Manish Butte

E1021K Homozygous Mutation in PIK3CD Leads to Activated PI3K-Delta Syndrome 1.

J Clin Immunol. 2020 Jan 17;:

Authors: Wang Y, Chen X, Yang Q, Tang W, Jia Y, Zhou L, An Y, Zhang Z, Tang X, Zhao X

Abstract
PURPOSE: Activated PI3Kδ syndrome 1 is a primary immunodeficiency disease, usually caused by heterozygous mutations in PIK3CD. We aimed to identify the cause of homozygous mutation at c.G3061A (p.E1021K) in a patient and the effect of allele dose in this mutation.
METHODS: Genomic DNA from the parent-child trio was analyzed by next-generation sequencing. We performed phenotypic analyses in the patient and in Pik3cdE1024K+/+ mice.
RESULTS: The patient was a girl harboring a homozygous mutation for p.E1021K in PIK3CD. At the age of 2 months, she began experiencing respiratory tract infections and lymphoproliferation, accompanied by bronchiectasis and extensive atelectasis in the lungs. She suffered from Haemophilus influenzae and Cytomegalovirus infections and experienced restricted growth and development. Whole-exome sequencing showed a region that included PIK3CD, with loss of heterozygosity (LOH) in chromosome 1 of the patient. The patient had not inherited any allele from her father in the LOH region. Copy number variation analysis showed no changes in the patient’s father and the patient. Ultra-deep sequencing of genomic DNA from the patient’s mother showed that the mutant allele frequency for c.G3061A was 1.64%. Thus, the presence of segmental maternal uniparental disomy and maternal gonosomal mosaicism resulted in the homozygous mutation. Lymphadenopathy, differentiation of activated T cells, and follicular B cells lymphopenia were found to be more prominent in Pik3cdE1024+/+ mice than in Pik3cdE1024+/- mice.
CONCLUSION: This report showed the coexistence of uniparental disomy and mosaicism in PIK3CD. Some immunological features were seen to be allele dose-dependent in the presence of p.E1021K mutation.

PMID: 31953711 [PubMed – as supplied by publisher]

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Increased activation of PI3 kinase-δ predisposes to B cell lymphoma.

Blood. 2020 Jan 15;:

Authors: Durandy A, Kracker S

Abstract
Activated PI3-kinase-δ syndrome (APDS) is a rare primary combined immunodeficiency caused by either dominant gain-of-function mutations in the PIK3CD gene encoding the catalytic subunit p110δ of phosphoinositide 3-kinase-δ (PI3K-δ) (referred to as type 1 APDS) or dominant loss-of-function mutations in the PIK3R1 gene encoding the p85α, p55α and p50α regulatory subunits (type 2 APDS). In types 1 and 2 APDS, the PI3K-δ hyperactivity resulting from the gene mutations leads to similar clinical presentations – characterized by increased susceptibility to bacterial and viral infections, and (to a lesser extent) by auto-immune manifestations. A hallmark of this disease is the occurrence of lymphoproliferation, which may even be life-threatening and require repeated surgical treatment. A major complication of APDS is the occurrence of malignancy (especially B lymphomas), which greatly worsens the prognosis. Here, we review the different neoplastic conditions observed in patients with APDS, and discuss the uncontrolled PI3K-δ activity in B and T cells that leads to malignant transformation.

PMID: 31942637 [PubMed – as supplied by publisher]

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Introduction to a Review Series on Understanding and Treating Primary Immunodeficiency.

Blood. 2020 Jan 15;:

Authors: Stevenson FK, Bollard CM

PMID: 31942630 [PubMed – as supplied by publisher]

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Virus specific T-cell Therapies for Patients with Primary Immune Deficiency.

Blood. 2020 Jan 15;:

Authors: Keller MD, Bollard CM

Abstract
Viral infections are common and are potentially life-threatening in patients with moderate to severe primary immunodeficiency disorders. Since T-cell immunity contributes to the control of many viral pathogens, adoptive immunotherapy with virus-specific T-cells has been a logical and effective way of combating severe viral disease in immunocompromised patients in multiple phase I and II clinical trials. Common viral targets include cytomegalovirus, Epstein-Barr virus, and adenovirus, though recent published studies have successfully targeted additional pathogens, including HHV6, BK virus and JC virus. Though most studies have utilized VSTs derived from allogenic stem cell donors, the use of banked VSTs derived from partially HLA-matched donors has shown efficacy in multi-center settings. Hence, this approach could shorten the time for patients to receive VST therapy thus improving accessibility. In this review, we discuss the usage of VSTs for patients with PID in clinical trials, as well as future potential targets and methods to broaden the applicability of virus-directed T-cell immunotherapy for this vulnerable patient population.

PMID: 31942610 [PubMed – as supplied by publisher]

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Improved transplant survival and long-term disease outcome in children with MHC class II deficiency.

