Research

Truly selective primary IgM deficiency is probably very rare.

Clin Exp Immunol. 2017 Oct 06;:

Authors: Janssen LM, Macken T, Creemers MC, Pruijt JF, Eijk JJ, de Vries E

Abstract
Isolated decreased serum-IgM has been associated with severe and/or recurrent infections, atopy and autoimmunity. However, the reported high prevalence of clinical problems in IgM-deficient patients may reflect the skewed tertiary center population studied so far. Also, many papers on IgM-deficiency have included patients with more abnormalities than just IgM-deficiency. We studied truly selective primary IgM deficiency according to the diagnostic criteria of the European Society for Immunodeficiencies ESID (true sIgMdef) by reviewing the literature (261 patients with primary decreased serum-IgM in 46 papers) and retrospectively analyzing all patients with decreased serum-IgM in a large teaching hospital in ‘s-Hertogenbosch, the Netherlands (1-July-2005 to 23-March-2016; n=8,049 IgM<0.4g/l; n=2,064 solitary [IgG+IgA normal/IgM

PMID: 28984901 [PubMed – as supplied by publisher]

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Influenza Vaccination in Patients with Common Variable Immunodeficiency (CVID).

Curr Allergy Asthma Rep. 2017 Oct 05;17(11):78

Authors: Mieves JF, Wittke K, Freitag H, Volk HD, Scheibenbogen C, Hanitsch LG

Abstract
PURPOSE OF REVIEW: Vaccination against influenza in patients with primary antibody deficiency is recommended. Common variable immunodeficiency (CVID) is the most frequent and clinically relevant antibody deficiency disease and is by definition characterized by an impaired vaccination response. The purpose of this review is to present the current knowledge of humoral and cellular vaccine response to influenza in CVID patients.
RECENT FINDINGS: Studies conducted in CVID patients demonstrated an impaired humoral response upon influenza vaccination. Data on cellular immune response are in part conflicting, with two out of three studies showing responses similar to healthy controls. Available data suggest a benefit from influenza vaccination in CVID patients. Therefore, annual influenza vaccination in patients and their close household contacts is recommended.

PMID: 28983790 [PubMed – in process]

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Dysregulation of Innate Lymphoid Cells in Common Variable Immunodeficiency.

Curr Allergy Asthma Rep. 2017 Oct 05;17(11):77

Authors: Maglione PJ, Cols M, Cunningham-Rundles C

Abstract
Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immune deficiency. With widespread use of immunoglobulin replacement therapy, non-infectious complications, such as autoimmunity, chronic intestinal inflammation, and lung disease, have replaced infections as the major cause of morbidity and mortality in this immune deficiency. The pathogenic mechanisms that underlie the development of these complications in CVID are not known; however, there have been numerous associated laboratory findings. Among the most intriguing of these associations is elevation of interferon signature genes in CVID patients with inflammatory/autoimmune complications, as a similar gene expression profile is found in systemic lupus erythematosus and other chronic inflammatory diseases. Linked with this heightened interferon signature in CVID is an expansion of circulating IFN-γ-producing innate lymphoid cells. Innate lymphoid cells are key regulators of both protective and pathogenic immune responses that have been extensively studied in recent years. Further exploration of innate lymphoid cell biology in CVID may uncover key mechanisms underlying the development of inflammatory complications in these patients and may inspire much needed novel therapeutic approaches.

PMID: 28983810 [PubMed – in process]

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Autoimmunity/inflammation in a monogenic primary immunodeficiency cohort.

Clin Transl Immunology. 2017 Sep;6(9):e155

Authors: Rae W, Ward D, Mattocks CJ, Gao Y, Pengelly RJ, Patel SV, Ennis S, Faust SN, Williams AP

