Research

Advances in clinical immunology in 2015.

J Allergy Clin Immunol. 2016 Dec;138(6):1531-1540

Authors: Chinen J, Notarangelo LD, Shearer WT

Abstract
Advances in clinical immunology in the past year included the report of practice parameters for the diagnosis and management of primary immunodeficiencies to guide the clinician in the approach to these relatively uncommon disorders. We have learned of new gene defects causing immunodeficiency and of new phenotypes expanding the spectrum of conditions caused by genetic mutations such as a specific regulator of telomere elongation (RTEL1) mutation causing isolated natural killer cell deficiency and mutations in ras-associated RAB (RAB27) resulting in immunodeficiency without albinism. Advances in diagnosis included the increasing use of whole-exome sequencing to identify gene defects and the measurement of serum free light chains to identify secondary hypogammaglobulinemias. For several primary immunodeficiencies, improved outcomes have been reported after definitive therapy with hematopoietic stem cell transplantation and gene therapy.

PMID: 27931534 [PubMed – in process]

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Genetic, immunological, and clinical features of patients with bacterial and fungal infections due to inherited IL-17RA deficiency.

Proc Natl Acad Sci U S A. 2016 Dec 07;:

Authors: Lévy R, Okada S, Béziat V, Moriya K, Liu C, Chai LY, Migaud M, Hauck F, Al Ali A, Cyrus C, Vatte C, Patiroglu T, Unal E, Ferneiny M, Hyakuna N, Nepesov S, Oleastro M, Ikinciogullari A, Dogu F, Asano T, Ohara O, Yun L, Della Mina E, Bronnimann D, Itan Y, Gothe F, Bustamante J, Boisson-Dupuis S, Tahuil N, Aytekin C, Salhi A, Al Muhsen S, Kobayashi M, Toubiana J, Abel L, Li X, Camcioglu Y, Celmeli F, Klein C, AlKhater SA, Casanova JL, Puel A

Abstract
Chronic mucocutaneous candidiasis (CMC) is defined as recurrent or persistent infection of the skin, nails, and/or mucosae with commensal Candida species. The first genetic etiology of isolated CMC-autosomal recessive (AR) IL-17 receptor A (IL-17RA) deficiency-was reported in 2011, in a single patient. We report here 21 patients with complete AR IL-17RA deficiency, including this first patient. Each patient is homozygous for 1 of 12 different IL-17RA alleles, 8 of which create a premature stop codon upstream from the transmembrane domain and have been predicted and/or shown to prevent expression of the receptor on the surface of circulating leukocytes and dermal fibroblasts. Three other mutant alleles create a premature stop codon downstream from the transmembrane domain, one of which encodes a surface-expressed receptor. Finally, the only known missense allele (p.D387N) also encodes a surface-expressed receptor. All of the alleles tested abolish cellular responses to IL-17A and -17F homodimers and heterodimers in fibroblasts and to IL-17E/IL-25 in leukocytes. The patients are currently aged from 2 to 35 y and originate from 12 unrelated kindreds. All had their first CMC episode by 6 mo of age. Fourteen patients presented various forms of staphylococcal skin disease. Eight were also prone to various bacterial infections of the respiratory tract. Human IL-17RA is, thus, essential for mucocutaneous immunity to Candida and Staphylococcus, but otherwise largely redundant. A diagnosis of AR IL-17RA deficiency should be considered in children or adults with CMC, cutaneous staphylococcal disease, or both, even if IL-17RA is detected on the cell surface.

PMID: 27930337 [PubMed – as supplied by publisher]

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Secondary antibody deficiency – causes and approach to diagnosis.

Clin Med (Lond). 2016 Dec;16(6):571-576

Authors: Srivastava S, Wood P

Abstract
Antibody deficiencies can occur in the context of primary disorders due to inherited genetic defects; however, secondary immune disorders are far more prevalent and can be caused by various diseases and their treatment, certain medications and surgical procedures. Immunoglobulin replacement therapy has been shown to be effective in reducing infections, morbidity and mortality in primary antibody deficiencies but secondary antibody deficiencies are in general poorly defined and there are no guidelines for the management of patients with this condition. Clinical decisions are based on experience from primary antibody deficiencies. Both primary and secondary antibody deficiencies can be associated with infections, immune dysregulation and end-organ damage, causing significant morbidity and mortality. Therefore, it is important to diagnose and treat these patients promptly to minimise adverse effects and improve quality of life. We focus on secondary antibody deficiency and describe the causes, diagnosis and treatment of this disorder.

PMID: 27927823 [PubMed – in process]

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Shift from intravenous or 16% subcutaneous replacement therapy to 20% subcutaneous immunoglobulin in patients with primary antibody deficiencies.

