Rheumatoid Arthritis: Witte T

Witte T. · Abteilung Klinische Immunologie, Zentrum Innere Medizin der Medizinischen Hochschule Hannover, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. · Ann N Y Acad Sci. · Pubmed #16126964 No free full text.

Abstract: Establishing the diagnosis of Sjögren's syndrome has been difficult in light of its nonspecific symptoms (dry eyes and mouth) and lack of both sensitive and specific laboratory markers. Recently, antibodies against alpha-fodrin have been characterized: first in animal models of Sjögren's syndrome, and later in humans. Antibodies against alpha-fodrin have been shown to be present in up to 98% of untreated patients. These antibodies are directed against an apoptotic cleavage product of alpha-fodrin. Anti-alpha-fodrin is clearly involved in the pathogenesis of murine models of Sjögren's syndrome. However, in humans, conflicting data have recently been generated with regard to the prevalence of antibodies against alpha-fodrin in the disease. These differences may be caused by interference of treatment with antibody concentrations, but may also reflect varying methods of patient selection. Further studies on untreated patients are needed to establish the diagnostic efficiency of antibodies against alpha-fodrin in Sjögren's syndrome, which may be a potential diagnostic marker in addition to antibodies against Ro. In this review, the potential of antifodrin antibodies as laboratory markers of Sjögren's syndrome is discussed.

Ulbricht KU, Schmidt RE, Witte T. · Abteilung Klinische Immunologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. · Autoimmun Rev. · Pubmed #12848967 No free full text.

Abstract: Alpha-fodrin is a part of the membrane skeleton and expressed in the majority of mammalian cells. It is cleaved in apoptosis by caspase 3. One of the cleavage products, a 120-kDa protein, represents a neoantigen. Antibodies against that cleavage product of alpha-fodrin have originally been described in a murine model of Sjögren's syndrome. In addition, they are also present in up to 93% of patients with Sjögren's syndrome, depending on the stringency of the classification used. Although antibodies against alpha-fodrin are observed in other diseases characterized by chronic apoptosis, they are a valuable laboratory marker in the evaluation of Sjögren's syndrome.

Witte T, Matthias T, Bierwirth J, Schmidt RE. · Department of Clinical Immunology, Medical School Hannover, Hannover, Germany. · Ann N Y Acad Sci. · Pubmed #17894005 No free full text.

Abstract: The significance of antibodies against alpha-fodrin compared to antibodies against Ro (SSA) as markers of Sjögren's syndrome has been controversially discussed. We therefore compared the association of alpha-fodrin and Ro antibodies with dry eyes and dry mouth in the general population. In 168 "normal" participants, the prevalence of IgA antibodies against alpha-fodrin was 5% and of IgG antibodies against alpha-fodrin was 3%. IgA antibodies against alpha-fodrin were present in 3 of 4 and IgG antibodies against alpha-fodrin in 2 of 4 participants with the combination of dry eyes and dry mouth (P = 0.0002 and 0.005). Only one participant had antibodies against Ro and had dry eyes but normal saliva production. Antibodies against alpha-fodrin are associated with sicca syndrome and may be valuable diagnostic markers in patients with Sjögren's syndrome lacking Ro antibodies.

Sack U, Conrad K, Csernok E, Frank I, Haass M, Krieger T, Seyfarth M, Schlosser U, Schmidt RE, Witte T. · Institute of Clinical Immunology and Transfusion Medicine, Medical Faculty of the University of Leipzig, Leipzig, Germany. · Ann N Y Acad Sci. · Pubmed #17785287 No free full text.

Abstract: The German Regional Group of EASI was established during the annual Meeting of the German Society of Immunology in Kiel in September 2005. Since this initial informative meeting, an active core group of about a dozen rheumatologists, immunologists, and laboratory specialists has been generating starter projects. In general, these projects do focus on clinically associated diagnostic questions, and do integrate a variety of specialists with profound knowledge in several related subjects. The aims of the German EASI group are to contribute to the definition of standards and to improve patient care. Therefore, the group is establishing guidelines for the diagnosis of autoimmune diseases, to standardize and improve their quality, combining the experience of clinical and laboratory specialists. The diagnostic activities focus currently on systemic lupus erythematosus (SLE) and on rheumatoid arthritis. These activities include laboratory investigations and diagnosis through clinical manifestations. Standardized diagnostics cannot be based solely on vague symptoms and positive laboratory tests. In laboratory diagnostics, standardization and implementation of objective methods for the detection of autoantibodies has been identified as a central challenge. Here, immune fluorescence techniques and the evaluation of RibP are used as first parameters that could improve SLE diagnostics. Furthermore, guidelines and proposals from scientific medical organizations, and in particular from other national EASI groups will be adapted to the German health system. A cornerstone of implementation is the identification and logistic preparation of existing serum banks, the definition of gaps that should be bridged, and, particularly, the definition and collection of adequate control groups. Through these measures, the German EASI group will provide a standardized diagnostic model of autoimmune disorders throughout Europe starting in the field of rheumatology. Diagnostics may become more rational, efficient, faster, and cost-efficient. Patients with autoimmune rheumatic disorders will profit from receiving an earlier and more accurate diagnosis, which again will allow earlier therapeutic intervention and lead to a better long-term clinical outcome.