Abstract
Primary immunodeficiencies (PIDs) are rare inborn errors of immunity that have a heterogeneous phenotype that can include severe susceptibility to life-threatening infections from multiple pathogens, unique sensitivity to a single pathogen, autoimmune/inflammatory (AI/I) disease, allergies and/or malignancy. We present a diverse cohort of monogenic PID patients with and without AI/I diseases who underwent clinical, genetic and immunological phenotyping. Novel pathogenic variants were identified in IKBKG, CTLA4, NFKB1, GATA2, CD40LG and TAZ as well as previously reported pathogenic variants in STAT3, PIK3CD, STAT1, NFKB2 and STXBP2. AI/I manifestations were frequently encountered in PIDs, including at presentation. Autoimmunity/inflammation was multisystem in those effected, and regulatory T cell (Treg) percentages were significantly decreased compared with those without AI/I manifestations. Prednisolone was used as the first-line immunosuppressive agent in all cases, however steroid monotherapy failed long-term control of autoimmunity/inflammation in the majority of cases and additional immunosuppression was required. Patients with multisystem autoimmunity/inflammation should be investigated for an underlying PID, and in those with PID early assessment of Tregs may help to assess the risk of autoimmunity/inflammation.

PMID: 28983403 [PubMed]

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Transcriptome analysis of CD34+ cells from myelodysplastic syndrome patients.

Leuk Res. 2017 Sep 08;62:40-50

Authors: Ou R, Huang J, Shen H, Liu Z, Zhu Y, Zhong Q, Zheng L, Yao M, She Y, Zhou S, Chen R, Li C, Zhang Q, Liu S

Abstract
The myelodysplastic syndrome (MDS) represents a heterogeneous group of clonal hematologic stem cell disorders with the characteristic of ineffective hematopoiesis leading to low blood counts, and a risk of progression to acute myeloid leukemia (AML). To understand specific molecular characteristics of different MDS subtypes with del(5q), we analyzed the gene expression profiles of CD34+ cells from MDS patients of different databases and its enriched pathways. 44 genes, such as MME and RAG1, and eight related pathways were identified to be commonly changed, indicating their conserved roles in MDS development. Additionally, U43604 was identified to be specifically changed in three subtypes with del(5q), including refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS) and refractory anemia with excess blasts (RAEB). C10orf10 and CD79B were specifically changed in RA patients with del(5q), while POU2AF1 were in RARS patients with del(5q). We also analyzed specific pathways of MDS subtypes, such as “Glycosaminoglycan biosynthesis-chondroitin sulfate” which was specific identified in RARS patients. Importantly, those findings can be validated well using another MDS database. Taken together, our analysis identified specific genes and pathways associated with different MDS subtypes with del(5q).

PMID: 28982058 [PubMed – as supplied by publisher]

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Late presenting atypical severe combined immunodeficiency (SCID) associated with a novel missense mutation in DCLRE1C.

Pediatr Allergy Immunol. 2017 Oct 05;:

Authors: Sundin M, Uhlin M, Gaballa A, Ramme K, Marits P, Nilsson J

Abstract
Immunodeficiency associated with mutations in the DNA cross-link repair 1C gene (DCLRE1C) can have variable clinical presentations including severe combined immunodeficiency (SCID), Omenn syndrome, atypical SCID or common variable immunodeficiency (CVID) (1-3). DCLRE1C encodes the protein Artemis, a nuclease with intrinsic 5′-3′ exonuclease activity on single-stranded DNA that is involved in non-homologous end joining (NHEJ). Artemis is essential for V(D)J recombination of the immunoglobulin and T-cell receptor genes that occur during B- and T-cell development.

PMID: 28981982 [PubMed – as supplied by publisher]

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Therapeutic Drug Monitoring Simulator for Antibiotic Dosage for Methicillin-Resistant Staphylococcus aureus Sepsis in a Patient with Primary Immunodeficiency on Peritoneal Dialysis.

J Nippon Med Sch. 2017;84(4):177-182

Authors: Narazaki H, Terada Y, Kaizu K, Jitsukawa T, Ito Y, Asano T

Abstract
Bacterial infections often cause fatal systemic infections in patients with primary immunodeficiency. To prevent unfortunate results, the selection, dose, and dosage of antibiotics are extremely important. Here, we report a case of Wiskott-Aldrich syndrome in a patient undergoing peritoneal dialysis because of chronic renal failure in whom methicillin-resistant Staphylococcus aureus sepsis developed. Because of the primary disease and complications, teicoplanin was the only chosen anti-S. aureus drug to prevent side effects. We used parameter estimation and dosage adjustment from a therapeutic drug monitoring simulation software program to overcome the challenges with teicoplanin treatment.

