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  • 1.
    Båge, Tove
    et al.
    Karolinska Inst, Div Pediat Dent.
    Lindberg, Johan
    KTH, School of Biotechnology (BIO), Gene Technology.
    Lundeberg, Joakim
    KTH, School of Biotechnology (BIO), Gene Technology.
    Modéer, Thomas
    Karolinska Inst, Div Pediat Dent.
    Yucel-Lindberg, Tülay
    Karolinska Inst, Div Pediat Dent.
    Microarray analysis of the regulation of TNFa-stimulated PGE2 production in gingival fibroblasts: special reference to intracellular signal transduction pathwaysArticle in journal (Other academic)
  • 2. Båge, Tove
    et al.
    Lindberg, Johan
    KTH, School of Biotechnology (BIO), Gene Technology.
    Lundeberg, Joakim
    KTH, School of Biotechnology (BIO), Gene Technology.
    Modéer, Thomas
    Yucel-Lindberg, Tülay
    Signal pathways JNK and NF-kappa B, identified by global gene expression profiling, are involved in regulation of TNF alpha-induced mPGES-1 and COX-2 expression in gingival fibroblasts2010In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 11, p. 241-Article in journal (Refereed)
    Abstract [en]

    Background: Prostaglandin E-2 (PGE(2)) is involved in several chronic inflammatory diseases including periodontitis, which causes loss of the gingival tissue and alveolar bone supporting the teeth. We have previously shown that tumor necrosis factor a (TNF alpha) induces PGE(2) synthesis in gingival fibroblasts. In this study we aimed to investigate the global gene expression profile of TNF alpha-stimulated primary human gingival fibroblasts, focusing on signal pathways related to the PGE(2)-synthesizing enzymes prostaglandin E synthases (PGES), as well as the upstream enzyme cyclooxygenase-2 (COX-2) and PGE(2) production. Results: Microarray and western blot analyses showed that the mRNA and protein expression of the inflammatory induced microsomal prostaglandin E synthase-1 (mPGES-1) was up-regulated by the cytokine TNF alpha, accompanied by enhanced expression of COX-2 and increased production of PGE(2). In contrast, the expression of the isoenzymes microsomal prostaglandin E synthase-2 (mPGES-2) and cytosolic prostaglandin E synthase (cPGES) was unaffected by TNF alpha treatment. Using oligonucleotide microarray analysis in a time-course factorial design including time points 1, 3 and 6 h, differentially expressed genes in response to TNF alpha treatment were identified. Enrichment analysis of microarray data indicated two positively regulated signal transduction pathways: c-Jun N-terminal kinase (JNK) and Nuclear Factor-kappa B (NF-kappa B). To evaluate their involvement in the regulation of mPGES-1 and COX-2 expression, we used specific inhibitors as well as phosphorylation analysis. Phosphorylation analysis of JNK (T183/Y185) and NF-kappa B p65 (S536) showed increased phosphorylation in response to TNF alpha treatment, which was decreased by specific inhibitors of JNK (SP600125) and NF-kappa B (Bay 11-7082, Ro 106-9920). Inhibitors of JNK and NF-kappa B also decreased the TNF alpha-stimulated up-regulation of mPGES-1 and COX-2 as well as PGE(2) production. Conclusion: In the global gene expression profile, the enrichment analysis of microarray data identified the two signal transduction pathways JNK and NF-kappa B as positively regulated by the cytokine TNF alpha. Inhibition of these TNF alpha-activated signal pathways reduced the expression of mPGES-1 and COX-2 as well as their end product PGE(2) in gingival fibroblasts. The involvement of the signal pathways JNK and NF-kappa B in the regulation of PGE(2) induced by TNF alpha may suggest these two pathways as possible attractive targets in the chronic inflammatory disease periodontitis.