Kahlmann D, Davalos-Misslitz AC, Ohl L, Stanke F, Witte T, Förster R. · Institute of Immunology, Hannover Medical School, Hannover, Germany. <> · BMC Genet. · Pubmed #17587445 links to  free full text

Abstract: BACKGROUND: The chemokine receptor CCR7 is a key organizer of the immune system. Gene targeting in mice revealed that Ccr7-deficient animals are severely impaired in the induction of central and peripheral tolerance. Due to these defects, Ccr7-deficient mice spontaneously develop multi-organ autoimmunity showing symptoms similar to those observed in humans suffering from connective tissue autoimmune diseases. However, it is unknown whether mutations of CCR7 are linked to autoimmunity in humans. RESULTS: DNA samples were collected from 160 patients suffering from connective tissue autoimmune disease (Sjogren's syndrome, n = 40; systemic lupus erythematosus, SLE, n = 20 and systemic sclerosis, n = 100) and 40 health subjects (n = 40). All participants in this study were of German descent. Samples were screened for single nucleotide polymorphisms (SNP) by sequencing the coding region of the CCR7 gene as well asthe exon flaking intron sites and parts of the regions encoding for the 5'- and 3'-UTR. CCR7 variants were rare. We identified six different sequence variants, which occurred in heterozygosis. The identified SNP were observed at position -60 C/T (observed 1x), +6,476 A/G (7x), +6,555 C/T (15x), +6,560 C/T (6x), +10,440 A/G (3x) and +11,475 C/A (1x). Four of these variants (+6,476 A/G, +6,555 C/T, +6,560 C/T and +10,440 A/G) display allelic frequencies between 1% and 5 % and were present in both patients and control groups. The variants +6,476 A/G, +6,555 C/T, +6,560 C/T are located in the intron 2, while the +10,440 A/G variant corresponds to a silent mutation in exon 3. The variants -60 C/T and +11,475 C/A which are located at the 5'-UTR and 3-UTR respectively, display allelic frequencies below 1%. No correlation between these variants and the autoimmune diseases investigated could be observed. However, reporter gene expression assay demonstrated that the mutation at the -60 C/T position in homozygosis leads to reduced luciferase activity. CONCLUSION: These results suggest that variants of CCR7 gene occur at an extremely low frequency in the German population and that neither Sjogren's syndrome, systemic lupus erythematosus, nor systemic sclerosis are associated with these variants. Nevertheless, the decreased luciferase activity observed in cells transfected with the promoter region bearing the -60 C/T mutation suggests that this CCR7 variant could potentially lead to increased susceptibility to autoimmunity.

Masilamani M, Nowack R, Witte T, Schlesier M, Warnatz K, Glocker MO, Peter HH, Illges H. · Immunology, Department of Biology, Faculty of Sciences, University of Konstanz, Konstanz, Germany. · Scand J Immunol. · Pubmed #15584974 No free full text.

Abstract: A soluble form of the complement receptor CD21 (sCD21) is shed from the lymphocyte surface. The amount of sCD21 in serum may modulate immunity as sCD21 levels are correlated with several clinical conditions. We report here the serum levels of sCD21 in juvenile arthritis (JA), systemic lupus erythematosus (SLE) and Sjogren's syndrome (SS). Using enzyme-linked immunosorbent assay, we determined sCD21 levels in SLE, SS and JA patients. Mann-Whitney test for nonparametric two-tail P value was performed to obtain statistical significance. Cytometrical analysis of synovial fluid leucocytes of JA patients was done on a FACSsort. While sCD21 levels in SLE and SS are reduced to levels previously found in rheumatoid arthritis (RA), JA sCD21 levels were normal. sCD21 levels did not correlate with clinical parameters and immunophenotype of synovial cells. CD4 T cells in the synovium were almost all of the CD45RO memory type and 13 of 40 patients displayed synovial expansion of gammadeltaT cells. CD21 shedding in JA differs from RA/SS/SLE. JA sCD21 levels in synovial fluid are always lower compared to blood levels of the same patients. Analysis of JA synovial T cells indicates a T-cell driven response.

