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Autoimmunity and Immune Dysregulation in Primary Immune Deficiency Disorders.

Curr Allergy Asthma Rep. 2015 Sep;15(9):53

Authors: Lehman HK

Abstract
Primary immune deficiencies are often associated with autoimmune disease due to the dysregulation of the immune system as a whole. In many immune deficiencies, lymphocytes may be present but dysfunctional, allowing for the development of excessive autoreactivity and resultant autoimmune disease. Autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy, autoimmune lymphoproliferative syndrome, immunodyregulation polyendocrinopathy enteropathy X-linked, IL-10/IL-10 receptor deficiencies, and PLCG2-associated antibody deficiency and immune dysregulation are disorders in which autoimmunity is a hallmark of the clinical disease presentation. In contrast, adaptive and innate immune deficiencies, which are typically defined by their infectious susceptibilities, can be associated with variable rates of autoimmune manifestations, predominantly autoimmune cytopenias. This review describes the immune dysregulation and autoimmune manifestations that may be encountered in various immune deficiencies.

PMID: 26233425 [PubMed – indexed for MEDLINE]

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Recurrent viral infections associated with a homozygous CORO1A mutation that disrupts oligomerization and cytoskeletal association.

J Allergy Clin Immunol. 2015 Oct 15;

Authors: Yee CS, Massaad MJ, Bainter W, Ohsumi TK, Föger N, Chan AC, Akarsu NA, Aytekin C, Ayvaz DÇ, Tezcan I, Sanal Ö, Geha RS, Chou J

Abstract
BACKGROUND: Coronin-1A (CORO1A) is a regulator of actin dynamics important for T-cell homeostasis. CORO1A deficiency causes T(-)B(+) natural killer-positive severe combined immunodeficiency or T-cell lymphopenia with severe viral infections. However, because all known human mutations in CORO1A abrogate protein expression, the role of the protein’s functional domains in host immunity is unknown.
OBJECTIVE: We sought to identify the cause of the primary immunodeficiency in 2 young adult siblings with a history of disseminated varicella, cutaneous warts, and CD4(+) T-cell lymphopenia.
METHODS: We performed immunologic, genetic, and biochemical studies in the patients, family members, and healthy control subjects.
RESULTS: Both patients had CD4(+) T-cell lymphopenia and decreased lymphocyte proliferation to mitogens. IgG, IgM, IgA, and specific antibody responses were normal. Whole-genome sequencing identified a homozygous frameshift mutation in CORO1A disrupting the last 2 C-terminal domains by replacing 61 amino acids with a novel 91-amino-acid sequence. The CORO1A(S401fs) mutant was expressed in the patients’ lymphocytes at a level comparable with that of wild-type CORO1A in normal lymphocytes but did not oligomerize and had impaired cytoskeletal association. CORO1A(S401fs) was associated with increased filamentous actin accumulation in T cells, severely defective thymic output, and impaired T-cell survival but normal calcium flux and cytotoxicity, demonstrating the importance of CORO1A oligomerization and subcellular localization in T-cell homeostasis.
CONCLUSIONS: We describe a truncating mutation in CORO1A that permits protein expression and survival into young adulthood. Our studies demonstrate the importance of intact CORO1A C-terminal domains in thymic egress and T-cell survival, as well as in defense against viral pathogens.

PMID: 26476480 [PubMed – as supplied by publisher]

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PID in Disguise: Molecular Diagnosis of IRAK-4 Deficiency in an Adult Previously Misdiagnosed With Autosomal Dominant Hyper IgE Syndrome.

J Clin Immunol. 2015 Oct 15;

Authors: Frans G, Moens L, Schrijvers R, Wuyts G, Bouckaert B, Schaballie H, Dupont L, Bossuyt X, Corveleyn A, Meyts I

Abstract
Autosomal recessive IL-1R-associated kinase 4 (IRAK-4) deficiency is a rare cause of recurrent pyogenic infections with limited inflammatory responses. We describe an adult female patient with severe lung disease who was phenotypically diagnosed as suffering from autosomal dominant Hyper IgE syndrome (AD HIES) because of recurrent skin infections with Staphylococcus aureus, recurrent pneumonia and elevated serum IgE levels. In contrast to findings in AD HIES patients, no abnormalities were found in the Th17 and circulating follicular helper T cell subsets. A panel-based sequencing approach led to the identification of a homozygous IRAK4 stop mutation (c.877C > T, p.Gln293*).

PMID: 26472314 [PubMed – as supplied by publisher]

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Report of the Tunisian Registry of Primary Immunodeficiencies: 25-Years of Experience (1988-2012).