  • 3. Davanian, Haleh
    et al.
    Båge, Tove
    Lindberg, Johan
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Lundeberg, Joakim
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Concha, Hernan Q.
    Chen, Margaret Sallberg
    Yucel-Lindberg, Tulay
    Signaling pathways involved in the regulation of TNF alpha-induced toll-like receptor 2 expression in human gingival fibroblasts2012In: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 57, no 3, p. 406-416Article in journal (Refereed)
    Abstract [en]

    Periodontitis is a chronic inflammatory disease characterized by a host inflammatory response against bacteria that leads to destruction of the supporting structures of the teeth. Bacterial components of pathogens in the periodontal pocket are recognized by toll-like receptors (TLRs) that trigger an inflammatory response. In this study, we investigated the effects of the pro-inflammatory cytokine tumor necrosis factor alpha (TNF alpha) on TLR2 expression in human gingival fibroblasts. In addition, we examined the signaling pathways involved in the regulation of TNF alpha-induced TLR2 expression. Our results showed that TNF alpha increased TLR2 mRNA and protein expression. Microarray analysis and the inhibition of specific signaling pathways demonstrated that c-Jun N-terminal kinases (JNK) and nuclear factor kappa B (NF-kappa B) were involved in the regulation of INF alpha-induced TLR2 expression in gingival fibroblasts. Furthermore, the prostaglandin E-2 (PGE(2)) regulatory enzyme cytosolic phospholipase A(2) (cPLA(2)) and the anti-inflammatory prostaglandin 15-deoxy-Delta(12.14)-prostaglandin J(2) (15d-PGJ(2)), were found to regulate TLR2 mRNA expression stimulated by TNF alpha. Our findings suggest that these pathways and mediators, through the regulation of TLR2 expression in gingival fibroblasts, may be involved in the pathogenesis of periodontitis. The study provides new insights into the molecular mechanisms underlying the regulation of TLR2, implicated in the chronic inflammatory disease periodontitis.

  • 4. Ka, S.
    et al.
    Lindberg, Johan
    KTH, School of Biotechnology (BIO), Gene Technology.
    Stromstedt, L.
    Fitzsimmons, C.
    Lindqvist, N.
    Lundeberg, Joakim
    KTH, School of Biotechnology (BIO), Gene Technology.
    Siegel, P. B.
    Andersson, L.
    Hallbook, F.
    Extremely Different Behaviours in High and Low Body Weight Lines of Chicken are Associated with Differential Expression of Genes Involved in Neuronal Plasticity2009In: Journal of neuroendocrinology (Print), ISSN 0953-8194, E-ISSN 1365-2826, Vol. 21, no 3, p. 208-216Article in journal (Refereed)
    Abstract [en]

    Long-term selection (> 45 generations) for low or high body weight from the same founder population has generated two extremely divergent lines of chickens, the low (LWS) and high weight (HWS) lines, which at the age of selection (56 days) differs by more than nine-fold in body weight. The HWS line chickens are compulsive feeders, whereas, in the LWS line, some individuals are anorexic and others have very low appetites. The involvement of the central nervous system in these behavioural differences has been experimentally supported. We compared a brain region at 0 and 56 days of age containing the major metabolic regulatory regions, including the hypothalamus and brainstem, using a global cDNA array expression analysis. The results obtained show that the long-term selection has produced minor but multiple expression differences. Genes that regulate neuronal plasticity, such as actin filament polymerisation and brain-derived neurotrophic factor, were identified as being differentially expressed. Genes involved in lipid metabolism were over-represented among differentially expressed genes. The expression data confirm that neural systems regulating feeding behaviours in these lines are different. The results suggest that the lines are set in separate developmental trajectories equipped with slightly different nervous systems. We suggest that the lines adapt behaviourally different to changing situations post hatch, such as the transition from dependence on yolk to feeding, in order to obtain energy. The present study has identified and exemplifies the kind of changes that may underlie the extreme differences in such behaviours.

  • 5.
    Klevebring, Daniel
    et al.
    KTH, School of Biotechnology (BIO), Gene Technology.
    Gry, Marcus
    KTH, School of Biotechnology (BIO), Gene Technology.
    Lindberg, Johan
    KTH, School of Biotechnology (BIO), Gene Technology.
    Eidefors, Anna
    Lundeberg, Joakim
    KTH, School of Biotechnology (BIO), Gene Technology.
    Automation of cDNA Synthesis and Labelling Improves Reproducibility2009In: Journal of Biomedicine and Biotechnology, ISSN 1110-7243, E-ISSN 1110-7251, Vol. 2009, p. 396808-Article in journal (Refereed)
    Abstract [en]