Momot T, Koch S, Hunzelmann N, Krieg T, Ulbricht K, Schmidt RE, Witte T. · Medizinische Hochschule Hannover, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. · Arthritis Rheum. · Pubmed #15146426 links to  free full text

Abstract: OBJECTIVE: Scleroderma is an autoimmune disorder of unknown etiology. A genetic contribution has been demonstrated, and genes influencing activation of the immune system have been potentially identified as candidate genes in this process. The repertoire of killer cell immunoglobulin-like receptors (KIRs) that are involved in the activation of T cells and natural killer cells is highly variable. Recently, an association of KIR2DS2 with vasculitis in patients with rheumatoid arthritis has been reported. Because scleroderma is characterized by an involvement of the vascular system, we sought to determine whether KIR2DS2 is associated with scleroderma. METHODS: We typed 9 KIR genes in 102 patients with scleroderma and in 100 blood donors, using polymerase chain reaction on genomic DNA. RESULTS: Twelve patients with scleroderma, compared with only 2 blood donors, had KIR phenotypes characterized by the presence of the activating KIR2DS2 and the absence of the corresponding inactivating KIR2DL2 (P = 0.005). CONCLUSION: The genetic combination of KIR2DS2+ and KIR2DL2- is associated with scleroderma.

de Seze J, Dubucquoi S, Fauchais AL, Hachulla E, Matthias T, Lefranc D, Hatron PY, Vermersch P, Witte T. · Department of Neurology, University of Lille, Lille, France. · J Rheumatol. · Pubmed #14994394 No free full text.

Abstract: OBJECTIVE: To investigate the diagnostic value of autoantibodies against alpha-fodrin in patients with Sjögren's syndrome (SS) with neurological manifestations compared to SS patients without neurological manifestations, a control group, and patients with other neurological autoimmune diseases including systemic lupus erythematosus (SLE) with neurological manifestations and multiple sclerosis (MS). METHODS: We evaluated alpha-fodrin autoantibodies in 31 patients with SS with neurological manifestations, 53 SS patients without neurological symptoms, 38 patients with SLE, 60 with MS, and 160 controls. RESULTS: Twenty of the 31 SS patients with neurological manifestations (64.5%) had an increased concentration of IgA and/or IgG anti-alpha-fodrin. This was not statistically different from that of SS patients without neurological symptoms (73.6%), but was higher than the number with SSA/SSB antibodies, which were found in 15 (48%) of our SS patients without neurological manifestations. When the results of the 2 tests were combined, 28 of the 31 (90.3%) patients had positive autoantibodies (alpha-fodrin and/or SSA/SSB). Alpha-fodrin antibodies were increased in 8 (13.3%) of the 60 patients with MS, in 6 (15.7%) of 38 patients with SLE, and in 10 (6.3%) of 160 controls. CONCLUSION: Our results confirm that alpha-fodrin antibodies are an additional diagnostic tool for SS. This test is of particular interest for patients with SS with neurological manifestations, in whom anti SSA/SSB antibodies are less frequently found.

Witte T, Matthias T, Oppermann M, Helmke K, Peter HH, Schmidt RE, Tishler M. · Abteilung Klinische Immunologie, Medizinische Hochschule, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. · J Rheumatol. · Pubmed #14528510 No free full text.

Abstract: OBJECTIVE: To compare the prevalence of antibodies against alpha-fodrin in Sjögren's syndrome (SS) classified according to San Diego and European Community Study Group (ESG) criteria. METHODS: The prevalence and mean concentrations of IgA and IgG autoantibodies against alpha-fodrin were determined and compared in patients with SS classified either according to San Diego criteria or to criteria of the ESG by ELISA. RESULTS: IgA antibodies against alpha-fodrin were detected in 88% and IgG antibodies against alpha-fodrin in 64% and either of these antibodies in 93% of 85 patients classified according to San Diego criteria. Antibodies against Ro were present in 38% of these sera. IgA antibodies against alpha-fodrin were detected in 61%, IgG antibodies against alpha-fodrin in 51%, and any of these antibodies in 73% of 51 patients classified according to the ESG criteria. The mean concentrations of both IgA and IgG antibodies against alpha-fodrin that seem to correlate with disease activity were higher in patients classified according to the San Diego criteria. CONCLUSION: Antibodies against alpha-fodrin are detectable in almost all sera obtained from patients with SS classified according to the San Diego criteria and are significantly more prevalent than antibodies against Ro. The lower prevalence of the autoantibodies in patients classified according to the ESG criteria reflects the lower specificity of these criteria for SS.

de Seze J, Dubucquoi S, Fauchais AL, Matthias T, Devos D, Castelnovo G, Stojkovic T, Ferriby D, Hachulla E, Labauge P, Lefranc D, Hatron PY, Vermersch P, Witte T. · Department of Neurology, University of Lille, France. · Neurology. · Pubmed #12874419 No free full text.

