Research

Into Action: Improving Access to Optimum Care for all Primary Immunodeficiency Patients.

J Clin Immunol. 2016 Apr 6;

Authors: Espinosa-Rosales FJ, Condino-Neto A, Franco JL, Sorensen RU

PMID: 27048657 [PubMed – as supplied by publisher]

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Copa Syndrome: a Novel Autosomal Dominant Immune Dysregulatory Disease.

J Clin Immunol. 2016 Apr 5;

Authors: Vece TJ, Watkin LB, Nicholas SK, Canter D, Braun MC, Guillerman RP, Eldin KW, Bertolet G, McKinley SD, de Guzman M, Forbes LR, Chinn I, Orange JS

Abstract
Inherently defective immunity typically results in either ineffective host defense, immune regulation, or both. As a category of primary immunodeficiency diseases, those that impair immune regulation can lead to autoimmunity and/or autoinflammation. In this review we focus on one of the most recently discovered primary immunodeficiencies that leads to immune dysregulation: “Copa syndrome”. Copa syndrome is named for the gene mutated in the disease, which encodes the alpha subunit of the coatomer complex-I that, in aggregate, is devoted to transiting molecular cargo from the Golgi complex to the endoplasmic reticulum (ER). Copa syndrome is autosomal dominant with variable expressivity and results from mutations affecting a narrow amino acid stretch in the COPA gene-encoding COPα protein. Patients with these mutations typically develop arthritis and interstitial lung disease with pulmonary hemorrhage representing a striking feature. Immunologically Copa syndrome is associated with autoantibody development, increased Th17 cells and pro-inflammatory cytokine expression including IL-1β and IL-6. Insights have also been gained into the underlying mechanism of Copa syndrome, which include excessive ER stress owing to the impaired return of proteins from the Golgi, and presumably resulting aberrant cellular autophagy. As such it represents a novel cellular disorder of intracellular trafficking associated with a specific clinical presentation and phenotype.

PMID: 27048656 [PubMed – as supplied by publisher]

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Improved outcomes on subcutaneous IgG in patients with humoral immunodeficiency and co-morbid bowel disease.

Clin Case Rep Rev. 2015 Jul 28;1(7):151-152

Authors: Shah SN, Todoric K, Tarrant TK

Abstract
Immunoglobulin replacement can be life-saving for certain individuals with immunodeficiencies. Subcutaneous IgG (SCIG) is an increasingly used method of replacement over intravenous IgG (IVIG), with potential advantages including fewer systemic side effects, no need for IV access, patient-reported improved quality of life, and decreased cost. However, while patients with certain associated co-morbidities, such as protein-losing enteropathy, may demonstrate more stable IgG levels when on SCIG compared to IVIG, the clinical significance of these experiences is not well described. Using retrospective chart review, we examined three cases in which SCIG and IVIG was administered to patients with either common variable immunodeficiency (CVID) or secondary humoral immunodeficiency and protein-losing gastrointestinal co-morbid disease. Both outpatient and inpatient records were reviewed for data regarding treatment with IVIG versus SCIG, reported frequency and severity of infections, hospitalizations, and IgG levels. All three patients demonstrated improvement in infection rate, stability of IgG levels, and co-morbid disease when on SCIG as compared to IVIG. These findings suggest that the pharmacokinetics of SCIG may translate into more consistent serum IgG levels, contributing to clinical improvement in immunodeficient patients with protein-losing comorbidities when compared to IVIG. Limitations to this study are small patient numbers, retrospective design, and potential therapeutic bias. Further characterization of the effects of co-morbid conditions on immunoglobulin replacement is critical to providing improved and informed patient care.

PMID: 27042340 [PubMed – as supplied by publisher]

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Clinical experiences in primary and secondary immunodeficiencies and immune-mediated conditions using Gammanorm(®).

