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T Dörner

Publications and source records attributed to T Dörner.

At least 19 recordsLinked to original sources
PubMed2006

Anti-proteasome autoantibodies contribute to anti-nuclear antibody patterns on human larynx carcinoma cells.

BACKGROUND: Autoantibodies to the 20S proteasome represent an unspecific but common serological phenomenon in patients with systemic autoimmune diseases. Interestingly, a high prevalence of these antibodies have been observed in patients with connective tissue diseases, where anti-nuclear antibodies (ANAs) serve as an important diagnostic screening test. OBJECTIVE: To disclose interference of anti-proteasome antibodies with known ANA patterns. METHODS: Anti-proteasome antibodies were isolated for comprehensive immunofluorescence analyses. The immunofluorescence pattern of human anti-proteasome antibodies was compared with a panel of monoclonal and polyclonal reference antibodies, and colocalisation was analysed using confocal microscopy. RESULTS: Anti-proteasome antibodies clearly contributed to the ANA patterns of their respective serum samples from patients with different rheumatic disorders. In addition to the nuclear pattern, proteasomal staining was also detectable in the cytoplasm, at the endoplasmic reticulum and perinuclear regions showing features overlapping with other known autoantibodies such as those to mitochondria. The specificity of anti-proteasome antibodies was proved by competition experiments and by colocalisation with monoclonal reference antibodies in confocal microscopy. CONCLUSION: In ANA diagnostics, interference of anti-proteasome antibodies will have to be taken into account, especially in the differentiation of anti-cytoplasmatic autoantibodies.

Adult↗
PubMed2006

Immunoproteasome subunit LMP2 expression is deregulated in Sjogren's syndrome but not in other autoimmune disorders.

BACKGROUND: The proteasome system has a pivotal role in the control of the immune response, which suggests that it might be involved in the pathogenesis of autoimmune disorders. OBJECTIVE: To investigate the expression profile of selected proteasomal genes in human peripheral blood mononuclear cells in patients with a variety of autoimmune diseases compared with healthy subjects. METHODS: Real time quantitative RT-PCR was used to analyse the mRNA expression pattern of the proteasome activator subunits PA28alpha and PA28beta and of constitutive proteasome and interferon-gamma-inducible immunoproteasome subunits in peripheral blood mononuclear cells. Simultaneously, protein expression of selected proteasome subunits was quantified by immunoblotting. RESULTS: Under systemic inflammatory conditions the proteasome subunits LMP2 (beta1i), LMP7 (beta5i), MECL1 (beta2i), and PA28alpha were expressed abundantly at the protein level in the vast majority of systemic autoimmune disorders. However, simultaneous mRNA and protein quantification showed a characteristic proteasome expression signature in primary Sjögren's syndrome. At the transcript level, the interferon-gamma-responsive subunits LMP2 (beta1i), MECL1 (beta2i), and the proteasome activator subunit PA28alpha were markedly up regulated. In contrast, LMP2 (beta1i) deficiency was evident at the protein level, indicating deregulation of proteasome expression in Sjögren's syndrome. CONCLUSIONS: These data provide evidence for a regulatory defect in the proteasome system in human autoimmune disorders, pointing to a unique role for LMP2 (beta1i) in the pathogenesis of primary Sjögren's syndrome.

Adult↗
PubMed2006

Dissemination of a Sjögren's syndrome-associated extranodal marginal-zone B cell lymphoma: circulating lymphoma cells and invariant mutation pattern of nodal Ig heavy- and light-chain variable-region gene rearrangements.

OBJECTIVE: Both the genesis and outgrowth of extranodal marginal-zone B cell lymphomas (MZLs) of the mucosa-associated lymphoid tissue (MALT) type are generally thought to represent antigen-driven processes. We undertook this study to analyze lymphoma progression and dissemination outside of the MALT-type lesions. METHODS: Histopathologic and Ig heavy- and light-chain variable-region gene (V(H/L)) analyses were performed in sequential tissue samples from a patient with primary Sjögren's syndrome (SS) with glandular (parotid) manifestations and subsequent nodal dissemination of a low-grade MZL. RESULTS: This MZL expressed a CD20+,CD27+,sIgM/kappa+,IgD-,CD5-,CD10-,Bcl-6-,CD23-,p53-,p21-,MDM2- phenotype and mutated V(H)1-69/D2-21/J(H)4alpha-V(kappa)A27/J(kappa)2 Ig rearrangements. Notably, circulating lymphoma cells from the parotid glands occurred transiently in the patient's blood, as detected by single-cell polymerase chain reaction. In addition, 2 minor B cell clones (clones 2 and 3, with V(H)3-07/D3-22/J(H)3b-V(lambda)3L/J(lambda)2/3 and V(H)3-64/D3-03/J(H)2-V(kappa)A19/J(kappa)2 rearrangements, respectively) were also detected in the parotid glands and blood, and 1 of these (clone 2) was also detected in the lymph nodes. Ig V(H/L) analyses revealed ongoing (antigen-driven) mutations of the glandular lymphoma rearrangements, but an invariant mutation pattern of their nodal counterparts. CONCLUSION: These data indicate coexpansion and transient (re)circulation of the lymphoma clone and 2 additional glandular B cell clones in a primary SS-associated extranodal MZL. Combined histologic and molecular features of the nodal lymphoma subclone reflect a process of "follicular colonization" that eventually froze the mutation machinery after accumulation of additional (antigen-driven) Ig V(H/L) mutations.

