Research

Subcutaneous Immunoglobulin Replacement Therapy in Patients with Primary Immunodeficiency in Routine Clinical Practice: The VISPO Prospective Multicenter Study.

Clin Drug Investig. 2015 Feb 12;

Authors: Vultaggio A, Azzari C, Milito C, Finocchi A, Toppino C, Spadaro G, Trizzino A, Baldassarre M, Paganelli R, Moschese V, Soresina A, Matucci A

Abstract
BACKGROUND AND OBJECTIVES: Subcutaneous immunoglobulin (SCIG) therapy is becoming increasingly popular as self-administration is possible because intravenous access is unnecessary, and there is a lower frequency of systemic adverse events. The aim of this study was to evaluate the shifting from intravenous immunoglobulins (IVIGs) replacement therapy to SCIG in patients with primary immunodeficiency (PID) in a routine real-life situation.
METHODS: In a multicenter prospective observational study, we enrolled 50 patients suffering from PID who were monitored for 24 months; 44 patients switched from IVIG and six from different SCIG preparations. The study preparation (human IgG 16 %, Vivaglobin(®), CSL Behring GmbH, Germany) was subcutaneously infused weekly (maximum volume 15 mL/site; maximum infusion rate 22 mL/h). The study endpoints were: annual rate of severe bacterial infections (SBIs), local adverse reactions, quality of life, days off school/work, and days of hospitalization.
RESULTS: Thirty-three of 39 (84.6 %) patients who completed the study experienced an infection or signs thereof. Only five SBIs were observed, corresponding to an annual rate of 0.056 episodes per patient in 44 subjects [intention-to-treat (ITT) population]. A significant decrease in both days of hospitalization (1.93 ± 4.08 vs. 0.64 ± 2.94) and days off school/work (15.27 ± 23.17 vs. 2.26 ± 4.45) was recorded at 24 months. Local reactions were observed in 14/50 (28 %) patients, mainly consisting of skin manifestations at the injection site. Only three (6.8 %) patients discontinued due to infusion site reactions. In patients shifting from IVIG to SCIG, the total mean score of Life Quality Index (LQI) improved from 76.9 ± 16.8 to 90.7 ± 11.6 (P < 0.01) at 6 months; there was an improvement also in the overall patients’ evaluation.
CONCLUSIONS: A total of 93.2 % patients tolerated the new route of administration and reported a significant improvement in their LQI. Our results from a routine clinical practice in a real-life population are consistent with those of phase III clinical studies.

PMID: 25672929 [PubMed – as supplied by publisher]

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BAFFR deficiency results in limited CD169+ macrophage function during viral infection.

J Virol. 2015 Feb 11;

Authors: Xu HC, Huang J, Khairnar V, Duhan V, Pandyra AA, Grusdat M, Shinde P, McIlwain DR, Maney SK, Gommerman J, Löhning M, Ohashi PS, Mak TW, Pieper K, Sic H, Speletas M, Eibel H, Ware CF, Tumanov AV, Kruglov AA, Nedospasov SA, Häusinger D, Recher M, Lang KS, Lang PA