PMID: 28978898 [PubMed – in process]

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Inflammatory Bowel Disease in Chronic Granulomatous Disease: an emerging problem over a twenty years’ experience.

Pediatr Allergy Immunol. 2017 Oct 05;:

Authors: Angelino G, De Angelis P, Faraci S, Rea F, Romeo EF, Torroni F, Tambucci R, Claps A, Francalanci P, Chiriaco M, Di Matteo G, Cancrini C, Palma P, D’Argenio P, Dall’Oglio L, Rossi P, Finocchi A

Abstract
BACKGROUND: Chronic Granulomatous Disease (CGD) is a primary immunodeficiency of phagocytes, characterized by life-threatening infections and hyperinflammation. Due to survival improvement, Inflammatory Bowel Disease (IBD) is becoming increasingly relevant. Here we report our 20-year experience.
METHODS: We retrospectively analyzed clinical, endoscopic and histologic features, as well as the management of CGD-IBD patients referred to the Bambino Gesù Children’s Hospital in Rome, Italy.
RESULTS: Out of 20 CGD patients, 9 presented with CGD-IBD at diagnosis and/or during follow-up. Symptoms occurred at a median age of 16 years (range 3.2-42), with a median delay of 6 months for endoscopic confirmation. Patients mainly complained of nonspecific diarrhea (55%), with discrepancy between symptom paucity and severe endoscopic appearance, mainly represented by extensive colonic involvement (44%). Histology revealed at least 2 characteristic features (epithelioid granulomas, pigmented macrophages, and increased eosinophils) in 78% of patients. Eight out of 9 patients received oral mesalamine and 5 required systemic steroids. One patient received azathioprine due to steroid dependence. No patient required biological therapy, or surgery. Clinical remission was obtained in all patients, but the majority complained of mild relapses. Two episodes of severe infection occurred early after steroid therapy.
CONCLUSIONS: Penetrance of CGD-IBD increases with age. Clinical manifestations may be subtle, and clinicians should have a low threshold to recommend endoscopy. Treatment with NSAIDs and/or steroids achieves a good response, but relapses usually occur. Infection surveillance is mandatory during treatment, in order to prevent opportunistic infections. A close collaboration between Immunologists and Gastroenterologists is pivotal, including combined follow-up. This article is protected by copyright. All rights reserved.

PMID: 28981976 [PubMed – as supplied by publisher]

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The ERM Protein Moesin Regulates CD8(+) Regulatory T Cell Homeostasis and Self-Tolerance.

J Immunol. 2017 Oct 04;:

Authors: Satooka H, Nagakubo D, Sato T, Hirata T

Abstract
The ezrin-radixin-moesin (ERM) proteins are a family of membrane-associated proteins that link membrane proteins with actin filaments in the cell cortex and regulate many cellular processes, including cell shape determination, membrane transport, and signal transduction. Lymphocytes predominantly express two ERM members, ezrin and moesin. Mutations in the moesin gene in humans are associated with primary immunodeficiency with profound lymphopenia, and moesin-deficient mice exhibit a similar lymphopenia phenotype. In this study, we show that aging moesin-deficient mice develop a systemic lupus erythematosus-like autoimmune phenotype, which is characterized by elevated serum autoantibody levels and glomerulonephritis. Younger moesin-deficient mice exhibited elevated basal levels of several Ig isotypes and enhanced Ab affinity maturation upon immunization. Germinal center B cells and follicular helper T cells spontaneously accumulated in unimmunized mice, and CD8(+)CD44(+)CD122(+)Ly49(+) regulatory T (CD8(+) Tregs) cells, which inhibit the expansion of follicular helper T cells, were severely reduced in these mice. Isolated CD8(+) Treg cells from moesin-deficient mice showed impaired proliferation in response to IL-15, which was accompanied by defects in STAT5 activation and IL-15Rα internalization, suggesting that moesin plays a key role in IL-15-mediated signaling. These findings underscore the importance of moesin in IL-15-dependent CD8(+) Treg cell homeostasis and, thus, the control of self-tolerance.

PMID: 28978692 [PubMed – as supplied by publisher]

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