    Background. Several technologies, such as in-depth sequencing and microarrays, enable large-scale interrogation of genomes and transcriptomes. In this study, we asses reproducibility and throughput by moving all laboratory procedures to a robotic workstation, capable of handling superparamagnetic beads. Here, we describe a fully automated procedure for cDNA synthesis and labelling for microarrays, where the purification steps prior to and after labelling are based on precipitation of DNA on carboxylic acid-coated paramagnetic beads. Results. The fully automated procedure allows for samples arrayed on a microtiter plate to be processed in parallel without manual intervention and ensuring high reproducibility. We compare our results to a manual sample preparation procedure and, in addition, use a comprehensive reference dataset to show that the protocol described performs better than similar manual procedures. Conclusions. We demonstrate, in an automated gene expression microarray experiment, a reduced variance between replicates, resulting in an increase in the statistical power to detect differentially expressed genes, thus allowing smaller differences between samples to be identified. This protocol can with minor modifications be used to create cDNA libraries for other applications such as in-depth analysis using next-generation sequencing technologies.

  • 6.
    Lindberg, Johan
    KTH, School of Biotechnology (BIO), Gene Technology.
    Transcriptional patterns in inflammatory disease2008Doctoral thesis, comprehensive summary (Other scientific)
    Abstract [en]

    In the studies this thesis is based upon, microarrays were applied to profilemRNA populations in biological samples to gain insights into transcriptionalpatterns and their relation to inflammatory disease.Rheumatoid arthritis (RA) is a chronic inflammatory disease, which leads todegradation of cartilage and bone. RA is characterized by synovial inflammationwith varying levels of tissue heterogeneity. This was confirmed by microarrayanalyses of multiple biopsies from the joints of 13 patients, which showed interindividualvariation in transcript populations to be higher than intra‐individualvariationTherapeutic antibodies targeting TNF‐α have revolutionized treatment of RA,although some patients do not respond well. Identification of non‐responders isimportant, not only because anti‐TNF treatment elevates the risk of infections,but also because of the cost of treatment. A proof‐of‐concept study to investigatetranscriptional effects of anti‐TNF treatment demonstrated that differencesbetween response groups could be identified and that these differences revealedbiological themes related to inflammatory disease.A subsequent study was therefore initiated with a larger cohort of 62 patients toinvestigate gene expression patterns in the synovium prior to anti‐TNFtreatment. Here, the heterogeneity was even more pronounced, thetranscriptional patterns were confounded by the presence of synovial aggregatesand only a weak therapy‐correlated signature was detected. The presence oflymphocyte aggregates was found to correlate to response to therapy, which isconsistent with previous findings indicating a higher level of inflammation ingood responding patients.Periodontitis is an inflammatory disease with many similarities to RA. Both areincurable chronic auto‐immune diseases, characterized by tissue destructionwith common genetic associations. Individuals with RA are at higher risk ofaccumulating significant periodontal problems than the general population. PGE2(prostaglandin E2) is known to stimulate inflammation and bone resorption inperiodontitis. In further studies, microarrays were applied in a time seriesdesign on human gingival fibroblats to explore the signal transduction pathwayscontrolling TNF‐α induced PGE2 synthesis in order to identify novel therapeutictargets. The JNK and NF‐kb pathways were identified as being differentiallyaffected by TNF‐a treatment. The transcriptional patterns were further verifiedusing antibodies against phosphorylated JNK/NF‐kb molecules and specificinhibitors of the JNK and NF‐kb signaling cascades.

  • 7.
    Lindberg, Johan
    et al.
    KTH, School of Biotechnology (BIO), Gene Technology.
    af Klint, Erik
    Department of Medicine, Karolinska Institute, Karolinska University Hospital.
    Catrina, Anca Irinel
    Department of Medicine, Karolinska Institute, Karolinska University Hospital.
    Nilsson, Peter
    KTH, School of Biotechnology (BIO), Gene Technology.
    Klareskog, Lars
    Department of Medicine, Karolinska Institute, Karolinska University Hospital.
    Ulfgren, Ann-Kristin
    Department of Medicine, Karolinska Institute, Karolinska University Hospital.
    Lundeberg, Joakim
    KTH, School of Biotechnology (BIO), Gene Technology.
    Effect of infliximab on mRNA expression profiles in synovial tissue of rheumatoid arthritis patients2006In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 8, no 6, p. R179-Article in journal (Refereed)
    Abstract [en]

