14 results on '"Abinun, M."'
Search Results
2. Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study
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Coulter, TI, Chandra, A, Bacon, CM, Babar, J, Curtis, J, Screaton, N, Goodlad, JR, Farmer, G, Steele, CL, Leahy, TR, Doffinger, R, Baxendale, H, Bernatoniene, J, Edgar, JD, Longhurst, HJ, Ehl, S, Speckmann, C, Grimbacher, B, Sediva, A, Milota, T, Faust, SN, Williams, AP, Hayman, G, Kucuk, ZY, Hague, R, French, P, Brooker, R, Forsyth, P, Herriot, R, Cancrini, C, Palma, P, Ariganello, P, Conlon, N, Feighery, C, Gavin, PJ, Jones, A, Imai, K, Ibrahim, MA, Markelj, G, Abinun, M, Rieux-Laucat, F, Latour, S, Pellier, I, Fischer, A, Touzot, F, Casanova, JL, Durandy, A, Burns, SO, Savic, S, Kumararatne, DS, Moshous, D, Kracker, S, Vanhaesebroeck, B, Okkenhaug, K, Picard, C, Nejentsev, S, Condliffe, AM, Cant, AJ, Chandra, Anita [0000-0002-9061-879X], Okkenhaug, Klaus [0000-0002-9432-4051], Nezhentsev, Sergey [0000-0002-7528-4461], and Apollo - University of Cambridge Repository
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Adult ,Male ,Adolescent ,bronchiectasis ,Class I Phosphatidylinositol 3-Kinases ,International Cooperation ,Immunology ,PPV, Pneumococcal polysaccharide vaccine ,HSCT, Hematopoietic stem cell transplantation ,Cohort Studies ,Mice ,Young Adult ,APDS, Activated phosphoinositide-3 kinase δ syndrome ,phosphoinositide 3-kinase inhibitor ,Immune Deficiencies, Infection, and Systemic Immune Disorders ,Recurrence ,PI3K, Phosphoinositide 3-kinase ,Surveys and Questionnaires ,BALF, Bronchoalveolar lavage fluid ,Activated phosphoinositide 3-kinase δ syndrome ,Animals ,Humans ,Immunology and Allergy ,Enzyme Inhibitors ,CMV, Cytomegalovirus ,Child ,HSV, Herpes simplex virus ,Respiratory Tract Infections ,CNS, Central nervous system ,Hematopoietic Stem Cell Transplantation ,Immunologic Deficiency Syndromes ,Immunoglobulins, Intravenous ,Infant ,GOF, Gain of function ,Herpesviridae Infections ,Antibiotic Prophylaxis ,Middle Aged ,PIK3CD gene ,Survival Analysis ,Lymphoproliferative Disorders ,Child, Preschool ,Mutation ,CT, Computed tomography ,p110δ-activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency ,Female ,immunodeficiency ,phosphoinositide 3-kinase δ ,OR, Odds ratio - Abstract
Background: Activated PI3-Kinase Delta Syndrome (APDS) is a recently described combined immunodeficiency resulting from gain-of-function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ).\ud Objective: To review the clinical, immunological, histopathological and radiological features of APDS in a large genetically-defined international cohort.\ud Methods: Clinical questionnaire, and review of medical notes, radiology histopathology and laboratory investigations of 53 APDS patients.\ud Results: Recurrent sino-pulmonary infections (96%) and non-neoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3Kδ in the central nervous system (CNS); consistent with this PI3Kδ is broadly expressed in the developing murine CNS. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60% in cohort); the incidence of bronchiectasis was greater than in common variable immunodeficiency (CVID). Elevated IgM (78%), IgG deficiency (43%) and CD4 lymphopenia (84%) were significant immunological features. No immunological marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and five patients underwent haematopoietic stem cell transplant (HSCT). Five patients died from complications of APDS.\ud Conclusion: APDS is a combined immunodeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of HSCT for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment.
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- 2017
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3. Mutations in CHD7 in patients with CHARGE syndrome cause T–B + natural killer cell + severe combined immune deficiency and may cause Omenn-like syndrome.
