Research

Human Immunodeficiencies Related to Defective APC/T Cell Interaction.

September 18, 2015 By Manish Butte

Human Immunodeficiencies Related to Defective APC/T Cell Interaction.

Front Immunol. 2015;6:433

Authors: Kallikourdis M, Viola A, Benvenuti F

Abstract
The primary event for initiating adaptive immune responses is the encounter between T lymphocytes and antigen presenting cells (APCs) in the T cell area of secondary lymphoid organs and the formation of highly organized intercellular junctions referred to as immune synapses (IS). In vivo live-cell imaging of APC-T cell interactions combined to functional studies unveiled that T cell fate is dictated, in large part, by the stability of the initial contact. Immune cell interaction is equally important during delivery of T cell help to B cells and for the killing of target cells by cytotoxic T cells and NK cells. The critical role of contact dynamics and synapse stability on the immune response is well illustrated by human immune deficiencies in which disease pathogenesis is linked to altered adhesion or defective cross-talk between the synaptic partners. The Wiskott-Aldrich syndrome (WAS) is a severe primary immunodeficiency caused by mutations in the Wiskott-Aldrich syndrome protein (WASp), a scaffold that promotes actin polymerization and links TCR stimulation to T cell activation. Absence or mutations in WASp affects intercellular APC-T cell communications by interfering with multiple mechanisms on both sides of the IS. The warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is caused by mutations in CXCR4, a chemokine receptor that in mutant form leads to impairment of APC-T cell interactions. Present evidences suggest that other recently characterized primary immune deficiencies caused by mutation in genes linked to actin cytoskeletal reorganization, such as WIP and DOCK8, may also depend on altered synapse stability. Here, we will discuss in details the mechanisms of disturbed APC-T cell interactions in WAS and WHIM. Moreover, we will summarize the evidence pointing to a compromised conjugate formation in WIP, DOCK8, and X-linked lymphoproliferative syndrome.

PMID: 26379669 [PubMed – as supplied by publisher]

Therapeutic Immunoglobulin Selected for High Antibody Titer to RSV also Contains High Antibody Titers to Other Respiratory Viruses.

September 18, 2015 By Manish Butte

Therapeutic Immunoglobulin Selected for High Antibody Titer to RSV also Contains High Antibody Titers to Other Respiratory Viruses.

Front Immunol. 2015;6:431

Authors: Orange JS, Du W, Falsey AR

Abstract
Specific antibodies against infections most relevant to patients with primary immunodeficiency diseases are not routinely evaluated in commercial polyclonal immunoglobulin preparations. A polyclonal immunoglobulin prepared from plasma of donors having high neutralizing antibody titers to respiratory syncytial virus (RSV) was studied for the presence of antibody titers against seven additional respiratory viruses. While donors were not selected for antibody titers other than against RSV, the immunoglobulin preparation had significantly higher titers to 6 of 7 viruses compared to those present in 10 commercially available therapeutic immunoglobulin products (p ≤ 0.01 to p ≤ 0.001). To consider this as a donor-specific attribute, 20 random donor plasma samples were studied individually and identified a significant correlation between the RSV antibody titer and other respiratory virus titers: donors with high RSV titers were more likely to have higher titers to other respiratory viruses. These findings suggest either some humoral antiviral response bias or more frequent viral exposure of certain individuals.

PMID: 26379667 [PubMed – as supplied by publisher]

Practice parameter for the diagnosis and management of primary immunodeficiency.

September 16, 2015 By Manish Butte

Practice parameter for the diagnosis and management of primary immunodeficiency.

J Allergy Clin Immunol. 2015 Sep 11;

Authors: Bonilla FA, Khan DA, Ballas ZK, Chinen J, Frank MM, Hsu JT, Keller M, Kobrynski LJ, Komarow HD, Mazer B, Nelson RP, Orange JS, Routes JM, Shearer WT, Sorensen RU, Verbsky JW, Bernstein DI, Blessing-Moore J, Lang D, Nicklas RA, Oppenheimer J, Portnoy JM, Randolph CR, Schuller D, Spector SL, Tilles S, Wallace D, Bonilla FA, Khan DA, Bernstein DI, Blessing-Moore J, Khan D, Lang D, Nicklas RA, Oppenheimer J, Portnoy JM, Randolph CR, Schuller D, Spector SL, Tilles S, Wallace D, Bonilla FA, Ballas ZK, Chinen J, Frank MM, Hsu JT, Keller M, Kobrynski LJ, Komarow HD, Mazer B, Nelson RP, Orange JS, Routes JM, Shearer WT, Sorensen RU, Verbsky JW

