Manish Butte

Eosinophilic colitis in a boy with a novel XIAP mutation: a case report.

BMC Pediatr. 2020 Apr 18;20(1):171

Authors: Tang J, Zhou X, Wang L, Hu G, Zheng B, Wang C, Lu Y, Jin Y, Guo H, Liu Z

Abstract
BACKGROUND: X-linked inhibitor of apoptosis (XIAP) deficiency is a rare primary immunodeficiency disease characterized by haemophagocytic lymphohistiocytosis, recurrent splenomegaly and inflammatory bowel disease (IBD). The only curative treatment is haematopoietic stem cell transplant (HSCT).
CASE PRESENTATION: Here, we report the case of a 22-month-old male with a long history of abdominal distension and anaemia. Clinical and laboratory findings were consistent with eosinophilic colitis. To identify the underlying disease, we performed exome sequencing, which showed an unreported frameshift mutation in the XIAP gene.
CONCLUSION: We present eosinophilic colitis as the initial manifestation of XIAP deficiency for the first time in this article, which expands the mutation spectrum and phenotype of this disease.

PMID: 32305064 [PubMed – as supplied by publisher]

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CNS lymphoma, the Irish experience: A retrospective review of neuropathologically confirmed cases over 10 years.

Clin Neuropathol. 2020 Apr 17;:

Authors: O’Connell K, Looby S, Gou P, Flavin R, Farrell M, Cryan JB, Beausang A, Brett FM

Abstract
BACKGROUND: Central nervous system (CNS) lymphoma is rare, representing 2% of all brain tumors. The commonest subtype is diffuse large B-cell lymphoma (DLBCL), with primary T-cell lymphomas (PCNSTL) accounting for ~ 2%.
OBJECTIVE: To determine the frequency and describe the key features of CNS lymphoma over a 10-year period in an Irish population.
MATERIALS AND METHODS: This retrospective review was carried out using the neuropathology database in Beaumont hospital, the largest of two national neurosurgical centers, to identify all cases of CNS lymphoma from 2007 to 2017. Clinical, radiological, morphological, immunophenotype, and molecular information was recorded where available.
RESULTS: We identified 149 cases of CNS lymphoma from 2007 to 2017, which equated to a cumulative incidence rate of 0.4/100,000 persons. Median age at diagnosis was 66 years, and 46% were male. 86% were classified as DLBCL (n = 128), 10% immunodeficiency-associated CNS lymphoma (n = 15), 3% PCNSTL (n = 4), and 1% (n = 2) cases of intravascular large B-cell lymphoma. Location in declining frequency was as follows: supratentorial (n = 125), infratentorial (n = 22), spinal (n = 1), and orbital (n = 1).
CONCLUSION: This is the first study in an Irish population to determine a cumulative incidence rate of CNS lymphoma, which is in line with larger international population-based registries. No significant trends in incidence rate have been observed from 2007 to 2017. DLBCL is the commonest subtype encountered. Rare variants including PCNSTL can pose a significant diagnostic challenge, and in this setting, molecular studies can be useful to confirm diagnoses.
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PMID: 32301694 [PubMed – as supplied by publisher]

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Clinical and immunological features of 44 common variable immunodeficiency patients: The experience of a single center in Turkey.

Allergol Immunopathol (Madr). 2020 Apr 13;:

Authors: Nepesov S, Aygun FD, Firtina S, Cokugras H, Camcioglu Y

Abstract
INTRODUCTION AND OBJECTIVES: Common variable immunodeficiency (CVID) is one of the most prevalent forms of primary immunodeficiency characterized by hypogammaglobinemia. Its heterogeneous clinical features include recurrent respiratory tract infections and other complications such as gastrointestinal, autoimmunity, and lymphoproliferative disorders. The aim of this article is to evaluate the general characteristics of CVID patients.
MATERIALS AND METHODS: Clinical and immunological features of 44 CVID patients were evaluated retrospectively with long-term follow-up. Patients who participated in the study were diagnosed according to the criteria of the European Society for Immunodeficiency Diseases (ESID).
RESULTS: The median age at onset of symptoms was 2.75 years (range six months to 17 years), and the median age at diagnosis was 7.75 years (range 4-20 years). The average delay in diagnosis was 4.6 years (range 1-14 years). Positive family history was 18.2%. Before treatment, patients’ median total serum IgG was 271.5mg/dL, median IgA was 7.5mg/dL, and median IgM was 21mg/dL. Infections were the most common clinical manifestation, and 63.6% of patients presented with sinopulmonary infection as the first manifestation. Bronchiectasis developed in 23 CVID subjects, while bronchiectasis was detected prior to CVID diagnosis in eight patients. All patients received immunoglobulin replacement therapy, and one patient died because of granulomatous lymphocytic interstitial lung disease (GLILD).
CONCLUSIONS: CVID is a heterogeneous group of immunologic disorders with unknown etiology. There are significant differences in the clinical presentation and prevalence of CVID-related complications among countries. Local guidelines for diagnosis and clinical follow-up are needed.

