[Rheumatology on the move].
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Antirheumatic Agents↗
Biomedical subjects
T Dörner
Publications and source records attributed to T Dörner.
[Cytometric analyses in systemic autoimmune diseases].
A number of autoantibodies play a significant role in collagen vascular diseases and represent diagnostic markers of some of these entities. Despite increasing knowledge of these serological findings, data are limited about potential disturbances of precursor cells that finally lead to the autoantibody producing plasma cells. Recent evidence of disturbed B cell homeostasis indicates that the peripheral B cell compartments in systemic lupus erythematodes (SLE) and Sjögren's syndrome are characteristically different to normal. Although the identification of autoreactive B cells in peripheral blood is still subject of ongoing studies, the differences in B cell subsets add to the understanding of the immunopathogenesis of these diseases and may provide new diagnostic clues and therapeutical avenues of these entities.
Autoimmune Diseases↗
Perturbations in the impact of mutational activity on Vlambda genes in systemic lupus erythematosus.
To assess the impact of somatic hypermutation and selective influences on the Vlambda light chain repertoire in systemic lupus erythematosus (SLE), the frequency and pattern of mutations were analyzed in individual CD19+ B cells from a patient with previously undiagnosed SLE. The mutational frequency of nonproductive and productive rearrangements in the SLE patient was greater (3.1 x 10(-2) vs 3.4 x 10(-2), respectively) than that in normal B cells (1.2 x 10(-2) vs 2.0 x 10(-2), both P < 0.001). The frequencies of mutated rearrangements in both the nonproductive and productive repertoires were significantly higher in the patient with SLE than in normal subjects. Notably, there were no differences in the ratio of replacement to silent (R/S) mutations in the productive and nonproductive repertoires of the SLE patient, whereas the R/S ratio in the framework regions of productive rearrangements of normal subjects was reduced, consistent with active elimination of replacement mutations in this region. The pattern of mutations was abnormal in the SLE patient, with a significant increase in the frequency of G mutations in both the productive and nonproductive repertoires. As in normal subjects, however, mutations were found frequently in specific nucleotide motifs, the RGYW/WRCY sequences, accounting for 34% (nonproductive) and 46% (productive) of all mutations. These data are most consistent with the conclusion that in this SLE patient, the mutational activity was markedly greater than in normal subjects and exhibited some abnormal features. In addition, there was decreased subsequent positive or negative selection of mutations. The enhanced and abnormal mutational activity along with disturbances in selection may play a role in the emergence of autoreactivity in this patient with SLE.
B-Lymphocytes↗
B cells, BAFF/zTNF4, TACI, and systemic lupus erythematosus.
B cells and B-cell/T-cell collaborations are instrumental in the pathophysiology of systemic lupus erythematosus (SLE). This commentary highlights in particular the newly discovered role of B-cell-activating factor (BAFF; also known as TALL-1, THANK, BlyS, and zTNF4) as a positive regulator of B-cell functions, such as B-cell activation and differentiation. Two members of the tumor necrosis factor(TNF)-receptor superfamily were recently identified as receptors for BAFF on B cells. The interaction between BAFF and its receptors may be important in the pathogenesis of lupus. Advances in our understanding of abnormalities in immune regulation in lupus might provide the opportunity to improve our current therapeutic approaches to this disorder.
Animals↗
Immunoglobulin Vkappa light chain gene analysis in patients with Sjögren's syndrome.
OBJECTIVE: Patients with Sjögren's syndrome (SS) have characteristic lymphocytic infiltration of the salivary glands with a previously reported predominance of Vkappa-bearing B cells and produce a variety of autoantibodies, indicating that there is a humoral autoimmune component in this syndrome. This study was undertaken to determine whether there are primary deviations of immunoglobulin V gene usage, differences in somatic hypermutation, defects of selection, or indications for perturbances of B cell maturation in SS. METHODS: Individual peripheral B cells from patients with SS were analyzed for their Ig V gene usage, and the findings were compared with results in normal controls. RESULTS: Molecular differences, as reflected by findings in the nonproductive Vkappa repertoire of the patients, were identified by an enhanced usage of Jkappa2 gene segments and a lack of mutational targeting toward RGYW/WRCY sequences compared with controls. A greater usage of Vkappa1 family members and a reduced frequency of Vkappa3 gene segments in the productive repertoire suggested differences in selection, possibly driven by antigen. Overall positive selection for mutations, especially for replacements in the complementarity-determining region and for mutations in RGYW/WRCY, similar to that found in controls, was detected. CONCLUSION: Disturbances of strictly regulated B cell maturation, during early B cell development as indicated by prominent Jkappa2 gene usage and during germinal center reactions as indicated by a lack of targeting of the hypermutation mechanism, might contribute to the emergence of autoimmunity in SS.