Int J Immunopathol Pharmacol. 2016 Dec 07;:

Authors: Canessa C, Iacopelli J, Pecoraro A, Spadaro G, Matucci A, Milito C, Vultaggio A, Agostini C, Cinetto F, Danieli MG, Gambini S, Marasco C, Trizzino A, Vacca A, De Mattia D, Martire B, Plebani A, Di Gioacchino M, Gatta A, Finocchi A, Licciardi F, Martino S, De Carli M, Moschese V, Azzari C

Abstract
In patients with primary antibody deficiencies, subcutaneous administration of IgG (SCIG) replacement is effective, safe, well-tolerated, and can be self-administered at home. A new SCIG replacement at 20% concentration (Hizentra(®)) has been developed and has replaced Vivaglobin(®) (SCIG 16%).An observational prospective multi-centric open-label study, with retrospective comparison was conducted in 15 Italian centers, in order to investigate whether and to what extent switching to Hizentra(®) would affect frequency of infusions, number of infusion sites, patients’ satisfaction, and tolerability in patients previously treated with Vivaglobin(®) or intravenous immunoglobulins (IVIG).Any variations of dosage, frequency and duration of the infusions, and of number of infusion sites induced by Hizentra(®) with respect to the former treatment were recorded. Practical advantages and disadvantages of Hizentra(®), with respect to the medicinal product formerly used, and the variations in patients’ therapy-related satisfaction were monitored by means of the TSQM (Treatment Satisfaction Questionnaire for Medication); number, frequency, and duration of infectious events and adverse effects were recorded.Eighty-two patients switched to Hizentra(®): 19 (23.2%) from IVIG and 63 (76.8%) from Vivaglobin(®) The mean interval between infusions was not affected by the shift (7.0 ± 2.0 days with previous treatment versus 7.1 ± 1.2 during Hizentra(®)). A decrease in the number of infusion sites with Hizentra(®) was recorded in 12 out of 56 patients for whom these data were available. At 6 months, 89.7% of patients were satisfied with Hizentra(®); no difference in terms of effectiveness, side effects, convenience, and global satisfaction was observed. No difference in the incidence of adverse events was reported.

PMID: 27927705 [PubMed – as supplied by publisher]

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Primary and secondary hemophagocytic lymphohistiocytosis have different patterns of T-cell activation, differentiation and repertoire.

Eur J Immunol. 2016 Dec 07;:

Authors: Ammann S, Lehmberg K, Zur Stadt U, Janka G, Rensing-Ehl A, Klemann C, Heeg M, Bode S, Fuchs I, Ehl S, HLH study of the GPOH

Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory syndrome characterized by hyperactivation of lymphocytes and histiocytes. T cells play a key role in HLH pathogenesis, but their differentiation pattern is not well characterized in patients with active HLH. We compared T-cell activation patterns between patients with familial HLH (1°HLH), 2°HLH without apparent infectious trigger (2°HLH) and 2°HLH induced by a viral infection (2°V-HLH). Polyclonal CD8(+) T cells are highly activated in 1°HLH and 2°V-HLH, but less in 2°HLH as assessed by HLA-DR expression and marker combination with CD45RA, CCR7, CD127, PD-1 and CD57. Absence of increased HLA-DR expression on T cells excluded active 1° HLH with high sensitivity and specificity. A high proportion of polyclonal CD127(-) CD4(+) T cells expressing HLA-DR, CD57, and high perforin expression is a signature of infants with 1°HLH, much less prominent in virus-associated 2°HLH. The similar pattern and extent of CD8(+) T-cell activation compared to 2° V-HLH is compatible with a viral trigger of 1°HLH. However, in most 1°HLH patients no triggering infection was documented and the unique activation of cytotoxic CD4(+) T cells indicates that the overall T-cell response in 1°HLH is different. This may reflect different pathways of pathogenesis of these two HLH variants. This article is protected by copyright. All rights reserved.

PMID: 27925643 [PubMed – as supplied by publisher]

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Reproductive health service utilization and social determinants among married female rural-to-urban migrants in two metropolises, China.

J Huazhong Univ Sci Technolog Med Sci. 2016 Dec;36(6):904-909

Authors: Liu ZY, Li J, Hong Y, Yao L

Abstract
Reproductive health (RH) education and services of female migrants in China have become an important health issue. This research aimed to investigate the RH knowledge and utilization among married female migrants, and to explore the influencing factors from the perspectives of population and sociology. We conducted a cross-section survey in Shenzhen and Wuhan, China, using the purposive sampling method. A total of 1021 rural-to-urban married migrants were recruited, with 997 valid survey results obtained. A face-to-face structured questionnaire survey was used, with primary focus on knowledge of fertility, contraception, family planning policy and sexual transmitted diseases/acquired immunodeficiency syndrome (STD/AIDs), and RH service utilization. The results showed that the RH service utilization (38.0%) was at a low level in married migrants and the accessibility of RH service was poor. Females who migrated to (OR=0.32) Wuhan obtained fewer RH consultations than those in Shenzhen. The workers with high school education received additional RH consultations and checkup services than those with other background education, apart from the white collar workers who received extra RH consultations and checkup services than the blue collar workers (P<0.05). We can draw a conclusion that the utilization of RH services in married female migrants remains at a low level in China. RH service utilization can be improved via the relevant health departments by enhancing the responsibility of maternal and health care in the community health service center.