Blood. 2020 Jan 13;:

Authors: Lum SH, Anderson C, McNaughton P, Engelhardt KR, MacKenzie B, Watson H, Al-Mousa HA, Al Herz W, Al-Saud B, Mohammed R, Al-Zahrani DM, AlGhamdi H, Goronfolah L, Nademi Z, Habibollah S, Flinn AM, Shillitoe B, Owens S, Williams E, Emonts M, Hambleton S, Abinun M, Flood T, Cant A, Gennery AR, Slatter M

Abstract
Major histocompatibility complex (MHC) class II deficiency is a rare but life-threatening primary combined immunodeficiency. Hematopoietic cell transplantation (HCT) remains the only curative treatment for this condition, but transplant survival in published series was poor. We analysed the outcome of 25 such patients undergoing first HCT at our centre between 1995 and 2018. Median age at diagnosis was 6.5 months (range, birth to 7.5 years). Median age at transplant was 21.4 months (range, 0.1-7.8 years). Donors were matched family donors (MFD) (n=6), unrelated donors (UD) (n=12) and haploidentical donors (HID) (n=7). PBSC was the stem cell source in 68% of patients. Conditioning was treosulfan-based in 84% of patients; 84% received either alemtuzumab (n=14) or ATG (n=8) as serotherapy.With a 2.9-year median follow-up, overall survival (OS) improved from 33% (95%CI, 46-68%) for the children transplanted before 2008 (n=6) to 94% (95% CI, 66-99%) for children transplanted after 2008 (n=19) (p=0.003). For HCT after 2008, the OS according to donor was 100% for MFD, 100% for UD and 85% for HID (p=0.40). None had grade III-IV acute or chronic GvHD. Latest median donor myeloid and lymphocyte chimerism was 100% (range, 0-100%) and 100% (range, 64-100%) respectively. Latest CD4+T-lymphocyte number was significantly lower in transplant survivors (n=14) compared to post-transplant controls (p=0.01). All survivors were off immunoglobulin replacement and had protective vaccine responses to tetanus and Haemophilus influenza. None had any significant infection or autoimmunity. Changing transplant strategy in our center has significantly improved outcomes for MHC class II deficiency.

PMID: 31932845 [PubMed – as supplied by publisher]

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Multidisciplinary Team Work to succeed: A Primary Immunodeficiency Unit experience.

J Investig Allergol Clin Immunol. 2020 Jan 14;:0

Authors: Barrios Y, Franco A, Alonso-Larruga A, Sánchez-Machín I, Poza-Guedes P, Gonzalez R, Matheu V

PMID: 31932269 [PubMed – as supplied by publisher]

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How mycobacteria take advantage of the weakness in human immune system in the modern world.

J Microbiol Immunol Infect. 2019 Dec 30;:

Authors: Chao WC, Yen CL, Wu CH, Shieh CC

Abstract
Tuberculosis (TB) infection remains a global health threat in recent decades partly due to a marked increase in the number of susceptible patients, including those with diabetes mellitus (DM) and who receive biologics. Immunity in TB infection is complex as Mycobacterium tuberculosis (MTB) is a highly adaptive pathogen and may evade the immune defense through various ways. Recent advances in TB immunity have revealed that granulomatous inflammation in TB infection is highly dynamic and the early influx of neutrophils may lead to excessive inflammation and pulmonary cavitation, which provide niches for MTB not only to survive but also to spread to other sites. Furthermore, reactive oxygen species have been found to play a crucial role among pathogenesis of TB infection in diabetics (DM-TB) through regulating inflammasome activation and the production of IL-1β, which in turn modulates the inflammatory network in TB infection, leading to dysfunctional inflammatory responses and tissue remodeling. To understand the exact immunological mechanisms underlying TB infection hence is essential for developing novel adjunctive host-directed therapy (HDT) aiming to alleviate excessive inflammation and tissue destruction and, at the same time, enhance the efficacy of currently available choices of anti-mycobacterial agents. Here we reviewed current epidemiological challenges of global TB control, novel immunological mechanisms underlying dysregulated inflammation in TB infection, especially in DM-TB, and some potential applications of adjunctive HDT in TB treatment.

PMID: 31926875 [PubMed – as supplied by publisher]

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Hematopoietic Cell Transplantation for MHC Class II Deficiency.

Front Pediatr. 2019;7:516

Authors: Lum SH, Neven B, Slatter MA, Gennery AR

Abstract
Major histocompatibility complex (MHC) class II deficiency is a rare and fatal primary combined immunodeficiency. It affects both marrow-derived cells and thymic epithelium, leading to impaired antigen presentation by antigen presenting cells and delayed and incomplete maturation of CD4+ lymphocyte populations. Affected children are susceptible to multiple infections by viruses, Pneumocystis jirovecii, bacteria and fungi. Immunological assessment usually shows severe CD4+ T-lymphocytopenia, hypogammaglobulinemia, and lack of antigen-specific antibody responses. The diagnosis is confirmed by absence of constitutive and inducible expression of MHC class II molecules on affected cell types which is the immunologic hallmark of the disease. Hematopoietic cell transplantation (HCT) is the only established curative therapy for MHC class II deficiency but it is difficult as affected children have significant comorbidities at the time of HCT. Optimization organ function, implementing a reduced toxicity conditioning regimen, improved T-cell depletion techniques using serotherapy and graft manipulation, vigilant infection surveillance, pre-emptive and aggressive therapy for infection and newer treatments for graft-versus-host disease have improved the transplant survival for children with MHC class II deficiency. Despite persistent low CD4+ T-lymphopenia reported in post-HCT patients, transplanted patients show normalization of antigen-specific T-lymphocyte stimulation and antibody production in response to immunization antigens. There is a need for a multi-center collaborative study to look at transplant survival of HCT and long-term disease outcome in children with MHC class II deficiency in the modern era of HCT.

PMID: 31921728 [PubMed]

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