Research

The 2015 IUIS Phenotypic Classification for Primary Immunodeficiencies.

J Clin Immunol. 2015 Oct 7;

Authors: Bousfiha A, Jeddane L, Al-Herz W, Ailal F, Casanova JL, Chatila T, Conley ME, Cunningham-Rundles C, Etzioni A, Franco JL, Gaspar HB, Holland SM, Klein C, Nonoyama S, Ochs HD, Oksenhendler E, Picard C, Puck JM, Sullivan KE, Tang ML

Abstract
There are now nearly 300 single-gene inborn errors of immunity underlying phenotypes as diverse as infection, malignancy, allergy, auto-immunity, and auto-inflammation. For each of these five categories, a growing variety of phenotypes are ascribed to Primary Immunodeficiency Diseases (PID), making PIDs a rapidly expanding field of medicine. The International Union of Immunological Societies (IUIS) PID expert committee (EC) has published every other year a classification of these disorders into tables, defined by shared pathogenesis and/or clinical consequences. In 2013, the IUIS committee also proposed a more user-friendly, phenotypic classification, based on the selection of key phenotypes at the bedside. We herein propose the revised figures, based on the accompanying 2015 IUIS PID EC classification.

PMID: 26445875 [PubMed – as supplied by publisher]

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Age-Dependent Defects of Regulatory B Cells in Wiskott-Aldrich Syndrome Gene Knockout Mice.

PLoS One. 2015;10(10):e0139729

Authors: Yokoyama T, Yoshizaki A, Simon KL, Kirby MR, Anderson SM, Candotti F

Abstract
The Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency characterized by recurrent infections, thrombocytopenia, eczema, and high incidence of malignancy and autoimmunity. The cellular mechanisms underlying autoimmune complications in WAS have been extensively studied; however, they remain incompletely defined. We investigated the characteristics of IL-10-producing CD19+CD1dhighCD5+ B cells (CD1dhighCD5+ Breg) obtained from Was gene knockout (WKO) mice and found that their numbers were significantly lower in these mice compared to wild type (WT) controls. Moreover, we found a significant age-dependent reduction of the percentage of IL-10-expressing cells in WKO CD1dhighCD5+ Breg cells as compared to age-matched WT control mice. CD1dhighCD5+ Breg cells from older WKO mice did not suppress the in vitro production of inflammatory cytokines from activated CD4+ T cells. Interestingly, CD1dhighCD5+ Breg cells from older WKO mice displayed a basal activated phenotype which may prevent normal cellular responses, among which is the expression of IL-10. These defects may contribute to the susceptibility to autoimmunity with age in patients with WAS.

PMID: 26448644 [PubMed – as supplied by publisher]

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Activating PI3Kδ mutations in a cohort of 669 patients with primary immunodeficiency.

Clin Exp Immunol. 2015 Oct 6;

Authors: Elgizouli M, Lowe DM, Speckmann C, Schubert D, Hülsdünker J, Eskandarian Z, Dudek A, Schmitt-Graeff A, Wanders J, Jørgensen SF, Fevang B, Salzer U, Nieters A, Burns S, Grimbacher B

Abstract
The gene PIK3CD codes for the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ) and is expressed solely in leukocytes. Activating mutations of PIK3CD have been described to cause an autosomal dominant immunodeficiency that shares clinical features with common variable immunodeficiency (CVID). We screened a cohort of 669 molecularly undefined primary immunodeficiency patients for five reported mutations (four gain of function mutations in PIK3CD and a loss of function mutation in PIK3R1) using pyrosequencing. PIK3CD mutations were identified in three siblings diagnosed with CVID and two sporadic cases with a combined immunodeficiency (CID). The PIK3R1 mutation was not identified in the cohort. Our patients with activated PI3Kδ syndrome (APDS) showed a range of clinical and immunological findings, even within a single family, but shared a reduction in naïve T cells. PIK3CD gain of function mutations are more likely to occur in patients with defective B and T cell responses and should be screened for in CVID and CID but are less likely in patients with a pure B cell/hypogammaglobulinaemia phenotype. This article is protected by copyright. All rights reserved.

PMID: 26437962 [PubMed – as supplied by publisher]

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Highlighting the problematic reliance on CD18 for diagnosing leukocyte adhesion deficiency type 1.

Immunol Res. 2015 Oct 5;

Authors: Levy-Mendelovich S, Rechavi E, Abuzaitoun O, Vernitsky H, Simon AJ, Lev A, Somech R

Abstract
Leukocyte adhesion deficiency type 1 (LAD-1) is an autosomal recessive primary immunodeficiency, hallmarked by defective polymorphonuclear transmigration. It is caused by mutations in the gene encoding CD18, which interfere with the CD18/CD11 heterodimerization and expression on leukocyte cell surface. LAD-1 diagnosis rests primarily on the measurement of CD18 expression. However, CD18 measurement entails its pitfalls. Here we present a cohort of ten LAD patients and a review of the relevant literature illustrating the difficulties in sole reliance on CD18 measurement for initial diagnosis. These include normal range expression in some mutations, great variability between patients with the same mutation and subjective interpretation of results. We think there is a need for additional markers as part of the initial LAD diagnostic algorithm. We suggest CD11a expression, which was near absent in all patients in our cohort. The dual use of CD18 and CD11a can increase testing sensitivity and prevent delayed diagnosis of LAD-1.