PMID: 32299645 [PubMed – as supplied by publisher]

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APRIL-dependent life-long plasmacyte maintenance and immunoglobulin production in humans.

J Allergy Clin Immunol. 2020 Apr 13;:

Authors: Yeh TW, Okano T, Naruto T, Yamashita M, Okamura M, Tanita K, Du L, Pan-Hammarström Q, Mitsuiki N, Okada S, Kanegane H, Imai K, Morio T

Abstract
BACKGROUND: Interactions between TNF ligand superfamily and TNF receptor superfamily play critical roles in B cell development and maturation. A proliferation-inducing ligand (APRIL), a member of the TNF ligand superfamily, is secreted from myeloid cells and known to induce the differentiation of memory B cells to plasmacytes.
OBJECTIVE: To elucidate the role of APRIL in B cell differentiation and immunoglobulin production through the analysis of complete APRIL deficiency in human.
METHODS: We performed whole exome sequencing (WES) in an adult common variable immunodeficiency patient. His parents were in a consanguineous marriage. TNFSF13 mRNA and protein expression were analyzed in the primary cells and plasma from the patient and in cDNA-transfected cells and supernatants of the cultures in vitro. Immunological analysis was performed using flow cytometry and next generation sequencing. Monocyte-derived dendritic cells differentiated from induced pluripotent stem cells (iPS-moDCs) were co-cultured with memory B cells from healthy controls to examine in vitro plasmacyte differentiation.
RESULTS: We identified a homozygous frameshift mutation in TNFSF13, the gene encoding APRIL, in the patient. APRIL mRNA and protein were completely absent in the monocytes and iPS-moDCs of the patient. In contrast to previous animal model studies, the patient showed hypogammaglobulinemia with markedly reduced plasmacytes in peripheral blood and clearly increased circulating marginal zone B cells. Although iPS-moDC-induced in vitro plasmacyte differentiation was reduced in the patient, recombinant APRIL supplementation corrected this abnormality.
CONCLUSION: The first APRIL deficiency in an adult common variable immunodeficiency patient revealed the role of APRIL in life-long maintenance of plasmacytes and immunoglobulin production in humans.

PMID: 32298700 [PubMed – as supplied by publisher]

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Multiplexed Proteomic Analysis for Diagnosis and Screening of Five Primary Immunodeficiency Disorders From Dried Blood Spots.

Front Immunol. 2020;11:464

Authors: Collins CJ, Yi F, Dayuha R, Whiteaker JR, Ochs HD, Freeman A, Su HC, Paulovich AG, Segundo GRS, Torgerson T, Hahn SH

