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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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Subcutaneous immunoglobulin in treating inflammatory neuromuscular disorders.

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Subcutaneous immunoglobulin in treating inflammatory neuromuscular disorders.

Ther Adv Neurol Disord. 2015 Jul;8(4):153-159

Authors: Yoon MS, Gold R, Kerasnoudis A

Abstract
OBJECTIVE: Intravenous immunoglobulin administration has long been used in the treatment of autoimmune neuromuscular disorders. Immunoglobulins may be administered by intramuscular, intravenous or subcutaneous routes.
METHODS: This is a report on the long-term clinical follow up of six patients with inflammatory neuromuscular disorders, that is, three chronic inflammatory demyelinating polyneuropathy (CIDP), one multifocal motor neuropathy (MMN), one inclusion body myositis (IBM) and one myasthenia gravis (MG), treated with subcutaneous immunoglobulins for a mean of 3.25 years.
RESULTS: One MMN and two CIDP patients received a weekly dose of subcutaneous immunoglobulins equivalent to intravenous immunoglobulin. One CIDP patient received a 50% dose reduction, the IBM patient received a 30% reduction and the MG patient a 20% reduction. The lower dose chosen in the majority of patients was based not only on clinical effects, but also on studies of primary immunodeficiency syndromes. One patient with CIDP showed clinical fluctuation, which was successfully treated with an adaptation of the dose of subcutaneous immunoglobulins, while the remaining patients with neuromuscular disorders had a stable clinical course for 2 years. No serious side effects were observed.
CONCLUSIONS: Our results suggest that subcutaneous immunoglobulins can be an attractive alternative therapy in autoimmune neuromuscular disorders.

PMID: 26136842 [PubMed – as supplied by publisher]

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Lymphoma-Like Syndrome: 4 Case Reports About Atypical Presentation of Primary Cytomegalovirus Infection in Immunocompetent Children.

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Lymphoma-Like Syndrome: 4 Case Reports About Atypical Presentation of Primary Cytomegalovirus Infection in Immunocompetent Children.

Medicine (Baltimore). 2015 Jul;94(26):e855

Authors: Vigué MG, Tuaillon E, Makinson A, Bullen GM, Foulongne V, Segondy M, Perre PV, Jeziorski E

Abstract
In immunocompetent persons, primary cytomegalovirus (CMV) infection is self-limited infection. Lymphoma-like syndromes have been sometimes described in adults but have not been described for children.Lymphoma-like syndromes (protracted fever, alteration of the general status, and clinical lymphoproliferative syndrome) were retrospectively recorded in children attending our hospital from 1999 to 2008 for primary CMV infection. Patients with immunodeficiency, coinfection (Epstein-Barr virus, toxoplasmosis, or mycobacterial), or biological criteria of mononucleosis-like syndrome were excluded.We report 4 cases of lymphoma-like syndrome. The median duration of fever was 21.5 days (range 15-27). Tonsillitis and hepatitis are most of the time missing. A probable malignant diagnosis was raised in 3 cases. Clinical outcome was protracted (15-35 days) but favorable.To our knowledge, our study is the first pediatric case series of lymphoma-like syndrome. This clinical presentation is a source of delayed diagnosis due to diagnosis pitfall.

PMID: 26131836 [PubMed – as supplied by publisher]

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Mutation analyses and prenatal diagnosis in families of X-linked severe combined immunodeficiency caused by IL2Rγ gene novel mutation.

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Mutation analyses and prenatal diagnosis in families of X-linked severe combined immunodeficiency caused by IL2Rγ gene novel mutation.