PMID: 26434744 [PubMed – as supplied by publisher]

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Diagnosis and Management of Cutaneous B-cell Lymphoma.

Dermatol Clin. 2015 Oct;33(4):835-840

Authors: Pinter-Brown LC

Abstract
The diagnosis of primary cutaneous B-cell lymphoma (CBCL) requires that the search for a more widespread lymphoma has been negative. The clinical presentation, outlook, and treatment options of the common types of CBCLs, with emphasis on differences or similarities to their nodal counterparts, are discussed. Treatment may range from observation to topical therapies to systemic therapies, depending on the histology, degree and area of skin involvement, patient performance, and comorbidities. Rare lymphomas, such as intravascular large B-cell lymphoma and Epstein-Barr virus-positive cutaneous lymphoproliferations that are associated with immunodeficiency, are also briefly described.

PMID: 26433853 [PubMed – as supplied by publisher]

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Good syndrome presenting with CD8+ T-Cell large granular lymphocyte leukemia.

Oncotarget. 2015 Sep 29;

Authors: Caperton C, Agrawal S, Gupta S

Abstract
Good Syndrome is an adult-onset combined immunodeficiency defined by hypogammaglobulinemia, low or absent number of B cells, T cell deficiency and thymic tumor. We have characterized CD8+ T cells from a patient with Good syndrome that presented with CD8+T-cell large granular lymphocytic leukemia (LGL). Characterization of peripheral blood CD8+ T cells revealed that majority of CD8+ T cells were terminally differentiated effector memory phenotype (TEMRA; CD8+CCR7-CD45RA+), and were PD-1high (CD279), ICOSlow (CD278), and granzymehigh. Almost all CD8+ T cells were IFN-γ+. CD8 Treg (CD8+CD183+CCR7+CD45RA-) were decreased. TEMRA phenotype along with CD279high, demonstrates that these are exhausted CD8+ T cells. This phenotype along with CD278low may also explain severe T cell functional deficiency in our patient. In the present patient, T-LGL appears to be a clonal expansion of CD279+granzyme+IFN-γ+CD8+TEMRA cells. To best of our knowledge this is the first case of CD8+T-cell LGL leukemia associated with Good syndrome.

PMID: 26429871 [PubMed – as supplied by publisher]

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The Prevalence of Selective Immunoglobulin M Deficiency (SIgMD) in Iranian Volunteer Blood Donors.

Hum Immunol. 2015 Sep 28;

Authors: Entezari N, Adab Z, Zeydi M, Saghafi S, Jamali M, Kardar GA, Pourpak Z

Abstract
BACKGROUND: Selective Immunoglobulin M Deficiency (SIgMD) is known as a rare primary immunodeficiency characterized by an isolated deficiency of serum IgM. Other immunoglobulin levels and T-cell immunity are usually normal; although IgE may be elevated. SIgMD can be asymptomatic or with various bacterial and viral infections. It can also be associated with autoimmune diseases or malignancies. In the present study, we report for the first time, the prevalence of SIgMD in Iranian healthy adult population.
MATERIALS AND METHODS: A total of 3436 healthy donors were examined in the study; from August, 2006 to April, 2008. Serum IgM concentration was measured using the nephelometric method. Due to the normal range of serum IgM in Iranian adults (39-283mg/dl), we considered serum IgM less than 30 mg/dl as IgM deficiency.
RESULTS: Among 3436 participants, 65% were male and 34% were female; aging from 17 to 72 years (38.18±10.78). Thirteen individuals were detected as IgM deficient subjects with the male to female ratio of 11/2, the prevalence of 0.37% and the frequency of 1/265. The mean serum IgM level was 24±4.56 (16-29mg/dl) in these cases. Among 13 IgM-deficient subjects, 7 cases were available for evaluating the clinical manifestations. In addition to atopic dermatitis which was the most common symptom in these patients, others were allergic rhinitis, food allergy, urinary tract infection and skin fungal infection. Two patients had no history of infectious disease or atopic conditions.
CONCLUSION: In the present study we could determine the prevalence of SIgMD in our adult population (0.37%). The most common comorbid condition was atopy. Neither severe or life-threatening infections, nor autoimmune diseases (based on their history but we didn’t screened autoantibodies ourselves) or malignancies were found in these patients. Further evaluation is recommended to elucidate the prevalence of SIgMD among patients with recurrent infections.

PMID: 26429316 [PubMed – as supplied by publisher]

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Granulomatous-lymphocytic interstitial lung disease and recurrent sinopulmonary infections in a patient with Good’s syndrome.