J Clin Immunol. 2015 Oct 13;

Authors: Mellouli F, Mustapha IB, Khaled MB, Besbes H, Ouederni M, Mekki N, Ali MB, Larguèche B, Hachicha M, Sfar T, Gueddiche N, Barsaoui S, Sammoud A, Boussetta K, Becher SB, Meherzi A, Guandoura N, Boughammoura L, Harbi A, Amri F, Bayoudh F, Jaballah NB, Tebib N, Bouaziz A, Mahfoudh A, Aloulou H, Mansour LB, Chabchoub I, Boussoffara R, Chemli J, Bouguila J, Hassayoun S, Hammami S, Habboul Z, Hamzaoui A, Ammar J, Barbouche MR, Bejaoui M

Abstract
PURPOSE: Primary immunodeficiencies (PIDs) are a large group of diseases characterized by susceptibility to not only recurrent infections but also autoimmune diseases and malignancies. The aim of this study was to describe and analyze the distribution, clinical features and eventual outcome of PID among Tunisian patients.
METHODS: We reviewed the record of 710 patients diagnosed with Primary Immunodeficiency Diseases (PIDs) from the registry of the Tunisian Referral Centre for PIDs over a 25-year period.
RESULTS: The male-to-female ratio was 1.4. The median age at the onset of symptoms was 6 months and at the time of diagnosis 2 years. The estimated prevalence was 4.3 per 100,000 populations. The consanguinity rate was found in 58.2 % of families. According to the International Union of Immunological Societies classification, spectrums of PIDs were as follows: combined T-cell and B-cell immunodeficiency disorders account for the most common category (28.6 %), followed by congenital defects of phagocyte (25.4 %), other well-defined immunodeficiency syndromes (22.7 %), predominant antibody deficiency diseases (17.7 %), diseases of immune dysregulation (4.8 %), defect of innate immunity (0.4 %) and complement deficiencies (0.4 %). Recurrent infections, particularly lower airway infections (62.3 %), presented the most common manifestation of PID patients. The overall mortality rate was 34.5 %, mainly observed with combined immunodeficiencies.
CONCLUSION: The distribution of PIDs was different from that reported in Western countries, with a particularly high proportion of Combined Immunodeficiencies and phagocyte defects in number and/or function. More is needed to improve PID diagnosis and treatment in our country.

PMID: 26464197 [PubMed – as supplied by publisher]

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Pathogenesis of Hemophagocytic Lymphohistiocytosis.

Hematol Oncol Clin North Am. 2015 Oct;29(5):895-902

Authors: Filipovich AH, Chandrakasan S

Abstract
Hemophagocytic Lymphohistiocytosis (HLH), an inherited life-threatening inflammatory disorder, has gained growing recognition not only in children but also increasingly in adults over the past 2 decades. HLH involves inborn defects in lymphocytes, which normally mediate control of infectious and inflammatory conditions within the immune system and in other tissues. In the context of inherited defects in cytotoxic cells and other immune cells, the disorder is classified as familial or primary HLH. Secondary HLH occurs in the settings of infections or underlying rheumatologic disorders. Secondary HLH also accompanies some lymphoid malignancies.

PMID: 26461149 [PubMed – in process]

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The Incidence and Prevalence of Common Variable Immunodeficiency Disease in Taiwan, A Population-Based Study.

PLoS One. 2015;10(10):e0140473

Authors: Tseng CW, Lai KL, Chen DY, Lin CH, Chen HH

Abstract
Common variable immunodeficiency (CVID) is one of the primary immunodeficiency diseases that occur in both children and adults. We present here a nationwide, population-based epidemiological study of CVID across all ages in Taiwan during 2002-2011. Using the International Classification of Diseases, Ninth Revision code 279.06, cases of CVID were identified from Taiwan’s National Health Insurance Research Database from January 2002 to December 2011. Age- and sex-specific incidence and prevalence rates were calculated. A total of 47 new cases of CVID during 2002-2011 were identified. Total prevalence rose from 0.13 per 100,000 in 2002 to 0.28 per 100,000 in 2011. The annual incidence rate during 2002-2011 was 0.019 per 100,000. Cases were equally distributed between males and females and males mostly occurred in younger patients. This nationwide population-based study showed that the incidence and prevalence of CVID in Taiwan were lower than that in Western countries.

PMID: 26461272 [PubMed – in process]

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Related Articles

Humoral Primary Immunodeficiencies in Chronic Rhinosinusitis.

Curr Allergy Asthma Rep. 2015 Aug;15(8):46

Authors: Nayan S, Alizadehfar R, Desrosiers M

Abstract
Chronic rhinosinusitis (CRS) may be the primary presenting symptom for primary immunodeficiencies (PID). PID can affect the humoral or the cellular immune system. This paper provides an overview of PID which affect the humoral immune system, with details around the diagnostic criteria, the epidemiology, the subtypes, the clinical manifestations, underlying molecular mechanisms, methods to screen for PID and the management of CRS in the context of PID. A high clinical suspicion of PID is required when assessing patients with CRS who are refractory to maximal medical therapy.

PMID: 26149586 [PubMed – indexed for MEDLINE]

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Genetics of hereditary hematological malignancies.

