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

February 11, 2015 By Manish Butte

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]

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

February 11, 2015 By Manish Butte

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]

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

February 11, 2015 By Manish Butte

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]

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

February 11, 2015 By Manish Butte

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]

The incidental pulmonary nodule in a child : Part 1: recommendations from the SPR Thoracic Imaging Committee regarding characterization, significance and follow-up.

February 7, 2015 By Manish Butte

The incidental pulmonary nodule in a child : Part 1: recommendations from the SPR Thoracic Imaging Committee regarding characterization, significance and follow-up.

Pediatr Radiol. 2015 Feb 6;

Authors: Westra SJ, Brody AS, Mahani MG, Guillerman RP, Hegde SV, Iyer RS, Lee EY, Newman B, Podberesky DJ, Thacker PG

Abstract
No guidelines are in place for the follow-up and management of pulmonary nodules that are incidentally detected on CT in the pediatric population. The Fleischner guidelines, which were developed for the older adult population, do not apply to children. This review summarizes the evidence collected by the Society for Pediatric Radiology (SPR) Thoracic Imaging Committee in its attempt to develop pediatric-specific guidelines.Small pulmonary opacities can be characterized as linear or as ground-glass or solid nodules. Linear opacities and ground-glass nodules are extremely unlikely to represent an early primary or metastatic malignancy in a child. In our review, we found a virtual absence of reported cases of a primary pulmonary malignancy presenting as an incidentally detected small lung nodule on CT in a healthy immune-competent child.Because of the lack of definitive information on the clinical significance of small lung nodules that are incidentally detected on CT in children, the management of those that do not have the typical characteristics of an intrapulmonary lymph node should be dictated by the clinical history as to possible exposure to infectious agents, the presence of an occult immunodeficiency, the much higher likelihood that the nodule represents a metastasis than a primary lung tumor, and ultimately the individual preference of the child’s caregiver. Nodules appearing in children with a history of immune deficiency, malignancy or congenital pulmonary airway malformation should not be considered incidental, and their workup should be dictated by the natural history of these underlying conditions.

PMID: 25655369 [PubMed – as supplied by publisher]

The Cause of Acute Respiratory Failure Predicts the Outcome of Noninvasive Ventilation in Immunocompromised Children.

February 5, 2015 By Manish Butte

The Cause of Acute Respiratory Failure Predicts the Outcome of Noninvasive Ventilation in Immunocompromised Children.

Klin Padiatr. 2015 Feb 4;

Authors: Fuchs H, Schoss J, Mendler MR, Lindner W, Hopfner R, Schulz A, Hoenig M, Steinbach D, Debatin KM, Hummler HD, Schmid M

Abstract
Background: Noninvasive ventilation (NIV) may be superior to conventional therapy in immunocompromised children with respiratory failure. Methods: Mortality, success rate, prognostic factors and side effects of NIV for acute respiratory failure (ARF) were investigated retrospectively in 41 in children with primary immunodeficiency, after stem cell transplantation or chemotherapy for oncologic disease. Results: In 11/41 (27%) children invasive ventilation was avoided and patients were discharged from ICU. In children with NIV failure ICU-mortality was 19/30 (63%). 8/11 (72%) children with NIV success had recurrence of ARF after 27 days. Only 4/11 (36%) children with first episode NIV success and 8/30 (27%) with NIV failure survived to hospital discharge. Lower FiO2, SpO2/FiO2 and blood culture positive bacterial sepsis were predictive for NIV success, while fungal sepsis or culture negative ARF were predictive for NIV failure. We observed catecholamine treatment in 14/41 (34%), pneumothorax in 2/41 (5%), mediastinal emphysema in 3/41 (7%), a life threatening nasopharyngeal hemorrhage and need for resuscitation during intubation in 5/41 (12%) NIV-episodes. Conclusions: The prognosis of ARF in immunocompromised children remains guarded independent of initial success or failure of NIV due to a high rate of recurrent ARF. Reversible causes like bacterial sepsis had a higher NIV response rate. Relevant side effects of NIV were observed.

