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Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies.

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Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies.

J Allergy Clin Immunol. 2015 Jul 7;

Authors: Ma CS, Wong N, Rao G, Avery DT, Torpy J, Hambridge T, Bustamante J, Okada S, Stoddard JL, Deenick EK, Pelham SJ, Payne K, Boisson-Dupuis S, Puel A, Kobayashi M, Arkwright PD, Kilic SS, El Baghdadi J, Nonoyama S, Minegishi Y, Mahdaviani SA, Mansouri D, Bousfiha A, Blincoe AK, French MA, Hsu P, Campbell DE, Stormon MO, Wong M, Adelstein S, Smart JM, Fulcher DA, Cook MC, Phan TG, Stepensky P, Boztug K, Kansu A, İkincioğullari A, Baumann U, Beier R, Roscioli T, Ziegler JB, Gray P, Picard C, Grimbacher B, Warnatz K, Holland SM, Casanova JL, Uzel G, Tangye SG

Abstract
BACKGROUND: Follicular helper T (TFH) cells underpin T cell-dependent humoral immunity and the success of most vaccines. TFH cells also contribute to human immune disorders, such as autoimmunity, immunodeficiency, and malignancy. Understanding the molecular requirements for the generation and function of TFH cells will provide strategies for targeting these cells to modulate their behavior in the setting of these immunologic abnormalities.
OBJECTIVE: We sought to determine the signaling pathways and cellular interactions required for the development and function of TFH cells in human subjects.
METHODS: Human primary immunodeficiencies (PIDs) resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Circulating follicular helper T (cTFH) cell subsets, memory B cells, and serum immunoglobulin levels were quantified and functionally assessed in healthy control subjects, as well as in patients with PIDs resulting from mutations in STAT3, STAT1, TYK2, IL21, IL21R, IL10R, IFNGR1/2, IL12RB1, CD40LG, NEMO, ICOS, or BTK.
RESULTS: Loss-of-function (LOF) mutations in STAT3, IL10R, CD40LG, NEMO, ICOS, or BTK reduced cTFH cell frequencies. STAT3 and IL21/R LOF and STAT1 gain-of-function mutations skewed cTFH cell differentiation toward a phenotype characterized by overexpression of IFN-γ and programmed death 1. IFN-γ inhibited cTFH cell function in vitro and in vivo, as corroborated by hypergammaglobulinemia in patients with IFNGR1/2, STAT1, and IL12RB1 LOF mutations.
CONCLUSION: Specific mutations affect the quantity and quality of cTFH cells, highlighting the need to assess TFH cells in patients by using multiple criteria, including phenotype and function. Furthermore, IFN-γ functions in vivo to restrain TFH cell-induced B-cell differentiation. These findings shed new light on TFH cell biology and the integrated signaling pathways required for their generation, maintenance, and effector function and explain the compromised humoral immunity seen in patients with some PIDs.

PMID: 26162572 [PubMed – as supplied by publisher]

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Current and emerging treatment options for Wiskott-Aldrich syndrome.

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Current and emerging treatment options for Wiskott-Aldrich syndrome.

Expert Rev Clin Immunol. 2015 Jul 9;:1-18

Authors: Worth AJ, Thrasher AJ

Abstract
Wiskott-Aldrich syndrome is a life-threatening primary immunodeficiency associated with a bleeding tendency, eczema and a high incidence of autoimmunity and malignancy. Stem cell transplantation offers the opportunity of cure for all these complications, and over the past 35 years there has been a remarkable improvement in survival following this treatment. Here, we review advances in management of clinical complications pre- and post-transplant, as well as discuss the morbidity Wiskott-Aldrich syndrome patients experience following treatment. For patients with a poorly matched stem cell donor, recent gene therapy trials demonstrate encouraging results and the potential of low-toxicity therapy for all patients.

PMID: 26159751 [PubMed – as supplied by publisher]

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Thrombocytopenia in common variable immunodeficiency patients – clinical course, management, and effect of immunoglobulins.

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Thrombocytopenia in common variable immunodeficiency patients – clinical course, management, and effect of immunoglobulins.

