Background Primary immunodeficiencies are a rare group of inborn diseases characterized by a broad clinical and genetic heterogeneity. Substantial advances in the identification of the underlying ...molecular mechanisms can be achieved through the study of patients with increased susceptibility to specific infections and immune dysregulation. We evaluated 3 siblings from a consanguineous family presenting with EBV-associated B-cell lymphoproliferation at an early age (12, 7½, and 14 months, respectively) and profound naive T-cell lymphopenia. Objective On the basis of the hypothesis of a rare inborn immunodeficiency of autosomal recessive inheritance, we sought to characterize the underlying genetic defect. Methods We performed genome-wide homozygosity mapping, followed by whole-exome sequencing. Results We identified a homozygous inherited missense mutation in the gene encoding Coronin-1A (CORO1A) in the 3 siblings. This mutation, p. V134M, results in the substitution of an evolutionarily conserved amino acid within the β-propeller domain, which abrogates almost completely the protein expression in the patients' cells. In addition to a significant diminution of naive T-cell numbers, we found impaired development of a diverse T-cell repertoire, near-to-absent invariant natural killer T cells, and severely diminished mucosal-associated invariant T cell numbers. Conclusions Our findings define a new clinical entity of a primary immunodeficiency with increased susceptibility to EBV-induced lymphoproliferation in patients associated with hypomorphic Coronin-1A mutation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background Expression of the pre–B-cell receptor (pre-BCR) by pre-BII cells constitutes a crucial checkpoint in B-cell differentiation. Mutations that affect the pre–B-cell receptor result in early ...B-cell differentiation blockades that lead to primary B-cell immunodeficiencies. BLNK adaptor protein has a key role in the pre–B-cell receptor signaling cascade, as illustrated by the abnormal B-cell development in the 4 patients with BLNK gene defects reported to date. However, the BLNK protein's precise function in human B-cell differentiation has not been completely specified. Methods B-cell development, including IgVH and Vk chain repertoires analysis, was studied in the bone marrow of a new case of BLNK deficiency in vitro and in vivo. Results Here, we report on a patient with agammaglobulinemia, with a total absence of circulating B cells. We detected a homozygous mutation in BLNK , which leads to the complete abrogation of BLNK protein expression. In the bone marrow, we identified a severe differentiation blockade at the pre–BI- to pre–BII-cell transition. IgVH gene rearrangements and selection of the IgH repertoire were normal, whereas the patient's pre-BI cells showed very restricted usage of the IgVκ repertoire. Complementation of bone marrow progenitors from the patient with the BLNK gene and transplantation into NOD/SCID/γcko mice allowed the complete restoration of B-cell differentiation and a normal usage of the IgVκ genes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
SMB cell subset Low (n = 30) Normal (n = 13) P value MZB cell subset Low (n = 17) Normal (n = 13) P value Normal (n = 13) Upper respiratory tract infections 13 11 NS 11 NS Lower respiratory tract ...infections 11 12 NS 9 NS Pneumonia 10 8 NS 2 .017 Bronchiectasis 6 3 NS 0 .041 Autoimmune diseases 2 3 NS 0 NS Splenomegaly 3 2 NS 0 NS Gastroenteritis 3 1 NS 6 .02 Invasive acute infection 4 1 NS 2 NS IgRT 17 6 .0008 11 NS No response to vaccines 9/14 3/11 NS 1/9 NS Normal CD40+IL4-induced proliferation 11/16 10/12 NS 9/9 NS Normal CD40 class-switch recombination 11/16 6/10 NS 9/9 NS Normal BAFF-induced proliferation 6/13 7/12 NS 2/6 NS Normal CpG-induced proliferation 6/13 8/12 NS 3/6 NS Normal anti-A/B allohemagglutinins 2/10 3/9 NS 5/7 NS Table II Characteristics of patients as a function of their SMB and MZB cell counts BAFF, B-cell activating factor; NS, not significant.Low SMB and MZB cell counts were defined as being at least 2 SDs below the age-adjusted normal value (NS, P > .05). Characteristic No. (%) or median (min; max) Sex: male 20 (45.4) Age at onset (y) 1.77 (0.06; 5.9) Age at diagnosis (y) 5.15 (0.33; 17.3) Age at last follow-up (y) 14.46 (4.17; 35.87) Time between symptom onset and diagnosis years 3.00 (0.0; 13.23) Follow-up period (y) 6.29 (0.23; 27.09) Patients with another case in their family 13 (29.5) IgG deficiency 6 (13.6) IgG and IgA deficiency 9 (20.4) IgG and IgM deficiency 3 (6.8) IgA and IgM deficiency 1 (2.2) IgG, IgA, and IgM deficiency 25 (56.8) Patients with upper respiratory tract infections 35 (79.5) Patients with lower respiratory tract infections 33 (75) * Repeated acute bronchitis 17 (38.6) * Pneumonia 20 (45.5) * Bronchiectasis 9 (20.4) Patients with gastroenteritis 10 (22.7) Patients with autoimmune diseases 5 (11.4) Patients with splenomegaly 5 (11.4) Patients with lymphoma 1 (2.2) Table E1 Demographic, clinical, and biological characteristics of patients