Abstract
The American Academy of Allergy, Asthma & Immunology (AAAAI) and the American College of Allergy, Asthma & Immunology (ACAAI) have jointly accepted responsibility for establishing the “Practice parameter for the diagnosis and management of primary immunodeficiency.” This is a complete and comprehensive document at the current time. The medical environment is a changing environment, and not all recommendations will be appropriate for all patients. Because this document incorporated the efforts of many participants, no single individual, including those who served on the Joint Task Force, is authorized to provide an official AAAAI or ACAAI interpretation of these practice parameters. Any request for information about or an interpretation of these practice parameters by the AAAAI or ACAAI should be directed to the Executive Offices of the AAAAI, the ACAAI, and the Joint Council of Allergy, Asthma & Immunology. These parameters are not designed for use by pharmaceutical companies in drug promotion.

PMID: 26371839 [PubMed – as supplied by publisher]

An 8 minute colorimetric paper-based reverse phase vertical flow serum microarray for screening of hyper IgE syndrome.

September 15, 2015 By Manish Butte

An 8 minute colorimetric paper-based reverse phase vertical flow serum microarray for screening of hyper IgE syndrome.

Analyst. 2015 Sep 14;

Authors: Reuterswärd P, Gantelius J, Andersson Svahn H

Abstract
Reverse phase microarrays are useful tools for affinity-based detection in hundreds of samples simultaneously. However, current methods typically require long assay times and fluorescent detection. Here we describe a paper-based Vertical Flow Microarray (VFM) assay as a rapid 8-minute colorimetric alternative for reverse phase microarray analysis. The VFM platform was optimized for detection of IgE with a detection limit of 1.9 μg mL(-1) in whole serum. Optimized conditions were then used to screen 113 serum samples simultaneously for hyper IgE syndrome (hIgE), a rare primary immunodeficiency characterized by elevated levels of IgE. The same set of samples were then analysed with a conventional planar microarray with fluorescent detection for head-to-head testing. Both assays found elevated levels in three out of four hIgE patient samples, whereas no control samples displayed elevated levels in either method. The comparison experiments showed a good correlation between the two assays, as determined from a linear correlation study (Pearson’s r = 0.76). Further, the assay-time reduction and reproducibility (intra assay CV = 12.4 ± 4.11%) demonstrate the applicability of the VFM platform for high throughput reverse phase screening.

PMID: 26365343 [PubMed – as supplied by publisher]

THE IMPORTANCE OF EDUCATING PEDIATRICIANS ABOUT PRIMARY IMMUNODEFICIENCY DISORDERS: A TERTIARY HOSPITAL EXPERIENCE.

September 12, 2015 By Manish Butte

THE IMPORTANCE OF EDUCATING PEDIATRICIANS ABOUT PRIMARY IMMUNODEFICIENCY DISORDERS: A TERTIARY HOSPITAL EXPERIENCE.

Georgian Med News. 2015 Sep;(246):66-72

Authors: Adeli M, Hendaus M, Imam L, Alhammadi A

Abstract
Primary immunodeficiency disorders (PIDs) are several genetic disorders that alter the essential components of the immune system leading to errors in differentiation, function or both of these components.There are more than 200 reported different PID diseases with more than 140 identified gene mutations, affecting almost six million individuals globally, but only 27,000-60,000 have being diagnosed.Early diagnosis of PIDs can markedly reduce morbidity and mortality via proper intervention The aim of the study was to estimate the knowledge and attitude of pediatric residents of PIDs.To the best of our knowledge, this is the first study that targets resident physicians in the field of PIDs. A prospective and cross-sectional study was conducted at Hamad Medical Corporation, the only tertiary care, academic and teaching hospital in the state of Qatar. The study took place between January, 2014 and April 30, 2014. A self-administered questionnaire was distributed to 68 pediatric residents (post-graduate year 1-4). In all, 68 eligible resident physicians were included in the study. Out of the 68 questionnaires distributed, 59 (86.7%) were returned by the end of the study. Among the participants, 18 (30.5%) were post-graduate year-1 (PGY-1), 18 (30.5%) PGY-2, 11 (18.6%) PGY-3, and 12 (20.3%) PGY-4.The mean overall score was 58.5 %. The mean score in the clinical presentation was 67.5%, in associated syndromes and diseases was 59%, in screening laboratory work up 55.3%, and in the section of laboratory investigations that suggest PIDs 52%. There is a significant lack of knowledge of PIDs among pediatric residents. In addition, a large number of pediatric physicians in training do not feel comfortable in diagnosing and managing young children with PIDs. Pediatric residency working hours rule restrict the luxury of having an allergy/immunology rotation during residency. A mutual effort in sharing diagnosis and management of patients with PIDs between pediatric residents and attending immunologists can ameliorate the lack of knowledge and improve the trainee’s confidence when facing such cases.

