Research

Gain-of-function mutations and immunodeficiency: at a loss for proper tuning of lymphocyte signaling.

Curr Opin Allergy Clin Immunol. 2015 Sep 24;

Authors: Arjunaraja S, Snow AL

Abstract
PURPOSE OF REVIEW: To present recent advances in the discovery and characterization of new immunodeficiency disorders linked to gain-of-function (GOF) mutations in immune signaling molecules.
RECENT FINDINGS: In the past 2 years, extensive cellular and molecular studies have illuminated the root causes of pathogenesis for several new monogenic primary immunodeficiency disorders (PIDs) linked to GOF mutations in signaling molecules. Here we discuss on two disorders (BENTA and APDS/PASLI) featuring shared clinical presentation (e.g. lymphoproliferation, selective antibody deficiencies, recurrent sinopulmonary infections). These findings highlight an emerging theme: both loss-of-function and gain-of-function mutations in key molecules can disrupt finely tuned immunoreceptor signaling modalities, resulting in the dysregulation of lymphocyte differentiation and impaired adaptive immunity.
SUMMARY: Continued research on the molecular pathogenesis of PIDs defined by hyperactive signaling molecules will better distinguish these and related disorders, and pinpoint tailored therapeutic interventions for ‘retuning’ the immune response in these patients.

PMID: 26406182 [PubMed – as supplied by publisher]

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Efficacy of Intravenous Immunoglobulin in Neurological Diseases.

Neurotherapeutics. 2015 Sep 23;

Authors: Lünemann JD, Quast I, Dalakas MC

Abstract
Owing to its anti-inflammatory efficacy in various autoimmune disease conditions, intravenous immunoglobulin (IVIG)-pooled IgG obtained from the plasma of several thousands individuals-has been used for nearly three decades and is proving to be efficient in a growing number of neurological diseases. IVIG therapy has been firmly established for the treatment of Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, and multifocal motor neuropathy, either as first-line therapy or adjunctive treatment. IVIG is also recommended as rescue therapy in patients with worsening myasthenia gravis and is beneficial as a second-line therapy for dermatomyositis and stiff-person syndrome. Subcutaneous rather than intravenous administration of IgG is gaining momentum because of its effectiveness in patients with primary immunodeficiency and the ease with which it can be administered independently from hospital-based infusions. The demand for IVIG therapy is growing, resulting in rising costs and supply shortages. Strategies to replace IVIG with recombinant products have been developed based on proposed mechanisms that confer the anti-inflammatory activity of IVIG, but their efficacy has not been tested in clinical trials. This review covers new developments in the immunobiology and clinical applications of IVIG in neurological diseases.

PMID: 26400261 [PubMed – as supplied by publisher]

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Astute Clinician Report: A Novel 10 bp Frameshift Deletion in Exon 2 of ICOS Causes a Combined Immunodeficiency Associated with an Enteritis and Hepatitis.

J Clin Immunol. 2015 Sep 23;

Authors: Robertson N, Engelhardt KR, Morgan NV, Barge D, Cant AJ, Hughes SM, Abinun M, Xu Y, Koref MS, Arkwright PD, Hambleton S

Abstract
ICOS encodes the Inducible T-cell Co-Stimulator (ICOS). Deficiency of this receptor in humans causes a common variable immunodeficiency (CVID) characterised by an absence of class-switched memory B cells and hypogammaglobulinemia. Three pathogenic mutations in ICOS have been described to date in a total of 13 cases. Here we report a novel homozygous 10 base pair frameshift deletion in exon 2 discovered by whole exome sequencing of two siblings from a family of Pakistani origin. Both patients presented in early childhood with diarrhea, colitis and transaminitis and one showed defective handling of human herpesvirus 6. Activated patient CD3(+)CD4(+) T lymphocytes demonstrated a complete absence of ICOS expression and, consistent with previous reports, we detected a reduction in circulating T follicular helper cells. Findings in this kindred emphasise the phenotypic variability of ICOS deficiency and, in particular, the variably impaired antiviral immunity that is a poorly understood facet of this rare disorder.