BMJ Case Rep. 2015;2015

Authors: Jensen ML, Bendstrup E, Hilberg O

Abstract
Good’s syndrome is a rare primary immunodeficiency associated with adult thymoma. Complications are mainly autoimmune manifestations and recurrent infections with encapsulated bacteria. Only one possible case of combined granulomatous-lymphocytic interstitial lung disease (GL-ILD) and Good’s syndrome have been described earlier, but the patient died at the time of diagnosis. This is the first case of GL-ILD in Good’s syndrome with a successful outcome. We present a case of a 43-year-old man with GL-ILD, who suffered from recurrent infections of Haemophilus influenzae and Pneumocystis jirovecii, with 8-year follow-up. After a thymectomy, he was diagnosed with Good’s syndrome and GL-ILD. He was treated with prophylactic pivampicillin, quinolones and cephalosporins for his recurrent P. jirovecii and H. influenzae infections, an approach that proved unsuccessful due to resistance, with relapse after cessation. He was stabilised with oral diaminodiphenyl-sulfone for P. jirovecii and colistimethate-sodium inhalations for H. influenzae, which is a new approach to prophylactic treatment.

PMID: 26424818 [PubMed – in process]

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Primary Immunodeficiencies Associated with EBV Disease.

Curr Top Microbiol Immunol. 2015;390:241-65

Authors: Cohen JI

Abstract
Epstein-Barr virus (EBV) infects nearly all humans and usually is asymptomatic, or in the case of adolescents and young adults, it can result in infectious mononucleosis. EBV-infected B cells are controlled primarily by NK cells, iNKT cells, CD4 T cells, and CD8 T cells. While mutations in proteins important for B cell function can affect EBV infection of these cells, these mutations do not result in severe EBV infection. Some genetic disorders affecting T and NK cell function result in failure to control EBV infection, but do not result in increased susceptibility to other virus infections. These include mutations in SH2D1A, BIRC4, ITK, CD27, MAGT1, CORO1A, and LRBA. Since EBV is the only virus that induces proliferation of B cells, the study of these diseases has helped to identify proteins critical for interactions of T and/or NK cells with B cells. Mutations in three genes associated with hemophagocytic lymphohistocytosis, PRF1, STXBP2, and UNC13D, can also predispose to severe chronic active EBV disease. Severe EBV infection can be associated with immunodeficiencies that also predispose to other viral infections and in some cases other bacterial and fungal infections. These include diseases due to mutations in PIK3CD, PIK3R1, CTPS1, STK4, GATA2, MCM4, FCGR3A, CARD11, ATM, and WAS. In addition, patients with severe combined immunodeficiency, which can be due to mutations in a number of different genes, are at high risk for various infections as well as EBV B cell lymphomas. Identification of proteins important for control of EBV may help to identify new targets for immunosuppressive therapies.

PMID: 26424649 [PubMed – in process]

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Determinants of the t(14;18) translocation and their role in t(14;18)-positive follicular lymphoma.

Cancer Causes Control. 2015 Sep 30;

Authors: Kelly RS, Roulland S, Morgado E, Sungalee S, Jouve N, Tumino R, Krogh V, Panico S, Polidoro S, Masala G, Sánchez MJ, Chirlaque MD, Sala N, Gurrea AB, Dorronsoro M, Travis RC, Riboli E, Gunter M, Murphy N, Vermeulen R, Bueno-de-Mesquita HB, Peeters PH, Trichopoulou A, Trichopoulos D, Lagiou P, Nieters A, Canzian F, Kaaks R, Boeing H, Weiderpass E, Stocks T, Melin B, Overvad K, Tjønneland A, Olsen A, Brennan P, Johansson M, Nadel B, Vineis P

Abstract
PURPOSE: The strong association between t(14;18) translocation and follicular lymphoma (FL) is well known. However, the determinants of this chromosomal aberration and their role in t(14;18) associated FL remain to be established.
METHODS: t(14;18) frequency within the B cell lymphoma 2 major breakpoint region was determined for 135 incident FL cases and 251 healthy controls as part of a nested case-control study within the European Prospective Investigation into Cancer cohort. Quantitative real-time PCR was performed in DNA extracted from blood samples taken at recruitment. The relationship between prevalence and frequency of the translocation with baseline anthropometric, lifestyle, and dietary factors in cases and controls was determined. Unconditional logistic regression was used to explore whether the risk of FL associated with these factors differed in t(14;18)(+) as compared to t(14;18)(-) cases.
RESULTS: Among incident FL cases, educational level (χ (2) p = 0.021) and height (χ (2) p = 0.025) were positively associated with t(14;18) prevalence, and cases with high frequencies [t(14;18)(HF)] were significantly taller (t test p value = 0.006). These findings were not replicated in the control population, although there were a number of significant associations with dietary variables. Further analyses revealed that height was a significant risk factor for t(14;18)(+) FL [OR 6.31 (95 % CI 2.11, 18.9) in the tallest versus the shortest quartile], but not t(14;18)(-) cases.
CONCLUSIONS: These findings suggest a potential role for lifestyle factors in the prevalence and frequency of the t(14;18) translocation. The observation that the etiology of FL may differ by t(14;18) status, particularly with regard to height, supports the subdivision of FL by translocation status.

PMID: 26424368 [PubMed – as supplied by publisher]

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