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Report on the First Survey of Iranian Patients with Hereditary Angioedema.

Iran J Immunol. 2015 Sep;12(3):209-18

Authors: Shahinpour S, Tavakol M, Abolhassani H, Mohammadinejad P, Movahedi M, Arshi S, Aghamohammadi A

Abstract
BACKGROUND: Hereditary angioedema (HAE) is a rare autosomal dominant primary immunodeficiency with complement system defect characterized by recurrent episodes of angioedema involving the skin or mucosa of the upper respiratory and gastrointestinal tracts.
OBJECTIVE: To characterize the clinical and laboratory data of hereditary angioedema in Iran.
METHODS: Patients with probable diagnosis of angioedema were enrolled in this study. Demographic and clinical data were documented in the designed questionnaire including history of attacks, triggering factors and laboratory data such as C4, C1 esterase inhibitor level and function.
RESULTS: Among 63 patients who were clinically suspicious for angioedema (23 males and 40 females), 8 cases (12.7%) were diagnosed with HAE. Among these 8 HAE patients, 3 were diagnosed with HAE type 1 and five patients were diagnosed with HAE type 2. The mean ages of HAE type 1 and type 2 patients were 25.6 ± 13.5 and 22.4 ± 12.32 years. The mean age of onset in HAE type 1 group was 8 ± 5 years and in HAE type 2 group was 18.8 ± 11.84 years. The mean diagnosis delay was 17.6 years in HAE type 1 patients and 2.6 years in HAE type 2. The most common clinical manifestation was facial swelling presented in all HAE patients followed by swelling of extremities which was present in 7 patients with HAE.
CONCLUSION: The clinical criteria of the Iranian patients with HAE were consistent with the known clinical patterns of the disease.

PMID: 26412639 [PubMed – in process]

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A novel common gamma chain mutation in a Chinese family with X-linked severe combined immunodeficiency (X-SCID; T(-)NK(-)B(+)).

Immunogenetics. 2015 Sep 26;

Authors: Tan W, Yu S, Lei J, Wu B, Wu C

Abstract
X-linked severe combined immunodeficiency (X-SCID) is one of the most common causes of primary immunodeficiencies in humans. A 4-month-old boy with recurrent pulmonary infection had decreased numbers of CD3(+), CD4(+), CD8(+) T lymphocytes, and NK cells and increased levels of CD19(+) B cells but no memory B cells or plasma cells. The production of cytokines by T cells and the activation of T and B cells were either absent or inefficient. While B cell levels were high, they were all IgM-positive, and the secretion of all Ig isotypes by activated B cells in vitro was defective. Genomic DNA sequencing revealed that the patient had missense mutations in the IL2RG (exon 5, 718 T > C) and IL7R genes (exon 2, 197 T > C; exon 4, 412G > A). Although the patient’s father and one of his sisters have the same missense homozygous mutations of the IL7R gene, neither of them exhibited the immunological phenotype of SCID. The results indicate that the IL2RG gene mutation or a combination of the IL7R and IL2RG mutations in the sick boy had resulted in T(-)NK(-)B(+) SCID.

PMID: 26409833 [PubMed – as supplied by publisher]

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Late-Onset Combined Immunodeficiency with a Novel IL2RG Mutation and Probable Revertant Somatic Mosaicism.

J Clin Immunol. 2015 Sep 26;

Authors: Okuno Y, Hoshino A, Muramatsu H, Kawashima N, Wang X, Yoshida K, Wada T, Gunji M, Toma T, Kato T, Shiraishi Y, Iwata A, Hori T, Kitoh T, Chiba K, Tanaka H, Sanada M, Takahashi Y, Nonoyama S, Ito M, Miyano S, Ogawa S, Kojima S, Kanegane H

Abstract
Primary immunodeficiency disease (PID) is caused by mutations of more than two hundred immunity-related genes. In addition to the heterogeneity of the diseases, the atypical presentation of each disease caused by hypomorphic mutations or somatic mosaicism makes genetic diagnosis challenging. Next-generation sequencing tests all genes simultaneously and has proven its innovative efficacy in genomics. We describe a male PID patient without any family history of immunodeficiency. This patient suffered from recurrent infections from 1 year of age. Laboratory analysis showed hypogammaglobulinemia. T, B, and NK cells were present, but the T cell proliferative response decreased. Whole-exome sequencing analysis identified an IL2RG p.P58T missense mutation. CD8(+) and CD56(+) cells showed revertant somatic mosaicism to the wild-type allele. A late-onset and atypical presentation of the X-linked severe combined immunodeficiency (X-SCID) phenotype might be associated with revertant somatic mosaicism in T and NK cells. This patient is the seventh reported case of X-SCID with revertant somatic mosaicism. His classical clinical management did not result in a molecular diagnosis because of the atypical presentation. The coverage that is provided by whole-exome sequencing of most PID genes effectively excluded differential diagnoses other than X-SCID. As next-generation sequencing becomes available in clinical practice, it will enhance our knowledge of PID and rescue currently undiagnosed patients.

PMID: 26407811 [PubMed – as supplied by publisher]

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Related Articles

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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