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Invasive Bacterial Infection in Patients with Interleukin-1 Receptor-associated Kinase 4 Deficiency: Case Report.

Medicine (Baltimore). 2016 Jan;95(4):e2437

Authors: Takada H, Ishimura M, Takimoto T, Kohagura T, Yoshikawa H, Imaizumi M, Shichijyou K, Shimabukuro Y, Kise T, Hyakuna N, Ohara O, Nonoyama S, Hara T

Abstract
Interleukin-1 receptor-associated kinase 4 (IRAK4) deficiency (OMIM #607676) is a rare primary immunodeficiency of innate immune defect. We identified 10 patients from 6 families with IRAK4 deficiency in Japan, and analyzed the clinical characteristics of this disease.Nine patients had homozygous c.123_124insA mutation, and 1 patient had c.123_124insA and another nonsense mutation (547C>T). Umbilical cord separation occurred on the 14th day after birth or thereafter. Two patients had no severe infections owing to the prophylactic antibiotic treatment. Severe invasive bacterial infections occurred before the age of 3 in the other 8 patients. Among them, 7 patients had pneumococcal meningitis. Five patients died of invasive bacterial infection during infancy, although intravenous antibiotic treatment was started within 24 hours after onset in 4 patients among them. Analysis of cerebrospinal fluid of the patients who had fatal meningitis revealed very low glucose levels with only mild pleocytosis.The clinical courses of invasive bacterial infections were often rapidly progressive despite the early, appropriate antibiotic treatment in IRAK4 deficiency patients. The early diagnosis and appropriate prophylaxis of invasive bacterial infections are necessary for the patients.

PMID: 26825884 [PubMed – in process]

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Genomewide Histone H3 Lysine 9 Acetylation Profiling in CD4+ T Cells Revealed Endoplasmic Reticulum Stress Deficiency in Patients with Acute-on-chronic Liver Failure.

Scand J Immunol. 2015 Nov;82(5):452-9

Authors: Jin L, Wang K, Liu H, Chen T, Yang Y, Ma X, Wang J, Li Y, Du D, Zhao Y, He Y

Abstract
Acute-on-chronic liver failure (ACLF) displayed ‘sepsis-like’ immune paralysis. Little is known about the role of CD4+ T lymphocytes, the primary regulator of innate and adopted immune system, played in ACLF. Acetylation of histone H3 lysine 9 (H3K9ac), a key epigenetic modification, tightly controls gene transcription. Whether and how does H3K9ac modification regulate CD4+ T cells in ACLF remains unclear. PBMCs were isolated from patients with ACLF, immune tolerance of chronic hepatitis B (CHB-T) and immune active of chronic hepatitis B (CHB-A). Then, CD4+ T lymphocytes were purified by magnetic microbeads, and the purity was confirmed by flow cytometry. H3K9ac variations were analysed in CD4+ T cells using chromatin immunoprecipitation microarray and then confirmed by quantitative PCR. Whole-genome H3K9 acetylation analyses were conducted by bioinformatics. A total of 70 genes were differently modified in H3K9ac between CHB-A and ACLF groups, while 44 genes were differently modified in H3K9ac between CHB-T and ACLF groups. Clustering algorithm analysis showed patients with ACLF displayed ‘sepsis-like’ immune paralysis. Functional analysis showed endoplasmic reticulum (ER) stress, or downstream pathway-related genes, such as BIP, ATF4, PER1, CSNK1D, IRF3, BNIP1, AKT1 and UBC, were differentially modified in ACLF. We profiled H3K9 acetyl modification in CD4+ T lymphocytes from HBV-infected patients with three different immune states, that is ACLF, immune tolerance and immune active phases. ACLF displayed ‘sepsis-like’ immune paralysis. ER stress in CD4+ T lymphocytes attributed to ACLF. This study provides some useful clues for revealing the mechanisms underlying ACLF.

PMID: 26173605 [PubMed – indexed for MEDLINE]

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Primary Antibody Deficiency in a Tertiary Referral Hospital: A 30-Year Experiment.

