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Carsten Speckmann,
Carla Neumann,
Stephan Borte,
Giancarlo la Marca,
Jörn Oliver Sass, Elisabeth Wiech,
Paul Fisch,
Klaus Schwarz,
Bernd Buchholz,
Michael Schlesier,
Kerstin Felgentreff,
Bodo Grimbacher,
Ines Santisteban,
Pawan Bali,
Michael S Hershfield,
Stephan Ehl
The Journal of allergy and clinical immunology 05/2012; 130(4):991-4. · 9.17 Impact Factor
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Jan Rohr,
Ulrich Pannicke,
Michaela Döring,
Annette Schmitt-Graeff, Elisabeth Wiech,
Andreas Busch,
Carsten Speckmann,
Ingo Müller,
Peter Lang,
Rupert Handgretinger,
Paul Fisch,
Klaus Schwarz,
Stephan Ehl
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ABSTRACT: We describe a girl presenting at age 6 years with a history of chronic ulcerating intestinal inflammation since 9 months of age. She exhibited a severe, steroid-dependent clinical course of intestinal inflammation over several years in the absence of serious infections.
Immunodeficiency was first considered at 6 years of age due to chronic lymphopenia. Immunophenotyping revealed low B and T cell counts with few naïve T cells, a skewed TCR repertoire, and TCR gamma/delta T cell predominance, suggesting a defect of lymphocyte development. Genetic and functional analyses identified a hypomorphic mutation in the DCLRE1C (ARTEMIS) gene compromising V(D)J recombination efficiency, but allowing residual T and B cell development. Hematopoetic stem cell transplantation reconstituted the lymphocyte compartment and cured the inflammatory bowel disease.
This report illustrates that a genetic disorder of lymphocyte development can present with chronic inflammatory bowel disease as the dominant phenotype in the absence of severe infection susceptibility.
Journal of Clinical Immunology 12/2009; 30(2):314-20. · 3.08 Impact Factor
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ABSTRACT: Several studies suggest a correlation between genome architecture and gene function. To elucidate mechanisms of gene positioning during cell differentiation and malignant transformation we investigated the nuclear positions of the BCL2 alleles and chromosome 18 territories in different layers of nonneoplastic cervical squamous epithelium and cervical squamous carcinomas in relation to gene expression. Fluorescence in situ hybridization and three-dimensional (3D) image analysis using tissue sections revealed that one BCL2 allele was located more peripherally than the other one in nuclei of the basal layer of nonneoplastic epithelium. During terminal cell differentiation the outer BCL2 allele showed a shift towards the nuclear center. In BCL2-expressing carcinomas the inner BCL2 allele was located more peripherally compared with the basal layer of nonneoplastic epithelium. Our results suggest a functional relevance of unequal allelic BCL2 gene positioning and support the hypothesis that transcriptional BCL2 activation is associated with BCL2 relocation towards the nuclear periphery.
Biophysics of Structure and Mechanism 08/2009; 38(6):793-806. · 2.44 Impact Factor
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Mirzokhid Rakhmanov,
Baerbel Keller,
Sylvia Gutenberger,
Christian Foerster,
Manfred Hoenig,
Gertjan Driessen,
Mirjam van der Burg,
Jacques J van Dongen, Elisabeth Wiech,
Marcella Visentini,
Isabella Quinti,
Antje Prasse,
Nadine Voelxen,
Ulrich Salzer,
Sigune Goldacker,
Paul Fisch,
Hermann Eibel,
Klaus Schwarz,
Hans-Hartmut Peter,
Klaus Warnatz
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ABSTRACT: The homeostasis of circulating B cell subsets in the peripheral blood of healthy adults is well regulated, but in disease it can be severely disturbed. Thus, a subgroup of patients with common variable immunodeficiency (CVID) presents with an extraordinary expansion of an unusual B cell population characterized by the low expression of CD21. CD21(low) B cells are polyclonal, unmutated IgM(+)IgD(+) B cells but carry a highly distinct gene expression profile which differs from conventional naïve B cells. Interestingly, while clearly not representing a memory population, they do share several features with the recently defined memory-like tissue, Fc receptor-like 4 positive B cell population in the tonsils of healthy donors. CD21(low) B cells show signs of previous activation and proliferation in vivo, while exhibiting defective calcium signaling and poor proliferation in response to B cell receptor stimulation. CD21(low) B cells express decreased amounts of homeostatic but increased levels of inflammatory chemokine receptors. This might explain their preferential homing to peripheral tissues like the bronchoalveolar space of CVID or the synovium of rheumatoid arthritis patients. Therefore, as a result of the close resemblance to the gene expression profile, phenotype, function and preferential tissue homing of murine B1 B cells, we suggest that CD21(low) B cells represent a human innate-like B cell population.
Proceedings of the National Academy of Sciences 08/2009; 106(32):13451-6. · 9.68 Impact Factor
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Carsten Speckmann,
Ulrich Pannicke, Elisabeth Wiech,
Klaus Schwarz,
Paul Fisch,
Wilhelm Friedrich,
Tim Niehues,
Kimberly Gilmour,
Karin Buiting,
Michael Schlesier,
Hermann Eibel,
Jan Rohr,
Andrea Superti-Furga,
Ute Gross-Wieltsch,
Stephan Ehl
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ABSTRACT: X-linked severe combined immunodeficiency is a life-threatening disorder caused by mutations in the gene encoding the interleukin-2 receptor gamma chain (IL2RG). Hypomorphic mutations and reversion of mutations in subpopulations of cells can result in variant clinical phenotypes, making diagnosis and treatment difficult. We describe a 5-year-old boy with mild susceptibility to infection who was investigated for a mutation in IL2RG due to persistent natural killer (NK)- and T-cell lymphopenia. A functionally relevant novel T466C point mutation was found in B, NK, and epithelial cells, whereas alpha/beta and gamma/delta T cells showed the normal gene sequence, suggesting reversion of the mutation in a common T-cell precursor. This genetic correction in T cells resulted in a diverse T-cell repertoire and significant immunity despite failure to produce specific antibodies linked to an intrinsic defect of mutant B cells. These observations confirm the potential of revertant T-cell precursors to reconstitute immune function, but questions remain on the longevity of revertant cells implicating the need for careful follow up and early consideration of hematopoietic stem cell transplantation (HSCT).
Blood 09/2008; 112(10):4090-7. · 9.90 Impact Factor
