sirolimus and Immunologic-Deficiency-Syndromes

Activated phosphoinositide 3-kinase δ syndrome (APDS), a recently described primary immunodeficiency,is caused by autosomal dominant mutation in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta(PIK3CD) gene encoding the p110δ catalytic subunit of PI3Kδ (APDS1) or the PIK3R1 gene that encodes the p85α regulatory subunit of PI3Kδ (APDS2). Gain-of-function mutation of PIK3CD in APDS1 leads to p110δ hyperactivity, with the result of the hyperphosphorylation of downstream mediators of Akt and mammalian target of rapamycin that cause a series of clinical symptoms. Few cases with APDS were reported in Asia.. We report a 6-year-old patient with a recurrent respiratory infection, cryptosporidium enteritis, lymphoproliferation, high serum immunoglobulin-M level, anemia, and inverted CD4+/CD8+ ratio. The whole exome sequencing confirmed a heterozygous missense mutation c.3061G>A（p.E1021K）in patient and her mother. Her mutant gene is inherited from her mother, but her mother has not any clinical symptoms.. Activated phosphoinositide 3-kinase δ syndrome.. The patient was received immunoglobulin (Ig) replacement therapy, antibiotics, and rapamycin treatment. Through effectively controlling infection and optimal timing of transplantation by adjusting the conditioning regimen, haploidentical Hematopoietic Stem Cell Transplantation(haplo-HSCT) from her brother was successfully performed.. The patient is in good condiion with a good quality of life after 20 months of follow-up.. We reported a rare APDS1 case with PIK3CD E1021K gene mutation, Successfully treated with haplo-HSCT. This case provided a reference for treating APDS with haplo-HSCT.

Topics: Child; Class I Phosphatidylinositol 3-Kinases; Cryptosporidiosis; Cryptosporidium; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunologic Deficiency Syndromes; Male; Mutation; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Primary Immunodeficiency Diseases; Quality of Life; Sirolimus

Topics: Allografts; Class I Phosphatidylinositol 3-Kinases; Class Ia Phosphatidylinositol 3-Kinase; Enzyme Inhibitors; Humans; Immunologic Deficiency Syndromes; Lymphoproliferative Disorders; Mutation; Phosphatidylinositol 3-Kinases; Primary Immunodeficiency Diseases; Respiratory Tract Infections; Sirolimus; Stem Cell Transplantation

We treated 14 patients with GATA2 deficiency using a nonmyeloablative allogeneic hematopoietic stem cell transplantation regimen. Four patients received peripheral blood stem cells from matched related donors (MRD), 4 patients received peripheral blood stem cells from matched unrelated donors (URD), 4 patients received hematopoietic stem cells from umbilical cord blood donors (UCB), and 2 patients received bone marrow cells from haploidentical related donors. MRD and URD recipients received conditioning with 3 days of fludarabine and 200 cGy total body irradiation (TBI). Haploidentical related donor recipients and UCB recipients received cyclophosphamide and 2 additional days of fludarabine along with 200 cGY TBI. MRD, URD, and UCB recipients received tacrolimus and sirolimus for post-transplantation immunosuppression, whereas haploidentical recipients received high-dose cyclophosphamide followed by tacrolimus and mycophenolate mofetil. Eight patients are alive with reconstitution of the severely deficient monocyte, B cell, and natural killer cell populations and reversal of the clinical phenotype at a median follow-up of 3.5 years. Two patients (1 URD recipient and 1 UCB recipient) rejected the donor graft and 1 MRD recipient relapsed with myelodysplastic syndrome after transplantation. We are currently using a high-dose conditioning regimen with busulfan and fludarabine in patients with GATA2 deficiency to achieve more consistent engraftment and eradication of the malignant myeloid clones.