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Gennery, A. R., Slatter, M. A., Rice, J., Hoefsloot, L. H., Barge, D., McLean-Tooke, A., Montgomery, T., Goodship, J. A., Burt, A. D., Flood, T. J., Abinun, M., Cant1, A. J., and Johnson, D.
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GENETIC mutation ,BIOLOGICAL variation ,GENETICS ,CHROMOSOME abnormalities ,IMMUNODEFICIENCY ,GENOTYPE-environment interaction - Abstract
More than 11 genetic causes of severe combined immunodeficiency (SCID) have been identified, affecting development and/or function of T lymphocytes, and sometimes B lymphocytes and natural killer (NK) cells. Deletion of 22q11.2 is associated with immunodeficiency, although less than 1% of cases are associated with T–B + NK + SCID phenotype. Severe immunodeficiency with CHARGE syndrome has been noted only rarely Omenn syndrome is a rare autosomal recessive form of SCID with erythroderma, hepatosplenomegaly, lymphadenopathy and alopecia. Hypomorphic recombination activating genes 1 and 2 mutations were first described in patients with Omenn syndrome. More recently, defects in Artemis, RMRP, IL7Rα and common gamma chain genes have been described. We describe four patients with mutations in CHD7, who had clinical features of CHARGE syndrome and who had T–B + NK + SCID (two patients) or clinical features consistent with Omenn syndrome (two patients). Immunodeficiency in patients with DiGeorge syndrome is well recognized − CHARGE syndrome should now be added to the causes of T–B + NK + SCID, and mutations in the CHD7 gene may be associated with Omenn-like syndrome. [ABSTRACT FROM AUTHOR]
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- 2008
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4. Value of bronchoalveolar lavage before haematopoietic stem cell transplantation for primary immunodeficiency or autoimmune diseases.
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Slatter, M. A., Rogerson, E. J., Taylor, C. E., Galloway, A., Clark, J. E., Flood, T. J., Abinun, M., Cant, A. J., and Gennery, A. R.
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HEMATOPOIETIC stem cells ,BONE marrow cells ,AUTOIMMUNE diseases ,IMMUNODEFICIENCY ,LUNG infections ,LUNG diseases ,BRONCHOALVEOLAR lavage ,LUNG disease diagnosis ,PATHOGENIC microorganisms - Abstract
Pulmonary infection, often insidious, is frequent in primary immunodeficiency (PID) and acquired immunodeficiency. Pulmonary complications are serious obstacles to success of haematopoietic SCT (HSCT) for these conditions. Bronchoalveolar lavage (BAL) permits identification of lower respiratory tract pathogens that may direct specific treatment and influence prognosis. There are no reports about the utility of pre-HSCT BAL for immunodeficient patients. We prospectively studied the value of ‘routine’ BAL before commencing transplantation in patients undergoing HSCT for severe immunological disease. Routine non-bronchoscopic BAL was performed under general anaesthetic, a few days before commencing pre-HSCT cytoreductive chemotherapy. Patients were categorized as symptomatic or asymptomatic with respect to pulmonary disease or infection. Samples were sent for microbiological processing. Complications arising from the procedure, pathogens isolated and treatments instituted were recorded. Results were available from 69/75 patients transplanted during the study period; 26 (38%) had pathogens identified (six asymptomatic patients), 10 (14.5%) developed complications post-procedure (two asymptomatic patients)—all recovered, 21 had management changes. There was no statistically significant difference in the number of positive isolates from severe combined or other immunodeficient patients, or of symptomatic or asymptomatic patients. Routine non-bronchoscopic BAL is safe in immunodeficient patients about to undergo HSCT, and leads to management changes.Bone Marrow Transplantation (2007) 40, 529–533; doi:10.1038/sj.bmt.1705776; published online 16 July 2007 [ABSTRACT FROM AUTHOR]
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- 2007
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5. Single centre experience of umbilical cord stem cell transplantation for primary immunodeficiency.
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Bhattacharya, A., Slatter, M. A., Chapman, C. E., Barge, D., Jackson, A., Flood, T. J., Abinun, M., Cant, A. J., and Gennery, A. R.
