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Altered lymphopoiesis and immunodeficiency in miR-142 null mice.

Blood. 2015 Apr 30;

Authors: Kramer NJ, Wang WL, Reyes EY, Kumar B, Chen CC, Ramakrishna C, Cantin EM, Vonderfecht SL, Taganov KD, Chau N, Boldin MP

Abstract
MicroRNAs (miRNAs) are a class of powerful post-transcriptional regulators implicated in the control of diverse biological processes, including regulation of hematopoiesis and the immune response. To define the biological functions of miR-142, which is preferentially and abundantly expressed in immune cells, we created a mouse line with targeted deletion of this gene. Our analysis of miR-142(-/-) mice revealed a critical role for this miRNA in the development and homeostasis of lymphocytes. Marginal zone B cells expand in the knockout spleen, while the number of T and B1 B cells in the periphery is reduced. Abnormal development of hematopoietic lineages in miR-142(-/-) animals is accompanied by a profound immunodeficiency, manifested by hypoimmunoglobulinemia and failure to mount a productive immune response to soluble antigens and virus. miR-142(-/-) B cells express elevated levels of BAFF receptor (BAFF-R) and as a result proliferate more robustly in response to BAFF stimulation. Lowering the BAFF-R gene dose in miR-142(-/-) mice rescues the B cell expansion defect, suggesting that BAFF-R is a bona fide miR-142 target through which it controls B cell homeostasis. Collectively, our results uncover miR-142 as an essential regulator of lymphopoiesis and suggest that lesions in this miRNA gene may lead to primary immunodeficiency.

PMID: 25931583 [PubMed – as supplied by publisher]

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Autoimmune lymphoproliferative syndrome-like disease in patients with LRBA mutation.

Clin Immunol. 2015 Apr 27;

Authors: Revel-Vilk S, Fischer U, Keller B, Nabhani S, Gámez-Díaz L, Rensing-Ehl A, Gombert M, Hönscheid A, Saleh H, Shaag A, Borkhardt A, Grimbacher B, Warnatz K, Elpeleg O, Stepensky P

Abstract
Mutations in LPS-responsive and beige-like anchor (LRBA) gene were recently described in patients with combined immunodeficiency, enteropathy and autoimmune cytopenia. Here, we extend the clinical and immunological phenotypic spectrum of LRBA associated disorders by reporting on three patients from two unrelated families who presented with splenomegaly and lymphadenopathy, cytopenia, elevated double negative T cells and raised serum Fas ligand levels resembling autoimmune lymphoproliferative syndrome (ALPS) and one asymptomatic patient. Homozygous loss of function mutations in LRBA were identified by whole exome analysis. Similar to ALPS patients, Fas mediated apoptosis was impaired in LRBA deficient patients, while apoptosis in response to stimuli of the intrinsic mitochondria mediated apoptotic pathway was even enhanced. This manuscript illustrates the phenotypic overlap of other primary immunodeficiencies with ALPS-like disorders and strongly underlines the necessity of genetic diagnosis in order to provide early correct diagnosis and subsequent care.

PMID: 25931386 [PubMed – as supplied by publisher]

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Dysfunctional BLK in common variable immunodeficiency perturbs B-cell proliferation and ability to elicit antigen-specific CD4+ T-cell help.

Oncotarget. 2015 Mar 14;

Authors: Compeer EB, Janssen W, van Royen-Kerkhof A, van Gijn M, van Montfrans JM, Boes M

Abstract
Common Variable Immunodeficiency (CVID) is the most prevalent primary antibody deficiency, and characterized by defective generation of high-affinity antibodies. Patients have therefore increased risk to recurrent infections of the respiratory and intestinal tract. Development of high-affinity antigen-specific antibodies involves two key actions of B-cell receptors (BCR): transmembrane signaling through BCR-complexes to induce B-cell differentiation and proliferation, and BCR-mediated antigen internalization for class-II MHC-mediated presentation to acquire antigen-specific CD4+ T-cell help.We identified a variant (L3P) in the B-lymphoid tyrosine kinase (BLK) gene of 2 related CVID-patients, which was absent in healthy relatives. BLK belongs to the Src-kinases family and involved in BCR-signaling. Here, we sought to clarify BLK function in healthy human B-cells and its association to CVID.BLK expression was comparable in patient and healthy B-cells. Functional analysis of L3P-BLK showed reduced BCR crosslinking-induced Syk phosphorylation and proliferation, in both primary B-cells and B-LCLs. B-cells expressing L3P-BLK showed accelerated destruction of BCR-internalized antigen and reduced ability to elicit CD40L-expression on antigen-specific CD4+ T-cells.In conclusion, we found a novel BLK gene variant in CVID-patients that causes suppressed B-cell proliferation and reduced ability of B-cells to elicit antigen-specific CD4+ T-cell responses. Both these mechanisms may contribute to hypogammaglobulinemia in CVID-patients.

PMID: 25926555 [PubMed – as supplied by publisher]

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Human mutations in methylenetetrahydrofolate dehydrogenase 1 impair nuclear de novo thymidylate biosynthesis.