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The CEC count was persistently higher at day 30 in patients with VE (median = 98/mL; range: 1-548) as compared to patients without VE (median = 4/mL; range: 2-52; P = .002) (Fig 1, A). ...the ...increase of CEC counts was significantly higher in patients with VE during the first month post-transplant (median δD0-D30 = 92; range: 16.5-547; P = .007) as compared to patients without (Fig 1, B).  No vascular event (n = 23) Vascular event (n = 11) Total patients (n = 34) Sex ratio female/male 9/14 3/8 12/22 Age: median (range) 3 y (0.5-14 y) 0.9 y (0.25-9 y) 3 and 5 y (0.25-14 y) Diagnosis    SCID 6 2 8 CID 8 5 13 HLH 5 3 8 Neutrophil disorders 3 1 5 Donor    Matched sibling donor 7 0 7 MUD 7 5 12 MMUD 4 2 6 Haploidentical donor 5 4 9 Defibrotide conditioning regimen 8 9 17 Bu/Flu/ATG 16 6 22 Bu/Flu/ThioTEPA/ATG 6 5 11 Mel/Flu/Alemtuzumab 1 0 1 Graft characteristics    In vitro T-depletion 5 6 11 No in vitro T-depletion 18 5 23 CD34 cell dose (106/kg) 8.2 (1.4-24.2) 13 (5-24.2) 10.5 (1.4-24.2) Engraftment day 19 (9-49) 18.5 (13-31) 19 (9-49) Rejection 2 1 3 GVHD 8 3 11 Grade 1-2 6 1 7 Grade 3-4 2 2 4 Time onset (days) 16.5 (2-60) 27 (10-47) 17 (2-60) CMV systemic replication 4 3 7 Severe sepsis 2 1 3 Duration of hospitalization post-HSCT (days) 78 (38-212) 92 (56-155) 83 (38-212) Death 3 5 8 Table I Hematopoietic transplantation characteristics For CD34 number, engraftment, time of onset of GVHD, and duration of post-HSCT hospitalization, median time is indicated with range in brackets.ATG, Antithymocyte globulin; Bu, busulfan; CID, combined immunodeficiency; CMV, cytomegalovirus; Flu, fludarabine; HLH, hemophagocytic lymphohistiocytosis; Mel, Melphalan; MMUD, mismatched unrelated donor; MUD, matched unrelated donor; SCID, severe combined immunodeficiency.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Durable HIV-1 remission after interruption of combined antiretroviral therapy (ART) has been reported in some adults who started treatment during primary infection; however, whether long-term ...remission in vertically infected children is possible was unknown. We report a case of a young adult perinatally infected with HIV-1 with viral remission despite long-term treatment interruption.
The patient was identified in the ANRS EPF-CO10 paediatric cohort among 100 children infected with HIV perinatally who started ART before 6 months of age. HIV RNA viral load and CD4 cell counts were monitored from birth. Ultrasensitive HIV RNA, peripheral blood mononuclear cell (PBMC)-associated HIV DNA, HIV-specific T-cell responses (ie, production of cytokines and capacity to suppress HIV infection), reactivation of the CD4 cell reservoir (measured by p24 ELISA and HIV RNA in supernatants upon phytohaemagglutinin activation of purified CD4 cells), and plasma concentrations of antiretroviral drugs were assessed after 10 years of documented control off therapy.
The infant was born in 1996 to a woman with uncontrolled HIV-1 viraemia and received zidovudine-based prophylaxis for 6 weeks. HIV RNA and DNA were not detected 3 days and 14 days after birth. HIV DNA was detected at 4 weeks of age. HIV RNA reached 2·17× 10(6) copies per mL at 3 months of age and ART was started. HIV RNA was undetectable 1 month later. ART was discontinued by the family at some point between 5·8 and 6·8 years of age. HIV RNA was undetectable at 6·8 years of age and ART was not resumed. HIV RNA has remained below 50 copies per mL and CD4 cell counts stable through to 18·6 years of age. After 11·5 years of control off treatment, HIV RNA was below 4 copies per mL and HIV DNA was 2·2 log10 copies per 10(6) PBMCs. The HLA genotype showed homozygosity at several loci (A*2301-, B*1503/4101, C*0210/0802, DRB1*1101-, and DQB1*0602-). HIV-specific CD8 T-cell responses and T-cell activation were weak.
Findings from this case suggest that long-term HIV-1 remission is possible in perinatally infected children who receive treatment early, with characteristics similar to those reported in adult HIV post-treatment controllers. Further studies are needed to understand the mechanisms associated with HIV remission and whether early treatment of infected children might favour the conditions needed to achieve HIV control after treatment discontinuation.
Agence de recherche ANRS (France Recherche Nord & Sud Sida-HIV Hépatites).
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