Immunotherapy. 2016 Mar 29;

Authors: Gardulf A

Abstract
Treatment for primary and secondary immunodeficiency disorders focuses on prevention and management of infections, using immunoglobulin G (IgG) replacement therapy with regular intravenous or subcutaneous IgG (SCIG) infusions. SCIG therapy has many advantages including improved efficacy and tolerability, enhanced patient satisfaction and lower costs. A number of SCIG preparations are available, including Gammanorm(®) (Octapharma AG), a ready-to-use 16.5% liquid preparation of IgG, with low viscosity, well suited to self-administration and a long history of use. Clinical experience with Gammanorm has shown that it is effective and well tolerated in children and adults, including pregnant women, for primary and secondary immunodeficiency disorders. Recent data also suggest SCIG may have a role in the treatment of certain immune-mediated conditions.

PMID: 27020964 [PubMed – as supplied by publisher]

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DNA polymerase-α regulates the activation of type I interferons through cytosolic RNA:DNA synthesis.

Nat Immunol. 2016 Mar 28;

Authors: Starokadomskyy P, Gemelli T, Rios JJ, Xing C, Wang RC, Li H, Pokatayev V, Dozmorov I, Khan S, Miyata N, Fraile G, Raj P, Xu Z, Xu Z, Ma L, Lin Z, Wang H, Yang Y, Ben-Amitai D, Orenstein N, Mussaffi H, Baselga E, Tadini G, Grunebaum E, Sarajlija A, Krzewski K, Wakeland EK, Yan N, de la Morena MT, Zinn AR, Burstein E

Abstract
Aberrant nucleic acids generated during viral replication are the main trigger for antiviral immunity, and mutations that disrupt nucleic acid metabolism can lead to autoinflammatory disorders. Here we investigated the etiology of X-linked reticulate pigmentary disorder (XLPDR), a primary immunodeficiency with autoinflammatory features. We discovered that XLPDR is caused by an intronic mutation that disrupts the expression of POLA1, which encodes the catalytic subunit of DNA polymerase-α. Unexpectedly, POLA1 deficiency resulted in increased production of type I interferons. This enzyme is necessary for the synthesis of RNA:DNA primers during DNA replication and, strikingly, we found that POLA1 is also required for the synthesis of cytosolic RNA:DNA, which directly modulates interferon activation. Together this work identifies POLA1 as a critical regulator of the type I interferon response.

PMID: 27019227 [PubMed – as supplied by publisher]

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IVIG in autoimmune disease – Potential next generation biologics.

Autoimmun Rev. 2016 Mar 24;

Authors: Zuercher AW, Spirig R, Morelli AB, Käsermann F

Abstract
Polyclonal plasma-derived IgG is a mainstay therapeutic of immunodeficiency disorders as well as of various inflammatory autoimmune diseases. In immunodeficiency the primary function of IVIG/SCIG is to replace missing antibody specificities, consequently a diverse Fab-based repertoire is critical for efficacy. Attempts to capture the Ig repertoire and express it as a recombinant IVIG product are currently ongoing. Likewise correction of the defective genes by gene therapy has also been tried. However, both approaches are far from becoming mainstream treatments. In contrast, some of the most important effector mechanisms relevant in therapy of autoimmunity are based on the Fc-portion of IgG; they include scavenging of complement and blockade/modulation of IgG receptors (Fc gamma receptor [FcγR] or the neonatal Fc receptor [FcRn]). These effects might be achieved with appropriately formulated Fc-fragments instead of full-length IgG, as suggested by a pilot study with monomeric plasma-derived Fc in children with ITP and in Kawasaki disease in the 1990’s. Since then it has been proposed that structured multimerization of Fc fragments might confer efficacy at much lower doses than with IVIG. Accordingly, various molecular strategies are currently being explored to achieve controlled Fc multimerization, e.g. by fusion of IgG1 Fc to the IgG2 hinge-region or to the IgM tail-piece. Safety considerations will be crucial in the evaluation of these new entities. In a different approach, mutant Fc fragments and monoclonal antibodies have been designed for blockade of the FcRn.

PMID: 27019051 [PubMed – as supplied by publisher]

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Evans Syndrome at Childhood-Onset Systemic Lupus Erythematosus Diagnosis: A Large Multicenter Study.