Adult↗
Immunoglobulin Vlambda light chain gene usage in patients with Sjögren's syndrome.
OBJECTIVE: To determine whether patients with Sjögren's syndrome (SS) have abnormalities in Ig Vlambda and Jlambda gene usage, differences in somatic hypermutation, defects in selection, or indications for perturbations of B cell maturation. METHODS: Individual peripheral B cells from SS patients were analyzed for their Vlambda gene usage by single-cell polymerase chain reaction amplification of genomic DNA and compared with those from normal controls. RESULTS: Molecular differences from controls in Vlambda-Jlambda recombination were identified that were reflected by findings in the nonproductive Vlambda repertoire of the patients, including enhanced rearrangement of Vlambda10A and Jlambda2/3 gene segments. In addition, a number of abnormalities in the productive repertoire were identified, indicating disordered selection. A greater usage of 4 Vlambda genes (2A2, 2B2, 2C, and 7A), representing 56% of all productive Vlambda rearrangements, was observed, suggesting positive selection of these genes. Overutilization of Jlambda2/3 and underutilization of Jlambda7 in both nonproductive and productive Vlambda rearrangements of SS patients compared with controls suggested decreased receptor editing in SS. The mutational frequency did not differ from that in controls, and positive selection of mutations into the productive V gene repertoire was found, similar to that in controls, although mutational targeting toward RGYW/WRCY motifs, typically found in controls, was not found in SS patients. CONCLUSION: Disturbed regulation of B cell maturation with abnormal selection, defects in editing Ig receptors, and abnormal mutational targeting may contribute to the emergence of autoimmunity in SS.
Aged↗
Immunoglobulin variable-region gene usage in systemic autoimmune diseases.
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Autoimmune Diseases↗
Validation of the sterilization procedure of allogeneic avital bone transplants using peracetic acid-ethanol.
Different procedures are available to inactivate bacteria and fungi, including their spores, as well as viruses in human bone transplants. The most efficient methods are considered to be gamma irradiation and thermal inactivation as well as chemical sterilization methods like the peracetic acid-ethanol treatment (PES). Following national and international standards or draft standards, the antimicrobial effectiveness of this procedure was evaluated. Due to the standardizable size as well as the clinical relevance, defatted human spongiosa cuboids (15x15x15 mm) served as model system. After treatment with PES for 2 and 4 hours, respectively, the titre of living micro-organisms was determined in the supernatant and the cuboid. A reduction in the titre of viable micro-organisms below the detection level (reduction factor >5 log10) was already achieved after an incubation time of 2 hours (Staphylococcus aureus, Enterococcus faecium, Pseudomonas aeruginosa, Bacillus subtilis, Clostridium sporogenes, Mycobacterium terrae, Candida albicans as well as spores of Bacillus subtilis). No viable micro-organisms could be detected in any of the PES-treated test cuboids. Spores of Aspergillus niger were also completely inactivated. The PES procedure proved to be a reliable method for the sterilization of human bone transplants derived from spongiosa.
Bacteria↗
The role of CD40-CD40 ligand (CD154) interactions in immunoglobulin light chain repertoire generation and somatic mutation.
To determine whether CD40 ligation influences the molecular and selective mechanisms that govern the development of the human Ig light chain repertoire, analysis of the Vkappa and Vlambda repertoires of CD19+ B cells obtained from a patient with X-linked hyper IgM syndrome (XHIM) and a nonfunctional CD154 was carried out. The nonproductive Vkappa and Vlambda repertoires were largely comparable to that of the normals with respect to V gene and J segment distribution as well as CDR3 length and VLJL joint complexity. Comparison of the nonproductive and productive repertoires indicated that a limited number of VL genes were positively and negatively selected in the XHIM patient. Although mutations were observed in the XHIM VL repertoires, the frequency of mutations was significantly lower than in normals. Typical targeting of these mutations into RGYW/WRCY motifs was significantly reduced and subsequent selection of RGYW/WRCY mutations, which is normally observed, was not found. These results indicate that CD40 ligation is not required for generation of the light chain repertoire, positive selection of some Vk rearrangements, negative selection of specific VL genes, and some degree of somatic mutation. Importantly, however, targeting of mutations to RGYW/WRCY motifs and subsequent selection of these mutated motifs does not occur in the absence of CD40 ligation.