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Witte T, Matthias T, Arnett FC, Peter HH, Hartung K, Sachse C, Wigand R, Braner A, Kalden JR, Lakomek HJ, Schmidt RE. · Abteilung Klinische Immunologie, Medizinische Hochschule Hannover, Germany. · J Rheumatol. · Pubmed #11093442 No free full text.

Abstract: OBJECTIVE: To determine the prevalence of IgA and IgG autoantibodies against alpha-fodrin in patients with primary and secondary Sjögren's syndrome (SS) and controls. METHODS: An ELISA detecting IgA and IgG antibodies against alpha-fodrin was developed. We examined the prevalence of IgA and IgG antibodies against alpha-fodrin in patients with primary and secondary SS, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA) and blood donors. RESULTS: IgA antibodies against alpha-fodrin were detected in 64% of patients with primary SS (n = 85), 47% of patients with secondary SS and SLE (n = 15), and 86% of patients with secondary SS and RA (n = 7). IgA autoantibodies against alpha-fodrin were detected in only one of 160 sera obtained from blood donors and in one of 50 and 2 of 12 sera obtained from SLE and RA patients without sicca syndrome, respectively. The prevalence of IgG antibodies against alpha-fodrin in SS was lower: they were detected in 55% of sera obtained from patients with primary SS, 40% of patients with secondary SS and SLE, and in 43% of patients with secondary SS and RA. Three of 160 sera from blood donors and one of 50 and 5 of 12 sera from SLE and RA patients without sicca syndrome, respectively, contained IgG antibodies against alpha-fodrin. CONCLUSION: IgA rather than IgG antibodies against alpha-fodrin are specific for and frequently observed in primary and secondary SS and are useful markers for this autoimmune disorder.

Witte T, Hartung K, Sachse C, Matthias T, Fricke M, Kalden JR, Lakomek HJ, Peter HH, Schmidt RE. · Abteilung Klinische Immunologie, Medizinische Hochschule Hannover, Germany. · Rheumatol Int. · Pubmed #10776689 No free full text.

Abstract: The prevalence and clinical and laboratory associations of IgM, IgG and IgA rheumatoid factors (RF) were determined in 352 patients with systemic lupus erythematosus (SLE). IgM, IgG, and IgA class RF were detected in 17.9%, 20.5%, and 20.5% of the sera, respectively. RF were associated with sicca syndrome, hypergammaglobulinemia, high titer of antinuclear antibodies, anemia, SSA- and SSB-antibodies, and with the presence of HLA-DR3. RF correlated negatively with nephritis and livedo racemosa. Moreover, we observed an association of RF and parameters of inflammatory activity such as elevated erythrocyte sedimentation rate (ESR) and leukopenia. Analysis of immunoglobulin classes revealed that laboratory parameters of inflammatory activity, SSA- and SSB-antibodies and HLA-DR3 correlated with IgA RF only. IgA RF define a subgroup of SLE patients characterized by distinct autoimmune phenomena and high disease activity in the absence of nephritis.

Aries PM, Witte T, Lamprecht P. · Poliklinik für Rheumatologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck. · Z Rheumatol. · Pubmed #17160656 No free full text.

Abstract: The annual meeting of the Clinical Immunology Workgroup focused on autoimmune vasculitides. The role of innate immunity, T- and B-cells, and innovative therapies for autoimmune vasculitides was discussed. Further topics of the meeting were the role of endothelial microparticles, ghrelin and leptin, regulatory and effector-memory T-cells in ANCA-associated vasculitides, as well as the lethal midline granuloma, intracytoplasmic cytokine-profile in Behcet's disease, autoantibodies in rheumatoid arthritis, polyarteritis nodosa with cranial manifestation, ILT6 as genetic marker in multiple sclerosis and Sjögren's syndrome, alpha-fodrin autoantibodies in multiple sclerosis, interferon-g autoantibodies in a patient with atypical mycobacteriosis, and autoreactive T-cells in murine lupus.

Witte T, Bierwirth J, Schmidt RE, Matthias T. · No affiliation provided · J Rheumatol. · Pubmed #16881136 links to  free full text

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