J Investig Allergol Clin Immunol. 2015;25(6):416-25

Authors: Mohammadinejad P, Pourhamdi S, Abolhassani H, Mirminachi B, Havaei A, Masoom SN, Sadeghi B, Ghajar A, Afarideh M, Parvaneh N, Mirsaeed-Ghazi B, Movahedi M, Gharagozlou M, Chavoushzadeh Z, Mahdaviani A, Zandieh F, Sherkat R, Sadeghi-Shabestari M, Faridhosseini R, Jabbari-Azad F, Ahanchian H, Zandkarimi M, Cherghi T, Fayezi A, Mohammadzadeh I, Amin R, Aleyasin S, Moghtaderi M, Ghaffari J, Bemanian M, Shafiei A, Kalantari N, Ahmadiafshar A, Khazaei HA, Mohammadi J, Nabavi M, Rezaei N, Aghamohammadi A

Abstract
BACKGROUND: Primary antibody deficiency (PAD) is the most common group of primary immunodeficiency disorders (PID), with a broad spectrum of clinical features ranging from severe and recurrent infections to asymptomatic disease.
OBJECTIVES: The current study was performed to evaluate and compare demographic and clinical data in the most common types of PAD.
MATERIALS AND METHODS: We performed a retrospective review of the medical records of all PAD patients with a confirmed diagnosis of common variable immunodeficiency (CVID), hyper IgM syndrome (HIgM), selective IgA deficiency (SIgAD), and X-linked agammaglobulinemia (XLA) who were diagnosed during the last 30 years at the Children’s Medical Center, Tehran, Iran.
RESULTS: A total number of 280 cases of PAD (125 CVID, 32 HIgM, 63 SIgAD, and 60 XLA) were enrolled in the study. The median (range) age at the onset of disease in CVID, HIgM, SIgAD, and XLA was 2 (0-46), 0.91 (0-9), 1 (0-26), and 1 (0-10) years, respectively. Gastrointestinal infections were more prevalent in CVID patients, as were central nervous system infections in XLA patients. Autoimmune complications were more prevalent in HIgM patients, malignancies in CVID patients, and allergies in SIgAD patients. The mortality rate for CVID, HIgM, and XLA was 27.2%, 28.1%, and 25%, respectively. No deaths were reported in SIgAD patients.
CONCLUSIONS: SIgAD patients had the best prognosis. While all PAD patients should be monitored for infectious complications, special attention should be paid to the finding of malignancy and autoimmune disorders in CVID and HIgM patients, respectively.

PMID: 26817138 [PubMed – in process]

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How effective are the 6 European Society of Immunodeficiency warning signs for primary immunodeficiency disease?

Ann Allergy Asthma Immunol. 2016 Feb;116(2):151-155.e1

Authors: Arslan S, Ucar R, Caliskaner AZ, Reisli I, Guner SN, Sayar EH, Baloglu I

Abstract
BACKGROUND: The European Society of Immunodeficiency (ESID) developed 6 warning signs to promote the awareness of adult primary immunodeficiency disease (PID).
OBJECTIVE: To screen adult patients for the presence of PID using these 6 warning signs to determine the effectiveness of this protocol.
METHODS: Questions related to the ESID warning signs for adult PID were added to the standard outpatient clinic file system and asked of 3,510 patients who were admitted to our clinic for any reason. Patients with signs and/or suspicion of PID based on their medical history underwent immunologic investigation.
RESULTS: In total, 24 patients were diagnosed as having a PID. The most common reason that patients with PID were admitted was frequent infection (n=18 [75%]), and the most common PID subgroup was common variable immunodeficiency (n=12 [50%]). Twenty patients with PID had at least one positive finding according to the ESID warning signs. Two patients with gastrointestinal concerns and 2 with dermatologic symptoms were also diagnosed as having a PID, although they did not have any of the ESID warning signs.
CONCLUSION: The ESID warning signs do not specify the need for symptoms to diagnose a PIDs and do not include a comprehensive list of all signs and symptoms of PIDs. As a result, more than infection-centric questions are needed to identify adult patients with immunodeficiencies.

PMID: 26815708 [PubMed – as supplied by publisher]

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Multiple malignancies in a female patient with common variable immunodeficiency syndrome.