PMID: 25650869 [PubMed – as supplied by publisher]

Immunological loss-of-function due to genetic gain-of-function in humans: autosomal dominance of the third kind.

February 4, 2015 By Manish Butte

Immunological loss-of-function due to genetic gain-of-function in humans: autosomal dominance of the third kind.

Curr Opin Immunol. 2015 Jan 30;32C:90-105

Authors: Boisson B, Quartier P, Casanova JL

Abstract
All the human primary immunodeficiencies (PIDs) recognized as such in the 1950s were Mendelian traits and, whether autosomal or X-linked, displayed recessive inheritance. The first autosomal dominant (AD) PID, hereditary angioedema, was recognized in 1963. However, since the first identification of autosomal recessive (AR), X-linked recessive (XR) and AD PID-causing genes in 1985 (ADA; severe combined immunodeficiency), 1986 (CYBB, chronic granulomatous disease) and 1989 (SERPING1; hereditary angioedema), respectively, the number of genetically defined AD PIDs has increased more rapidly than that of any other type of PID. AD PIDs now account for 61 of the 260 known conditions (23%). All known AR PIDs are caused by alleles with some loss-of-function (LOF). A single XR PID is caused by gain-of-function (GOF) mutations (WASP-related neutropenia, 2001). In contrast, only 44 of 61 AD defects are caused by LOF alleles, which exert dominance by haploinsufficiency or negative dominance. Since 2003, up to 17 AD disorders of the third kind, due to GOF alleles, have been described. Remarkably, six of the 17 genes concerned also harbor monoallelic (STAT3), biallelic (C3, CFB, CARD11, PIK3R1) or both monoallelic and biallelic (STAT1) LOF alleles in patients with other clinical phenotypes. Most heterozygous GOF alleles result in auto-inflammation, auto-immunity, or both, with a wide range of immunological and clinical forms. Some also underlie infections and, fewer, allergies, by impairing or enhancing immunity to non-self. Malignancies are also rare. The enormous diversity of immunological and clinical phenotypes is thought provoking and mirrors the diversity and pleiotropy of the underlying genotypes. These experiments of nature provide a unique insight into the quantitative regulation of human immunity.

PMID: 25645939 [PubMed – as supplied by publisher]

Splice-Correction Strategies for Treatment of X-Linked Agammaglobulinemia.

February 2, 2015 By Manish Butte

Splice-Correction Strategies for Treatment of X-Linked Agammaglobulinemia.

Curr Allergy Asthma Rep. 2015 Mar;15(3):510

Authors: Bestas B, Turunen JJ, Blomberg KE, Wang Q, Månsson R, El Andaloussi S, Berglöf A, Smith CI

Abstract
X-linked agammaglobulinemia (XLA) is a primary immunodeficiency disease caused by mutations in the gene coding for Bruton’s tyrosine kinase (BTK). Deficiency of BTK leads to a developmental block in B cell differentiation; hence, the patients essentially lack antibody-producing plasma cells and are susceptible to various infections. A substantial portion of the mutations in BTK results in splicing defects, consequently preventing the formation of protein-coding mRNA. Antisense oligonucleotides (ASOs) are therapeutic compounds that have the ability to modulate pre-mRNA splicing and alter gene expression. The potential of ASOs has been exploited for a few severe diseases, both in pre-clinical and clinical studies. Recently, advances have also been made in using ASOs as a personalized therapy for XLA. Splice-correction of BTK has been shown to be feasible for different mutations in vitro, and a recent proof-of-concept study demonstrated the feasibility of correcting splicing and restoring BTK both ex vivo and in vivo in a humanized bacterial artificial chromosome (BAC)-transgenic mouse model. This review summarizes the advances in splice correction, as a personalized medicine for XLA, and outlines the promises and challenges of using this technology as a curative long-term treatment option.

PMID: 25638286 [PubMed – as supplied by publisher]

Frequency and risk factors of low immunoglobulin levels in patients with inflammatory bowel disease.

February 2, 2015 By Manish Butte

Frequency and risk factors of low immunoglobulin levels in patients with inflammatory bowel disease.