Abstract
The B cell activating factor of the TNF family (BAFF) is critical for B-cell development and humoral immunity in mice and humans. While the role of BAFF in B cells has been widely described, its role in innate immunity remains unknown. Using BAFFR deficient mice we characterized BAFFR related innate and adaptive immune functions following infection with vesicular stomatitis virus (VSV) and lymphocytic choriomeningitis virus (LCMV). We identified a critical role for BAFFR signalling in the generation and maintenance of the CD169(+) macrophage compartment. Consequently, Baffr(-/-) mice exhibited limited induction of innate type I interferon production after viral infection. Lack of BAFFR signalling reduced virus amplification and presentation following viral infection, resulting in highly reduced anti-viral adaptive immune responses. As a consequence, BAFFR deficient mice showed exacerbated and fatal disease after viral infection. Mechanistically, transient lack of B cells in Baffr(-/-) animals resulted in limited lymphotoxin expression, which was critical for maintenance of CD169(+) cells. In conclusion, BAFFR signalling affects both innate and adaptive immune activation during viral infections.
IMPORTANCE: Viruses cause acute and chronic infections in humans resulting in millions of deaths every year. Innate immunity is critical for the outcome of a viral infection. Innate type I interferon production can limit viral replication while adaptive immune priming by innate immune cells induces pathogen specific immunity with long term protection. Here we show that BAFFR deficiency not only perturbed B cells, but also resulted in limited CD169(+) macrophages. These macrophages are critical in amplifying viral particles to trigger type I interferon production and initiate adaptive immune priming. Consequently, BAFFR deficiency resulted in reduced enforced viral replication, limited type I interferon production, and reduced adaptive immunity when compared to BAFFR competent controls. As a result, BAFFR deficient mice were predisposed to fatal viral infections. Thus, BAFFR expression is critical for innate immune activation and anti-viral immunity.

PMID: 25673724 [PubMed – as supplied by publisher]

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Overview of recombinant human hyaluronidase-facilitated subcutaneous infusion of IgG in primary immunodeficiencies.

Immunotherapy. 2014;6(5):553-67

Authors: Wasserman RL

Abstract
Subcutaneous administration of immunoglobulin (IGSC) in a home setting, compared with intravenous administration, can improve patient quality of life. During IGSC, however, the subcutaneous extracellular matrix inhibits flow and fluid entry into the vascular compartment, which limits the amount of drug delivered. Recombinant human hyaluronidase (rHuPH20) increases the absorption and dispersion of infused fluids and drugs. Results from a Phase III, prospective, open-label, noncontrolled study of patients with primary immunodeficiencies indicated that IGSC infusion, facilitated by rHuPH20, is well tolerated and delivers infusion volumes at treatment intervals and rates equivalent to intravenous administration. This drug evaluation provides an overview of rHuPH20 and results of clinical studies of IGSC infusion facilitated by rHuPH20 in patients with primary immunodeficiencies.

PMID: 24896624 [PubMed – indexed for MEDLINE]

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Immunodeficiency and Autoimmune Enterocolopathy Linked to NFAT5 Haploinsufficiency.

J Immunol. 2015 Feb 9;

Authors: Boland BS, Widjaja CE, Banno A, Zhang B, Kim SH, Stoven S, Peterson MR, Jones MC, Su HI, Crowe SE, Bui JD, Ho SB, Okugawa Y, Goel A, Marietta EV, Khosroheidari M, Jepsen K, Aramburu J, López-Rodríguez C, Sandborn WJ, Murray JA, Harismendy O, Chang JT

Abstract
The link between autoimmune diseases and primary immunodeficiency syndromes has been increasingly appreciated. Immunologic evaluation of a young man with autoimmune enterocolopathy and unexplained infections revealed evidence of immunodeficiency, including IgG subclass deficiency, impaired Ag-induced lymphocyte proliferation, reduced cytokine production by CD8(+) T lymphocytes, and decreased numbers of NK cells. Genetic evaluation identified haploinsufficiency of NFAT5, a transcription factor regulating immune cell function and cellular adaptation to hyperosmotic stress, as a possible cause of this syndrome. Inhibition or deletion of NFAT5 in normal human and murine cells recapitulated several of the immune deficits identified in the patient. These results provide evidence of a primary immunodeficiency disorder associated with organ-specific autoimmunity linked to NFAT5 deficiency.

PMID: 25667416 [PubMed – as supplied by publisher]

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XIAP deficiency syndrome in humans.