Proc Natl Acad Sci U S A. 2015 Jan 13;112(2):400-5

Authors: Field MS, Kamynina E, Watkins D, Rosenblatt DS, Stover PJ

Abstract
An inborn error of metabolism associated with mutations in the human methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) gene has been identified. The proband presented with SCID, megaloblastic anemia, and neurologic abnormalities, but the causal metabolic impairment is unknown. SCID has been associated with impaired purine nucleotide metabolism, whereas megaloblastic anemia has been associated with impaired de novo thymidylate (dTMP) biosynthesis. MTHFD1 functions to condense formate with tetrahydrofolate and serves as the primary entry point of single carbons into folate-dependent one-carbon metabolism in the cytosol. In this study, we examined the impact of MTHFD1 loss of function on folate-dependent purine, dTMP, and methionine biosynthesis in fibroblasts from the proband with MTHFD1 deficiency. The flux of formate incorporation into methionine and dTMP was decreased by 90% and 50%, respectively, whereas formate flux through de novo purine biosynthesis was unaffected. Patient fibroblasts exhibited enriched MTHFD1 in the nucleus, elevated uracil in DNA, lower rates of de novo dTMP synthesis, and increased salvage pathway dTMP biosynthesis relative to control fibroblasts. These results provide evidence that impaired nuclear de novo dTMP biosynthesis can lead to both megaloblastic anemia and SCID in MTHFD1 deficiency.

PMID: 25548164 [PubMed – indexed for MEDLINE]

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Curative haploidentical BMT in a murine model of X-linked chronic granulomatous disease.

Int J Hematol. 2015 Apr 29;

Authors: Takeuchi Y, Takeuchi E, Ishida T, Onodera M, Nakauchi H, Otsu M

Abstract
Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder characterized by defective microbial killing in phagocytes. Long-term prognosis for CGD patients is generally poor, highlighting the need to develop minimally toxic, curative therapeutic approaches. We here describe the establishment of a mouse model in which X-linked CGD can be cured by allogeneic bone marrow transplantation. Using a combination of non-myeloablative-dose total body irradiation and a single injection of anti-CD40 ligand monoclonal antibody, transplantation of whole bone marrow cells achieved long-lasting mixed chimerism in X-linked CGD mice in a haploidentical transplantation setting. Stable mixed chimerism was maintained for up to 1 year even at a low range (<20 % donor cells), indicating induction of donor-specific tolerance. The regimen induced mild myelosuppression without severe acute complications. Stable chimerism was therapeutic, as it suppressed cutaneous granuloma formation in an in vivo test suited for evaluation of treatment efficacy in murine CGD models. These results warrant future development of a simplified allogeneic hematopoietic cell transplantation regimen that would benefit CGD patients by allowing the use of haploidentical donor grafts without serious concerns of severe treatment-related toxicity.

PMID: 25921405 [PubMed – as supplied by publisher]

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Strategies for B-cell receptor repertoire analysis in primary immunodeficiencies: from severe combined immunodeficiency to common variable immunodeficiency.

Front Immunol. 2015;6:157

Authors: IJspeert H, Wentink M, van Zessen D, Driessen GJ, Dalm VA, van Hagen MP, Pico-Knijnenburg I, Simons EJ, van Dongen JJ, Stubbs AP, van der Burg M

Abstract
The antigen receptor repertoires of B- and T-cells form the basis of the adaptive immune response. The repertoires should be sufficiently diverse to recognize all possible pathogens. However, careful selection is needed to prevent responses to self or harmless antigens. Limited antigen receptor repertoire diversity leads to immunodeficiency, whereas unselected or misdirected repertoires can result in autoimmunity. The antigen receptor repertoire harbors information about abnormalities in many immunological disorders. Recent developments in next generation sequencing allow the analysis of the antigen receptor repertoire in much greater detail than ever before. Analyzing the antigen receptor repertoire in patients with mutations in genes responsible for the generation of the antigen receptor repertoire will give new insights into repertoire formation and selection. In this perspective, we describe strategies and considerations for analysis of the naive and antigen-selected B-cell repertoires in primary immunodeficiency patients with a focus on severe combined immunodeficiency and common variable immunodeficiency.

PMID: 25904919 [PubMed]

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Protein microarrays: a new tool for the study of autoantibodies in immunodeficiency.

Front Immunol. 2015;6:138

Authors: Rosenberg JM, Utz PJ

Abstract
Autoimmunity is highly coincident with immunodeficiency. In a small but growing number of primary immunodeficiencies, autoantibodies are diagnostic of a given disease and implicated in disease pathogenesis. In order to improve our understanding of the role of autoantibodies in immunodeficiencies and to discover novel autoantibodies, new proteomic tools are needed. Protein microarrays have the ability to screen for reactivity to hundreds to many thousands of unique autoantigens simultaneously on a single chip using minimal serum input. Here, we review different types of protein microarrays and how they can be useful in framing the study of primary and secondary immunodeficiencies.

