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Veit Krenn

Publications and source records attributed to Veit Krenn.

29 records · Page 2Linked to original sources
PubMed2004

Immunization with glucose-6-phosphate isomerase induces T cell-dependent peripheral polyarthritis in genetically unaltered mice.

Rheumatoid arthritis is a chronic inflammatory disease primarily affecting the joints. The search for arthritogenic autoantigens that trigger autoimmune responses in rheumatoid arthritis has largely focused on cartilage- or joint-specific Ags. In this study, we show that immunization with the ubiquitously expressed glycolytic enzyme glucose-6-phosphate isomerase (G6PI) induces severe peripheral symmetric polyarthritis in normal mice. In genetically unaltered mice, T cells are indispensable for both the induction and the effector phase of G6PI-induced arthritis. Arthritis is cured by depletion of CD4(+) cells. In contrast, Abs and FcgammaR(+) effector cells are necessary but not sufficient for G6PI-induced arthritis in genetically unaltered mice. Thus, the complex pathogenesis of G6PI-induced arthritis in normal mice differs strongly from the spontaneously occurring arthritis in the transgenic K/B x N model where Abs against G6PI alone suffice to induce the disease. G6PI-induced arthritis demonstrates for the first time the induction of organ-specific disease by systemic autoimmunity in genetically unaltered mice. Both the induction and effector phase of arthritis induced by a systemic autoimmune response can be dissected and preventive and therapeutic strategies evaluated in this model.

Animals↗
PubMed2004

CD38 low IgG-secreting cells are precursors of various CD38 high-expressing plasma cell populations.

Despite the important role immunoglobulin G (IgG)-secreting plasma cells play in memory immune responses, the differentiation and homeostasis of these cells are not completely understood. Here, we studied the differentiation of human IgG-secreting cells ex vivo and in vitro, identifying these cells by the cellular affinity matrix technology. Several subpopulations of IgG-secreting cells were identified among the cells isolated from tonsils and bone marrow, particularly differing in the expression levels of CD9, CD19, and CD38. CD38 low IgG-secreting cells were present exclusively in the tonsils. A major fraction of these cells appeared to be early plasma cell precursors, as upon activation of B cells in vitro, IgG secretion preceded up-regulation of CD38, and on tonsillar sections, IgG-containing, CD38 low cells with a plasmacytoid phenotype were found in follicles, where plasma cell differentiation starts. A unitary phenotype of migratory peripheral blood IgG-secreting cells suggests that all bone marrow plasma cell populations share a common precursor cell. These data are compatible with a multistep model for plasma cell differentiation and imply that a common CD38 low IgG-secreting precursor gives rise to a diverse plasma cell compartment.

ADP-ribosyl Cyclase↗
PubMed2004

Array technology and proteomics in autoimmune diseases.

Two new technologies (tissue microarrays (TMAs) and proteomics) have generated a great amount of data in life science. High-density TMAs allow for the simultaneous analysis of proteins and RNA by various methods (immunohistochemistry, in situ hybridization, FISH) on a large scale and under highly standardized conditions. Proteomics includes a variety of techniques that are partly high throughput. These techniques aim at the innovation of proteins, the description of the domain structure, the determination of protein sequences and epitope characterization, and ultimately the definition of protein function and protein reactivities in immunologic processes. Proteins that have been characterized accordingly require validation mostly at the morphologic level of defined tissue, linking proteomics to TMAs. In autoimmune diseases, array-based antigenic fingerprinting of autoantibodies will drive the development and the selection of antigen-specific diagnostic tools and therapies. The powerful combination of genomics and proteomics formed in tissue arrays has the potential to change the way the biology of autoimmunity is studied. Novel targets of drug discovery, based on antigen-specific therapies to induce anergy, or regulatory T-cells using the targeted autoantigens of individual patients could be developed in the coming decades.

Autoimmune Diseases↗
PubMed2003

Cell-wall alterations as an attribute of Mycobacterium tuberculosis in latent infection.

Ziehl-Neelsen (ZN) staining is the key technique for diagnosis of mycobacterial infections; however, a high percentage of patients exhibit positive signs of tuberculosis, as indicated by pathology, culture of mycobacteria, and polymerase chain-reaction analysis, and yet show negative results on ZN staining. In this report we present evidence that such ZN-negative specimens represent Mycobacterium tuberculosis bacilli in a dormant state with distinct cell-wall alterations: the classical cell-wall composition-dependent ZN staining of M. tuberculosis in lung sections gradually discontinued with persistence of infection, both in mice and in human patients; in contrast, detection of mycobacteria by cell-wall composition-independent staining using a polyclonal anti-M. bovis Bacille-Calmette-Guérin serum continued with persistence of infection. These findings have important implications for diagnosis, as well as for both chemotherapy and development of vaccine strategies.'