Pediatr Blood Cancer. 2016 Mar 28;

Authors: Lube GE, Ferriani MP, Campos LM, Terreri MT, Bonfá E, Magalhães CS, Aikawa NE, Piotto DP, Peracchi OA, Dos Santos MC, Appenzeller S, Ferriani VP, Pereira RM, Silva CA

Abstract
BACKGROUND: Evans syndrome (ES) in childhood-onset systemic lupus erythematosus (cSLE) patients has been rarely reported and limited to small populations.
PROCEDURES: A retrospective multicenter cohort study (Brazilian cSLE group) was performed in 10 Pediatric Rheumatology services including 850 patients with cSLE. ES was assessed at disease diagnosis and defined by the combination of immune thrombocytopenia and autoimmune hemolytic anemia.
RESULTS: ES was observed in 11 of 850 (1.3%) cSLE patients. The majority of them had hemorrhagic manifestations (91%) and active disease (82%). All patients with ES were hospitalized and none died. Comparisons of cSLE patients with and without ES at diagnosis revealed similar frequencies of female gender, multiorgan involvement, autoantibodies profile, and low complement (P > 0.05). Patients with ES had a lower frequency of malar rash (9% vs. 53%, P = 0.003) and musculoskeletal involvement (18% vs. 69%, P = 0.001) than those without this complication. The frequencies of intravenous methylprednisolone (82% vs. 43%, P = 0.013) and intravenous immunoglobulin use (64% vs. 3%, P < 0.0001) were significantly higher in the ES group, with similar current prednisone dose between groups (1.1 [0.76-1.5] vs. 1.0 mg/kg/day [0-30], P = 0.195).
CONCLUSIONS: Our large multicenter study identified ES as a rare and severe initial manifestation of active cSLE with good outcome. Diagnosis is challenging due to the lack of typical signs and symptoms of lupus and the requirement to exclude infection and primary immunodeficiency.

PMID: 27018636 [PubMed – as supplied by publisher]

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Mutation in IRF2BP2 is responsible for a familial form of common variable immunodeficiency disorder.

J Allergy Clin Immunol. 2016 Mar 23;

Authors: Keller MD, Pandey R, Li D, Glessner J, Tian L, Henrickson SE, Chinn IK, Monaco-Shawver L, Heimall J, Hou C, Otieno FG, Jyonouchi S, Calabrese L, van Montfrans J, Orange JS, Hakonarson H

Abstract
BACKGROUND: Genome-wide association studies have shown a pattern of rare copy number variations and single nucleotide polymorphisms in patients with common variable immunodeficiency disorder (CVID), which was recognizable by a support vector machine (SVM) algorithm. However, rare monogenic causes of CVID might lack such a genetic fingerprint.
OBJECTIVE: We sought to identify a unique monogenic cause of familial immunodeficiency and evaluate the use of SVM to identify patients with possible monogenic disorders.
METHODS: A family with multiple members with a diagnosis of CVID was screened by using whole-exome sequencing. The proband and other subjects with mutations associated with CVID-like phenotypes were screened through the SVM algorithm from our recent CVID genome-wide association study. RT-PCR, protein immunoblots, and in vitro plasmablast differentiation assays were performed on patient and control EBV lymphoblastoids cell lines.
RESULTS: Exome sequencing identified a novel heterozygous mutation in IRF2BP2 (c.1652G>A:p.[S551N]) in affected family members. Transduction of the mutant gene into control human B cells decreased production of plasmablasts in vitro, and IRF2BP2 transcripts and protein expression were increased in proband versus control EBV-immortalized lymphoblastoid cell lines. The SVM algorithm categorized the proband and subjects with other immunodeficiency-associated gene variants in TACI, BAFFR, ICOS, CD21, LRBA, and CD27 as genetically dissimilar from polygenic CVID.
CONCLUSION: A novel IRFBP2 mutation was identified in a family with autosomal dominant CVID. Transduction experiments suggest that the mutant protein has an effect on B-cell differentiation and is likely a monogenic cause of the family’s CVID phenotype. Successful grouping by the SVM algorithm suggests that our family and other subjects with rare immunodeficiency disorders cluster separately and lack the genetic pattern present in polygenic CVID cases.

PMID: 27016798 [PubMed – as supplied by publisher]

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