Research

Current screening approaches for antibody deficiency.

August 16, 2016 By Manish Butte

Current screening approaches for antibody deficiency.

Curr Opin Allergy Clin Immunol. 2015 Dec;15(6):547-55

Authors: Holding S, Jolles S

Abstract
PURPOSE OF REVIEW: Diagnostic delay is a major problem for rare diseases including primary antibody deficiency (PAD). The aim of this review is to discuss the opportunities and challenges of current and future screening approaches for antibody deficiency, to reduce the delay and its impact on patients. (Figure is included in full-text article.)
RECENT FINDINGS: Diagnostic delay in PAD is known to result in increased morbidity, mortality, and permanent functional impairment. Approaches to prevent this have been only partially successful and the delay may still be many years as the clinical presentation of PAD is highly variable and may be at any age, making screening difficult. Patients often have numerous healthcare encounters generating repeated cycles of laboratory and clinical data before the diagnosis is made. Low immunoglobulin levels result in alterations in laboratory tests not directly aimed at measuring immunoglobulins. We describe these and highlight the growing evidence in support of using calculated globulin which is part of the liver function test profile as a screening tool for antibody deficiency. Additional approaches include using embedded algorithms to analyse data generated by repeated clinical encounters (e.g. infections, antibiotics, cytopenias), potentially in combination with laboratory results such as calculated globulin, to help bring forward the diagnosis of PAD in patients in whom this has not yet been considered.
SUMMARY: There is a strong case for the use of calculated globulin in screening for antibody deficiency. Further work is required to integrate laboratory results with clinical data to reduce diagnostic delay in patients with hitherto unsuspected antibody deficiency.

PMID: 26513714 [PubMed – indexed for MEDLINE]

Perceived Health in Patients with Primary Immune Deficiency.

August 16, 2016 By Manish Butte

Perceived Health in Patients with Primary Immune Deficiency.

J Clin Immunol. 2015 Oct;35(7):638-50

Authors: Seeborg FO, Seay R, Boyle M, Boyle J, Scalchunes C, Orange JS

Abstract
PURPOSE: Perceived health (PH) is a subjective measure of global health of individuals. While many studies have evaluated outcomes in patients with primary immune deficiency (PID), published literature evaluating PH among patients with PID is sparse. We evaluated the results of the largest self-reported survey of patients with PID to determine the factors that may contribute to differences in PH.
METHODS: Data from a National Survey of Patients with Primary Immune Deficiency Diseases conducted by the Immune Deficiency Foundation was studied. Multivariate logistic regression was employed for data analysis.
RESULTS: Thirty percent of the patients perceived their health status as excellent or very good (EVG), 31 % as good (G), and 39 % as fair, poor or very poor (P). Older patients were less likely to have EVG-PH compared to G-PH. Ones with college degrees were more likely to have P-PH compared to G-PH, and less likely to have EVG-PH. Patients who were acutely ill and hospitalized in the past 12 months, ones with limited activity, and chronic diseases, were more likely to have P-PH compared to G-PH. Patients with “on demand” access to specialty care and ones on regular IVIG had higher OR of having EVG-PH as opposed to G-PH. Patients cared for mostly by an immunologist were less likely to have P-PH compared to G-PH.
CONCLUSIONS: Our results emphasize the importance of PH in clinical practice. We suggest that recognizing the factors that drive PH in patients with PID is important for the development of disease prevention and health promotion programs, and delivery of appropriate health and social services to individuals with PID.

PMID: 26453585 [PubMed – indexed for MEDLINE]

Secondary antibody deficiencies.

August 16, 2016 By Manish Butte

Secondary antibody deficiencies.

Curr Opin Allergy Clin Immunol. 2015 Dec;15(6):505-13

Authors: Dhalla F, Misbah SA

Abstract
PURPOSE OF REVIEW: Antibody deficiency can occur in the context of primary immune deficiency due to inherited genetic defects or secondary to a variety of causes. This review aims to summarize current data concerning the causes of secondary antibody deficiency and where possible evidence regarding the use of prophylactic replacement immunoglobulin. (Figure is included in full-text article.)
RECENT FINDINGS: Advances in immune-mediated therapies ranging from monoclonal antibodies to novel B-cell-targeted therapeutics are responsible for an expansion in the possible iatrogenic causes of antibody deficiency.
SUMMARY: Causes of secondary antibody deficiency include B-cell lymphoproliferative disease, notably chronic lymphocytic leukaemia and multiple myeloma, protein losing states, disorders of lymphatic circulation, increased immunoglobulin catabolism and a growing number of therapeutic agents. At-risk patients should be closely monitored for the development of hypogammaglobulinaemia, B-cell function should be defined where appropriate with specific antibody responses to immunization antigens and where there is a significant burden of infections patients should be treated with prophylactic antibiotics and/or replacement immunoglobulin.

