Research

Agammaglobulinemia: causative mutations and their implications for novel therapies.

July 16, 2014 By Manish Butte

Agammaglobulinemia: causative mutations and their implications for novel therapies.

Expert Rev Clin Immunol. 2013 Dec;9(12):1205-21

Authors: Berglöf A, Turunen JJ, Gissberg O, Bestas B, Blomberg KE, Smith CI

Abstract
Agammaglobulinemias are primary (inherited) immunodeficiencies characterized by the lack of functional B-cells and antibodies, and are caused by mutations in genes encoding components of the pre-B-cell or B-cell receptor, or their signaling pathways. The known genetic defects do not account for all agammaglobulinemic patients, suggesting that novel mutations underlying the disease remain to be found. While efficient, the current life-maintaining therapy with immunoglobulins and antibiotics is non-curative, prompting research into alternative treatment strategies that aim at rescuing the expression of the affected protein, thus giving rise to functional B-cells. These include gene therapy, which could be used to correct the defective gene or replace it with a functional copy. For a number of genetic defects, another alternative is to modulate the splicing of the affected transcripts. While these technologies are not yet ready for clinical trials in agammaglobulinemia, advances in genomic targeting are likely to make this option viable in the near future.

PMID: 24215410 [PubMed – indexed for MEDLINE]

N-wasp is essential for the negative regulation of B cell receptor signaling.

July 16, 2014 By Manish Butte

N-wasp is essential for the negative regulation of B cell receptor signaling.

PLoS Biol. 2013 Nov;11(11):e1001704

Authors: Liu C, Bai X, Wu J, Sharma S, Upadhyaya A, Dahlberg CI, Westerberg LS, Snapper SB, Zhao X, Song W

Abstract
Negative regulation of receptor signaling is essential for controlling cell activation and differentiation. In B-lymphocytes, the down-regulation of B-cell antigen receptor (BCR) signaling is critical for suppressing the activation of self-reactive B cells; however, the mechanism underlying the negative regulation of signaling remains elusive. Using genetically manipulated mouse models and total internal reflection fluorescence microscopy, we demonstrate that neuronal Wiskott-Aldrich syndrome protein (N-WASP), which is coexpressed with WASP in all immune cells, is a critical negative regulator of B-cell signaling. B-cell-specific N-WASP gene deletion causes enhanced and prolonged BCR signaling and elevated levels of autoantibodies in the mouse serum. The increased signaling in N-WASP knockout B cells is concurrent with increased accumulation of F-actin at the B-cell surface, enhanced B-cell spreading on the antigen-presenting membrane, delayed B-cell contraction, inhibition in the merger of signaling active BCR microclusters into signaling inactive central clusters, and a blockage of BCR internalization. Upon BCR activation, WASP is activated first, followed by N-WASP in mouse and human primary B cells. The activation of N-WASP is suppressed by Bruton’s tyrosine kinase-induced WASP activation, and is restored by the activation of SH2 domain-containing inositol 5-phosphatase that inhibits WASP activation. Our results reveal a new mechanism for the negative regulation of BCR signaling and broadly suggest an actin-mediated mechanism for signaling down-regulation.

PMID: 24223520 [PubMed – indexed for MEDLINE]

Primary cutaneous marginal zone lymphoma with sequential development of nodal marginal zone lymphoma in a patient with selective immunoglobulin A deficiency.

July 16, 2014 By Manish Butte

Primary cutaneous marginal zone lymphoma with sequential development of nodal marginal zone lymphoma in a patient with selective immunoglobulin A deficiency.

J Cutan Pathol. 2013 Dec;40(12):1035-41

Authors: Wobser M, Kerstan A, Kneitz H, Goebeler M, Kunzmann V, Rosenwald A, Geissinger E

Abstract
Multiple lymphoma subtypes occurring within one patient is rare in the context of B-cell lymphoma, and only few such cases have been reported in association with primary cutaneous marginal zone lymphoma (PCMZL). We herein describe the case of a 43-year-old patient who was diagnosed with PCMZL and subsequently developed a clonally unrelated nodal marginal zone lymphoma (MZL). At the time of diagnosis of PCMZL, multiple skin lesions were present. The atypical lymphoid infiltrate showed monotypic expression of immunoglobulin light chain lambda and heavy chain (IgM) on immunohistochemistry and an identical B-cell clone. No sign of systemic lymphoma was present in staging examinations. Complete remission was achieved utilizing rituximab. After a 3-year clinical course of repetitive cutaneous relapses and remissions, the patient additionally developed nodal lymphoma involvement by MZL which, however, harbored an immunophenotype and a genetic clone distinct from the cutaneous lymphoma counterpart. Therefore, the rare occurrence of two different types of MZL with sequential evolution was diagnosed. In this uncommon case, we hypothesize that selective immunoglobulin A deficiency may play a promoting role for the metachronous development of the two MZL that occurred in our patient.