Gastroenterol Rep (Oxf). 2015 Jan 30;

Authors: Rai T, Wu X, Shen B

Abstract
BACKGROUND AND AIMS: Inflammatory bowel diseases (IBD) are considered to be dysregulated, immune-mediated disorders; and immunosuppressive medications are the mainstay of their treatment. Clinically, we have often observed low serum immunoglobulin (Ig) levels in these patients. The aim of this study was to assess the frequency and risk factors of secondary humoral immunodeficiency in IBD patients.
METHODS: We conducted a cross-sectional study of eligible IBD patients with Crohn’s disease (CD), ulcerative colitis (UC), indeterminate colitis (IC) or restorative proctocolectomy with ileal pouch, who having serum Ig measured. Demographic and clinical variables were measured. Univariate and multivariate analyses were performed.
RESULTS: A total of 324 patients was included, with a mean age of 38.8 years and 158 (48.8%) being male. Low IgG, IgG1, IgA, and IgM were found in 22.7%, 23.4%, 7.9%, and 10.9% of patients, respectively. The shared risk factors for a low IgG or IgM level were increasing age [odds ratio (OR) = 1.13; 95% confidence interval (CI) 1.03-1.23 for low IgG level and OR = 1.33; 95% CI 1.15-1.56 for low IgM level] and hypoalbuminemia (OR = 1.83; 95% CI 1.01-3.33 for low IgG level and OR = 3.17; 95% CI 1.23-8.15 for low IgM level). In addition, thioprine use was associated with low IgA level (OR = 2.76; 95% CI 1.03-7.39). IBD disease duration was a risk factor for low IgG1 level (OR = 1.40; 95% CI 1.12-1.76). The presence of concurrent primary sclerosing cholangitis (OR = 0.064; 95% CI 0.007-0.60) and the use of biologics (OR = 0.16; 95% CI 0.033-0.79) were associated with normal IgG1 level. IgG level was lower in CD patients than that in UC/IC and ileal pouch patients (P = 0.042). IgG and IgA levels were elevated in patients with inflammatory conditions of the pouch (P = 0.01; P = 0.003, respectively).
CONCLUSIONS: Low Ig level appears to be common in IBD patients. Increasing age, disease duration and hypoalbuminemia appeared to be risk factors. The findings may provide rationale for targeted therapy to boost humoral immunity in selected patients with IBD.

PMID: 25638221 [PubMed – as supplied by publisher]

Clinical and Immunological Features of Common Variable Immunodeficiency in China.

January 31, 2015 By Manish Butte

Clinical and Immunological Features of Common Variable Immunodeficiency in China.

Chin Med J (Engl). 2015 5th February;128(3):310-315

Authors: Lin LJ, Wang YC, Liu XM

Abstract
Background: Common variable immunodeficiency (CVID) is one of the most common symptomatic primary immunodeficiency syndromes. The purpose of this article was to broaden our knowledge about CVID for better diagnosis and treatment. Methods: Clinical and immunological features of 40 Chinese patients with CVID were analyzed retrospectively. Results: The median age at onset was 11-year-old (range 4-51 years). The median age at diagnosis was 14.5-year-old (range 5-66 years). The average time of delay in diagnosis was 5.3 years (range 1-41 years). The most common main complaint was fever due to infections (35 cases, 87.5%). Pneumonia (28 cases, 70%) was the most common type of infections. Bronchiectasis was present in 6 patients (15%). Autoimmune disease was detected in 6 cases of CVID, and malignancy in 2 cases. The median total serum levels of IgG, IgA, and IgM at diagnosis were 1.07 g/L, 0.07 g/L, and 0.28 g/L, respectively. The percentages of CD3- /CD19 + B-cells were 1%-3.14%. Conclusions: Infection is the most frequent presentation of CVID. Patients with unexplainable infections should receive further examination including serum immunoglobulin (Ig) and lymphocyte subset analysis. Regular and sufficient substitution with Ig is recommended.

PMID: 25635425 [PubMed – as supplied by publisher]