Topics: Adolescent; Adult; Allografts; Antineoplastic Agents; Bone Marrow Transplantation; Child; Cord Blood Stem Cell Transplantation; Female; Follow-Up Studies; GATA2 Transcription Factor; Genetic Diseases, Inborn; Hematopoietic Stem Cell Transplantation; Humans; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Male; Middle Aged; Sirolimus; Tacrolimus; Transplantation Conditioning; Unrelated Donors; Vidarabine; Whole-Body Irradiation

Topics: Autoimmune Diseases; Humans; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Osteochondrodysplasias; Sirolimus

Topics: Humans; Immunologic Deficiency Syndromes; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Sirolimus

Topics: Adolescent; Aminopeptidases; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Female; Humans; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Mutation; Phenotype; Purpura, Thrombocytopenic, Idiopathic; Serine Endopeptidases; Sirolimus; T-Lymphocytes

Cytoskeletal regulatory protein dysfunction has been etiologically linked to inherited diseases associated with immunodeficiency and autoimmunity, but the mechanisms involved are incompletely understood. Here, we show that conditional

Topics: Animals; Autoimmune Diseases; Autoimmunity; Cell Differentiation; Homeostasis; Immunologic Deficiency Syndromes; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Mice, Knockout; Proto-Oncogene Proteins c-akt; Rapamycin-Insensitive Companion of mTOR Protein; Receptors, Antigen, T-Cell; Regulatory-Associated Protein of mTOR; Signal Transduction; Sirolimus; T-Lymphocytes; TOR Serine-Threonine Kinases; Transcriptome; Wiskott-Aldrich Syndrome Protein Family

Topics: Genetic Predisposition to Disease; Humans; Immunologic Deficiency Syndromes; Interleukin-2 Receptor alpha Subunit; Sirolimus

Heterozygous gain-of-function mutations in PI3K110δ lead to lymphadenopathy, lymphoid hyperplasia, EBV and cytomegalovirus viremia, and sinopulmonary infections.. The known role of natural killer (NK) cell function in the control of EBV and cytomegalovirus prompted us to investigate the functional and phenotypic effects of PI3K110δ mutations on NK cell subsets and cytotoxic function.. Mutations in patients were identified by using whole-exome or targeted sequencing. We performed NK cell phenotyping and functional analysis of patients' cells using flow cytometry, standard Cr. PI3K110δ mutations led to an altered NK cell developmental phenotype and cytotoxic dysfunction. Impaired NK cell cytotoxicity was due to decreased conjugate formation with susceptible target cells and abrogated activation of cell machinery required for target cell killing. These defects were restored partially after initiation of treatment with rapamycin in 3 patients.. We describe novel NK cell functional deficiency caused by PI3K110δ mutation, which is a likely contributor to the severe viremia observed in these patients. Rapamycin treatment partially restores NK cell function, providing a further rationale for its use in patients with this disease.

Topics: Cell Differentiation; Cells, Cultured; Class I Phosphatidylinositol 3-Kinases; Cytomegalovirus; Cytomegalovirus Infections; Cytotoxicity, Immunologic; Epstein-Barr Virus Infections; Exome Sequencing; Herpesvirus 4, Human; Heterozygote; Humans; Immunologic Deficiency Syndromes; Immunological Synapses; Immunophenotyping; Killer Cells, Natural; Lymphocyte Activation; Microscopy, Confocal; Mutation; Phosphatidylinositol 3-Kinases; Sirolimus; Viremia

One of the most frequent non-infectious complications of humoral immunodeficiencies with a CVID-like pattern is a particular form of inflammatory lung disease which is called granulomatous-lymphocytic interstitial lung disease (GLILD). Its development worsens patient prognosis, with a significant decrease in survival. Currently, there are no unified guidelines regarding its management, and different combinations of immunosuppressants have been used with variable success.. Clinical and radiological data were collected from patient's medical charts. Flow cytometry was performed to characterize the immunological features with special focus in regulatory T cells (Tregs).. A 16-year-old girl with Kabuki syndrome and a 12-year-old boy, both with a CVID-like humoral immunodeficiency on immunoglobulin replacement treatment, developed during follow-up an inflammatory complication radiologically, clinically, and histologically compatible with GLILD. They required treatment, and sirolimus was started, with very good response and no serious side effects.. These 2 cases provide insight into the underlying local and systemic immune anomalies involved in the development of GLILD, including the possible role of Tregs. Combined chemotherapy is commonly used as treatment for GLILD when steroids fail, but there have been some reports of successful monotherapy. As far as we know, these are the first 2 GLILD patients treated successfully with sirolimus, suggesting the advisability of further study of mTOR inhibitors as a more targeted treatment for GLILD, if impairment in Tregs is demonstrated.