PMID: 24274426 [PubMed – indexed for MEDLINE]

Functional assessment of the mutational effects of human IRAK4 and MyD88 genes.

July 16, 2014 By Manish Butte

Functional assessment of the mutational effects of human IRAK4 and MyD88 genes.

Mol Immunol. 2014 Mar;58(1):66-76

Authors: Yamamoto T, Tsutsumi N, Tochio H, Ohnishi H, Kubota K, Kato Z, Shirakawa M, Kondo N

Abstract
Human interleukin-1 receptor-associated kinase 4 (IRAK4) deficiency and myeloid differentiating factor 88 (MyD88) deficiency syndromes are two primary immune-deficiency disorders with innate immune defects. Although new genetic variations of IRAK4 and MyD88 have recently been deposited in the single nucleotide polymorphism (SNP) database, the clinical significance of these variants has not yet been established. Therefore, it is important to establish methods for assessing the association of each gene variation with human diseases. Because cell-based assays, western blotting and an NF-κB reporter gene assay, showed no difference in protein expression and NF-κB activity between R12C and wild-type IRAK4, we examined protein-protein interactions of purified recombinant IRAK4 and MyD88 proteins by analytical gel filtration and NMR titration. We found that the variant of IRAK4, R12C, as well as R20W, located in the death domain of IRAK4 and regarded as a SNP, caused a loss of interaction with MyD88. Our studies suggest that not only the loss of protein expression but also the defect of Myddosome formation could cause IRAK4 and MyD88 deficiency syndromes. Moreover a combination of in vitro functional assays is effective for confirming the pathogenicity of mutants found in IRAK4 and MyD88-deficiency patients.

PMID: 24316379 [PubMed – indexed for MEDLINE]

Primary Immunodeficiency Diseases: A 30-year Patient Registry from the Referral Center for Primary Immunodeficiencies in Greece.

July 16, 2014 By Manish Butte

Primary Immunodeficiency Diseases: A 30-year Patient Registry from the Referral Center for Primary Immunodeficiencies in Greece.

J Clin Immunol. 2014 Jul 1;

Authors: Michos A, Raptaki M, Tantou S, Tzanoudaki M, Spanou K, Liatsis M, Constantinidou N, Paschali E, Varela I, Moraloglou O, Bakoula C, Kanariou M

Abstract
Primary Immunodeficiencies (PID) represent a group of heterogeneous immune diseases with important biological significance. We reviewed the records of children diagnosed with PID in the Referral Center for PID in our country in order to describe the epidemiological, clinical and laboratory characteristics of immunodeficient patients. During a 30-year period, 147 patients (101 males, 68.7 %), with a mean age of 6.5 years at the time of diagnosis, were diagnosed with PID. The most prevalent diagnoses of PID were: “Combined Immunodeficiency” in 46 (31.3 %) patients, “Well-defined immunodeficiency syndrome” in 35 (23.1 %) patients, “Predominantly antibody deficiency” in 30 (20.4 %) patients and “Congenital defect of phagocyte function or both” in 28 (19 %) patients. There was a higher prevalence of males with “Combined immunodeficiency” (p < 0.033) and “Predominantly antibody deficiency” (p < 0.02) compared to females. The median age of children at the onset of symptoms and at the time of diagnosis was 0.5y (IQR: 0.1-2.5) and 2y (IQR: 0.6-7.2), respectively. The median diagnostic delay was 0.9y (IQR: 0.2-4.8). This period was shorter for patients with “Combined immunodeficiency” [median 0.3y (IQR: 0.1-1)], and longer for those with “Predominantly antibody deficiency” [median 3.2y (IQR: 0.2-5.9) or “Disease of immune dysregulation” [median 3.2y (IQR: 0.1-6.6)]. Comparing the rates in our population with those of the European Registry (ESID), the rates of “Combined immunodeficiencies”, “Well-defined syndromes” and “Congenital birth defects and/or function of phagocytes” were significantly higher in this study (p <0,001). PID registry analysis improves knowledge in the field of Immunology and enhances awareness, early detection, diagnosis, and management of this rare but significant group of diseases.

PMID: 24981038 [PubMed – as supplied by publisher]

Clinical Experience With an L-Proline-Stabilized 10 % Intravenous Immunoglobulin (Privigen®): Real-Life Effectiveness and Tolerability.

July 16, 2014 By Manish Butte

Clinical Experience With an L-Proline-Stabilized 10 % Intravenous Immunoglobulin (Privigen®): Real-Life Effectiveness and Tolerability.