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STEM cell transplantation ,IMMUNODEFICIENCY ,MORTALITY ,IMMUNOSUPPRESSION ,GRAFT versus host disease ,HEMATOPOIETIC stem cells - Abstract
Summary:Primary immunodeficiencies (PID) are an important cause of childhood mortality. Haematopoietic stem cell transplantation (HSCT) is the best treatment for many PID. Umbilical cord stem cells are an alternative source of HSC. There is little data regarding outcome of umbilical cord stem cell transplantation (UCSCT) for PID. Our single centre experience is reported. A retrospective study of 14 of 148 patients transplanted for PID, who have received 15 UCSCT was performed, with specific regard to graft-versus-host disease (GvHD) and immune reconstitution. Eight patients with severe combined immunodeficiency (SCID), and six with other combined immunodeficiencies were treated. Of the patients, 12 received unrelated cords, and two had sibling transplants. Median age at transplant was 3.5 months, median nucleated cell dose was 0.8 × 10
8 /kg. All engrafted. Median time to neutrophil engraftment was 22 days, median time to platelet engraftment was 51 days. One developed significant grade III GvHD post transplantation. In total, 11 patients had full donor T and six full donor B-cell chimerism, six of nine patients >1 year post-BMT had normal IgG levels and specific antibody responses to tetanus and Hib vaccines; two are being assessed. Two patients died of multi-organ failure related to pre-existing infection and inflammatory complications respectively. UCSCT should be considered for patients requiring stem cell therapy for PID.Bone Marrow Transplantation (2005) 36, 295–299. doi:10.1038/sj.bmt.1705054; published online 20 June 2005 [ABSTRACT FROM AUTHOR]- Published
- 2005
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6. Thyroid dysfunction after bone marrow transplantation for primary immunodeficiency without the use of total body irradiation in conditioning.
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Slatter, M. A., Gennery, A. R., Cheetham, T. D., Bhattacharya, A., Crooks, B. N. A., Flood, T. J., Cant, A. J., and Abinun, M.
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IMMUNODEFICIENCY ,BONE marrow transplantation ,HYPOTHYROIDISM ,OSTEOPETROSIS - Abstract
Summary:Thyroid dysfunction, a common long-term complication following bone marrow transplantation (BMT), is frequently associated with total body irradiation (TBI) given in the pre-BMT conditioning protocol. We report our preliminary observation of the prevalence of thyroid dysfunction in children transplanted for primary immunodeficiency (PID) who were given cytoreductive conditioning with busulphan and cyclophosphamide, but without TBI. We evaluated thyroid-stimulating hormone (TSH) and free thyroxine (fT4) in 83 survivors transplanted between 1987 and 2002. We found nine children (10.8%) with clinical and/or biochemical thyroid dysfunction at 4 months to 4.5 years post-BMT of which three had positive antithyroid microsomal antibodies. Two patients were classified as primary and seven as compensated hypothyroidism (hyperthyrotropinaemia). Four patients with clinical features of hypothyroidism received replacement thyroxine, while five of the seven patients with compensated hypothyroidism remain off thyroxine because we suspect this may be a transient phenomenon.Abnormalities of thyroid function including severe primary hypothyroidism may occur post-BMT in children receiving chemotherapy conditioning without TBI. Thyroid function should be assessed regularly in this group of patients.Bone Marrow Transplantation (2004) 33, 949-953. doi:10.1038/sj.bmt.1704456 Published online 8 March 2004 [ABSTRACT FROM AUTHOR]
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- 2004
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7. Polysaccharide antibody responses are impaired post bone marrow transplantation for severe combined immunodeficiency, but not other primary immunodeficiencies.