Female↗
PubMed2006

Signalling pathways in B cells: implications for autoimmunity.

Following investigations of the pathogenic role of autoantibodies in rheumatic diseases, preclinical and clinical studies suggest a more central role of B cells in the maintenance of the disease process beyond just being precursors of (auto)antibody-producing plasma cells. Detailed analyses have implicated a number of surface molecules and subsequent downstream signalling pathways in the regulation of the events induced by BCR engagement. In this review, we discuss the potential role of molecules involved in altered B cell longevity, especially molecules involved in apoptosis (bcl-2, bcl-x, mutations in the Fas/Fas-L pathway), as well as molecules that might alter activation thresholds of B cells (CD19, CD21, CD22, lyn, SHP, SHIP-1) in the development of autoimmunity. Although focused on intrinsic B cell abnormalities, the complexity of interactions of B cells with other immune cells also makes it possible that increased B cell activation can be induced by distortions in the interaction with other cells. Further delineation of these alterations of B cell function in autoimmune conditions will allow development of more precise B cell-directed therapies beyond drastic B cell depletion, with the potential to improve the risk-benefit ratio of the treatments of autoimmune diseases.

Animals↗
PubMed2006

[Sjögren's syndrome. Current aspects from a rheumatological point of view].

Sjögren's syndrome is an autoimmune disease of the exocrine glands characterized by the leading symptoms of keratoconjunctivitis and stomatitis sicca based on a complex pathogenesis. The prevalence is about 0.5-1%; primary Sjögren's syndrome is differentiated from secondary Sjögren's syndrome associated with other autoimmune disorders. The diagnosis is established by the presence of subjective complaints and objective evidence of sicca symptoms, anti-Ro(SSA)/La(SSB) antibodies, and/or focal lymphocytic infiltration of the glandular tissue. In addition to the typical sicca symptomatology, which is managed symptomatically by substitution and stimulation therapy, some patients exhibit extraglandular manifestations. Complaints involving the musculoskeletal system and inner ear dominate and are treated by the rheumatologist. The indication for base therapy is tailored to individual needs, but the efficacy of this approach has not been established in studies. About 5-10% of the patients with primary Sjögren's syndrome develop a B-cell non-Hodgkin's lymphoma. The disease requires interdisciplinary management including, among others, ophthalmologists, dentists, and otorhinolaryngologists, depending on the clinical picture.

Antibodies, Antinuclear↗
PubMed2005

[Autoantibodies and antibody-secreting cells].

Autoantibodies are a hallmark of systemic and organ-specific autoimmune diseases. They contribute both directly and indirectly to the pathogenesis of these diseases. There is now a rising interest in cells that secrete (auto)antibodies. Antibody-secreting cells are plasma blasts and plasma cells that differentiate from B cells following antigen encounter. The view held by the immunology community for decades was that (auto)antibodies are produced by short-lived cells arising from chronic (auto)antigen-mediated B cell stimulation. However, it was recently shown that plasma cells can survive in niches in the bone marrow and inflamed tissues for months to years. These long-lived plasma cells continuously secrete (auto)antibodies without the need for any additional antigen stimulation. They are resistant to immuno-suppressants and are not eliminated by B-cell depleting therapies. Depending on which antibodies are secreted, this plasma cell memory may play an important role in maintaining protective humoral immunity or in the pathogenesis of autoimmune diseases. Consequently, strategies targeting long-lived autoreactive plasma cells may provide new therapeutic options in the treatment of autoimmune diseases.

Animals↗
PubMed2005

Molecular basis of immunoglobulin variable region gene usage in systemic autoimmunity.