Genet Mol Res. 2015;14(2):6164-6172

Authors: Bai QL, Liu N, Kong XD, Xu XJ, Zhao ZH

Abstract
We investigated the feasibility of interleukin-2 recep-tor gamma (IL2Rγ) gene based on gene mutation analysis and pre-natal diagnosis of X-linked severe combined immunodeficiency (X-SCID). Blood samples of patients and their parents of X-SCID (family 1) and X-SCID (family 2) were collected. IL2Rγ gene sequences of the 2 families were analyzed using bi-directional direct sequencing by polymerase chain reaction. DNA sequence changes in the IL2Rγ gene exon region and shear zone were also analyzed. We also sequenced the IL2Rγ gene in 100 healthy individuals. Prenatal genetic diagnoses for a high-risk fetus in family 1 were performed by chorionic villus sampling after determining each family’s genotypes. The suspect fe-male in family 1 underwent carrier detection. Two novel mutations of IL2Rγ gene were identified, including c.361-363delGAG (p.E121del) in the patient and his mother in family 1, and c.510-511insGAACT (p.W173X) heterozygous mutation in the proband’s mother in family 2. These mutations were absent in the 100 controls. Prenatal diagnosis of early pregnancy in the female fetus of family 1 was performed; the fetus was heterozygous, which was confirmed at postnatal follow-up. The suspect female in family 1 showed no mutation in carrier detection. The novel p.E121del and p.W173X mutations in IL2Rγ may have been the primary causes of disease in 2 families with X-SCID. In couples with an X-SCID reproductive history, prenatal gene mutation analysis of IL2Rγ can effectively prevent the birth of children with X-SCID and carrier detection for suspected females.

PMID: 26125817 [PubMed – as supplied by publisher]

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Glycans Instructing Immunity: The Emerging Role of Altered Glycosylation in Clinical Immunology.

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Glycans Instructing Immunity: The Emerging Role of Altered Glycosylation in Clinical Immunology.

Front Pediatr. 2015;3:54

Authors: Lyons JJ, Milner JD, Rosenzweig SD

Abstract
Protein glycosylation is an important epigenetic modifying process affecting expression, localization, and function of numerous proteins required for normal immune function. Recessive germline mutations in genes responsible for protein glycosylation processes result in congenital disorders of glycosylation and can have profound immunologic consequences. Genetic mutations in immune signaling pathways that affect glycosylation sites have also been shown to cause disease. Sugar supplementation and in vivo alteration of glycans by medication holds therapeutic promise for some of these disorders. Further understanding of how changes in glycosylation alter immunity may provide novel treatment approaches for allergic disease, immune dysregulation, and immunodeficiency in the future.

PMID: 26125015 [PubMed]

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Application of Whole Genome and Rna Sequencing to Investigate the Genomic Landscape of Common Variable Immunodeficiency.

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Application of Whole Genome and Rna Sequencing to Investigate the Genomic Landscape of Common Variable Immunodeficiency.

Clin Immunol. 2015 Jun 26;

Authors: van Schouwenburg PA, Davenport EE, Kienzler AK, Marwah I, Wright B, Lucas M, Malinauskas T, Martin HC, WGS500 Consortium, Lockstone HE, Cazier JB, Chapel HM, Knight JC, Patel SY

Abstract
Common Variable Immunodeficiency Disorders (CVIDs) are the most prevalent cause of primary antibody failure. CVIDs are a highly variable disease and a genetic cause has been identified in <5% of patients. Here, we performed whole genome sequencing (WGS) of 34 CVID patients (94% sporadic) and combined them with transcriptomic profiling (RNA-sequencing of B cells) from three patients and three healthy controls. By using an extensive analysis strategy we found variants in CVID disease genes TNFRSF13B, TNFRSF13C, LRBA and NLRP12 and enrichment of variants in known and novel disease pathways. Pathways identified include B-cell receptor signalling, non-homologous end-joining, regulation of apoptosis, T cell regulation and ICOS signalling. Our data confirm a polygenic nature of CVID and suggest individual-specific aetiologies in many cases. Together out data show that WGS in combination with RNA-sequencing allows for a better understanding of CVIDs and the identification of novel disease associated pathways.

PMID: 26122175 [PubMed – as supplied by publisher]

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