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Slatter, M A, Bhattacharya, A, Flood, T J, Spickett, G P, Cant, A J, Abinun, M, and Gennery, A R
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BONE marrow transplant complications ,POLYSACCHARIDES ,IMMUNE response ,IMMUNODEFICIENCY ,IMMUNOLOGY - Abstract
Summary:Established treatment of severe combined immunodeficiencies (SCID) and other primary immunodeficiencies (PID) is bone marrow transplantation (BMT). Normal lymphocyte numbers and protein antigen responses are present within 2 years of BMT, polysaccharide antibody responses appear last. Streptococcus pneumoniae infection causes significant morbidity and mortality post-BMT. Previous studies have shown good protein antigen responses post-BMT for SCID and PID, but had not examined the polysaccharide responses. We retrospectively analysed pneumococcal polysaccharide (PPS) responses in our patient series.In total, 22 SCID and 12 non-SCID PID were evaluated, all >2 years post BMT: 17 SCID, 12 PID received chemotherapy conditioning; 17 SCID, three PID had T-cell depleted (TCD) BMT, others had nonconditioned whole marrow BMT. All had normal Haemophilus influenza B and tetanus antibody responses. Of 22 SCID, 13 vs 11/12 PID responded to PPS vaccine (P=0.05). There was no association with donor age, GvHD, B-cell chimerism, or IgG2 level. Fewer TCD marrow recipients responded to PPS (P=0.04). Analysis of the SCID group showed no association of PPS response with type of marrow received. This is the first study to specifically examine PPS antibody responses following SCID and PID BMT. Pneumococcal conjugate vaccine antibody responses should be examined in these children.Bone Marrow Transplantation (2003) 32, 225-229. doi:10.1038/sj.bmt.1704109 [ABSTRACT FROM AUTHOR]
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- 2003
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8. Neonatal bone marrow transplantation for severe combined immunodeficiency.
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Kane, L., Gennery, A. R., Crooks, B. N. A., Flood, T. J., Abinun, M., and Cant, A. J.
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BONE marrow transplantation ,NEWBORN infants ,IMMUNODEFICIENCY ,NEONATOLOGY ,GRAFT versus host disease ,IMMUNITY - Abstract
Aims -- To evaluate outcome following neonatal bone marrow transplantation (BMT) for severe combined immunodeficiency (SCID) when there is a family history of a previously affected sibling, and to compare results with those published for in utero BMT. Methods -- A retrospective review of cases referred and transplanted between 1987 and 1999, focusing on infectious and graft versus host disease (GvHD) complications after BMT, and T and B lymphocyte function. Thirteen patients received 18 stem cell transplants: four whole marrow, one cord blood, 10 parental T cell depleted (TCD) haplo-identical, and three TCD unrelated donor BMT. Nine were conditioned with busulphan and cyclophosphamide. Results -- All are alive and well (six months to 11.5 years after BMT). Six had grade I-II acute GvHD and two chronic GvHD (now resolved). Three had a top up BMT for poor T cell function, one had a third BMT for graft failure and chronic GvHD, and one had a third BMT for graft failure. Twelve have good in vitro proliferation to T cell mitogens, and all have normal serum IgA levels. Three receive intravenous immunoglobulin; for one of these, it is less than one year since BMT. Nine are above the 2nd centile, and 10 of 12 old enough to be assessed have normal neuro- development. Conclusion -- These results are better than those published for in utero BMT for SCID. Early postnatal BMT should be the preferred option in neonatal SCID. [ABSTRACT FROM AUTHOR]
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- 2001
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9. Bone marrow transplantation for CD40 ligand deficiency: a single centre experience.
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Khawaja, K., Gennery, A. R., Flood, T. J., Abinun, M., and Cant, A. J.