J Clin Immunol. 2014 Jul 1;

Authors: Dorsey MJ, Ho V, Mabudian M, Soler-Palacín P, Domínguez-Pinilla N, Rishi R, Rishi R, Wong D, Rojavin M, Hubsch A, Berger M

Abstract
PURPOSE: This retrospective study evaluated the effectiveness and tolerability in clinical practice of an L-proline-stabilized 10 % intravenous immunoglobulin (IVIG; Privigen®) in patients with primary (PID) or secondary immunodeficiency (SID).
METHODS: Patients from 6 centers in Europe and the US were treated with individually determined regimens of Privigen® for ≥3 months. Serum immunoglobulin G (IgG) trough levels, annualized rates of infection, hospitalization and antibiotics use, and the incidence of adverse events (AEs) were analyzed.
RESULTS: Of 72 patients, three infants with severe combined immunodeficiency (SCID) were analyzed separately. The remaining 69 patients (52.2 % male; median age 38 years [range: 0.1-90.0]) with PID (82.6 %) or SID (17.4 %) received a mean (±standard deviation) Privigen® dose of 532 ± 250 mg/kg/month resulting in trough serum IgG levels of 407-1,581 mg/dL (median: 954 mg/dL). Ten patients (14.5 %) experienced 11 serious bacterial infections over 22.0 ± 15.0 months of treatment (0.087 events/patient/year, upper one-sided 99 % confidence interval: 0.170), the most common being pneumonia (11.6 %). The rates for any infection and hospitalization were 1.082 events/patient/year and 3.63 days/patient/year, respectively. Two patients with severe disease accounted for 303 of 460 hospital days. Across all 72 patients, 13 (18.1 %) patients experienced AEs, including 10 (13.9 %) patients with AEs at least possibly related to Privigen®, including headache (8.3 %), fever, and chills (2.8 % each). No related serious AEs were reported. One infant with SCID died due to severe viral infection.
CONCLUSIONS: Despite the heterogeneous population, effectiveness and tolerability of Privigen® in clinical practice closely matched those reported in clinical studies.

PMID: 24981039 [PubMed – as supplied by publisher]

Defective functions of polymorphonuclear neutrophils in patients with common variable immunodeficiency.

July 16, 2014 By Manish Butte

Defective functions of polymorphonuclear neutrophils in patients with common variable immunodeficiency.

Immunol Res. 2014 Jul 1;

Authors: Casulli S, Coignard-Biehler H, Amazzough K, Shoai-Tehrani M, Bayry J, Mahlaoui N, Elbim C, Kaveri SV

Abstract
Common variable immunodeficiency (CVID) is a heterogeneous antibody deficiency condition with alterations in T cell regulation and function, dendritic and B-cell compartment and represents the most frequent cause of symptomatic primary immunodeficiency. We addressed whether CVID is associated with abnormalities in the polymorphonuclear neutrophil (PMN) compartment, an important component of innate immunity and plays a key role in host defenses against invading microorganisms. We used flow cytometry to examine PMN phenotypic and functional abnormalities in CVID patients, using whole-blood conditions in order to avoid artifacts due to isolation procedures. We demonstrated that PMN from CVID patients displays, at resting state, a decreased expression of CD15, CD11b and CD16b, which might be related to an abnormality in neutrophil maturation. In addition, these neutrophils exhibit a decrease in degranulation, phagocytosis and reactive oxygen species production, as well as an increased death by apoptosis. These PMN abnormalities observed in CVID patients could result in an increased risk for recurrent bacterial infections.

PMID: 24981124 [PubMed – as supplied by publisher]

Inflammatory manifestations in a single-center cohort of patients with chronic granulomatous disease.

July 16, 2014 By Manish Butte

Inflammatory manifestations in a single-center cohort of patients with chronic granulomatous disease.

J Allergy Clin Immunol. 2014 Jun 27;

Authors: Magnani A, Brosselin P, Beauté J, de Vergnes N, Mouy R, Debré M, Suarez F, Hermine O, Lortholary O, Blanche S, Fischer A, Mahlaoui N