PMID: 26399252 [PubMed – as supplied by publisher]

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Combined autoimmune cytopenias presenting in childhood.

Pediatr Blood Cancer. 2015 Sep 23;

Authors: Al Ghaithi I, Wright NA, Breakey VR, Cox K, Warias A, Wong T, O’Connell C, Price V

Abstract
BACKGROUND: Pediatric patients with chronic and/or refractory autoimmune multi-lineage cytopenias present challenges in both diagnosis and management. Increasing availability of diagnostic testing has revealed an underlying immune dysfunction in patients previously diagnosed with Evans Syndrome. However, the data are sparse and the majority of patients are adults.
PROCEDURE: We performed a retrospective chart review to document the natural history of 23 pediatric patients with autoimmune multi-lineage cytopenias followed at three tertiary care pediatric hematology clinics.
RESULTS: Investigations revealed seven patients (30.4%) with an autoimmune lymphoproliferative-like syndrome and six patients (26.1%) with other primary immunodeficiencies. Only one (4.3%) patient was suspected to have systemic lupus erythematosus and six patients (26.1%) had other types of autoimmunity. Treatment consisted of immunosuppressive therapy, intravenous gammaglobulin, and splenectomy. Supportive care included granulocyte-colony stimulating factor, and blood product transfusions. Two patients (8.7%) died. Complete remission was achieved in 3 patients (13.0%); of the remaining, 14 patients (60.9%) had chronic immune thrombocytopenic purpura, 10 patients (43.5%) chronic autoimmune neutropenia, and 4 patients (17.4%) chronic autoimmune hemolytic anemia with a median follow up of 5 years (2 months-12 years).
CONCLUSIONS: These data suggest that pediatric patients presenting with autoimmune multi-lineage cytopenias should undergo investigation for underlying immune dysregulation, including autoimmune lymphoproliferative syndrome, other primary immunodeficiencies and autoimmune disorders. The development of an international registry for such patients is imperative to improve the understanding of their complex natural history. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc.

PMID: 26397379 [PubMed – as supplied by publisher]

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Primary Immunodeficiency Diseases in Saudi Arabia: a Tertiary Care Hospital Experience over a Period of Three Years (2010-2013).

J Clin Immunol. 2015 Sep 22;

Authors: Al-Saud B, Al-Mousa H, Al Gazlan S, Al-Ghonaium A, Arnaout R, Al-Seraihy A, Elshorbagi S, Elsayed N, Afzal J, Al-Dhekri H, Al-Muhsen S

Abstract
PURPOSE: Primary immunodeficiencies (PID) are a group of heterogeneous diseases. Epidemiological studies from databases worldwide show geographical variation. In this study the objective is to determine the spectrum of PID in Saudi Arabia by analyzing the database in a referral tertiary hospital.
METHODS: This is a prospective data collection by interviews and medical chart review for all PID patients followed at the King Faisal Specialist Hospital & Research Center (KFSH&RC) from May 2010 to April 2013.
RESULTS: A total of 502 patients presented (53 % male and 47 % female). Combined immunodeficiencies were the most common (59.7 %), followed by predominantly antibody deficiencies (12.3 %), congenital defects of phagocyte (9.4 %), combined immunodeficiencies with associated or syndromic features (6.2 %), disease of immune dysregulation (6 %), complement deficiencies (5.8), and defects in innate immunity (0.6 %). The most common combined immunodeficiencies phenotype was T-B-SCID (17 %). The patients’ ages ranged from less than 1 year old to 78 years, and 394 patients (78.2 %) are in the paediatrics age group (<14 years). The overall mean age of symptoms onset was 17 months and the overall mean delay in diagnosis was 21.6 months. Recurrent infections were the most common occurring clinical presentation (66 %), followed by family history (26 %). Consanguinity was found in 75 % of the patients. A total of 308 (61 %) patients had undergone stem cell transplantation (SCT).
CONCLUSION: The study revealed that combined immunodeficiencies are not uncommon and are the most frequent occurring diagnosis in our patient population. This study is a prerequisite to establish a national registry of primary immunodeficiency in Saudi Arabia.