PMID: 26406183 [PubMed – indexed for MEDLINE]

Alterations in primary motor cortex neurotransmission and gene expression in hemi-parkinsonian rats with drug-induced dyskinesia.

August 16, 2016 By Manish Butte

Alterations in primary motor cortex neurotransmission and gene expression in hemi-parkinsonian rats with drug-induced dyskinesia.

Neuroscience. 2015 Dec 3;310:12-26

Authors: Lindenbach D, Conti MM, Ostock CY, Dupre KB, Bishop C

Abstract
Treatment of Parkinson’s disease (PD) with dopamine replacement relieves symptoms of poverty of movement, but often causes drug-induced dyskinesias. Accumulating clinical and pre-clinical evidence suggests that the primary motor cortex (M1) is involved in the pathophysiology of PD and that modulating cortical activity may be a therapeutic target in PD and dyskinesia. However, surprisingly little is known about how M1 neurotransmitter tone or gene expression is altered in PD, dyskinesia or associated animal models. The present study utilized the rat unilateral 6-hydroxydopamine (6-OHDA) model of PD/dyskinesia to characterize structural and functional changes taking place in M1 monoamine innervation and gene expression. 6-OHDA caused dopamine pathology in M1, although the lesion was less severe than in the striatum. Rats with 6-OHDA lesions showed a PD motor impairment and developed dyskinesia when given L-DOPA or the D1 receptor agonist, SKF81297. M1 expression of two immediate-early genes (c-Fos and ARC) was strongly enhanced by either L-DOPA or SKF81297. At the same time, expression of genes specifically involved in glutamate and GABA signaling were either modestly affected or unchanged by lesion and/or treatment. We conclude that M1 neurotransmission and signal transduction in the rat 6-OHDA model of PD/dyskinesia mirror features of human PD, supporting the utility of the model to study M1 dysfunction in PD and the elucidation of novel pathophysiological mechanisms and therapeutic targets.

PMID: 26363150 [PubMed – indexed for MEDLINE]

The Ying and Yang of STAT3 in Human Disease.

August 16, 2016 By Manish Butte

The Ying and Yang of STAT3 in Human Disease.

J Clin Immunol. 2015 Oct;35(7):615-23

Authors: Vogel TP, Milner JD, Cooper MA

Abstract
The transcription factor signal transducer and activator of transcription 3 (STAT3) is a critical regulator of multiple, diverse cellular processes. Heterozgyous, germline, loss-of-function mutations in STAT3 lead to the primary immune deficiency Hyper-IgE syndrome. Heterozygous, somatic, gain-of-function mutations in STAT3 have been reported in malignancy. Recently, germline, heterozygous mutations in STAT3 that confer a gain-of-function have been discovered and result in early-onset, multi-organ autoimmunity. This review summarizes what is known about the role of STAT3 in human disease.

PMID: 26280891 [PubMed – indexed for MEDLINE]

Clinical characteristics and genetic profiles of 174 patients with X-linked agammaglobulinemia: Report from Shanghai, China (2000-2015).

August 12, 2016 By Manish Butte

Clinical characteristics and genetic profiles of 174 patients with X-linked agammaglobulinemia: Report from Shanghai, China (2000-2015).

Medicine (Baltimore). 2016 Aug;95(32):e4544

Authors: Chen XF, Wang WF, Zhang YD, Zhao W, Wu J, Chen TX

Abstract
X-linked agammaglobulinemia (XLA) is a humoral primary immunodeficiency. XLA patients typically present with very low numbers of peripheral B cells and a profound deficiency of all immunoglobulin isotypes. Most XLA patients carry mutations in Bruton tyrosine kinase (BTK) gene.The genetic background and clinical features of 174 Chinese patients with XLA were investigated. The relationship between specific BTK gene mutations and severity of clinical manifestations was also examined. Mutations were graded from mild to severe based on structural and functional prediction through bioinformatics analysis.One hundred twenty-seven mutations were identified in 142 patients from 124 families, including 45 novel mutations and 82 recurrent mutations that were distributed over the entire BTK gene sequence. Variation in phenotypes was observed, and there was a tendency of association between genotype and age of disease onset.This report constitutes the largest group of patients with BTK mutations in China. A genotype-phenotype correlation was observed in this study. Early diagnosis of congenital agammaglobulinemia should be based on clinical symptoms, family history, and molecular analysis of the BTK gene.

PMID: 27512878 [PubMed – as supplied by publisher]

Advances of gene therapy for primary immunodeficiencies.

August 11, 2016 By Manish Butte

Advances of gene therapy for primary immunodeficiencies.

F1000Res. 2016;5

Authors: Candotti F

Abstract
In the recent past, the gene therapy field has witnessed a remarkable series of successes, many of which have involved primary immunodeficiency diseases, such as X-linked severe combined immunodeficiency, adenosine deaminase deficiency, chronic granulomatous disease, and Wiskott-Aldrich syndrome. While such progress has widened the choice of therapeutic options in some specific cases of primary immunodeficiency, much remains to be done to extend the geographical availability of such an advanced approach and to increase the number of diseases that can be targeted. At the same time, emerging technologies are stimulating intensive investigations that may lead to the application of precise genetic editing as the next form of gene therapy for these and other human genetic diseases.