PMID: 25904912 [PubMed]

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Mast cell interleukin-1 beta, neutrophil interleukin-17 and epidermal antimicrobial proteins in the neutrophilic urticarial dermatosis in Schnitzler’s syndrome.

Br J Dermatol. 2015 Apr 22;

Authors: de Koning HD, van Vlijmen-Willems IM, Rodijk-Olthuis D, van der Meer JW, Zeeuwen PL, Simon A, Schalkwijk J

Abstract
BACKGROUND: Schnitzler’s syndrome (SchS) is an autoinflammatory disease characterized by a chronic urticarial rash, a monoclonal component, and signs of systemic inflammation. Interleukin-1 beta (IL-1β) is pivotal in the pathophysiology.
OBJECTIVES: Here we investigated the cellular source of pro-inflammatory mediators in skin of SchS patients.
METHODS: Skin biopsies of lesional and non-lesional skin from eight SchS patients and healthy controls, cryopyrin-associated periodic syndrome (CAPS), delayed-pressure urticaria (DPU) and cold contact urticaria (CCU) patients were used. We studied in vivo IL-1β, IL-17 and antimicrobial protein (AMP) expression in resident skin cells and infiltrating cells. In addition we investigated the in vitro effect of IL-1β, IL-17 and poly:IC stimulation on cultured epidermal keratinocytes.
RESULTS: Remarkably, we found IL-1β-positive dermal mast cells both in lesional and non-lesional skin of SchS patients, but not in normal control skin, CCU, and fewer in CAPS. IL-17-positive neutrophils were only observed in lesional SchS and DPU skin. In lesional SchS epidermis, mRNA and protein expression levels of AMPs were strongly increased compared to non-lesional skin and that of healthy controls. When exposed to IL-1β, poly:IC, or IL-17, patient and control primary human keratinocytes produced AMPs in similar amounts.
CONCLUSIONS: To conclude, dermal mast cells of SchS patients produce IL-1β. This presumably leads to activation of keratinocytes and neutrophil influx, and further amplification of inflammation by IL-17 (from neutrophils and mast cells) and epidermal AMP production leading to chronic histamine-independent neutrophilic urticarial dermatosis. This article is protected by copyright. All rights reserved.

PMID: 25904179 [PubMed – as supplied by publisher]

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Single-cell mass cytometry of TCR signaling: amplification of small initial differences results in low ERK activation in NOD mice.

Proc Natl Acad Sci U S A. 2014 Nov 18;111(46):16466-71

Authors: Mingueneau M, Krishnaswamy S, Spitzer MH, Bendall SC, Stone EL, Hedrick SM, Pe’er D, Mathis D, Nolan GP, Benoist C

Abstract
Signaling from the T-cell receptor (TCR) conditions T-cell differentiation and activation, requiring exquisite sensitivity and discrimination. Using mass cytometry, a high-dimensional technique that can probe multiple signaling nodes at the single-cell level, we interrogate TCR signaling dynamics in control C57BL/6 and autoimmunity-prone nonobese diabetic (NOD) mice, which show ineffective ERK activation after TCR triggering. By quantitating signals at multiple steps along the signaling cascade and parsing the phosphorylation level of each node as a function of its predecessors, we show that a small impairment in initial pCD3ζ activation resonates farther down the signaling cascade and results in larger defects in activation of the ERK1/2-S6 and IκBα modules. This nonlinear property of TCR signaling networks, which magnifies small initial differences during signal propagation, also applies in cells from B6 mice activated at different levels of intensity. Impairment in pCD3ζ and pSLP76 is not a feedback consequence of a primary deficiency in ERK activation because no proximal signaling defect was observed in Erk2 KO T cells. These defects, which were manifest at all stages of T-cell differentiation from early thymic pre-T cells to memory T cells, may condition the imbalanced immunoregulation and tolerance in NOD T cells. More generally, this amplification of small initial differences in signal intensity may explain how T cells discriminate between closely related ligands and adopt strongly delineated cell fates.

PMID: 25362052 [PubMed – indexed for MEDLINE]

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Successful hematopoietic cell transplantation in a patient with X-linked agammaglobulinemia and acute myeloid leukemia.

Pediatr Blood Cancer. 2015 Apr 20;

Authors: Abu-Arja RF, Chernin LR, Abusin G, Auletta J, Cabral L, Egler R, Ochs HD, Torgerson TR, Lopez-Guisa J, Hostoffer RW, Tcheurekdjian H, Cooke KR

Abstract
X-linked agammaglobulinemia (XLA) is a primary immunodeficiency characterized by marked reduction in all classes of serum immunoglobulins and the near absence of mature CD19(+) B-cells. Although malignancy has been observed in patients with XLA, we present the first reported case of acute myeloid leukemia (AML) in a patient with XLA. We also demonstrate the complete correction of the XLA phenotype following allogeneic hematopoietic cell transplantation for treatment of the patient’s leukemia. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc.

PMID: 25900577 [PubMed – as supplied by publisher]

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