Cent Eur J Immunol. 2015;40(1):83-90

Authors: Pituch-Noworolska A, Siedlar M, Kowalczyk D, Szaflarska A, Błaut-Szlósarczyk A, Zwonarz K

Abstract
Common variable immunodeficiency (CVID) is a primary immunodeficiency of humoral immunity with heterogeneous clinical features. Diagnosis of CVID is based on hypogammaglobulinaemia, low production of specific antibodies, and disorders of cellular immunity. The standard therapy includes replacement of specific antibodies with human immunoglobulin, prophylaxis, and symptomatic therapy of infections. High prevalence of autoimmunity is characteristic for CVID, most commonly: thrombocytopaenia and neutropaenia, celiac disease, and systemic autoimmune diseases. The study included seven children diagnosed with CVID and treated with immunoglobulin substitution from 2 to 12 years. Thrombocytopenia was diagnosed prior to CVID in four children, developed during immunoglobulin substitution in three children. In one boy with CVID and thrombocytopaenia, haemolytic anaemia occurred, so a diagnosis of Evans syndrome was established. Therapy of thrombocytopaenia previous to CVID included steroids and/or immunoglobulins in high dose, and azathioprine. In children with CVID on regular immunoglobulin substitution, episodes of acute thrombocytopaenia were associated with infections and were treated with high doses of immunoglobulins and steroids. In two patients only chronic thrombocytopaenia was noted. Splenectomy was necessary in one patient because of severe course of thrombocytopaenia. The results of the study indicated a supportive role of regular immunoglobulin substitution in patients with CVID and chronic thrombocytopaenia. However, regular substitution of immunoglobulins in CVID patients did not prevent the occurrence of autoimmune thrombocytopaenia episodes or exacerbations of chronic form. In episodes of acute thrombocytopaenia or exacerbations of chronic thrombocytopaenia, infusions of immunoglobulins in high dose are effective, despite previous regular substitution in the replacing dose.

PMID: 26155188 [PubMed]

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In vitro interferon γ improves the oxidative burst activity of neutrophils in patients with chronic granulomatous disease with a subtype of gp91phox deficiency.

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In vitro interferon γ improves the oxidative burst activity of neutrophils in patients with chronic granulomatous disease with a subtype of gp91phox deficiency.

Cent Eur J Immunol. 2015;40(1):54-60

Authors: Filiz S, Uygun DF, Köksoy S, Şahin E, Yeğin O

Abstract
AIM OF THIS STUDY: Chronic granulomatous disease (CGD) is a genetically heterogeneous primary immunodeficiency caused by a defect in phagocyte production of oxygen metabolites, and resulting in infections produced by catalase-positive microorganisms and fungi. Interferon γ (IFN-γ) has a multitude of effects on the immune system. Although preliminary studies with CGD patients on treatment with IFN-γ showed that it enhanced phagocytosis and superoxide production, ongoing studies did not reveal a significant increase of this function. Here we investigated the oxidative capacity of phagocytes in different subtypes of CGD patients on treatment with IFN-γ in vitro.
MATERIAL AND METHODS: Fifty-seven patients with CGD from 14 immunology centres were enrolled to our multi-centre study. Twenty-one patients were studied as controls. Oxidative burst assay with dihydrorhodamine 123 (DHR) was used and the stimulation index (SI) was calculated with respect to CGD subtypes in both neutrophils and monocytes before, and then one and 24 hours after adding IFN-γ.
RESULTS: Upon comparison of the SIs of the patients’ neutrophils before in vitro IFN-γ at hour 0, and after adding IFN-γ at hour 1 and 24 were compared, and the differences were determined between hours 0-24 and hours 1-24. This difference was especially apparent between hours 1-24. In CGD subtypes, particularly in gp91phox subtype, it was seen that, following in vitro IFN-γ, SIs of neutrophils began to increase after hour 1, and that increase became more apparent at hour 24.
CONCLUSIONS: Our study showed that IFN-γ treatment may increase the oxidative bursting activity by increasing the superoxide production in neutrophils, particularly in gp91phox subtype.

PMID: 26155184 [PubMed]

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Leukocyte telomere length in relation to pancreatic cancer risk: a prospective study.

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Leukocyte telomere length in relation to pancreatic cancer risk: a prospective study.

