1 and 3 presented with more severe symptoms than patient 2.Endoscopy and histology indicated nonspecific colitis for patients 1 and 3 but Crohn's disease-like colitis for patient 2.Compound heterozygous mutations in LRBA were found in patient 1,and homozygous mutations in LRBA were found in patient 2 and patient 3.Only patient 2 responded well to traditional immunosuppressive treatment.Residual expression of the LRBA protein in patients 1 and 3 was very low,but in patient 2,a more than 0.5-fold in expression of the LRBA protein was found compared to that in the control.After HSCT,patient 1 had increased LRBA protein expression.We summarized the genetic information of 86 patients,and the mutations in patients 1 and 3 were novel mutations.CONCLUSION We described three Chinese LRBA-deficient patients,two of whom carried novel mutations.These patients had no genotype-phenotype correlations,but their residual LRBA protein expression might be associated with disease outcome and could be an indicator for HSCT.
