Research

Streptococcus pneumoniae serotype 6C presenting as recurrent prosthetic knee joint infection in a patient with a history of congenital asplenia and underlying autoimmune disease: a case report and literature review.

July 19, 2014 By Manish Butte

Streptococcus pneumoniae serotype 6C presenting as recurrent prosthetic knee joint infection in a patient with a history of congenital asplenia and underlying autoimmune disease: a case report and literature review.

Diagn Microbiol Infect Dis. 2013 Dec;77(4):376-9

Authors: Roberts AL, Hewlett AL, Yu J, Nahm MH, Fey PD, Iwen PC

Abstract
This report describes a case of primary Streptococcus pneumoniae bacteremia with prosthetic joint infection caused by serotype 6C with recurrent infection in a patient with a history of congenital asplenia and underlying autoimmune disease. Isolates from the primary and recurrent infections were determined to be indistinguishable by pulsed-field gel electrophoresis. This study expands the conditions associated with recurrent invasive pneumococcal disease caused by serotype 6C.

PMID: 24139971 [PubMed – indexed for MEDLINE]

Sequential asymptomatic enterovirus infections in a patient with MHC class II primary immunodeficiency.

July 18, 2014 By Manish Butte

Sequential asymptomatic enterovirus infections in a patient with MHC class II primary immunodeficiency.

J Clin Microbiol. 2014 Jul 16;

Authors: Driss N, Mellouli F, Ben Yahia A, Touzi H, Barbouche MR, Triki H, Bejaoui M

Abstract
Patients with primary immunodeficiencies are usually susceptible to enterovirus infections and have higher risks to develop severe clinical forms. We report a unique description of a boy with MHC-ClassII deficiency infected by 9 different enterovirus serotypes during a 2-years-period, with very mild clinical symptoms; probably due to the immunoglobulin therapy he was receiving.

PMID: 25031436 [PubMed – as supplied by publisher]

Primary immunodeficiencies underlying fungal infections.

July 17, 2014 By Manish Butte

Primary immunodeficiencies underlying fungal infections.

Curr Opin Pediatr. 2013 Dec;25(6):736-47

Authors: Lanternier F, Cypowyj S, Picard C, Bustamante J, Lortholary O, Casanova JL, Puel A

Abstract
PURPOSE OF REVIEW: We review the primary immunodeficiencies (PIDs) underlying an increasing variety of superficial and invasive fungal infections. We also stress that the occurrence of such fungal infections should lead physicians to search for the corresponding single-gene inborn errors of immunity. Finally, we suggest that other fungal infections may also result from hitherto unknown inborn errors of immunity, at least in some patients with no known risk factors.
RECENT FINDINGS: An increasing number of PIDs are being shown to underlie fungal infectious diseases in children and young adults. Inborn errors of the phagocyte NADPH oxidase complex (chronic granulomatous disease), severe congenital neutropenia (SCN) and leukocyte adhesion deficiency type I confer a predisposition to invasive aspergillosis and candidiasis. More rarely, inborn errors of interferon-γ immunity underlie endemic mycoses. Inborn errors of interleukin-17 immunity have recently been shown to underlie chronic mucocutaneous candidiasis (CMC), while inborn errors of caspase recruitment domain-containing protein 9 (CARD9) immunity underlie deep dermatophytosis and invasive candidiasis.
SUMMARY: CMC, invasive candidiasis, invasive aspergillosis, deep dermatophytosis, pneumocystosis, and endemic mycoses can all be caused by PIDs. Each type of infection is highly suggestive of a specific type of PID. In the absence of overt risk factors, single-gene inborn errors of immunity should be sought in children and young adults with these and other fungal diseases.

PMID: 24240293 [PubMed – indexed for MEDLINE]

Selective demethylation and altered gene expression are associated with ICF Syndrome in human induced pluripotent stem cells and mesenchymal stem cells.

July 17, 2014 By Manish Butte

Selective demethylation and altered gene expression are associated with ICF Syndrome in human induced pluripotent stem cells and mesenchymal stem cells.

Hum Mol Genet. 2014 Jul 15;

Authors: Huang K, Wu Z, Liu Z, Hu G, Yu J, Chang KH, Kim KP, Le T, Faull KF, Rao N, Gennery A, Xue Z, Wang CY, Pellegrini M, Fan G

Abstract
Immunodeficiency, Centromeric Instability, and Facial Anomalies Type I (ICF1) Syndrome is a rare genetic disease caused by mutations in DNMT3B, a de novo DNA methyltransferase. However, the molecular basis of how DNMT3B-deficiency leads to ICF1 pathogenesis is unclear. Induced pluripotent stem cell (iPSC) technology facilitates the study of early human developmental diseases via facile in vitro paradigms. Here, we generate iPSCs from ICF Type 1 Syndrome patient fibroblasts followed by directed differentiation of ICF1-iPSCs to mesenchymal stem cells (MSCs). By performing genome-scale bisulfite sequencing, we find that DNMT3B-deficient iPSCs exhibit global loss of non-CG methylation and select CG hypomethylation at gene promoters and enhancers. Further unbiased scanning of ICF1 iPSC methylomes also identifies large megabase regions of CG hypomethylation typically localized in centromeric and subtelomeric regions. RNA sequencing of ICF1 and control iPSCs reveals abnormal gene expression in ICF1 iPSCs relevant to ICF Syndrome phenotypes, some directly associated with promoter or enhancer hypomethylation. Upon differentiation of ICF1 iPSCs to mesenchymal stem cells (MSCs), we find virtually all CG hypomethylated regions remained hypomethylated when compared to either wild-type iPSC-derived MSCs or primary bone-marrow MSCs. Collectively, our results show specific methylome and transcriptome defects in both ICF1-iPSCs and differentiated somatic cell lineages, providing a valuable stem cell system for further in vitro study of the molecular pathogenesis of ICF1 Syndrome.

PMID: 25027325 [PubMed – as supplied by publisher]

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]