Abstract
BACKGROUND: Chronic granulomatous disease (CGD) is a rare phagocytic disorder that results in not only infections but also potentially severe inflammatory manifestations that can be difficult to diagnose and treat.
OBJECTIVE: To describe inflammatory manifestations in a single-center cohort of patients with CGD.
METHODS: Medical records of patients treated at Necker-Enfants Malades Hospital (Paris, France) between 1968 and 2009 and registered at the French National Reference Center for Primary Immunodeficiencies (CEREDIH) were retrospectively reviewed.
RESULTS: In a study population of 98 patients, a total of 221 inflammatory episodes were recorded in 68 individuals (69.4%). The incidence rate of inflammatory episodes was 0.15 per person-year (0.18 in patients with X-linked [XL] CGD and 0.08 in patients with autosomal-recessive [AR] CGD). The most commonly affected organs were the gastrointestinal tract (in 88.2% of the patients), lungs (26.4%), the urogenital tract (17.6%), and eyes (8.8%). Inflammation at other sites (the skin, central nervous system, and tympanum) and autoimmune manifestations (lupus, arthritis, etc) were recorded in 19.1% and 10.3% of the patients, respectively. Granuloma was found in 50% of the 44 histological analyses reviewed. The risk of inflammatory episodes was 2-fold higher in patients with XL-CGD than in patients with AR-CGD (relative risk, 2.22; 95% CI, 1.43-3.46).
CONCLUSIONS: Patients with XL-CGD have a higher risk of developing inflammatory episodes than do patients with AR-CGD. Although the most commonly affected organ is the gastrointestinal tract, other sites can be involved, making the management of patients with CGD a complex, multidisciplinary task.

PMID: 24985400 [PubMed – as supplied by publisher]

Chronic granulomatous disease with pulmonary mass-like opacities secondary to hypersensitivity pneumonitis: a case report.

July 16, 2014 By Manish Butte

Chronic granulomatous disease with pulmonary mass-like opacities secondary to hypersensitivity pneumonitis: a case report.

J Med Case Rep. 2014 Jul 2;8(1):242

Authors: Katsuya Y, Hojo M, Kawai S, Kawai T, Onodera M, Sugiyama H

Abstract
INTRODUCTION: Chronic granulomatous disease, one of the primary immunodeficiency syndromes, is characterized by failure of phagocytic capacity due to loss of reactive oxygen species production, as well as formation of granulomas in organs. Clinically, dysregulated inflammation by excessive cytokine production due to loss of reactive oxygen species production is suggested as a cause of noninfectious inflammatory problems such as chronic granulomatous disease colitis. We experienced a rare case of a patient with chronic granulomatous disease with unique pathological and radiological presentations of hypersensitive pneumonitis, which to our knowledge has never been previously reported.
CASE PRESENTATION: A 20-year-old Japanese man with chronic granulomatous disease was referred due to cough and abnormal chest imaging findings. Computed tomography of his chest showed diffuse, bilateral, centrilobular nodules and multiple mass lesions in lower lobes that do not fit a common image of hypersensitivity pneumonitis. Pathological findings of both nodules and mass lesions on surgical lung biopsy were homogeneous, and excessive granulomas in the bronchioles and alveolar duct as well as lymphocytic alveolitis were seen, all consistent with hypersensitivity pneumonitis. The radiological and laboratory abnormalities did not improve after antigen avoidance; however, they disappeared after high-dose steroid therapy.
CONCLUSIONS: When we encounter a case of hypersensitive pneumonitis showing atypical pulmonary mass-like opacities in a patient with chronic granulomatous disease, we should consider hyperinflammatory status and excessive granuloma formation of chronic granulomatous disease and start with high-dose steroid therapy as treatment.

PMID: 24989247 [PubMed – as supplied by publisher]

Characterization of five newly isolated bacteriophages active against Pseudomonas aeruginosa clinical strains.

July 16, 2014 By Manish Butte

Characterization of five newly isolated bacteriophages active against Pseudomonas aeruginosa clinical strains.

Folia Microbiol (Praha). 2014 Jul 4;

Authors: Kwiatek M, Mizak L, Parasion S, Gryko R, Olender A, Niemcewicz M

Abstract
Pseudomonas aeruginosa is an opportunistic pathogen that causes serious infections, especially in patients with immunodeficiency. It exhibits multiple mechanisms of resistance, including efflux pumps, antibiotic modifying enzymes and limited membrane permeability. The primary reason for the development of novel therapeutics for P. aeruginosa infections is the declining efficacy of conventional antibiotic therapy. These clinical problems caused a revitalization of interest in bacteriophages, which are highly specific and have very effective antibacterial activity as well as several other advantages over traditional antimicrobial agents. Above all, so far, no serious or irreversible side effects of phage therapy have been described. Five newly purified P. aeruginosa phages named vB_PaeM_WP1, vB_PaeM_WP2, vB_PaeM_WP3, vB_PaeM_WP4 and vB_PaeP_WP5 have been characterized as potential candidates for use in phage therapy. They are representatives of the Myoviridae and Podoviridae families. Their host range, genome size, structural proteins and stability in various physical and chemical conditions were tested. The results of these preliminary investigations indicate that the newly isolated bacteriophages may be considered for use in phagotherapy.

PMID: 24993480 [PubMed – as supplied by publisher]