Topics: Abnormalities, Multiple; Adolescent; Biomarkers; Child; Face; Female; Hematologic Diseases; Humans; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Lung Diseases, Interstitial; Male; Sirolimus; T-Lymphocytes, Regulatory; Vestibular Diseases

Topics: Administration, Oral; Adult; Betamethasone; Biopsy; Drug Resistance; Drug Therapy, Combination; Female; Humans; Immunoglobulins, Intravenous; Immunologic Deficiency Syndromes; Lichen Planus; Middle Aged; Photopheresis; Salvage Therapy; Sirolimus; Skin; Treatment Outcome

Topics: Adolescent; Adult; Child; Child, Preschool; Class I Phosphatidylinositol 3-Kinases; Europe; Humans; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Middle Aged; Primary Immunodeficiency Diseases; Registries; Sirolimus; Societies, Medical; Young Adult

Premature T-cell immunosenescence with CD57

Topics: CD57 Antigens; Cell Differentiation; Cellular Senescence; Class I Phosphatidylinositol 3-Kinases; Cytokines; Humans; Immunologic Deficiency Syndromes; Immunophenotyping; Lymphocyte Count; Phosphatidylinositol 3-Kinases; Primary Immunodeficiency Diseases; Sirolimus; T-Lymphocyte Subsets; Telomere Shortening

Activated phosphoinositide 3-kinase δ (PI3Kδ) syndrome is a newly defined and relatively common primary immunodeficiency, which is caused by heterozygous gain-of-function (GOF) mutations in PIK3CD or PIK3R1. Here, we report a novel de novo GOF mutation (c.1570 T > A, p.Y524N) in PIK3CD in a 6-year-old Chinese girl. The patient suffered recurrent sinopulmonary infection, bronchiectasis, lymphoproliferation, herpesvirus infection, and distinctive nodular lymphoid hyperplasia of mucosal surfaces. Immunological analysis revealed increased CD4+ T cell senescence and B cell immaturity. Further analysis revealed an increase in almost all CD4+ T cell subsets to varying degrees, including effector T cells and Treg cells. Increased levels of plasma T cell-related cytokines corroborated these results. Hyperactivation of the PI3Kδ-Akt-mTOR signaling pathway was also confirmed. Treatment with rapamycin ameliorated the lymphoproliferative immunodeficiency caused by hyperactivation of mTOR. These results expand genetic spectrum of APDS and will facilitate further study of the genotype-phenotype correlation in those with PIK3CD mutations.

Topics: Adolescent; Case-Control Studies; CD4-Positive T-Lymphocytes; Cellular Senescence; Child; Child, Preschool; Class I Phosphatidylinositol 3-Kinases; Female; Gain of Function Mutation; Genotype; Humans; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Infant; Infant, Newborn; Phenotype; Primary Immunodeficiency Diseases; Sequence Analysis, DNA; Signal Transduction; Sirolimus; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory

We aimed to report the clinical manifestations and immunological features of activated phosphatidylinositol 3-kinase δ syndrome 1 (APDS1) in a Chinese cohort. Moreover, we investigated the efficacy and safety of rapamycin therapy for Chinese patients with APDS1.. Fifteen Chinese patients with APDS1 from 14 unrelated families were enrolled in this study. These patients were diagnosed based on clinical features, immunological phenotype, and whole-exome sequencing. Four patients were treated with rapamycin, and the clinical efficacy and safety of rapamycin were observed. The changes of phosphorylation of Akt and mammalian target of rapamycin (mTOR) signaling pathway after rapamycin treatment were detected by flow cytometry and real-time PCR.. The common clinical manifestations of the patients included lymphadenopathy (93%), recurrent sinopulmonary infections (93%), hepatosplenomegaly (93%), and diarrhea (78%). Epstein-Barr virus (EBV) (80%) and fungus (Aspergillus) (47%) were the most common pathogens. Immunological phenotype included elevated Immunoglobulin (Ig) M levels (100%), decreased naive T cells, increased senescent T cells, and expanded transitional B cells. Whole-exome sequencing indicated that 13 patients had heterogeneous PIK3CD E1021K mutations, 1 patient had heterogeneous E1025G mutation and 1 patient had heterogeneous Y524N mutation. Gain-of-function (GOF) PIK3CD mutations increased the phosphorylation of the Akt-mTOR signaling pathway. Four patients underwent rapamycin therapy, experiencing substantial improvement in clinical symptoms and immunological phenotype. Rapamycin inhibited the activated Akt-mTOR signaling pathway.. We described 15 Chinese patients with APDS1. Treatment with the mTOR inhibitor rapamycin improved patient outcomes.

Topics: Adolescent; Child; Child, Preschool; Class I Phosphatidylinositol 3-Kinases; Class Ia Phosphatidylinositol 3-Kinase; Cohort Studies; Female; Hepatomegaly; Humans; Immunoglobulin M; Immunologic Deficiency Syndromes; Infant; Lymphadenopathy; Male; Mutation; Oncogene Protein v-akt; Phosphorylation; Precursor Cells, B-Lymphoid; Primary Immunodeficiency Diseases; Respiratory Tract Infections; Signal Transduction; Sirolimus; T-Lymphocytes; TOR Serine-Threonine Kinases

Topics: Child, Preschool; Class I Phosphatidylinositol 3-Kinases; Humans; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Male; Prednisolone; Primary Immunodeficiency Diseases; Rituximab; Sirolimus; T-Lymphocytes

Heterozygous gain of function mutations in the gene encoding p110δ subunit of PI3K have been recently associated with activated PI3K-δ syndrome (APDS), a novel combined immune deficiency characterized by recurrent sinopulmonary infections, lymphopenia, reduced class-switched memory B cells, lymphadenopathy, CMV and/or EBV viremia and EBV-related lymphoma. Here we report a dominant gain of function PIK3CD mutation (E1021K) in a patient presenting with recurrent otitis media, massive splenomegaly, and persistent EBV-viraemia. The immunological studies showed low IgA level, but normal IgM, IgG, and normal antibody response to diphtheria and tetanus toxoid vaccination. Analysis of B lymphocyte subsets revealed abnormal expansion of transitional B cells, and low percentage of switched CD27

Topics: B-Lymphocyte Subsets; Child, Preschool; Class I Phosphatidylinositol 3-Kinases; Early Diagnosis; Female; Humans; Immunologic Deficiency Syndromes; Lymphopenia; Mutation; Otitis; Phosphatidylinositol 3-Kinases; Primary Immunodeficiency Diseases; Respiratory Tract Infections; Sirolimus; Spleen; Splenomegaly; T-Lymphocyte Subsets

Topics: Adaptor Proteins, Signal Transducing; Adolescent; Adult; Child; Chronic Disease; Diarrhea; Female; Genetic Predisposition to Disease; Humans; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Phenotype; Recurrence; Sirolimus; Treatment Outcome; Weight Gain; Young Adult

Topics: Child, Preschool; Class I Phosphatidylinositol 3-Kinases; Humans; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Male; Primary Immunodeficiency Diseases; Sirolimus