Amino Acid Motifs↗
Smaller role for pol eta?
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Amino Acid Motifs↗
Prolactin enhances the in vitro production of IgG in peripheral blood mononuclear cells from patients with systemic lupus erythematosus but not from healthy controls.
OBJECTIVES: Recent evidence suggests that prolactin (PRL) plays a part in the pathogenesis of systemic lupus erythematosus (SLE). Because B cell hyperreactivity and autoantibodies are characteristic hallmarks of SLE, this study aimed at assessing the impact of this pituitary hormone on IgG production by stimulating peripheral blood mononuclear cells (PBMC) with PRL. METHODS: PBMC from 11 patients with SLE assessed by the ECLAM score and eight healthy controls were incubated with PRL and cultured for seven days. IgG production was measured by enzyme linked immunosorbent assay (ELISA). RESULTS: Spontaneous IgG production of SLE PBMC was significantly enhanced compared with that found in healthy controls. After PRL stimulation, the IgG concentrations of supernatants from SLE PBMC were significantly higher than those of unstimulated PBMC (median 394 ng/ml). Of note, the physiological concentration of PRL (20 ng/ml) induced IgG production more effectively (median 1139 ng/ml) than PRL at 100 ng/ml (median 1029 ng/ml). In contrast, preincubation with PRL did not stimulate IgG production in normal PBMC. A significant correlation between PRL induced IgG production and the disease activity (ECLAM) of the patients with SLE was seen. Moreover, the maximum amount of PRL induced IgG depended on the serum PRL concentrations of the patients with SLE. CONCLUSIONS: The results suggest that PBMC from patients with SLE have an extraordinarily high susceptibility to PRL, showing the most striking effect at a concentration usually found in vivo. This indicates a potential role for mild hyperprolactinaemia in the pathogenesis of SLE, influencing both IgG production and disease activity.
Adolescent↗
Disturbed peripheral B lymphocyte homeostasis in systemic lupus erythematosus.
In patients with active systemic lupus erythematosus (SLE), a marked B lymphocytopenia was identified that affected CD19(+)/CD27(-) naive B cells more than CD19(+)/CD27(+) memory B cells, leading to a relative predominance of CD27-expressing peripheral B cells. CD27(high)/CD38(+)/CD19(dim)/surface Ig(low)/CD20(-)/CD138(+) plasma cells were found at high frequencies in active but not inactive SLE patients. Upon immunosuppressive therapy, CD27(high) plasma cells and naive CD27(-) B cells were markedly decreased in the peripheral blood. Mutational analysis of V gene rearrangements of individual B cells confirmed that CD27(+) B cells coexpressing IgD were memory B cells preferentially using V(H)3 family members with multiple somatic mutations. CD27(high) plasma cells showed a similar degree of somatic hypermutation, but preferentially employed V(H)4 family members. These results indicate that there are profound abnormalities in the various B cell compartments in SLE that respond differently to immunosuppressive therapy.
ADP-ribosyl Cyclase↗
Targeting and selection of mutations in human Vlambda rearrangements.
The impact of somatic hypermutation on the lambda light chain repertoire of individual IgM+ peripheral B cells in the absence (nonproductive rearrangements) and presence (productive rearrangements) of selective influences was analyzed. In the 27 mutated nonproductive VlambdaJlambda, rearrangements obtained from individual peripheral B cells, a significantly greater mutational frequency was observed in the complementarity-determining region (CDR) in comparison to the framework region (FR), whereas the mutational frequencies in both the CDR and FR of the 100 mutated productive VlambdaJlambda rearrangements were significantly greater. R mutations were introduced comparably in CDR and FR of nonproductive VlambdaJlambda rearrangements, but were significantly decreased in FR of productive VlambdaJlambda rearrangements. The majority of codons defined as hot spots for R mutations were within CDR in both the nonproductive and productive VlambdaJlambda rearrangements. Targeting of mutations to RGYW/WRCY motifs was observed such that 38% of all mutations in the nonproductive VlambdaJlambda rearrangements were within RGYW/WRCY motifs. Mutations in RGYW/WRCY motifs were positively selected and accounted for >50% of all mutations in the mutated productive VlambdaJlambda rearrangements. These data indicate that targeting of the mutational machinery and selection of mutations in these targeted motifs play major roles in influencing nucleotide changes in VlambdaJlambda rearrangements.
Base Sequence↗
The influence of CD40-CD154 interactions on the expressed human V(H) repertoire: analysis of V(H) genes expressed by individual B cells of a patient with X-linked hyper-IgM syndrome.
