Research

History of Graft-versus-Host Disease.

Exp Hematol. 2016 May 25;

Authors: Vriesendorp HM, Heidt PJ

Abstract
Nuclear warfare at the end of World War II motivates Dick W. van Bekkum to study Total Body Irradiation (TBI) in animal models. After high dose TBI mice die from ‘primary disease’ or bone marrow aplasia. Intravenous administration of allogeneic bone marrow (BM) cells delays mortality, but does not prevent it. Initially the delayed deaths are said to be due to ‘secondary disease’ which is later renamed Graft-versus-Host Disease (GvHD). GvHD is caused by donor T-lymphocytes that destroy recipient cells in skin, intestinal mucosa, bile ducts and lymph nodes. GvHD is opposed by Host-versus-Graft Disease (HvGD): host T-lymphocytes destroying the administered allogeneic BM cells, including the administered T lymphocytes of the BM donor. In 1960 van Bekkum becomes the director of the Radiobiological Institute of the Dutch Organization for Applied Scientific Research TNO in Rijswijk, The Netherlands where he builds a multi-disciplinary team that defines the variables controlling the outcome of a BM transplant. The team publishes their early results in the Journal of Experimental Hematology [1, 2]. Later, protocols for bone marrow transplantation in patients with Severe Combined Immunodeficiency Disease (SCID), leukemia, lymphoma and other diseases of the hemopoietic system are established. This review honors the scientific contributions made by Dick van Bekkum and his team in defining the four dominant variables for improving the therapeutic ratio of allogeneic BM transplantation and in fostering the international collaboration necessary to translate this knowledge into current clinical practice.

PMID: 27235758 [PubMed – as supplied by publisher]

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Primary immunodeficiencies associated with eosinophilia.

Allergy Asthma Clin Immunol. 2016;12:27

Authors: Navabi B, Upton JE

Abstract
BACKGROUND: Eosinophilia is not an uncommon clinical finding. However, diagnosis of its cause can be a dilemma once common culprits, namely infection, allergy and reactive causes are excluded. Primary immunodeficiency disorders (PID) are among known differentials of eosinophilia. However, the list of PIDs typically reported with eosinophilia is small and the literature lacks an inclusive list of PIDs which have been reported with eosinophilia. This motivated us to review the literature for all PIDs which have been described to have elevated eosinophils as this may contribute to an earlier diagnosis of PID and further the understanding of eosinophilia.
METHODS: A retrospective PubMed, and Google Scholar search using the terms “eosinophilia” and “every individual PID” as classified by Expert Committee of the International Union of Immunological Societies with the limit of the English language was performed. Results were assessed to capture case(s) which reported eosinophilia in the context of PID conditions. Absolute eosinophil counts (AEC) were retrieved from manuscripts whenever reported.
RESULTS: In addition to the typical PID conditions described with eosinophilia, we document that MHC class II deficiency, CD3γ deficiency, STAT1 deficiency (AD form), Kostmann disease, cyclic neutropenia, TCRα deficiency, Papillon-Lefevre syndrome, CD40 deficiency, CD40L deficiency, anhidrotic ectodermal dysplasia with immune deficiency, ataxia-telangiectasia, common variable immunodeficiency disorders (CVID), Blau syndrome, CARD9 deficiency, neonatal onset multisystem inflammatory disease or chronic infantile neurologic cutaneous and articular syndrome (NOMID/CINCA), chronic granulomatous disease, MALT1 deficiency and Roifman syndrome have been noted to have elevated eosinophils. Severe eosinophilia (>5.0 × 10(9)/L) was reported in Omenn syndrome, Wiskott Aldrich syndrome, ADA deficiency, autoimmune lymphoproliferative syndrome, immunodysregulation polyendocrinopathy enteropathy X-linked, STAT3 deficiency, DOCK8 deficiency, CD40 deficiency, MHC II deficiency, Kostmann disease, Papillon-Lefevre syndrome, and CVID.
CONCLUSIONS: This literature review shows that there is an extensive list of PIDs which have been reported with eosinophilia. This list helps clinicians to consider an extended differential diagnoses when tasked with exclusion of PID as a cause for eosinophilia.

PMID: 27222657 [PubMed]

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Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase δ syndrome 2: A cohort study.