Cancer Epidemiol Biomarkers Prev. 2014 Nov;23(11):2447-54

Authors: Campa D, Mergarten B, De Vivo I, Boutron-Ruault MC, Racine A, Severi G, Nieters A, Katzke VA, Trichopoulou A, Yiannakouris N, Trichopoulos D, Boeing H, Quirós JR, Duell EJ, Molina-Montes E, Huerta JM, Ardanaz E, Dorronsoro M, Khaw KT, Wareham N, Travis RC, Palli D, Pala V, Tumino R, Naccarati A, Panico S, Vineis P, Riboli E, Siddiq A, Bueno-de-Mesquita HB, Peeters PH, Nilsson PM, Sund M, Ye W, Lund E, Jareid M, Weiderpass E, Duarte-Salles T, Kong SY, Stepien M, Canzian F, Kaaks R

Abstract
BACKGROUND: Several studies have examined leukocyte telomere length (LTL) as a possible predictor for cancer at various organ sites. The hypothesis originally motivating many of these studies was that shorter telomeres would be associated with an increase in cancer risk; the results of epidemiologic studies have been inconsistent, however, and suggested positive, negative, or null associations. Two studies have addressed the association of LTL in relation to pancreatic cancer risk and the results are contrasting.
METHODS: We measured LTL in a prospective study of 331 pancreatic cancer cases and 331 controls in the context of the European Prospective Investigation into Cancer and Nutrition (EPIC).
RESULTS: We observed that the mean LTL was higher in cases (0.59 ± 0.20) than in controls (0.57 ± 0.17), although this difference was not statistically significant (P = 0.07), and a basic logistic regression model showed no association of LTL with pancreas cancer risk. When adjusting for levels of HbA1c and C-peptide, however, there was a weakly positive association between longer LTL and pancreatic cancer risk [OR, 1.13; 95% confidence interval (CI), 1.01-1.27]. Additional analyses by cubic spline regression suggested a possible nonlinear relationship between LTL and pancreatic cancer risk (P = 0.022), with a statistically nonsignificant increase in risk at very low LTL, as well as a significant increase at high LTL.
CONCLUSION: Taken together, the results from our study do not support LTL as a uniform and strong predictor of pancreatic cancer.
IMPACT: The results of this article can provide insights into telomere dynamics and highlight the complex relationship between LTL and pancreatic cancer risk.

PMID: 25103821 [PubMed – indexed for MEDLINE]

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[Cell death of salivary gland epithelial cells and involvement of HTLV-I in Sjögren's syndrome].

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[Cell death of salivary gland epithelial cells and involvement of HTLV-I in Sjögren’s syndrome].

Nihon Rinsho Meneki Gakkai Kaishi. 2014;37(3):117-24

Authors: Nakamura H

Abstract
Chronic sialadenitis in Sjögren’s syndrome (SS) is associated with cell death induced by Fas or cytotoxic granules. Furthermore, tumor necrosis factor-related apoptosis inducing ligand or toll-like receptor3 are known to induce apoptosis in the salivary gland epithelial cells (SGECs) derived from patients with SS. Anti-apoptotic molecules that are closely related to epidermal growth factor are known to inhibit apoptosis. Epidemiologically, high prevalence of HTLV-I in primary Sjögren’s syndrome (SS) patients has been found in an endemic area. However, by comparison of radiographic imaging with mononuclear cells (MNCs) infiltration of LSGs, we have found that there are significantly fewer abnormalities determined by sialography in HTLV-I-seropositive SS patients in comparison with HTLV-I-seronegative SS patients irrespective of similar grade of MNCs infiltration. In HTLV-I-seropositive SS patients, low frequency of salivary gland destruction was observed and this phenomenon was associated with frequency of the ectopic germinal center (GC). Then, we show cytokine profile in culture supernatant of salivary gland epithelial cells co-cultured with HCT-5 established from spinal fluid of patients with HAM. Up-regulation of adhesion molecule or migration factor was observed in culture supernatant. On the other hand, co-cultured cell lysate showed apoptotic and anti-apoptotic molecules without increase of apoptosis. Detailed molecular mechanisms in these processes are under study.

PMID: 24974922 [PubMed – indexed for MEDLINE]

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Evaluation of Severe Combined Immunodeficiency and Combined Immunodeficiency Pediatric Patients on the Basis of Cellular Radiosensitivity.

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Evaluation of Severe Combined Immunodeficiency and Combined Immunodeficiency Pediatric Patients on the Basis of Cellular Radiosensitivity.