Semin Cell Dev Biol. 2015 Feb 6;

Authors: Latour S, Aguilar C

Abstract
The X-linked inhibitor of apoptosis (XIAP) deficiency, also known as the X-linked lymphoproliferative syndrome type 2 (XLP-2), is a rare primary immunodeficiency. XIAP-deficiency is characterized by a key triad of clinical manisfestations, which consist of a high susceptibility to develop hemophagocytic lymphohistiocytosis (HLH) frequently triggered by Epstein-Barr virus (EBV) infection, recurrent splenomegaly and inflammatory bowel disease (IBD) with the features of a Crohn’s disease. XIAP deficiency can be considered as one of the genetic causes for inherited IBD. XIAP is an anti-apoptotic molecule, but it is also involved in many other pathways. Recent findings demonstrate the role of XIAP in innate immunity and in the negative regulation of inflammation. In this review, we focus on the clinical aspects, the molecular etiology and the immunopathogenesis of XIAP deficiency. We also discuss recent progress in the understanding of XIAP function in relation to the pathophysiology of XLP-2.

PMID: 25666262 [PubMed – as supplied by publisher]

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Monocyte/macrophage-Specific NADPH Oxidase Contributes to Antimicrobial Host Defense in X-CGD.

J Clin Immunol. 2015 Feb 10;

Authors: Okura Y, Yamada M, Kuribayashi F, Kobayashi I, Ariga T

Abstract
BACKGROUND: Chronic granulomatous disease (CGD) is a primary immunodeficiency disease that is characterized by susceptibility to bacterial and fungal infections. Various mutations in CYBB encoding the gp91(phox) subunit of the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase impair the respiratory burst of all types of phagocytic cells and result in X-linked CGD (X-CGD).
PURPOSE: We here sought to evaluate the underlying cause in an attenuated phenotype in an X-CGD patient. The patient is a 31-year-old male who had been diagnosed as having X-CGD based on the absence of nitroblue tetrazolium reduction and the presence of a CYBB mutation at the age of 1 year. He has been in good health after overcoming recurrent bacterial infections in infancy.
METHODS: We investigated genomic DNA analysis of CYBB gene, residual activity of NADPH oxidase, and expression of gp91(phox) in both polymorphonuclear leukocytes (PMNs) and monocytes/macrophages in the present patient.
RESULTS: Although his underlying germline mutation, c.1016C>A (p.P339H) in the CYBB gene, was identified in both PMNs and monocytes, the expression and functional activity of gp91(phox) retained in monocytes/macrophages, in stark contrast to markedly reduced PMNs.
CONCLUSIONS: Our results indicate that residual reactive oxygen intermediates (ROI) production in PMNs plays an important role in infantile stage in X-CGD, but thereafter retained function of monocytes/macrophages might compensate for the function of NADPH oxidase deficient PMNs and might be an important parameter for predicting the prognosis of X-CGD patients.

PMID: 25666294 [PubMed – as supplied by publisher]

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Primary Ficolin-3 deficiency – Is it associated with increased susceptibility to infections?

Immunobiology. 2015 Jan 19;

Authors: Michalski M, Świerzko AS, Pągowska-Klimek I, Niemir ZI, Mazerant K, Domżalska-Popadiuk I, Moll M, Cedzyński M

Abstract
Ficolin-3 (also called H-ficolin or Hakata antigen) is the most potent activator of the lectin pathway of complement in vitro. Its genetically determined deficiency in Caucasians is associated with a frame-shift mutation +1637delC (rs28357092) of the FCN3 gene. When it was described for the first time, it was postulated to be strictly associated with enhanced susceptibility to infections. At present, with our knowledge extended by several other patients that issue seems to be more complicated and less clear-cut. Two new cases of primary Ficolin-3 deficiency are reported here: a 50-year old male, suffering from membranous nephropathy and an 11-month old male infant who was operated on to repair congenital heart disease. Based on those cases and a literature review, we conclude that the clinical consequences of congenital Ficolin-3 deficiency are still unclear and such questions as whether it may be life-threatening or acts as a disease modifier remain to be elucidated.

PMID: 25662573 [PubMed – as supplied by publisher]

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IRAK-4 and MyD88 deficiencies impair IgM responses against T-independent bacterial antigens.