Analysis of the V(H)DJ(H) repertoire of peripheral blood IgM(+) B cells from a patient with X-linked hyper-IgM syndrome (X-HIgM) was undertaken to determine whether the distribution of V(H) families in the productive repertoire might be regulated by in vivo CD40-CD154 interactions. The distribution of V(H) genes in the non-productive repertoire of IgM(+) B cells was comparable in X-HIgM and normals. Unlike the normal productive V(H) repertoire, however, in the X-HIgM patient the V(H)4 family was found at almost the same frequency as the V(H)3 family. This reflected a diminution in the positive selection of the V(H)3 family observed in normals and the imposition of positive selection of the V(H)4 family in the X-HIgM patient. Unique among the V(H)3 genes, V(H)3-23/DP-47 was positively selected in both normals and the X-HIgM patient. No major differences in the usage of J(H) or D segments or the complementarity-determining region (CDR) 3 were noted, although the foreshortening of the CDR3 noted in the mutated V(H) rearrangements of normals was absent in the X-HIgM patient. Finally, a minor degree of somatic hypermutation was noted in the X-HIgM patient. These results have suggested that specific influences on the composition of the V(H) repertoire in normals require CD40-CD154 interactions.
CD40 Antigens↗
Treatment of acute exacerbation of systemic lupus erythematosus with high-dose intravenous immunoglobulin.
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Acute Disease↗
Antinuclear antibody- and extractable nuclear antigen-related diseases.
In 1948, the observation of the LE cell phenomenon in a patient with systemic lupus erythematosus (SLE) began the discovery of a broad variety of autoantibodies directed to nuclear antigens called antinuclear antibodies (ANA). Nowadays, different ANA serve as important diagnostic parameters for differentiating most of the connective tissue diseases, such as SLE, neonatal lupus syndromes, Sjögren's syndrome, scleroderma, autoimmune myositis, mixed connective tissue disease and other overlaps. This overview summarizes the history of ANA and their detection methods, in part to introduce the subsequent papers dealing with special topics of ANA-related diseases in this issue. Furthermore, the pathogenic role of these autoantibodies in targeting non-organ-specific intracellular antigens as a functional important constituent of a subcellular particle or multimolecular complex is addressed. Notably, some of these autoantibodies have functioned as significant tools for cell biologists to elucidate the subcellular structures and functions of these autoantigens. In the future, we can expect further advances to answer such important questions as why these antigens are targets of autoantibodies, what is their pathogenic impact and what are the triggers of autoimmunity?
Animals↗
Use of immunoglobulin variable-region genes by normal subjects and patients with systemic lupus erythematosus.
Antibodies to specific autoantigens are serological hallmarks of systemic autoimmune diseases. These autoantibodies are thought to represent a consequence of immune dysregulation in these conditions, and, in part, have been shown to be involved in their pathologic consequences. However, the mechanisms that lead to the production of autoantibodies are still unknown. The observation that certain autoantibodies are frequently encoded by a limited number of immunoglobulin (Ig) variable-region gene segments suggested that a bias in the development of the Ig repertoire might play a role in the tendency to develop autoimmunity. Whether the use of these individual gene segments is random or different in normal subjects and patients with systemic autoimmune disorders remains a matter of controversy. New approaches for the analysis of variable-region genes from unstimulated individual human B cells employing the single-cell polymerase chain reaction have provided new insights in the B cell repertoire of both normal subjects and patients with systemic autoimmune diseases. Using this approach, the analysis of nonproductive and productive Ig variable-region gene rearrangements made it possible to distinguish molecular processes, as manifested in the nonproductive repertoire, from subsequent selection influences. An initial study in a patient with systemic lupus erythematosus has led to the hypothesis that the molecular generation of the B cell repertoire is similar in patients and normal subjects but subsequent influences and, most notably, extensive mutations and receptor editing differ significantly in shaping the peripheral IgV gene use by persons with autoimmune diseases.
Animals↗
Significance of autoantibodies in neonatal lupus erythematosus.
Autoantibodies produced by the mother and transported into the fetal circulation are of significant importance in the diagnosis of neonatal lupus syndromes. These humoral autoimmune findings provide an unique opportunity to assess the pathogenic role of autoantibodies against the Ro(SS-A)/La(SS-B) complex, most notably for congenital heart block. Current knowledge about the involved autoantibody-autoantigen systems, including recent therapeutic concepts of these autoimmune syndromes, is summarized.
Animals↗