Rinsho Ketsueki. 2015 Oct;56(10):1969-77

Authors: Takagi M

Abstract
Familial predisposition to hematological malignancies has been recognized. Some of these malignancies are part of a well-characterized familial cancer predisposition syndrome, while others are independent of cancer predisposition, and demonstrate unique familial leukemia/lymphoma syndromes. Primary immunodeficiency is also strongly associated with the development of lymphoid malignancy. Primary immunodeficiency and leukemia/lymphoma are based on the same concept, which involves differentiation blockage. Bone marrow failure syndrome is also known to be associated with susceptibility to hematological malignancy development. Bone marrow failure syndrome exhibiting myeloid differentiation is also characterized as an aspect of primary immunodeficiency. Recent progress in genome wide association studies (GWAS) identified several single nucleotide polymorphisms (SNP) associated with leukemia/lymphoma development. Some of these genes were found to be functionally related to hematological malignancies. These discoveries are contributing to elucidation of the genetic background of leukemia/lymphoma development.

PMID: 26458435 [PubMed – in process]

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Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency.

J Clin Invest. 2015 Oct 12;

Authors: Walter JE, Rosen LB, Csomos K, Rosenberg JM, Mathew D, Keszei M, Ujhazi B, Chen K, Lee YN, Tirosh I, Dobbs K, Al-Herz W, Cowan MJ, Puck J, Bleesing JJ, Grimley MS, Malech H, De Ravin SS, Gennery AR, Abraham RS, Joshi AY, Boyce TG, Butte MJ, Nadeau KC, Balboni I, Sullivan KE, Akhter J, Adeli M, El-Feky RA, El-Ghoneimy DH, Dbaibo G, Wakim R, Azzari C, Palma P, Cancrini C, Capuder K, Condino-Neto A, Costa-Carvalho BT, Oliveira JB, Roifman C, Buchbinder D, Kumanovics A, Franco JL, Niehues T, Schuetz C, Kuijpers T, Yee C, Chou J, Masaad MJ, Geha R, Uzel G, Gelman R, Holland SM, Recher M, Utz PJ, Browne SK, Notarangelo LD

Abstract
Patients with mutations of the recombination-activating genes (RAG) present with diverse clinical phenotypes, including severe combined immune deficiency (SCID), autoimmunity, and inflammation. However, the incidence and extent of immune dysregulation in RAG-dependent immunodeficiency have not been studied in detail. Here, we have demonstrated that patients with hypomorphic RAG mutations, especially those with delayed-onset combined immune deficiency and granulomatous/autoimmune manifestations (CID-G/AI), produce a broad spectrum of autoantibodies. Neutralizing anti-IFN-α or anti-IFN-ω antibodies were present at detectable levels in patients with CID-G/AI who had a history of severe viral infections. As this autoantibody profile is not observed in a wide range of other primary immunodeficiencies, we hypothesized that recurrent or chronic viral infections may precipitate or aggravate immune dysregulation in RAG-deficient hosts. We repeatedly challenged Rag1S723C/S723C mice, which serve as a model of leaky SCID, with agonists of the virus-recognizing receptors TLR3/MDA5, TLR7/-8, and TLR9 and found that this treatment elicits autoantibody production. Altogether, our data demonstrate that immune dysregulation is an integral aspect of RAG-associated immunodeficiency and indicate that environmental triggers may modulate the phenotypic expression of autoimmune manifestations.

PMID: 26457731 [PubMed – as supplied by publisher]

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BCGitis and BCGosis in children with primary immunodeficiency – imaging characteristics.

Pediatr Radiol. 2015 Oct 10;

Authors: Shrot S, Barkai G, Ben-Shlush A, Soudack M

Abstract
BACKGROUND: When administered to an immune-compromised patient, BCG (Bacille Calmette-Guérin) can cause disseminated and life-threatening infections.
OBJECTIVE: To describe the imaging findings in children with primary immunodeficiency and BCG-related infections.
MATERIALS AND METHODS: We reviewed the imaging findings of children with primary immunodeficiency treated at a children’s hospital during 2012-2014 with localized or disseminated BCG infection. Imaging modalities included US, CT and radiography.
RESULTS: Nine children with primary immunodeficiency had clinical signs of post-vaccination BCGitis; seven of these children showed disseminated disease and two showed only regional lesions with characteristic ipsilateral lymphadenopathy. Overall, lymphadenopathy was the most prevalent feature (n = 8) and characteristically appeared as a ring-enhancing hypodense (CT) or hypoechoic (US) lesion. Visceral involvement with multiple abscesses appeared in the spleen (n = 2), liver (n = 1) and bones (n = 1). All lesions regressed following appropriate anti-tuberculosis treatment.
CONCLUSION: BCG infection needs to be considered in children with typical findings and with suspected primary immunodeficiency.

PMID: 26454840 [PubMed – as supplied by publisher]

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