The p110δ subunit of phosphatidylinositol-3-OH kinase (PI(3)K) is selectively expressed in leukocytes and is critical for lymphocyte biology. Here we report fourteen patients from seven families who were heterozygous for three different germline, gain-of-function mutations in PIK3CD (which encodes p110δ). These patients presented with sinopulmonary infections, lymphadenopathy, nodular lymphoid hyperplasia and viremia due to cytomegalovirus (CMV) and/or Epstein-Barr virus (EBV). Strikingly, they had a substantial deficiency in naive T cells but an over-representation of senescent effector T cells. In vitro, T cells from patients exhibited increased phosphorylation of the kinase Akt and hyperactivation of the metabolic checkpoint kinase mTOR, enhanced glucose uptake and terminal effector differentiation. Notably, treatment with rapamycin to inhibit mTOR activity in vivo partially restored the abundance of naive T cells, largely 'rescued' the in vitro T cell defects and improved the clinical course.

Topics: Antibiotics, Antineoplastic; Cell Differentiation; Cells, Cultured; Cellular Senescence; Class I Phosphatidylinositol 3-Kinases; Cytomegalovirus Infections; Epstein-Barr Virus Infections; Female; Genes, Dominant; Germ-Line Mutation; Humans; Immunoblotting; Immunologic Deficiency Syndromes; Male; Pedigree; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Sirolimus; T-Lymphocytes; TOR Serine-Threonine Kinases; Viremia

IPEX syndrome (immune deficiency, polyendocrinopathy, enteropathy, X-linked) is a disorder or regulatory T cell (Treg) function which can result in early death due to infection or complications related to autoimmunity. Therapeutic options for these patients can include allogeneic stem cell transplantation (SCT) or the use of immunosuppressive regimens to control the manifestations of autoimmunity. We report a patient with IPEX syndrome who was managed with rapamycin and subsequently developed EBV induced lymphoma.

Topics: Child; Epstein-Barr Virus Infections; Genetic Diseases, X-Linked; Herpesvirus 4, Human; Humans; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Infant; Lymphoma; Male; Polyendocrinopathies, Autoimmune; Protein-Losing Enteropathies; Sirolimus; Syndrome

Mutations of the Bruton's tyrosine kinase (btk) gene cause X-linked agammaglobulinemia (XLA) in humans and X-linked immune deficiency (Xid) in mice. To establish the BTK role in B-cell activation we examined the responses of wild-type and Xid B cells to stimulation through surface IgM and CD40, the transducers of thymus independent-type 2 and thymus-dependent activation, respectively. Wild-type BTK was necessary for proliferation induced by soluble anti-IgM (a prototype for thymus independent-type 2 antigen), but not for responses to soluble CD40 ligand (CD40L, the B-cell activating ligand expressed on T-helper cells). In the absence of wild-type BTK, B cells underwent apoptotic death after stimulation with anti-IgM. In the presence of wild-type but not mutated BTK, anti-IgM stimulation reduced apoptotic cell death. In contrast, CD40L increased viability of both wild-type and Xid B cells. Importantly, viability after stimulation correlated with the induced expression of bcl-XL. In fresh ex vivo small resting B cells from wild-type mice there was only barely detectable bcl-XL protein, but there was more in the larger, low-density ("activated") splenic B cells and peritoneal B cells. In vitro Bcl-XL induction following ligation of sIgM-required BTK, was cyclosporin A (CsA)-sensitive and dependent on extracellular Ca2+. CD40-mediated induction of bcl-x required neither wild-type BTK nor extracellular Ca2+ and was insensitive to CsA. These results indicate that BTK lies upstream of bcl-XL in the sIgM but not the CD40 activation pathway. bcl-XL is the first induced protein to be placed downstream of BTK.

Topics: Agammaglobulinaemia Tyrosine Kinase; Animals; Apoptosis; B-Lymphocytes; bcl-X Protein; CD40 Ligand; Cell Survival; Immunologic Deficiency Syndromes; Lymphocyte Activation; Lymphocyte Cooperation; Membrane Glycoproteins; Mice; Mice, Inbred CBA; Polyenes; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Receptors, Antigen, B-Cell; Sirolimus; T-Lymphocytes