Animals↗
PubMed2003

Disruption of cardiac Ena-VASP protein localization in intercalated disks causes dilated cardiomyopathy.

Vasodilator-stimulated phosphoprotein (VASP) and mammalian enabled (Mena) are actin cytoskeleton and signaling modulators. Ena-VASP proteins share an identical domain organization with an NH2-terminal Ena VASP homology (EVH1) domain, which mediates the binding of these proteins to FPPPP-motif containing partners such as zyxin and vinculin. VASP and Mena are abundantly expressed in the heart. However, previous studies showed that disruption by gene targeting of VASP or Mena genes in mice did not reveal any cardiac phenotype, whereas mice lacking both VASP and Mena died during embryonic development. To determine the in vivo function of Ena-VASP proteins in the heart, we used a dominant negative strategy with cardiac-specific expression of the VASP-EVH1 domain. Transgenic mice with cardiac myocyte-restricted, alpha-myosin heavy chain promoter-directed expression of the VASP-EVH1 domain were generated. Overexpression of the EVH1 domain resulted in specific displacement of both VASP and Mena from cardiac intercalated disks. VASP-EVH1 transgenic mice developed dilated cardiomyopathy with myocyte hypertrophy and bradycardia, which resulted in early postnatal lethality in mice with high levels of transgene expression. The results demonstrate that Ena-VASP proteins may play an important role in intercalated disk function at the interface between cardiac myocytes.

Animals↗
PubMed2003

Differential gene expression in the periprosthetic membrane: lubricin as a new possible pathogenetic factor in prosthesis loosening.

About 10% of hip endoprostheses will loosen after 10 years. Prosthesis loosening is caused by two different pathomechanisms: aseptic loosening (AL) and septic loosening (SL). This study evaluated differences in gene expression in AL and SL. Eight hybridizations were performed on PIQOR cDNA arrays. Objects of the study were periprosthetic interface tissue samples from two patients with SL and three patients with AL. Tissue parts directly adjacent to the site of RNA isolation were analyzed immuno/histopathologically in order to overcome the problem of tissue heterogeneity. Thirty-three genes were found constantly differentially expressed, among which were cd11b, cd18, cd68, osteopontin and ferritin heavy-chain upregulated in AL and collagen types 1alpha-1, 3alpha-1, integrin alpha-1, thrombospondin2 and nidogen upregulated in SL. The most striking finding was the strong upregulation (from 20-fold to 323-fold) of megakaryocyte stimulating factor (msf) in all aseptic cases and one of the two septic cases, which was confirmed by real-time reverse transcription-polymerase chain reaction. In this study, msf is linked to prosthesis loosening for the first time. The upregulation in AL suggests an important pathogenetic role: the msf splice product lubricin is responsible for the lubrication of healthy joints, but its excellent lubrication ability may disturb the tight interaction between bone and prosthesis and thereby contribute to prosthesis loosening.

Aged↗
PubMed2002

Morphological and molecular pathology of the B cell response in synovitis of rheumatoid arthritis.

The synovitis of rheumatoid arthritis (RA) was long regarded merely as an unspecific chronic inflammatory process of minor diagnostic value and therefore did not play a major role in the understanding of the pathogenesis of RA. It is only in recent years, along with the observation that T and B cells are expanded oligoclonally in synovial tissue and that B cells are able to undergo a local germinal center (GC) reaction, that the synovial tissue has come to be regarded as a site of specific immune processes. The analysis of the immunoglobulin (Ig) gene repertoire had great impact on the understanding of B cell response in lymphatic organs and was subsequently applied to B cells from RA patients. The analyses of the variable (V) regions of the Ig heavy (H) and light (lambda) chains suggested that an antigen specific activation and differentiation of B cells into plasma cells (Plc) takes place in the chronically inflamed synovial tissue of patients with RA. It seems that in a subset of RA patients the synovial tissue develops into an ectopic lymphoid tissue that supports a local GC reaction. Ectopic GC are characteristic of RA; however, they are in general absent from synovitis of osteoarthritis (OA). Here the accumulation of Plc follows a different mechanism. Highly mutated VH genes suggest that in OA memory B cells migrate into the synovial tissue with subsequent differentiation into Plc but without further V gene diversification. Therefore in synovitis two patterns of B cell activation can be differentiated: the maturative and the accumulative type. These two patterns are not definitely disease linked. The maturative type is only found in RA whereas the accumulative type occurs in both diseases. Clinically RA is defined via serum antibodies to the constant region of Ig, so-called rheumatoid factor. However, the spectrum of autoreactive B cells in RA patients is wide and is based on the study of antibody specificities in serum, in synovial fluid and B cell lines derived from peripheral blood, bone marrow, synovial fluid and synovial tissue. These analyses defined non-organ-specific and organ-specific antigens. One can reasonably assume that the disease is far too complex to be explained by only a single antigen. There is a whole combination of antigens acting in a multistep manner that is responsible for RA pathogenesis. It can be hypothesized that chronic synovitis, which is the underlying mechanism of joint destruction, follows a three-step process: (a) initiation, (b) destruction, and (c) perpetuation. The characterization of antigens driving the local synovial B cell maturation and accumulation could lead to an understanding of the process perpetuating the disease. Identification of arthritogenic antigens may yield new avenues for diagnostics and immunotherapy but also a new approach for prevention by vaccines with antigens probably defined by synovial B cell reactivity.