PMID: 26395454 [PubMed – as supplied by publisher]

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A novel FOXP3 mutation causing fetal akinesia and recurrent male miscarriages.

Clin Immunol. 2015 Sep 17;

Authors: Rae W, Gao Y, Bunyan D, Holden S, Gilmour K, Patel S, Wellesley D, Williams A

Abstract
Potential reviewers may include; •Dr Stephen Jolles, University of Wales Hospital, jollessr@cardiff.ac.uk •Prof Magda Carneiro-Sampaio, Hospital da Clinicas sa FMUSP, magdascs@usp.br •Prof John Routes, Medical College of Wisconsin, jroutes@mcw.edu •Dr Eleonora Gambineri, University of Florence and Anna Meyer Children’s Hospital, eleonora.gambineri@unifi.it.

PMID: 26387632 [PubMed – as supplied by publisher]

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Prevalence of BTK mutations in male Algerian patterns with agammaglobulinemia and severe B cell lymphopenia.

Clin Immunol. 2015 Sep 17;

Authors: Boushaki S, Tahiat A, Meddour Y, Chan KW, Chaib S, Benhalla N, Smati L, Bensnouci A, Lau YL, Magdinier F, Djidjik R

Abstract
X linked agammaglobulinemia (XLA) is the first described primary immunodeficiency and the most common form of agammaglobulinemia. It is characterized by susceptibility to recurrent infections, profound decrease of all immunoglobulin isotypes and very low level of B lymphocytes in peripheral blood. The disorder is caused by mutations in the Bruton’s Tyrosine Kinase (BTK). Nine male patients suspected to have XLA from nine unrelated families were enrolled in this study. We performed sequencing of the BTK gene in all nine patients, and in the patients’ relatives when possible. The XLA diagnosis was confirmed for six patients with six different mutations; we identified a novel mutation (c.1522G>A) and five known mutations. One third of nine unrelated patients do not have mutations in BTK and thus likely suffer from autosomal recessive agammaglobulinemia in the setting of consanguinity. Our results support that the autosomal recessive agammaglobulinemia can be more common in Algeria.

PMID: 26387629 [PubMed – as supplied by publisher]

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The effects of RelB deficiency on lymphocyte development and function.

J Autoimmun. 2015 Sep 15;

Authors: Sharfe N, Merico D, Karanxha A, Macdonald C, Dadi H, Ngan B, Herbrick JA, Roifman CM

Abstract
Multiple receptors that control cell growth and inflammation activate the NFκB pathway that comprises of two pathways. Dysfunction of the classical pathway leads to impaired adaptive and innate immunity in humans. In contrast the exact role of the alternative NFκB pathway mediated by RelB in humans remains largely elusive. We have recently identified deleterious mutations in RelB in patients with combined immunodeficiency and autoimmunity. We studied here the biological effects of RelB deficiency on the immune system. We show that the thymus in this patient is dysplastic and consequently new thymus emigrants are rare and there is an accumulation of CD45 RO(+) T cells with an increase in CD62L(+) central memory cells. The TCR repertoire of these cells appears skewed with selective clonal expansion. In vitro responses to T cell mitogens were markedly depressed and so were PHA induced IL2 and IFNγ production. In addition, the TH1 promoting T bet and STAT1 were reduced. In contrast, hyper-activation was seen in response to anti-CD3 and CD28. T cell dependent antibody responses were low to absent in all patients. We found that BAFF-R was reduced and CD40 signaling aberrant. Critically, CD27(+) memory cells were absent. We have shown here for the first time the role of RelB on lymphocyte development in humans. In the absence of RelB, B cells development is arrested, resulting in poor production of immunoglobulins and specific antibodies. T cell maturation in the thymus appears altered with reduced output and production of a skewed T cell repertoire with expansion of clones which are likely the cause of the autoimmune features observed in these patients.