J Mol Diagn. 2015 Jul 4;

Authors: Lobachevsky P, Woodbine L, Hsiao KC, Choo S, Fraser C, Gray P, Smith J, Best N, Munforte L, Korneeva E, Martin RF, Jeggo PA, Martin OA

Abstract
Pediatric patients with severe or nonsevere combined immunodeficiency have increased susceptibility to severe, life-threatening infections and, without hematopoietic stem cell transplantation, may fail to thrive. A subset of these patients have the radiosensitive (RS) phenotype, which may necessitate conditioning before hematopoietic stem cell transplantation, and this conditioning includes radiomimetic drugs, which may significantly affect treatment response. To provide statistical criteria for classifying cellular response to ionizing radiation as the measure of functional RS screening, we analyzed the repair capacity and survival of ex vivo irradiated primary skin fibroblasts from five dysmorphic and/or developmentally delayed pediatric patients with severe or nonsevere combined immunodeficiency and combined immunodeficiency. We developed a mathematical framework for the analysis of γ histone 2A isoform X foci kinetics to quantitate DNA-repair capacity, thus establishing crucial criteria for identifying RS. The results, presented in a diagram showing each patient as a point in a 2D RS map, were in agreement with findings from the assessment of cellular RS by clonogenic survival and from the genetic analysis of factors involved in the nonhomologous end-joining repair pathway. We provide recommendations for incorporating into clinical practice the functional assays and genetic analysis used for establishing RS status before conditioning. This knowledge would enable the selection of the most appropriate treatment regimen, reducing the risk for severe therapy-related adverse effects.

PMID: 26151233 [PubMed – as supplied by publisher]

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Deletion of WASp and N-WASp in B cells cripples the germinal center response and results in production of IgM autoantibodies.

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Deletion of WASp and N-WASp in B cells cripples the germinal center response and results in production of IgM autoantibodies.

J Autoimmun. 2015 Jul 1;

Authors: Dahlberg CI, Torres ML, Petersen SH, Baptista MA, Keszei M, Volpi S, Grasset EK, Karlsson MC, Walter JE, Snapper SB, Notarangelo LD, Westerberg LS

Abstract
Humoral immunodeficiency caused by mutations in the Wiskott-Aldrich syndrome protein (WASp) is associated with failure to respond to common pathogens and high frequency of autoimmunity. Here we addressed the question how deficiency in WASp and the homologous protein N-WASp skews the immune response towards autoreactivity. Mice devoid of WASp or both WASp and N-WASp in B cells formed germinal center to increased load of apoptotic cells as a source of autoantigens. However, the germinal centers showed abolished polarity and B cells retained longer and proliferated less in the germinal centers. While WASp-deficient mice had high titers of autoreactive IgG, B cells devoid of both WASp and N-WASp produced mainly IgM autoantibodies with broad reactivity to autoantigens. Moreover, B cells lacking both WASp and N-WASp induced somatic hypermutation at reduced frequency. Despite this, IgG1-expressing B cells devoid of WASp and N-WASp acquired a specific high affinity mutation, implying an increased BCR signaling threshold for selection in germinal centers. Our data provides evidence for that N-WASp expression alone drives WASp-deficient B cells towards autoimmunity.

PMID: 26143192 [PubMed – as supplied by publisher]

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Granulomatous and lymphocytic interstitial lung disease: a spectrum of pulmonary histopathologic lesions in common variable immunodeficiency-histologic and immunohistochemical analyses of 16 cases.

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Granulomatous and lymphocytic interstitial lung disease: a spectrum of pulmonary histopathologic lesions in common variable immunodeficiency-histologic and immunohistochemical analyses of 16 cases.

Hum Pathol. 2015 Jun 1;

Authors: Rao N, Mackinnon AC, Routes JM

Abstract
Common variable immunodeficiency is a primary immunodeficiency of unknown etiology characterized by low serum immunoglobulin G, a decreased ability to make specific antibodies, and variable T-cell defects. Approximately 10-30% of patients with common variable immunodeficiency develop clinical evidence of a diffuse parenchymal lung disease with a constellation of histopathologic findings termed granulomatous and lymphocytic interstitial lung disease. In this study, we characterized the histologic and immunohistochemical features in a series of 16 cases diagnosed by open lung biopsy. Peribronchiolar and interstitial lymphocytic infiltration, granulomatous inflammation, and organizing pneumonia were consistent features; interstitial fibrosis with architectural remodeling was also found in a subgroup of patients. By immunohistochemistry, a predominance of CD4+ T lymphocytes with variable numbers of CD8+ T cells and B cells was present, with a striking absence of FOXP3-positive T-regulatory cells. This heretofore unrecognized immunohistochemical finding needs further investigation for a potential role in the pathogenesis of the condition. The presence of interstitial fibrosis with or without architectural remodeling in a subset of patients also needs additional study, for effect on prognosis.

PMID: 26138782 [PubMed – as supplied by publisher]

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