J Allergy Clin Immunol. 2016 Apr 21;

Authors: Elkaim E, Neven B, Bruneau J, Mitsui-Sekinaka K, Stanislas A, Heurtier L, Lucas CL, Matthews H, Deau MC, Sharapova S, Curtis J, Reichenbach J, Glastre C, Parry DA, Arumugakani G, McDermott E, Kilic SS, Yamashita M, Moshous D, Lamrini H, Otremba B, Gennery A, Coulter T, Quinti I, Stephan JL, Lougaris V, Brodszki N, Barlogis V, Asano T, Galicier L, Boutboul D, Nonoyama S, Cant A, Imai K, Picard C, Nejentsev S, Molina TJ, Lenardo M, Savic S, Cavazzana M, Fischer A, Durandy A, Kracker S

Abstract
BACKGROUND: Activated phosphoinositide 3-kinase δ syndrome (APDS) 2 (p110δ-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency [PASLI]-R1), a recently described primary immunodeficiency, results from autosomal dominant mutations in PIK3R1, the gene encoding the regulatory subunit (p85α, p55α, and p50α) of class IA phosphoinositide 3-kinases.
OBJECTIVES: We sought to review the clinical, immunologic, and histopathologic phenotypes of APDS2 in a genetically defined international patient cohort.
METHODS: The medical and biological records of 36 patients with genetically diagnosed APDS2 were collected and reviewed.
RESULTS: Mutations within splice acceptor and donor sites of exon 11 of the PIK3R1 gene lead to APDS2. Recurrent upper respiratory tract infections (100%), pneumonitis (71%), and chronic lymphoproliferation (89%, including adenopathy [75%], splenomegaly [43%], and upper respiratory tract lymphoid hyperplasia [48%]) were the most common features. Growth retardation was frequently noticed (45%). Other complications were mild neurodevelopmental delay (31%); malignant diseases (28%), most of them being B-cell lymphomas; autoimmunity (17%); bronchiectasis (18%); and chronic diarrhea (24%). Decreased serum IgA and IgG levels (87%), increased IgM levels (58%), B-cell lymphopenia (88%) associated with an increased frequency of transitional B cells (93%), and decreased numbers of naive CD4 and naive CD8 cells but increased numbers of CD8 effector/memory T cells were predominant immunologic features. The majority of patients (89%) received immunoglobulin replacement; 3 patients were treated with rituximab, and 6 were treated with rapamycin initiated after diagnosis of APDS2. Five patients died from APDS2-related complications.
CONCLUSION: APDS2 is a combined immunodeficiency with a variable clinical phenotype. Complications are frequent, such as severe bacterial and viral infections, lymphoproliferation, and lymphoma similar to APDS1/PASLI-CD. Immunoglobulin replacement therapy, rapamycin, and, likely in the near future, selective phosphoinositide 3-kinase δ inhibitors are possible treatment options.

PMID: 27221134 [PubMed – as supplied by publisher]

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Long-Term Tolerability, Safety, and Efficacy of Recombinant Human Hyaluronidase-Facilitated Subcutaneous Infusion of Human Immunoglobulin for Primary Immunodeficiency.

J Clin Immunol. 2016 May 25;

Authors: Wasserman RL, Melamed I, Stein MR, Engl W, Sharkhawy M, Leibl H, Puck J, Rubinstein A, Kobrynski L, Gupta S, Grant AJ, Ratnayake A, Richmond WG, Church J, Yel L, Gelmont D

Abstract
PURPOSE: Treatment of primary immunodeficiency diseases (PIDD) with subcutaneous (SC) infusions of IgG preceded by injection of recombinant human hyaluronidase (rHuPH20) (IGHy) to increase SC tissue permeability was evaluated in two consecutive, prospective, non-controlled, multi-center studies.
METHODS: Subjects >4 years of age received SC IgG replacement at a weekly dose equivalent of 108 % of their previous intravenous (IV) dose, facilitated by prior injection of 75 U/g IgG of rHuPH20. Starting with weekly SC infusions, the interval was increased (ramped-up) to a 3- or 4-week schedule.
RESULTS: Eighty-three subjects (24 < 18 years; 59 ≥ 18 years) received 2729 infusions (excluding ramp-up) at a mean dose of 0.155 g/kg/week in the pivotal and 0.156 g/kg/week in the extension study. IGHy exposure exceeded 30 months in 48 subjects. During 187.7 subject-years of IGHy exposure, 2005 adverse events (AEs) (10.68 per subject-year) occurred. The rate of related systemic AEs during consecutive 1-year periods remained low; the rate of related local AEs decreased from 3.68/subject-year in months 1-12 to approximately 1.50/subject-year after 30 months of treatment. Fifteen subjects transiently developed anti-rHuPH20 binding antibody. There was no difference in AE rates in these subjects before and after the first titer increase to ≥1:160. The rate of infections during IGHy exposure was 2.99 per subject-year and did not increase during the studies. Annual infection rates were 3.02 in subjects <18 years and 2.98 in subjects ≥18 years.
CONCLUSIONS: Long-term replacement therapy with IGHy was safe and effective in 83 pediatric and adult subjects with PIDD.