PMID: 26355318 [PubMed – in process]

Adaptive immune defects in a patient with leukocyte adhesion deficiency type III with a novel mutation in FERMT3.

September 12, 2015 By Manish Butte

Adaptive immune defects in a patient with leukocyte adhesion deficiency type III with a novel mutation in FERMT3.

Pediatr Allergy Immunol. 2015 Sep 11;

Authors: Suratannon N, Yeetong P, Srichomthong C, Amarinthnukrowh P, Chatchatee P, Sosothikul D, van Hagen PM, van der Burg M, Wentink M, Driessen GJ, Suphapeetiporn K, Shotelersuk V

Abstract
Leukocyte adhesion deficiency (LAD) is a rare primary immunodeficiency disease characterized by impairment of phagocyte adhesion. Three subtypes have been classified by distinct phases of the adhesion cascade. LAD-III is caused by defects in signaling pathways used for integrin activation in all hematopoietic cell types leading to recurrent infections with poor platelet aggregation resembling Glanzmann’s thrombasthenia. Mutations in FERMT3 have been identified to underlie LAD-III. FERMT3 encodes kindlin-3, one of the focal adhesion proteins which contain a FERM domain located at the carboxyl terminus binding to β-integrin cytoplasmic tails. This article is protected by copyright. All rights reserved.

PMID: 26359933 [PubMed – as supplied by publisher]

Genomic Investigations unmask Mycoplasma amphoriforme, a new respiratory pathogen.

September 12, 2015 By Manish Butte

Genomic Investigations unmask Mycoplasma amphoriforme, a new respiratory pathogen.

Clin Infect Dis. 2015 Feb 1;60(3):381-8

Authors: Gillespie SH, Ling CL, Oravcova K, Pinheiro M, Wells L, Bryant JM, McHugh TD, Bébéar C, Webster D, Harris SR, Seth-Smith HM, Thomson NR

Abstract
BACKGROUND: Mycoplasma amphoriforme has been associated with infection in patients with primary antibody deficiency (PAD). Little is known about the natural history of infection with this organism and its ability to be transmitted in the community.
METHODS: The bacterial load was estimated in sequential sputum samples from 9 patients by quantitative polymerase chain reaction. The genomes of all available isolates, originating from patients in the United Kingdom, France, and Tunisia, were sequenced along with the type strain. Genomic data were assembled and annotated, and a high-resolution phylogenetic tree was constructed.
RESULTS: By using high-resolution whole-genome sequencing (WGS) data, we show that patients can be chronically infected with M. amphoriforme manifesting as a relapsing-remitting bacterial load, interspersed by periods when the organism is undetectable. Importantly, we demonstrate transmission of strains within a clinical environment. Antibiotic resistance mutations accumulate in isolates taken from patients who received multiple courses of antibiotics.
CONCLUSIONS: Mycoplasma amphoriforme isolates form a closely related species responsible for a chronic relapsing and remitting infection in PAD patients in the United Kingdom and from immunocompetent patients in other countries. We provide strong evidence of transmission between patients attending the same clinic, suggesting that screening and isolation may be necessary for susceptible patients. This work demonstrates the critical role that WGS can play in rapidly unraveling the biology of a novel pathogen.

PMID: 25344534 [PubMed – indexed for MEDLINE]

Primary non-necrotizing granulomatous hypophysitis mimicking pituitary adenomas.

September 12, 2015 By Manish Butte

Primary non-necrotizing granulomatous hypophysitis mimicking pituitary adenomas.