Singapore Med J. 2014 Oct;55(10):e162-4

Authors: Todorovic M, Balint B, Andjelic B, Mihaljevic B

Abstract
We herein present the case of a 55-year-old woman with a previous history of malignancies–uterine adenocarcinoma, basal cell carcinoma (which occurred twice consecutively), recurrent respiratory infections due to common variable immunodeficiency (CVID), and systemic granulomatous disease diagnosed at a later age. The patient suffered from diffuse large B cell lymphoma (DLBCL), which was successfully treated with R-CHOP chemotherapy, and continued with immunoglobulin supplementation. The patient was free of lymphoma and infectious complications for over 20 months despite her persistent immunodeficiency, but eventually developed colorectal adenocarcinoma. To the best of our knowledge, this is the first reported case of CVID associated with multiple solid tumours and DLBCL.

PMID: 25631905 [PubMed – indexed for MEDLINE]

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Long-term follow-up of ninety eight Iranian patients with primary immune deficiency in a single tertiary centre.

Allergol Immunopathol (Madr). 2016 Jan 20;

Authors: Nabavi M, Arshi S, Bemanian MH, Aghamohammadi A, Mansouri D, Hedayat M, Nateghian A, Noorbakhsh S, Ehsanipour F, Faranoush M, Shakeri R, Mesdaghi M, Taghvaei B, Ghalebaghi B, Babaie D, Bahrami A, Fallahpour M, Esmaeilzadeh H, Ali Hamidieh A, Rekabi M, Ahmadian J, Eslami N, Shokri S, Afshar M, Jalali F, Akbarpour N, Molatefi R, Rezaei N

Abstract
PURPOSE: The aim was to describe the clinical manifestations, complications and long-term outcome of a cohort of Iranian patients with primary immune deficiency (PID).
METHOD: We retrospectively studied the demographic, clinical and immunological characteristics of the PID patients in a single tertiary centre, from January 1989 to July 2014. The patients were classified according to the International Union of Immunological Societies Expert Committee on PID.
RESULTS: 98 patients were diagnosed with and followed-up for 15 disorders. The mean age at onset and diagnosis and the diagnostic delay were 8±10, 14.2±13.1 and 6.1±7 years, respectively. Parental consanguinity rate was 57%. Predominantly Antibody Deficiency was the most common diagnosis (n=63), followed by congenital defects of phagocytes (n=16), combined immunodeficiencies (n=12), well defined syndromes (n=4) and defects in innate immunity (n=3). Recurrent sinopulmonary infection was the most common presentation. Active infections were treated appropriately, in addition to prophylactic therapy with IVIG and antimicrobials. Not all the patients were compliant with prophylactic regimens due to cost and unavailability. One SCID patient underwent successful bone marrow transplantation. The total mortality rate was 19% during the follow-up period (7.8±7.6 years). The mean age of living patients at the time of study was 23±11.7 years.
CONCLUSIONS: Physicians awareness of PID has been rising dramatically in Iran, ensuring an increasing number of patients being diagnosed and treated. More effective treatment services, including health insurance coverage and drug availability are needed to improve the outcome of PID patients.

PMID: 26803694 [PubMed – as supplied by publisher]

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F-actin remodeling defects as revealed in primary immunodeficiency disorders.

Clin Immunol. 2016 Jan 20;

Authors: Janssen WJ, Geluk HC, Boes M

Abstract
Primary immunodeficiencies (PIDs) are a heterogeneous group of immune-related diseases. PIDs develop due to defects in gene-products that have consequences to immune cell function. A number of PID-proteins is involved in the remodeling of filamentous actin (f-actin) to support the generation of a contact zone between the antigen-specific T cell and antigen presenting cell (APC): the immunological synapse (IS). IS formation is the first step towards T-cell activation and essential for clonal expansion and acquisition of effector function. We here evaluated PIDs in which aberrant f-actin-driven IS formation may contribute to the PID disease phenotypes as seen in patients. We review examples of such contributions to PID phenotypes from literature, and highlight cases in which PID-proteins were evaluated for a role in f-actin polymerization and IS formation. We conclude with the proposition that patient groups might benefit from stratifying them in distinct functional groups in regard to their f-actin remodeling phenotypes in lymphocytes.