This review focuses on the immunoglobulin variable region (IgV) chain gene usage in patients with systemic autoimmune diseases, with particular emphasis on systemic lupus erythematosus (SLE), a condition known to be associated with the production of a number of characteristic autoantibodies as an abnormality. The IgV repertoire is shaped by a variety of molecular and selective influences that are difficult to distinguish. Studies of IgV gene rearrangement by PCR of individual B cells permitted insight in the differential impact of these processes, including somatic hypermutation and indications of receptor editing/revision. Although the majority of current data indicate that there is no major molecular abnormality in V(D)J recombination in SLE patients, abnormalities in subsequent events, such as the degree of receptor editing and somatic hypermutation, and positive and negative selection fundamentally alter the composition of the peripheral B-cell repertoire. Identification of the mechanisms that influence the IgV gene and B-cell repertoire may allow new therapeutic approaches in autoimmunity.

Autoantibodies↗
PubMed2005

Antibodies against protein Z and fetal loss: current perspectives.

Protein Z (PZ) is a vitamin K-dependent plasma protein that serves as a cofactor for the inactivation of factor Xa. A number of investigators found low PZ levels in patients with haemorrhagic as well as thromboembolic diseases, although there is no clear evidence of a pathogenic link between PZ deficiency and these clinical disorders. Nevertheless, low PZ levels have been found in association with early fetal losses, especially those occurring before the 15th week of gestation and in patients with detectable antiphospholipid and anti-PZ antibodies. The current diagnostic relevance and therapeutic consequences of these parameters will be discussed.

Antibodies↗
PubMed2005

Sufficient penetration of peracetic acid into drilled human femoral heads.

Chemical sterilisation methods for musculoskeletal transplants have the problem of penetration into all tissue strata. The present study examined if a peracetic acid/ethanol solution penetrated to a sufficient extent into specifically prepared femoral heads. To this effect, 10 femoral heads have been provided with drillings (diameter 2 mm, depth 10 mm) at a distance of 15 mm (series B) and placed in a diffusion chamber with sterilisation solution. From an additional central drilling at the femoral neck junction, the sample drawing was made after 30 min each over a period of 4 h for the iodometric determination of peracetic acid (PAA) concentration. Ten femoral heads, which did contain only the central drilling, served as controls (series A). In 9 of the examined femoral heads of series A the defined minimum concentration of PAA of 0.2% (inactivation of bacteria, spores, fungi) has been clearly exceeded over the complete period of measurement. About 0.8% PAA (inactivation of viruses) was achieved within 4 h only with six femoral heads. Nine out of the 10 examined femoral heads in series B show a clearly improved penetration behaviour which was expressed in smaller standard deviations, a faster increase in concentration, as well as in higher starting and final concentrations (approx. 0.9%) of PAA. Previous drying in air leads to a faster penetration into the centre of the bone. Standardised drilling of de-cartilaged femoral heads creates favourable conditions for the penetration of the PAA sterilisation solution into the whole tissue and guarantees a sufficient inactivation of microorganisms.

Bone Transplantation↗
PubMed2005

Structurally derived mutations define congenital heart block-related epitopes within the 200-239 amino acid stretch of the Ro52 protein.

Congenital heart block is a passively transferred autoimmune condition, which affects the children of mothers with Ro/SSA autoantibodies. During pregnancy, the antibodies are transported across the placenta and affect the fetus. We have previously demonstrated that antibodies directed to the 200-239 amino acid (aa) stretch of the Ro52 component of the Ro/SSA antigen correlate with the development of congenital heart block. In this report, we investigated the antibody-antigen interaction of this target epitope in detail at a molecular and structural level. Peptides representing aa 200-239 (p200) with structurally derived mutations were synthesized to define the epitopes recognized by two Ro52 human monoclonal antibodies, S3A8 and M4H1, isolated from patient-derived phage display libraries. Analyses by ELISA, circular dichroism and MALDI-TOF-MS demonstrate that the antibody recognition is dependent on a partly alpha-helical fold within the putative leucine zipper of the 200-239 aa stretch and that the two human anti-p200 monoclonal antibodies, M4H1 and S3A8, recognize different epitopic structures within the p200 peptide. In addition, we investigated the representation of each fine specificity within the sera of mothers with children born with congenital heart block, and in such sera, antibodies of the S3A8 idiotype were more commonly detected and at higher levels than M4H1-like antibodies.

Amino Acid Sequence↗
PubMed2004

Correlation of circulating CD27high plasma cells and disease activity in systemic lupus erythematosus.