Blood. 2014 Dec 4;124(24):3561-71

Authors: Maglione PJ, Simchoni N, Black S, Radigan L, Overbey JR, Bagiella E, Bussel JB, Bossuyt X, Casanova JL, Meyts I, Cerutti A, Picard C, Cunningham-Rundles C

Abstract
IRAK-4 and MyD88 deficiencies impair interleukin 1 receptor and Toll-like receptor (TLR) signaling and lead to heightened susceptibility to invasive bacterial infections. Individuals with these primary immunodeficiencies have fewer immunoglobulin M (IgM)(+)IgD(+)CD27(+) B cells, a population that resembles murine splenic marginal zone B cells that mount T-independent antibody responses against bacterial antigens. However, the significance of this B-cell subset in humans is poorly understood. Using both a 610 carbohydrate array and enzyme-linked immunosorbent assay, we found that patients with IRAK-4 and MyD88 deficiencies have reduced serum IgM, but not IgG antibody, recognizing T-independent bacterial antigens. Moreover, the quantity of specific IgM correlated with IgM(+)IgD(+)CD27(+) B-cell frequencies. As with mouse marginal zone B cells, human IgM(+)CD27(+) B cells activated by TLR7 or TLR9 agonists produced phosphorylcholine-specific IgM. Further linking splenic IgM(+)IgD(+)CD27(+) B cells with production of T-independent IgM, serum from splenectomized subjects, who also have few IgM(+)IgD(+)CD27(+) B cells, had reduced antibacterial IgM. IRAK-4 and MyD88 deficiencies impaired TLR-induced proliferation of this B-cell subset, suggesting a means by which loss of this activation pathway leads to reduced cell numbers. Thus, by bolstering the IgM(+)IgD(+)CD27(+) B-cell subset, IRAK-4 and MyD88 promote optimal T-independent IgM antibody responses against bacteria in humans.

PMID: 25320238 [PubMed – indexed for MEDLINE]

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Use of ruxolitinib to successfully treat chronic mucocutaneous candidiasis caused by gain-of-function signal transducer and activator of transcription 1 (STAT1) mutation.

J Allergy Clin Immunol. 2015 Feb;135(2):551-553.e3

Authors: Higgins E, Al Shehri T, McAleer MA, Conlon N, Feighery C, Lilic D, Irvine AD

PMID: 25662309 [PubMed – in process]

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PD-1 is not required for natural or peripherally induced regulatory T cells: Severe autoimmunity despite normal production of regulatory T cells.

Eur J Immunol. 2014 Dec;44(12):3560-72

Authors: Ellestad KK, Thangavelu G, Ewen CL, Boon L, Anderson CC

Abstract
The expression of the coinhibitor PD-1 on T cells is important for the establishment of immune homeostasis. We previously found that PD-1 is particularly critical for the control of self-tolerance during lymphopenia-induced proliferation of recent thymic emigrants (RTEs). Previous studies suggested that PD-1 modulates the generation of Treg cells, particularly peripherally induced Treg (pTreg) cells, and controls Th17 cells. However, these conclusions were derived indirectly from studies on the ligand PD-L1, and not PD-1 itself. Herein we directly tested whether T-cell PD-1 expression was needed for Treg cell generation and examined if a paucity of Treg cells or enhanced Th17 cells could explain the severe lymphopenia-potentiated autoimmunity caused by PD-1 KO RTEs. Employing the murine FoxP3(EGFP) reporter system to simultaneously monitor conversion of WT and PD-1 KO T cells to pTreg cells in the same animal, we found that PD-1 deficiency did not inhibit pTreg cell generation or lead to Th17-cell-mediated autoimmunity. Surprisingly, pTreg cell numbers were increased in PD-1 KO versus WT cell populations. Furthermore, we noted an increased conversion to pTreg cells by RTEs. Our data suggest that the primary role for PD-1 is to restrain T-cell activation/proliferation to self-Ags rather than promote generation of Treg cells.

PMID: 25236923 [PubMed – indexed for MEDLINE]

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