Arthritis, Rheumatoid↗
PubMed2002

Expression of the integrin alpha Ebeta 7 identifies unique subsets of CD25+ as well as CD25- regulatory T cells.

Regulatory CD25(+)CD4(+) T cells are considered as important players in T cell homeostasis and self-tolerance. Here we report that the integrin alpha(E)beta(7), which recognizes epithelial cadherin, identifies the most potent subpopulation of regulatory CD25(+) T cells. Strikingly, CD25-negative alpha(E)+CD4(+) T cells displayed regulatory activity. Both alpha(E)+ subsets, CD25(+) and CD25(-), express CTLA-4, suppress T cell proliferation in vitro, and protect mice from colitis in the severe combined immunodeficient model (SCID) in vivo. Whereas alpha(E)+CD25(+) T cells produce almost no cytokines, alpha(E)+CD25(-) T cells represent a unique subset in which high IL-2, IFN-gamma and T helper 2-cytokine production is linked with suppressive function. Thus, the integrin alpha(E)beta(7) can be regarded as a novel marker for subsets of highly potent, functionally distinct regulatory T cells specialized for crosstalk with epithelial environments.

Animals↗
PubMed2002

Extensive plasma cell infiltration with crystal IgG inclusions and mutated IgV(H) gene in an osteoarthritis patient with lymphoplasmacellular synovitis. A case report.

The presence of immunoglobulin crystal inclusions in plasma cells from plasmacytomas and B-NHLs (linked to overstimulation and overproduction) has been frequently reported. Our case describes a lymphoplasmacellular synovitis in a patient with osteoarthritis (OA) showing an unusually high plasma cell infiltration and for the first time crystals in plasma cells. Using immunohistochemistry. these crystals were identified as being IgG with a balanced lambda/kappa ratio. IgV(H) gene analysis (n = 5 clones) showed that they were somatically mutated (R/S of CDR > 3): in one case, an insertion of 9 nucleotides on the CDR2 region was observed. High R/S values in the CDR indicated antigen selectivity and affinity (4/5). Since no germinal centers could be detected and the analyzed B cells showed antigen selectivity, it may be concluded that already antigenically activated B cells migrated into the synovium and locally differentiated into plasma cells, leading to the extensive infiltration observed. Rheumatoid fibroblasts were shown to support terminal B cell differentiation. Our data suggests that the ability of fibroblasts to activate B cells is not only restricted to RA, but also occurs in OA. The intense plasma cell infiltration contributed to further cartilage damage by altering the microenvironment of the nourishing synovial tissue or by the local production of pathogenic autoantibodies.

Amino Acid Sequence↗
PubMed2002

Synovial tissue of the hip at power Doppler US: correlation between vascularity and power Doppler US signal.

PURPOSE: To correlate power Doppler ultrasonographic (US) findings of the vascularity of synovial tissue of the hip joint with the results of histopathologic examination of the same tissue to assess the value of power Doppler US in the visualization of synovitis. MATERIALS AND METHODS: The hip joints of 24 patients with osteoarthritis (n = 15) or rheumatoid arthritis (n = 9) of the hip joint were examined with US before arthroplasty. The vascularity of the synovial membrane was classified qualitatively by using power Doppler US. During surgery, a section of the synovial tissue examined at power Doppler US preoperatively was resected. The vascularity of the tissue specimen was investigated and graded qualitatively by a pathologist who was not aware of the US findings. Visual qualitative grading was controlled by means of analysis of the US images and histopathologic specimens with a digital image evaluation system. Correlations between power Doppler US and histopathologic examination findings were calculated by using Spearman rank correlation and Pearson correlation tests. RESULTS: The correlation between the qualitative power Doppler US results and the qualitative vascularity grades was 0.92 (P <.01, Spearman rho). The correlation between quantitative and qualitative results was 0.93 (P <.01, Spearman rho) for US imaging and 0.97 (P <.01, Spearman rho) for histopathologic examination. CONCLUSION: Study results showed power Doppler US to be reliable for qualitative grading of the vascularity of synovial tissue of the hip.

Adult↗