Turk Neurosurg. 2014;24(5):688-94

Authors: Yildirim AE, Divanlioglu D, Cetinalp NE, Sahin S, Kulacoglu S, Belen AD

Abstract
AIM: The authors review their experience in the endoscopic endonasal transsphenoidal treatment of 5 patients, finally diagnosed as primary hypophysitis but initially assumed to be pituitary adenomas.
MATERIAL AND METHODS: A retrospective study was undertaken to review 5 cases of primary non-necrotizing granulomatous hypophysitis (1.61%) through 310 endoscopic transsphenoidally operated cases with the diagnosis of pituitary adenoma between 2009 and 2013. All 5 cases were female without any background of autoimmunity or recent pregnancy. The initial presumptive diagnosis was pituitary adenoma for all patients. The endocrinological diagnoses of the patients were suspected Cushing’s Disease, anterior pituitary deficiency with hyponatremia, hyperprolactinemia, and acromegaly. One of the patients had normal hormonal levels. All patients had macroadenomas including one invasive adenoma with skull base involvement. One of the patients (20%) had visual field defects. All patients underwent endoscopic endonasal transsphenoidal surgery (EETS).
RESULTS: All patients had improvement of hormonal levels postoperatively except the one with anterior pituitary deficiency who required long term hormone replacement after the surgery. Mean follow-up duration was 14.8 months.
CONCLUSION: Primary granulomatous hypophysitis without any known etiological factors is very rare in the literature. It can mimic pituitary adenomas in radiological and endocrinological aspects. EETS is an effective and safe treatment especially for visual and compression symptoms.

PMID: 25269037 [PubMed – indexed for MEDLINE]

CVID Associated with Systemic Amyloidosis.

September 9, 2015 By Manish Butte

CVID Associated with Systemic Amyloidosis.

Case Reports Immunol. 2015;2015:879179

Authors: Esenboga S, Çagdas Ayvaz D, Saglam Ayhan A, Peynircioglu B, Sanal O, Tezcan I

Abstract
Common variable immunodeficiency (CVID) is a frequent primary immune deficiency (PID), which consists of a heterogeneous group of disorders and can present with recurrent infections, chronic diarrhea, autoimmunity, chronic pulmonary and gastrointestinal diseases, and malignancy. Secondary amyloidosis is an uncommon complication of CVID. We report an unusual case of a 27-year-old male patient who presented with recurrent sinopulmonary infections, chronic diarrhea, and hypogammaglobulinemia and was diagnosed with CVID. The patient was treated with intravenous immunoglobulin (IVIg) therapy once every 21 days and daily trimethoprim-sulfamethoxazole for prophylaxis. Two years after initial diagnosis, the patient was found to have progressive decline in IgG levels (as low as 200-300 mg/dL) despite regular Ig infusions. The laboratory tests revealed massive proteinuria and his kidney biopsy showed accumulation of AA type amyloid. We believe that the delay in the diagnosis of CVID and initiation of Ig replacement therapy caused chronic inflammation due to recurrent infections in our patient and this led to an uncommon and life-threatening complication, amyloidosis. Patients with CVID require regular follow-up for the control of infections and assessment of adequacy of Ig replacement therapy. Amyloidosis should be kept in the differential diagnosis when managing patients with CVID.

PMID: 26346511 [PubMed]

Patient-derived iPS cells as a tool for gene therapy research.

September 9, 2015 By Manish Butte

Patient-derived iPS cells as a tool for gene therapy research.

Rinsho Ketsueki. 2015;56(8):1016-24

Authors: Otsu M

Abstract
Gene therapy targeting hematopoietic stem cells (HSC) can now be recognized as a curative treatment option for patients with genetic disorders, including primary immunodeficiency (PID) diseases. Despite an increasing number of successfully treated cases, the therapeutic benefits still vary considerably among trials. To further optimize HSC gene therapy, it is hoped that a research model system capable of faithful recapitulation of the disease phenotypes can be established. Recently, a new model system that may meet this goal has become a reality; that is, patient-derived induced pluripotent stem cells (iPSCs). iPSCs are useful for modeling genetic disorders, because of their potential to differentiate into various types of somatic cells while retaining the specific genetic mutations. They are also susceptible to genetic manipulation in vitro, thus enabling pre-clinical assessment of candidate treatment strategies for their performance. This article introduces a proof that patient-derived iPSCs represent an invaluable tool for modelling genetic diseases such as PIDs, and also provide an indispensable research model usable for the development of ideal therapeutic modalities.

PMID: 26345561 [PubMed – in process]