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BONE marrow transplantation ,BACTERIAL diseases ,CIRRHOSIS of the liver ,T cells ,PNEUMOCYSTIS pneumonia ,HISTOLOGY ,THERAPEUTIC use of immunoglobulins ,AGE distribution ,CHROMOSOMES ,GENETICS ,GLYCOPROTEINS ,HISTOCOMPATIBILITY testing ,HYPERGAMMAGLOBULINEMIA ,IMMUNOSUPPRESSION ,LIVER diseases ,OPPORTUNISTIC infections ,PROGNOSIS ,TREATMENT effectiveness ,RETROSPECTIVE studies ,DISEASE complications ,THERAPEUTICS - Abstract
Background: CD40 ligand (CD40L) deficiency is a rare X linked immunodeficiency disorder leading to recurrent bacterial infection, with cryptosporidial enteritis and subsequent hepatic cirrhosis. Bone marrow transplantation offers the only cure.Objective: To analyse retrospectively the outcome of bone marrow transplantation for this condition in one centre.Design: A retrospective case note analysis was performed, identifying all patients with CD40L deficiency who had undergone bone marrow transplantation between May 1988 and December 2000. Details of pre-existing infection, pretransplantation immunological and infective data, transplant procedure (particularly donor type and HLA match), conditioning regimen, and marrow manipulation were analysed. Post-transplantation data including infective episodes, engraftment details, immune function, complications, and outcome were recorded.Results: Eight boys (age 1-14 years, median 5.75) had transplants. Six received T cell depleted unrelated donor marrow. Four survive and have normal immune function. Six had previous Pneumocystis carinii pneumonia and three had histological liver damage. Survival was associated with younger age at transplantation and normal liver histology.Conclusions: Bone marrow transplantation can be curative in CD40L deficiency. Better outcome is associated with younger age at transplantation and normal liver histology. [ABSTRACT FROM AUTHOR]- Published
- 2001
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10. CAMPATH-1M T-cell depleted BMT for SCID: long-term follow-up of 19 children treated 1987–98 in a single center.
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Gennery, AR, Dickinson, AM, Brigham, K, Barge, D, Spickett, GP, Curtis, A, Spencer, V, Jackson, A, Cavanagh, G, Carter, V, Palmer, P, Flood, TJ, Cant, AJ, and Abinun, M
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IMMUNODEFICIENCY ,IMMUNITY ,BONE marrow transplantation ,BONE marrow purging ,JUVENILE diseases - Abstract
Background: SCID can be cured by BMT. Depletion of mature T cells from BM has enabled HLA non-identical stem-cell transplantation. We report the outcome of 30 patients treated with 37 T-cell depleted BMT procedures using CAMPATH-1M in vitro between 1987-98 in a single center. Methods: Immune reconstitution and quality-of-life were assessed in 19 longterm survivors. All but two received pre-transplant conditioning. T- and B-cell chimerism, numbers and function were analyzed during a median follow-up of 5.3 years (range 1.33-12). Results: The overall engraftment rate was 59%, six children required repeated BMT and the survival rate was 63%. All have donor T cells, 58% normal T-cell numbers and 74% normal T-cell function. Of 17 evaluated, 16 patients (94%) have normal IgM and IgG levels, and production of specific Abs to protein Ags, but only 5/16 (31%) have a good response to pneumococcal polysaccharide. Early and late post-BMT complications were rare and there were no delayed deaths. Only one child continues on long-term i.v. Ig 4-years post-BMT. Eleven children died (37%). Discussion: CAMPATH-1M T-cell depleted BMT for SCID resulted in 63% survival. Deaths of 11 children were mainly due to pre-existing infections. Seventeen of 19 long-term survivors have normal immune function and good quality-of-life. [ABSTRACT FROM AUTHOR]
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- 2001
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11. In vitro T cell depletion using Campath 1M for mismatched BMT for severe combined immunodeficiency (SCID).
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Dickinson, A M, Reid, M M, Abinun, M, Peak, J, Brigham, K, Dunn, J, and Cant, A J
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T cells ,BONE marrow transplantation ,ALLELES ,IMMUNODEFICIENCY - Abstract
Bone marrow transplantation is the only curative treatment for children with severe combined immunodeficiency (SCID). In the absence of an HLA-identical sibling, haploidentical parental donor marrow can be used provided it is depleted of T cells to prevent otherwise inevitable GVHD. Campath 1M has been successfully used for this procedure in several centres. In our centre 17 SCID patients plus one with combined immunodeficiency (CID) were transplanted with Campath 1M T cell-depleted bone marrow. Progenitor cell recovery, before and after T cell depletion, was monitored using granulocyte–macrophage colony-forming cell assays (GMCFU) and CD34 analysis. The numbers of GMCFU/kg transplanted correlated with engraftment and survival post-transplant and monitoring CD34
+ cell numbers in the T cell-depleted marrow pretransplant may be an additional indicator of successful engraftment. Use of a buffy coat marrow preparation with restriction of the number of T cells to <5 × 105 /kg was associated with graft failure in four and death in five of eight children, probably because too few stem cells were infused. T cell depletion of a mononuclear cell preparation of donor marrow with no arbitrary ceiling of infused T cells is highly effective at preventing clinically important GVHD and cured nine out of 10 children transplanted with such material. [ABSTRACT FROM AUTHOR]- Published
- 1997
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12. Anhidrotic ectodermal dysplasia and immunodeficiency: the role of NEMO.