PMID: 27220317 [PubMed – as supplied by publisher]

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Lung transplantation for non-cystic fibrosis bronchiectasis.

Respir Med. 2016 Jun;115:60-5

Authors: Rademacher J, Ringshausen FC, Suhling H, Fuge J, Marsch G, Warnecke G, Haverich A, Welte T, Gottlieb J

Abstract
BACKGROUND: Lung transplantation (LTx) is a well-established treatment for end-stage pulmonary disease. However, data regarding microbiology and outcome of patients with non-cystic fibrosis bronchiectasis (NCFB) after lung transplantation are limited.
METHODS: A retrospective analysis between August 1992 and September 2014 of all patients undergoing lung transplantation at our program of all recipients with a primary diagnosis of bronchiectasis was performed. Microbiology of sputum and bronchoalveolar lavage specimens, lung function and clinical parameters pre- and post-LTx were assessed retrospectively. Overall survival was compared to the total cohort of lung transplant recipients at institution. The survival and development of chronic lung allograft dysfunction (CLAD) was compared in patients with and without chronic Pseudomonas aeruginosa (PSA) infection after LTx.
RESULTS: 34 patients were transplanted. Median age at transplantation was 40 (IQR 33-52) years. The most common etiologies of bronchiectasis were idiopathic (41%), chronic obstructive pulmonary disease (COPD) (21%) and post-infectious (15%). The most common organism of pre- and posttransplant chronic airway infection was PSA. One-year Kaplan-Meier survival for patients with bronchiectasis was 85% and 5-year survival was 73% and similar to the entire cohort. All three patients with an associated diagnosis of immunodeficiency died due to infection and sepsis within the first year. Patients with persistent colonization with Pseudomonas aeruginosa after transplantation had worse long-term survival by trend and developed chronic lung allograft dysfunction more frequently.
CONCLUSIONS: Overall survival of patients with bronchiectasis after LTx is comparable to other underlying diseases. A reduced survival was observed in patients with the underlying diagnosis of immunodeficiency.

PMID: 27215505 [PubMed – in process]

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Low Circulating Natural Killer Cell Counts are Associated With Severe Disease in Patients With Common Variable Immunodeficiency.

EBioMedicine. 2016 Apr;6:222-30

Authors: Ebbo M, Gérard L, Carpentier S, Vély F, Cypowyj S, Farnarier C, Vince N, Malphettes M, Fieschi C, Oksenhendler E, Schleinitz N, Vivier E, DEFI Study Group

Abstract
Natural Killer (NK) cells have been shown to exert antiviral and antitumoural activities. Nevertheless most available data are derived from mouse models and functions of these cells in human remain unclear. To evaluate the impact of low circulating NK cell counts and to provide some clues to the role of NK cells in natural conditions, we studied a large cohort of patients with common variable immunodeficiency (CVID) included in a multicenter cohort of patients with primary hypogammaglobulinaemia. Patients were classified into three groups on the basis of their NK cell counts: severe and mild NK cell lymphopenia (<50 and 50-99×10(6)/L respectively), and normal NK cell counts (>100×10(6)/L). Clinical events were analyzed and compared between these three groups of patients. During study period, 457 CVID patients were included: 99 (21.7%) with severe NK cell lymphopenia, 118 (25.8%) with mild NK cell lymphopenia and 240 (52.5%) with normal NK cell counts. Non-infectious complications (57% vs. 36% and 35%), and, particularly, granulomatous complications (25.3% vs. 13.6% and 8.8%), were more frequent in patients with severe NK cell lymphopenia than in other groups. Invasive infections (68.7% vs. 60.2% and 48.8%), including bacteraemia (22.2% vs. 5.9% and 8.3%) and infectious pneumonia (63.6% vs. 59.3% and 44.2%), were also more frequent in this population. However, no difference was observed for viral infections and neoplasms. Low circulating NK cell counts are associated with more severe phenotypes of CVID, which may indicate a protective role of these immune cells against severe bacterial infections and other complications and non-redundant immune functions when the adaptive immune response is not optimal.