PMID: 27924513 [PubMed – in process]

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A Novel CYBB Mutation in Chronic Granulomatous Disease in Iran.

Iran J Allergy Asthma Immunol. 2016 Oct;15(5):426-429

Authors: Tajik S, Badalzadeh M, Fazlollahi MR, Houshmand M, Zandieh F, Khandan S, Pourpak Z

Abstract
Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder due to a genetic defect in one of the components of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. This complex is composed of membrane-bound gp91-phox and p22-phox subunits, and cytosolic subunits consisting of p47-phox, p67-phox, and p40-phox. A mutation in CYBB gene encoding gp91-phox located on chromosome Xp21.1, leads to X-linked CGD. Herein, we report a 4-year-old Iranian boy presented with episodes of recurrent fever, cervical lymphadenopathy, and abdominal abscesses. Mutation analysis of the CYBB gene in the patient indicated a one-nucleotide deletion, c.316delT, resulting in p.W106GfsX.

PMID: 27917630 [PubMed – in process]

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Familial Mediterranean fever mutations lift the obligatory requirement for microtubules in Pyrin inflammasome activation.

Proc Natl Acad Sci U S A. 2016 Nov 22;:

Authors: Van Gorp H, Saavedra PH, de Vasconcelos NM, Van Opdenbosch N, Vande Walle L, Matusiak M, Prencipe G, Insalaco A, Van Hauwermeiren F, Demon D, Bogaert DJ, Dullaers M, De Baere E, Hochepied T, Dehoorne J, Vermaelen KY, Haerynck F, De Benedetti F, Lamkanfi M

Abstract
Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease worldwide. It is caused by mutations in the inflammasome adaptor Pyrin, but how FMF mutations alter signaling in FMF patients is unknown. Herein, we establish Clostridium difficile and its enterotoxin A (TcdA) as Pyrin-activating agents and show that wild-type and FMF Pyrin are differentially controlled by microtubules. Diverse microtubule assembly inhibitors prevented Pyrin-mediated caspase-1 activation and secretion of IL-1β and IL-18 from mouse macrophages and human peripheral blood mononuclear cells (PBMCs). Remarkably, Pyrin inflammasome activation persisted upon microtubule disassembly in PBMCs of FMF patients but not in cells of patients afflicted with other autoinflammatory diseases. We further demonstrate that microtubules control Pyrin activation downstream of Pyrin dephosphorylation and that FMF mutations enable microtubule-independent assembly of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) micrometer-sized perinuclear structures (specks). The discovery that Pyrin mutations remove the obligatory requirement for microtubules in inflammasome activation provides a conceptual framework for understanding FMF and enables immunological screening of FMF mutations.

PMID: 27911804 [PubMed – as supplied by publisher]

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FDG PET-CT imaging of therapeutic response in granulomatous lymphocytic interstitial lung disease (GLILD) in common variable immunodeficiency (CVID).

Clin Exp Immunol. 2016 Nov 28;:

Authors: Jolles S, Carne E, Brouns M, El-Shanawany T, Williams P, Marshall C, Fielding P

Abstract
Common variable immunodeficiency (CVID) is the most common severe adult primary immunodeficiency and is characterized by a failure to produce antibodies leading to recurrent predominantly sinopulmonary infections. Improvements in the prevention and treatment of infection with immunoglobulin replacement and antibiotics have resulted in malignancy, autoimmune, inflammatory and lymphoproliferative disorders emerging as major clinical challenges in the management of patients who have CVID. In a proportion of CVID patients, inflammation manifests as granulomas that frequently involve the lungs, lymph nodes, spleen and liver and may affect almost any organ. Granulomatous lymphocytic interstitial lung disease (GLILD) is associated with a worse outcome. Its underlying pathogenic mechanisms are poorly understood and there is limited evidence to inform how best to monitor, treat or select patients to treat. We describe the use of combined 2-[(18)F]-fluoro-2-deoxy-d-glucose positron emission tomography and computed tomography (FDG PET-CT) scanning for the assessment and monitoring of response to treatment in a patient with GLILD. This enabled a synergistic combination of functional and anatomical imaging in GLILD and demonstrated a widespread and high level of metabolic activity in the lungs and lymph nodes. Following treatment with rituximab and mycophenolate there was almost complete resolution of the previously identified high metabolic activity alongside significant normalization in lymph node size and lung architecture. The results support the view that GLILD represents one facet of a multi-systemic metabolically highly active lymphoproliferative disorder and suggests potential utility of this imaging modality in this subset of patients with CVID.

PMID: 27896807 [PubMed – as supplied by publisher]

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Immunodeficiency Presenting as an Undiagnosed Disease.

Pediatr Clin North Am. 2017 Feb;64(1):27-37

Authors: Routes JM, Verbsky JW

Abstract
Although primary immunodeficiencies typically present with recurrent, chronic, or severe infections, autoimmune manifestations frequently accompany these disorders and may be the initial clinical manifestations. The presence of 2 or more autoimmune disorders, unusual severe atopic disease, or a combination of these disorders should lead a clinician to consider primary immunodeficiency disorders.

PMID: 27894450 [PubMed – in process]

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