PMID: 26385063 [PubMed – as supplied by publisher]

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Management of adverse events in the treatment of patients with immunoglobulin therapy: A review of evidence.

Autoimmun Rev. 2015 Sep 15;

Authors: Cherin P, Marie I, Michallet M, Pelus E, Dantal J, Crave JC, Delain JC, Vaillard JF

Abstract
Immunoglobulin (IG) therapy is actually used for a broad range of diseases including primary and secondary immunodeficiency disorders, and autoimmune diseases. This therapy is available for intravenous (IV) and subcutaneous (SC) administration. The efficacy of the IG therapy has been demonstrated in numerous studies and across different diseases. Generally, IG infusions are well tolerated; however some well-known adverse reactions, ranging from mild to severe, are associated with the therapy. The most common adverse reactions including headache, nausea, myalgia, fever, chills, chest discomfort, skin and anaphylactic reactions, could arise immediately during or after the infusion. Delayed events could be more severe and include migraine headaches, aseptic meningitis, haemolysis renal impairment and thrombotic events. This paper reviews all the potential adverse events related to the IG therapy and establishes a comprehensive guideline for the management of these events. Moreover it resumes the opinions and clinical experience of expert endorsers on the utilisation of the treatment. Published data were classified into levels of evidence and the strength of the recommendation was given for each intervention according to the GRADE system.

PMID: 26384525 [PubMed – as supplied by publisher]

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Modeling the prevalence of immunodeficiency-associated long-term vaccine-derived poliovirus excretors and the potential benefits of antiviral drugs.

BMC Infect Dis. 2015;15(1):379

Authors: Duintjer Tebbens RJ, Pallansch MA, Thompson KM

Abstract
BACKGROUND: A small number of individuals with B-cell-related primary immunodeficiency diseases (PIDs) may exhibit long-term (prolonged or chronic) excretion of immunodeficiency-associated vaccine-derived polioviruses (iVDPVs) following infection with oral poliovirus vaccine (OPV). These individuals pose a risk of live poliovirus reintroduction into the population after global wild poliovirus eradication and subsequent OPV cessation. Treatment with polio antiviral drugs may potentially stop excretion in some of these individuals and thus may reduce the future population risk.
METHODS: We developed a discrete event simulation model to characterize the global prevalence of long-term iVDPV excretors based on the best available evidence. We explored the impact of different assumptions about the effectiveness of polio antiviral drugs and the fraction of long-term excretors identified and treated.
RESULTS: Due to the rarity of long-term iVDPV excretion and limited data on the survival of PID patients in developing countries, uncertainty remains about the current and future prevalence of long-term iVDPV excretors. While the model suggests only approximately 30 current excretors globally and a rapid decrease after OPV cessation, most of these excrete asymptomatically and remain undetected. The possibility that one or more PID patients may continue to excrete iVDPVs for several years after OPV cessation represents a risk for reintroduction of live polioviruses after OPV cessation, particularly for middle-income countries. With the effectiveness of a single polio antiviral drug possibly as low as 40 % and no system in place to identify and treat asymptomatic excretors, the impact of passive use of a single polio antiviral drug to treat identified excretors appears limited. Higher drug effectiveness and active efforts to identify long-term excretors will dramatically increase the benefits of polio antiviral drugs.
CONCLUSIONS: Efforts to develop a second polio antiviral compound to increase polio antiviral effectiveness and/or to maximize the identification and treatment of affected individuals represent important risk management opportunities for the polio endgame. Better data on the survival of PID patients in developing countries and more longitudinal data on their exposure to and recovery from OPV infections would improve our understanding of the risks associated with iVDPV excretors and the benefits of further investments in polio antiviral drugs.

PMID: 26382043 [PubMed – as supplied by publisher]

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