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Carrol, E.D., Gennery, A.R., Flood, T.J., Spickett, G.P., and Abinun, M.
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ECTODERMAL dysplasia ,IMMUNODEFICIENCY ,IMMUNOLOGICAL adjuvants - Abstract
Discusses the role of the gene encoding nuclear factor kappa-beta essential modulator in anhidrotic ectodermal dysplasia and immunodeficiency. Essential role of the protein in the activation of the transcription factor that affects human development, skin homeostasis and immunity; Implications on acute pediatrics.
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- 2003
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13. Clinical and immunological overlap between autoimmune lymphoproliferative syndrome and common variable immunodeficiency
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Rensing-Ehl, A., Warnatz, K., Fuchs, S., Schlesier, M., Salzer, U., Draeger, R., Bondzio, I., Joos, Y., Janda, A., Gomes, M., Abinun, M., Hambleton, S., Cant, A., Shackley, F., Flood, T., Waruiru, C., Beutel, K., Siepermann, K., Dueckers, G., and Niehues, T.
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IMMUNOLOGY , *LYMPHOPROLIFERATIVE disorders , *AUTOIMMUNITY , *IMMUNODEFICIENCY , *B cells , *APOPTOSIS , *CELL death , *CELLULAR signal transduction - Abstract
Abstract: Autoimmune lymphoproliferative syndrome (ALPS) is mainly caused by defects in the CD95 pathway. Raised CD3+TCRαβ+CD4−CD8− double negative T cells and impaired T cell apoptosis are hallmarks of the disease. In contrast, the B cell compartment has been less well studied. We found an altered distribution of B cell subsets with raised transitional B cells and reduced marginal zone B cells, switched memory B cells and plasma blasts in most of 22 analyzed ALPS patients. Moreover, 5 out of 66 ALPS patients presented with low IgG and susceptibility to infection revealing a significant overlap between ALPS and common variable immunodeficiency (CVID). In patients presenting with lymphoproliferation, cytopenia, hypogammaglobulinemia and impaired B cell differentiation, serum biomarkers were helpful in addition to apoptosis tests for the identification of ALPS patients. Our observations may indicate a role for apoptosis defects in some diseases currently classified as CVID. [Copyright &y& Elsevier]
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- 2010
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14. The clinical and biological overlap between Nijmegen Breakage Syndrome and Fanconi anemia
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Gennery, A.R., Slatter, M.A., Bhattacharya, A., Barge, D., Haigh, S., O'Driscoll, M., Coleman, R., Abinun, M., Flood, T.J., Cant, A.J., and Jeggo, P.A.
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HUMAN chromosome abnormality diagnosis , *RADIATION , *BONE marrow , *IMMUNE system - Abstract
Fanconi anemia (FA), an autosomal recessive chromosomal instability syndrome, is characterized clinically by developmental abnormalities, growth retardation, progressive bone marrow failure, pancytopenia, and pronounced cancer predisposition. Nijmegen Breakage Syndrome (NBS) is a related disorder that shares overlapping clinical features, principally, developmental delay, microcephaly, and cancer predisposition. The diagnosis has relied on chromosomal instability following exposure to DNA cross-linking agents in FA and to ionizing radiation (IR) in NBS. We describe two patients who clinically had FA, but showed sensitivity to both DNA cross-linking agents and ionizing radiation, and who were found to have a rare mutation in the NBS gene. The importance of genetic diagnosis with respect to treatment and prognosis is discussed. [Copyright &y& Elsevier]
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- 2004
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