PMID: 27211564 [PubMed – in process]

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Autoimmunity and Primary Immunodeficiency Disorders.

J Clin Immunol. 2016 May 23;

Authors: Allenspach E, Torgerson TR

Abstract
Advances in DNA sequencing technologies have led to a quickening in the pace at which new genetic immunodeficiency disorders have been identified. Among the newly identified defects are a number of disorders that present primarily with autoimmunity as opposed to recurrent infections. These “immune dysregulation” disorders have begun to cluster together to form an increased understanding of some of the basic molecular mechanisms that underlie the establishment and maintenance of immune tolerance and the development of autoimmunity. This review will present three major themes that have emerged in our understanding of the mechanisms that underlie autoimmunity and immune dysregulation in humans.

PMID: 27210535 [PubMed – as supplied by publisher]

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Impairment of dendritic cell functions in patients with Adaptor Protein-3 (AP-3) complex deficiency.

Blood. 2016 May 13;

Authors: Prandini A, Salvi V, Colombo F, Moratto D, Lorenzi L, Vermi W, De Francesco MA, Notarangelo LD, Porta F, Plebani A, Facchetti F, Sozzani S, Badolato R

Abstract
Hermansky-Pudlak type-2 syndrome (HPS2) is a primary immunodeficiency due to Adaptor Protein-3 (AP-3) complex deficiency. HPS2 patients present neutropenia, partial albinism, and impaired lysosomal vesicles formation in hematopoietic cells. Given the role of dendritic cells (DCs) in the immune response, we studied monocyte-derived DCs (moDCs) and plasmacytoid DCs (pDCs) in two HPS2 siblings. Mature HPS2 moDCs showed impaired expression of CD83 and DC-LAMP, low levels of MIP1-β/CCL4, MIG/CXCL9 and severe defect of IL-12 secretion. DCs in lymph-node biopsies from the same patients showed in a large fraction of DC-LAMP(+) cells a diffuse cytoplasm reactivity, instead of the classical dot-like stain. In addition, analysis of pDCs-related functions of blood-circulating mononuclear cells revealed reduced IFN-α secretion in response to Herpes simplex virus-1 (HSV-1) while granzyme-B induction upon IL-3/IL-10 stimulation was normal. Finally, T cell costimulatory activity, as measured by mixed lymphocyte reaction (MLR) assay, was lower in patients, suggesting that function and maturation of DCs is abnormal in patients with HPS2.

PMID: 27207797 [PubMed – as supplied by publisher]

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Neonatal screening for severe combined immunodeficiency in Brazil.

J Pediatr (Rio J). 2016 May 17;

Authors: Kanegae MP, Barreiros LA, Mazzucchelli JT, Hadachi SM, Guilhoto LM, Acquesta AL, Genov IR, Holanda SM, Di Gesu RS, Goulart AL, Dos Santos AM, Bellesi N, Costa-Carvalho BT, Condino-Neto A

Abstract
OBJECTIVE: To apply, in Brazil, the T-cell receptor excision circles (TRECs) quantification technique using real-time PCR in newborn screening for severe combined immunodeficiency (SCID) and assess the feasibility of implementing it on a large scale in Brazil.
METHODS: 8715 newborn blood samples were collected on paper filter and, after DNA elution, TRECs were quantified by real-time PCR. The cutoff value to determine whether a sample was abnormal was determined by ROC curve analysis, using SSPS.
RESULTS: The concentration of TRECs in 8682 samples ranged from 2 to 2181TRECs/μL of blood, with mean and median of 324 and 259TRECs/μL, respectively. Forty-nine (0.56%) samples were below the cutoff (30TRECs/μL) and were reanalyzed. Four (0.05%) samples had abnormal results (between 16 and 29TRECs/μL). Samples from patients previously identified as having SCID or DiGeorge syndrome were used to validate the assay and all of them showed TRECs below the cutoff. Preterm infants had lower levels of TRECs than full-term neonates. The ROC curve showed a cutoff of 26TRECs/μL, with 100% sensitivity for detecting SCID. Using this value, retest and referral rates were 0.43% (37 samples) and 0.03% (3 samples), respectively.
CONCLUSION: The technique is reliable and can be applied on a large scale after the training of technical teams throughout Brazil.

PMID: 27207231 [PubMed – as supplied by publisher]

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