CD27 is a useful marker in assessing the number of circulating B cells and B cell subsets because it permits one step identification of the major B cell compartments, CD27- naïve and CD27+ memory B cells as well as CD27high plasma cells. Abnormalities in the distribution ofCD27+ B cell subsets are useful in assessing disease activity in patients with systemic lupus erythematosus (SLE). In particular, the frequency of CD27high plasma cells significantly correlates with lupus activity in both children and adults with SLE. Conventional immunosuppressive therapies affect the number of CD27- naïve B cells and CD27high plasma cells, but do not target CD27+ memory B cells. These results suggest that disease flares may relate to the retention of CD27+ memory B cells after conventional immunosuppressive therapy and that new therapies that target these cells specifically may offer new opportunities to induce remission in SLE.

B-Lymphocytes↗
PubMed2003

Immune hemolysis-serological and clinical aspects.

The differential diagnosis of anemia must consider immune hemolytic anemias as a frequent cause. Whereas detection of anti-red blood cell (RBC) alloantibodies frequently induced by immunogenic stimuli (transfusion, pregnancy) is performed by routine serology, diagnosing autoimmune hemolytic anemias or drug-induced hemolytic anemias remains a challenge, usually requiring close collaboration of a number of disciplines. Positive direct antiglobulin test (Coombs' test) represents a central criterion in diagnosing immune hemolytic anemias, leading to further detailed analyses. The most-severe type of immune-mediated hemolysis is acute intravascular hemolysis after ABO incompatible RBC transfusion. This review highlights underlying biochemical aspects, immunohematological diagnostics, and the clinical relevance of RBC allo- and autoantibodies, including paroxysmal nocturnal hemoglobinemia and drug-induced hemolysis. Finally, current and partly experimental therapeutic strategies of immune hemolytic anemias are summarized.

ABO Blood-Group System↗
PubMed2003

Comparison of immunoglobulin heavy chain rearrangements between peripheral and glandular B cells in a patient with primary Sjögren's syndrome.

Myoepithelial sialadenitis (MESA) of the major salivary glands is a characteristic feature of primary Sjögren's syndrome (pSS). To delineate systemic and organ-specific influences on B cells in a patient with pSS and benign MESA, individual B cells were simultaneously obtained from the peripheral blood and inflamed parotid gland. Immunoglobulin variable heavy chain (VH) rearrangements in single sorted CD19+ B cells were subsequently amplified, sequenced and analysed. Despite the presence of two clonal expansions using VH1-08 and VH2-70 segments, respectively, the majority of glandular B cells were polyclonal, resembling the VH gene usage and mutational pattern of the corresponding blood population. However, striking differences were observed in the proportion of cells expressing mutated VH rearrangements (blood, 28.9% versus parotid, 80.4%; P < 0.0001). Moreover, the glandular productive VH rearrangements differed significantly from their blood counterparts by a higher mutational frequency (P < 0.0001), shorter CDR3 lengths (P = 0.001) and a less frequent usage of JH6 (P = 0.0292), indicating an accumulation of memory B cells in the inflamed parotid. Thus, both preferential influx/homing of memory B cells and local proliferation may contribute to the pattern of benign MESA in pSS. Notably, one of the glandular clonal rearrangements (using VH1-08) was also detected in the patient's peripheral repertoire.

Aged↗
PubMed2003

Perturbations of peripheral B lymphocyte homoeostasis in children with systemic lupus erythematosus.

OBJECTIVE: To investigate the distribution of peripheral B cell subpopulations of children with active and inactive systemic lupus erythematosus (SLE) compared with healthy controls. METHODS: Peripheral B cell subpopulations of 11 children with SLE (6 with active and 5 with inactive disease) and 14 age matched normal healthy children were analysed. Active disease was diagnosed in children with a flare of SLE, who received treatment by i.v. cyclophosphamide or i.v. methylprednisolone pulse to control the disease. Additionally, the peripheral B cells of the children with SLE were compared with those of 13 consecutive patients with adult onset SLE. RESULTS: No major difference was found in the frequency and total number of CD27(-)/CD19(+) naïve B cells and CD27(+)/CD19(+) memory B cells between patients with active and inactive lupus and healthy controls, but there was a significant increase in CD27(high) expressing plasma blasts in patients with active SLE. These cells coexpress CD38(+), HLA-DR(dim), surface Ig(low) and lack the expression of CD20 but are clearly positive for intracellular Ig, indicative of early plasma cells. Most CD138(+) cells coexpress CD27(high)/CD19(+). The enhanced frequency of peripheral plasma blasts in children with active SLE is consistent with previous findings in adult patients with SLE, whereas a relative predominance of CD27(+) memory B cells was only identified in the adult patients. CONCLUSIONS: Profound abnormalities in the distribution of B cell compartments are more pronounced in older patients with SLE, but an enhanced frequency and cell number of peripheral plasma blasts is characteristic of both diseases during active stages. Thus detection of CD27(high) plasma blasts significantly correlates with active lupus in both children and adults.

Adolescent↗