Abstract
Early detection of Primary Immunodeficiencies Disorders (PIDDs) is of paramount importance for effective treatment and disease management. Many PIDDs would be strong candidates for newborn screening (NBS) if robust screening methods could identify patients from dried blood spots (DBS) during the neonatal period. As majority of congenital PIDDs result in the reduction or absence of specific proteins, direct quantification of these target proteins represents an attractive potential screening tool. Unfortunately, detection is often limited by the extremely low protein concentrations in blood cells and limited blood volume present in DBS. We have recently developed a robust novel method for quantification of low abundance proteins in DBS for PIDDs using peptide immunoaffinity enrichment coupled to selected reaction monitoring (immuno-SRM). Here, we further generated a multiplexed Immuno-SRM panel for simultaneous screening of eight signature peptides representing five PIDD-specific and two cell-type specific proteins from DBS. In samples from 28 PIDD patients including two carriers, representing X-Linked Agammaglobulinemia (XLA), Wiskott-Aldrich Syndrome (WAS), X-Linked Chronic Granulomatous Disease (XL-CGD), DOCK8 Deficiency and ADA deficiency, peptides representing each disease are significantly reduced relative to normal controls and patient identification had excellent agreement with clinical and molecular diagnosis. Also included in the multiplex panel are cell specific markers for platelets (CD42) and Natural Killer Cells (CD56). In patients with WAS, CD42 levels were found to be significantly reduced consistent with characteristic thrombocytopenia. A patient with WAS analyzed before and after bone marrow transplant showed normalized WAS protein and platelet CD42 after treatment highlighting the ability of immuno-SRM to monitor the effects of PIDD treatment. The assay was readily reproduced in two separate laboratories with similar analytical performance and complete agreement in patient diagnosis demonstrating the effective standardized methods. A high-throughput Immuno-SRM method screens PIDD-specific peptides in a 2.5-min runtime meeting high volume NBS workflow requirements was also demonstrated in this report. This high-throughput method returned identical results to the standard Immuno-SRM PIDD panel. Immuno-SRM peptide analysis represents a robust potential clinical diagnostic for identifying and studying PIDD patients from easily collected and shipped DBS and supports a significant potential for early PIDD diagnosis through newborn screening.

PMID: 32296420 [PubMed – in process]

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Serum Free Light Chains in Common Variable Immunodeficiency Disorders: Role in Differential Diagnosis and Association With Clinical Phenotype.

Front Immunol. 2020;11:319

Authors: Scarpa R, Pulvirenti F, Pecoraro A, Vultaggio A, Marasco C, Ria R, Altinier S, Compagno N, Firinu D, Plebani M, De Carli M, Matucci A, Vianello F, Vacca A, Spadaro G, Quinti I, Agostini C, Milito C, Cinetto F

Abstract
We report on an observational, multicenter study of 345 adult CVID patients, designed to assess the diagnostic value and the clinical association of serum free light chain (sFLC) pattern in Common Variable Immunodeficiency disorders (CVID). Sixty CVID patients were tested twice in order to assess intraindividual variability of sFLC. As control groups we included 138 patients affected by undefined primary antibody defects (UAD), lymphoproliferative diseases (LPDs), and secondary antibody deficiencies not related to hematological malignancies (SID). CVID patients presented lower κ and λ chain concentration compared to controls, showing low intraindividual sFLC variability. On the basis of the sFLC pattern, patients were classified into four groups: κ-λ+, κ+λ-, κ-λ-, κ+λ+. The most common pattern in CVID patients was κ-λ- (51%), followed by κ-λ+, (25%), κ+λ+ (22%), and κ+λ- (3%). In UAD, LPD, and SID groups κ+λ+ was the most common pattern observed. By analyzing the possible association between sFLC patterns and disease-related complications of CVID, we observed that patients belonging to the κ-λ- group presented more commonly unexplained enteropathy compared to the κ+λ+ group and showed higher frequency of bronchiectasis and splenomegaly compared to both the κ-λ+ and κ+λ+ patients. When compared to the other groups, κ-λ- had also lower serum IgG, IgA, and IgM concentrations at diagnosis, lower frequency of CD27+IgD-IgM- switched memory B cells, and higher frequency of CD21low B cells, receiving earlier CVID diagnosis. Thus, lower levels of sFLC might be an epiphenomenon of impairment in B cell differentiation, possibly leading κ-λ- patients to a higher risk for bacterial infections and chronic lung damage. Based on these results, we suggest adding sFLC assay to the diagnostic work-up of hypogammaglobulinemia and during follow-up. The assay may be useful to differentiate CVID from other causes of hypogammaglobulinemia and to early detect monoclonal lymphoproliferation occurring over years. Moreover, since the sFLC pattern seems to be related to disease phenotypes and clinical manifestations of CVID and after confirmation by further studies, sFLC assay might be considered a promising prognostic tool for identifying patients at higher risk of developing enteropathy and chronic lung damage or splenomegaly. This will allow designing a tailored follow-up for CVID patients.

PMID: 32296413 [PubMed – in process]

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