Genetics of severe combined immunodeficiency

Severe Combined Immunodeficiency(SCID)is an inherited group of rare,lifethreatening disorders due to the defect in T cell development and function.Clinical manifestations are characterised by recurrent and severe bacterial,viral,and fungal opportunistic infections that start from early infancy period.Haematopoietic stem cell transplantation(HSCT)is the treatment of choice.The pattern of inheritance of SCID may be X-linked or autosomal recessive.Though the diagnosis of SCID is usually established by flow cytometry-based tests,genetic diagnosis is often needed for genetic counselling,prognostication,and modification of pre-transplant chemotherapeutic agents.This review aims to highlight the genetic aspects of SCID.

Gene therapy and genome editing for primary immunodeficiency diseases

In past two decades the gene therapy using genetic modified autologous hematopoietic stem cells(HSCs)transduced with the viral vector has become a promising alternative option for treating primary immunodeficiency diseases(PIDs).Despite of some pitfalls at early stage clinical trials,the field of gene therapy has advanced significantly in the last decade with improvements in viral vector safety,preparatory regime for manufacturing high quality virus,automated CD34 cell purification.Hence,the overall outcome from the clinical trials for the different PIDs has been very encouraging.In addition to the viral vector based gene therapy,the recent fast moving forward developments in genome editing using engineered nucleases in HSCs has provided a new promising platform for the treatment of PIDs.This review provides an overall outcome and progress in gene therapy clinical trials for SCID-X,ADA-SCID,WAS,X-CGD,and the recent developments in genome editing technology applied in HSCs for developing potential therapy,particular in the key studies for PIDs.

Activity of superior interferon α against HIV-1 in severe combined immunodeficient mice reconstituted with human peripheral blood leukocytes

Background Interferon （IFN） can inhibit human immunodeficiency virus type 1 （HIV-1） replication in vitro and in clinic.However, IFN therapy for HIV infection was limited by its moderate antiviral efficacy and its frequent adverse effects. In the present study we evaluated the anti-HIV efficacy of a novel synthesized superior interferon α （slFNα）.Methods We performed in vitro experiments with HIV-1 IIB infected MT4 cells, and evaluated in vivo anti-HIV efficacy of slFNα in severe combined immunodeficient （SClD） mice reconstituted with human peripheral blood leukocytes （hu-PBL-SClD mice）.Results We found that the 50% effective concentrations （EC5o） of slFNα against the replication of HIV-1 in MT4 cells was 0.06 ng/ml, representing stronger antiviral activity than interferon-α in vitro. In the hu-PBL-SCID mice, a dose-dependent protection pattern was observed： with 0.45 μg and 1.35 μg slFNα daily treatments, parts of SCID mice were protected from HIV infection, whereas 2.25 μg sIFNα daily treatments resulted in a terminally complete protection.Conclusions slFNα shows good anti-HIV activity both in vitro and in SCID mice, may be a promising anti-HIV agent deserving clinical investigation, especially considering the potential of IFN-α to inhibit HIV replication in patients infected with drug-resistant variants or co-infected with hepatitis C virus （HCV）.

Delayed-onset adenosine deaminase deficiency with a novel synonymous mutation and a case series from China

Background Adenosine deaminase(ADA)is a key enzyme in the purine salvage pathway.Genetic defects of the ADA gene can cause a subtype of severe combined immunodeficiency.To date,few Chinese cases have been reported.Methods We retrospectively reviewed the medical records of patients diagnosed with ADA deficiency in Beijing Children's Hospital and summarized the previously published ADA deficiency cases from China in the literature.Results Nine patients were identified with two novel mutations(W272X and Q202=).Early-onset infection,thymic abnor-malities and failure to thrive were the most common manifestations of Chinese ADA-deficient patients.The ADA genotype has a major effect on the clinical phenotype.Notably,a novel synonymous mutation(c.606G>A,p.Q202=)was identified in a delayed-onset patient,which affected pre-mRNA splicing leading to a frameshift and premature truncation of the protein.Furthermore,the patient showed γδT cells expansion with an increased effect or phenotype,which may be associated with the delayed onset of disease.In addition,we reported cerebral aneurysm and intracranial artery stenosis for the first time in ADA deficiency.Five patients died with a median age of four months,while two patients received stem cell transplantation and are alive.Conclusions This study described the first case series of Chinese ADA-deficient patients.Early-onset infection,thymic abnormalities and failure to thrive were the most common manifestations in our patients.We identified a synonymous muta-tion that affected pre-mRNA splicing in the ADA gene,which had never been reported in ADA deficiency.Furthermore,we reported cerebral aneurysm in a delayed-onset patient for the first time.Further study is warranted to investigate the underlying mechanisms.

Clinical phenotype of a Chinese patient with RIPK1 deficiency due to novel mutation

Accumulating evidence indicates that RIPK1 is associated with inflammation and apoptotic.RIPK1 deficiency leads to proinflammatory signaling impaired.However,only few patients with homozygous loss-of-function mutation in RIPK1 gene had been reported until now.Here,we report a Chinese combined immunodeficiency patient.He had recurrent infection,diarrhea after 3 months old.Immune function indicated that T,B and NK cells decreased significantly but immunoglobulins approximately remained normal.Whole-exome sequencing indicated that he had novel compound heterozygous mutations(c.998 C>A from his mother and c.1934 C>T from his father)in RIPK1 gene,which were confirmed by Sanger sequencing.Our study reports novel mutations in RIPK1 gene and new phenotype of patient with RIPK1 deficiency.