PMID: 27508076 [PubMed]

HTLV-1 Tax Functions as a Ubiquitin E3 Ligase for Direct IKK Activation via Synthesis of Mixed-Linkage Polyubiquitin Chains.

August 11, 2016 By Manish Butte

HTLV-1 Tax Functions as a Ubiquitin E3 Ligase for Direct IKK Activation via Synthesis of Mixed-Linkage Polyubiquitin Chains.

PLoS Pathog. 2016 Apr;12(4):e1005584

Authors: Wang C, Long W, Peng C, Hu L, Zhang Q, Wu A, Zhang X, Duan X, Wong CC, Tanaka Y, Xia Z

Abstract
The HTLV-1 oncoprotein Tax plays a key role in CD4+ T cell transformation by promoting cell proliferation and survival, mainly through permanent activation of the NK-κB pathway and induction of many NF-κB target genes. Elucidating the underlying molecular mechanism is therefore critical in understanding HTLV-1-mediated transformation. Current studies have suggested multiple but controversial mechanisms regarding Tax-induced IKK activation mainly due to blending of primary Tax-induced IKK activation events and secondary IKK activation events induced by cytokines secreted by the primary Tax-induced IKK-NF-κB activation events. We reconstituted Tax-stimulated IKK activation in a cell-free system to dissect the essential cellular components for primary IKK activation by Tax and studied the underlying biochemical mechanism. We found that Tax is a putative E3 ubiquitin ligase, which, together with UbcH2, UhcH5c, or UbcH7, catalyzes the assembly of free mixed-linkage polyubiquitin chains. These free mixed-linkage polyubiquitin chains are then responsible for direct IKK activation by binding to the NEMO subunit of IKK. Our studies revealed the biochemical function of Tax in the process of IKK activation, which utilizes the minimal cellular ubiquitination components for NF-κB activation.

PMID: 27082114 [PubMed – indexed for MEDLINE]

Eosinophilia in an Acutely Limping Child: An Easy Guess of Rare Systemic Aetiology!

August 10, 2016 By Manish Butte

Eosinophilia in an Acutely Limping Child: An Easy Guess of Rare Systemic Aetiology!

J Clin Diagn Res. 2016 Jun;10(6):SD03-4

Authors: Sharma H, Kondekar SV, Ahmed M, Rathi S

Abstract
Painful limping child is often considered due to septic arthritis. Iliopsoas abscess (IPA) is rare in adults and children. The aetiology is often related to tuberculosis of spine. Hereby we report a case of staphylococcal IPA where incidental evaluations led to obvious diagnosis of a rare primary immunodeficiency syndrome called Job syndrome or hyperimmunoglobulin E and Eosinophilia Syndrome (HIES). This was the first case of IPA in a case of immunodeficiency syndrome including HIES.

PMID: 27504370 [PubMed]

A nationwide survey of common viral infections in childhood among patients with primary immunodeficiency diseases.

August 9, 2016 By Manish Butte

A nationwide survey of common viral infections in childhood among patients with primary immunodeficiency diseases.

J Infect. 2016 Aug 3;

Authors: Nanishi E, Hoshina T, Takada H, Ishimura M, Nishio H, Uehara T, Mizuno Y, Hasegawa S, Ohga S, Nagao M, Igarashi M, Yajima S, Kusumoto Y, Onishi N, Sasahara Y, Yasumi T, Heike T, Hara T, PID-Infection Study Group

Abstract
OBJECTIVES: Patients with primary immunodeficiency diseases (PID) are highly susceptible to various microorganisms. However, no population-based studies have been performed among common viral pathogens, such as respiratory syncytial virus (RSV), rotavirus (RV), varicella-zoster virus (VZV) and influenza virus (IV). The objective of this study was to reveal the clinical burden of these four infections among PID patients in Japan.
METHODS: We conducted a nationwide survey by sending questionnaires to 898 hospitals with pediatric departments throughout Japan.
RESULTS: Nine hundred ten PID patients from 621 hospitals were registered (response rate: 69.2%). Fifty-four of the patients were hospitalized due to these viral infections. The durations of hospitalization due to RSV and RV infections differed significantly in the PID patients with and without cellular immunodeficiency (12.0 vs 6.5 days, p = 0.041; and 14.0 vs 6.0 days, p = 0.031, respectively). There was no significant difference in the duration of hospitalization in PID patients with and without cellular immunodeficiency who were hospitalized with IV infections (7.3 vs 6.1 days, p = 0.53).
CONCLUSIONS: Special attention should be paid to PID patients with compromised cellular immunity who present with RSV and RV infection due to their high risk for severe disease.

PMID: 27498293 [PubMed – as supplied by publisher]