PMID: 26802313 [PubMed – as supplied by publisher]

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Recruitment of A20 by the C-terminal domain of NEMO suppresses NF-κB activation and autoinflammatory disease.

Proc Natl Acad Sci U S A. 2016 Jan 22;

Authors: Zilberman-Rudenko J, Shawver LM, Wessel AW, Luo Y, Pelletier M, Tsai WL, Lee Y, Vonortas S, Cheng L, Ashwell JD, Orange JS, Siegel RM, Hanson EP

Abstract
Receptor-induced NF-κB activation is controlled by NEMO, the NF-κB essential modulator. Hypomorphic NEMO mutations result in X-linked ectodermal dysplasia with anhidrosis and immunodeficiency, also referred to as NEMO syndrome. Here we describe a distinct group of patients with NEMO C-terminal deletion (ΔCT-NEMO) mutations. Individuals harboring these mutations develop inflammatory skin and intestinal disease in addition to ectodermal dysplasia with anhidrosis and immunodeficiency. Both primary cells from these patients, as well as reconstituted cell lines with this deletion, exhibited increased IκB kinase (IKK) activity and production of proinflammatory cytokines. Unlike previously described loss-of-function mutations, ΔCT-NEMO mutants promoted increased NF-κB activation in response to TNF and Toll-like receptor stimulation. Investigation of the underlying mechanisms revealed impaired interactions with A20, a negative regulator of NF-κB activation, leading to prolonged accumulation of K63-ubiquitinated RIP within the TNFR1 signaling complex. Recruitment of A20 to the C-terminal domain of NEMO represents a novel mechanism limiting NF-κB activation by NEMO, and its absence results in autoinflammatory disease.

PMID: 26802121 [PubMed – as supplied by publisher]

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Primary immunodeficiencies worldwide: an updated overview from the Jeffrey Modell Centers Global Network.

Immunol Res. 2016 Jan 22;

Authors: Modell V, Quinn J, Orange J, Notarangelo LD, Modell F

Abstract
Primary immunodeficiencies (PI) are defects of the immune system that cause severe, sometimes life-threatening, infections if not diagnosed and treated appropriately. Many patients with PI are undiagnosed, under-diagnosed, or misdiagnosed. To raise awareness and assure earliest diagnosis, appropriate treatment, and proper care management, the Jeffrey Modell Foundation (JMF) implemented a physician education and public awareness program beginning in 2003. Data are requested annually from physician experts within the Jeffrey Modell Centers Network (JMCN), consisting of 602 expert physicians, at 253 academic institutions, in 206 cities, and 84 countries spanning six continents. Center Directors reported on patients’ specific PI defects and treatment modalities including immunoglobulins, transplantation, and gene therapy as well as data on gender and age. Center Directors also provided physician-reported patient outcomes as well as pre- and post-diagnosis differences. Costs were assigned to these factors. In collaboration with the Network, JMF advocated, funded, and implemented population-based newborn screening for severe combined immunodeficiency and T cell lymphopenia, covering 96.2 % of all newborns in the US. Finally, 21 JMF Centers participated in a polio surveillance study of patients with PI who either received or have been exposed to the oral polio vaccine. These initiatives have led to an overall better understanding of the immune system and will continue to improve quality of life for those with PI.

PMID: 26802037 [PubMed – as supplied by publisher]

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Hyper-IgE Syndrome in an Infant.

J Cutan Med Surg. 2016 Jan 22;

Authors: Giberson M, Finlayson L

Abstract
BACKGROUND: Hyper-immunoglobulin E syndrome (HIES) is a rare primary immunodeficiency disorder that affects multiple systems. One of the early findings is a papulopustular rash, which has a wide differential diagnosis.
METHOD: The authors report the case of a male newborn diagnosed with HIES. He presented with papulopustular dermatitis on the scalp. The authors also present a review of current theory on the pathophysiology, clinical presentation, and management of HIES.
CONCLUSION: Although HIES is a multisystem disorder, many of the manifestations of HIES may present after the neonatal period. The cutaneous manifestations of HIES are usually present shortly after birth, and the presentation of pustules in a newborn may be one of the reasons a dermatologist would be asked to assess a patient in the neonatal period.

PMID: 26801049 [PubMed – as supplied by publisher]

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