    We examined the gene expression profiles in arthroscopic biopsies retrieved from 10 rheumatoid arthritis patients before and after anti-TNF treatment with infliximab to investigate whether such profiles can be used to predict responses to the therapy, and to study effects of the therapy on the profiles. Responses to treatment were assessed using European League Against Rheumatism response criteria. Three patients were found to be good responders, five patients to be moderate responders and two patients to be nonresponders. The TNF-alpha status of the biopsies from each of the patients before treatment was also investigated immunohistochemically, and it was detected in biopsies from four of the patients, including all three of the good responders. The gene expression data demonstrate that all patients had unique gene expression signatures, with low intrapatient variability between biopsies. The data also revealed significant differences between the good responding and nonresponding patients (279 differentially expressed genes were detected, with a false discovery rate < 0.025). Among the identified genes we found that MMP-3 was significantly upregulated in good responders (log(2) fold change, 2.95) compared with nonresponders, providing further support for the potential of MMP-3 as a marker for good responses to therapy. An even more extensive list of 685 significantly differentially expressed genes was found between patients in whom TNF-alpha was found and nonresponders, indicating that TNF-alpha could be an important biomarker for successful infliximab treatment. Significant differences were also observed between biopsies taken before and after anti-TNF treatment, including 115 differentially expressed genes in the good responding group. Interestingly, the effect was even stronger in the group in which TNF-a was immunohistochemically detected before therapy. Here, 1,058 genes were differentially expressed, including many that were novel in this context (for example, CXCL3 and CXCL14). Subsequent Gene Ontology analysis revealed that several 'themes' were significantly over-represented that are known to be affected by anti-TNF treatment in inflammatory tissue; for example, immune response (GO:0006955), cell communication (GO:0007154), signal transduction (GO:0007165) and chemotaxis (GO:0006935). No genes reached statistical significance in the moderately responding or nonresponding groups. In conclusion, this pilot study suggests that further investigation is warranted on the usefulness of gene expression profiling of synovial tissue to predict and monitor the outcome of rheumatoid arthritis therapies.

  • 8.
    Lindberg, Johan
    et al.
    KTH, School of Biotechnology (BIO), Gene Technology.
    af Klint, Erik
    Department of Rheumatology, Karolinska Institutet, Karolinska University Hospital.
    Ulfgren, Ann-Kristin
    Department of Rheumatology, Karolinska Institutet, Karolinska University Hospital.
    Stark, André
    Department of Orthopedics, Karolinska University Hospital.
    Andersson, Tove
    KTH, School of Biotechnology (BIO), Gene Technology.
    Nilsson, Peter
    KTH, School of Biotechnology (BIO), Gene Technology.
    Klareskog, Lars
    Department of Rheumatology, Karolinska Institutet, Karolinska University Hospital.
    Lundeberg, Joakim
    KTH, School of Biotechnology (BIO), Gene Technology.
    Variability in synovial inflammation in rheumatoid arthritis investigated by microarray technology2006In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 8, no 2Article in journal (Refereed)
    Abstract [en]

    In recent years microarray technology has been used increasingly to acquire knowledge about the pathogenic processes involved in rheumatoid arthritis. The present study investigated variations in gene expression in synovial tissues within and between patients with rheumatoid arthritis. This was done by applying microarray technology on multiple synovial biopsies obtained from the same knee joints. In this way the relative levels of intra-patient and inter-patient variation could be assessed. The biopsies were obtained from 13 different patients: 7 by orthopedic surgery and 6 by rheumatic arthroscopy. The data show that levels of heterogeneity varied substantially between the biopsies, because the number of genes found to be differentially expressed between pairs of biopsies from the same knee ranged from 6 to 2,133. Both arthroscopic and orthopedic biopsies were examined, allowing us to compare the two sampling methods. We found that the average number of differentially expressed genes between biopsies from the same patient was about three times larger in orthopedic than in arthroscopic biopsies. Using a parallel analysis of the tissues by immunohistochemistry, we also identified orthopedic biopsies that were unsuitable for gene expression analysis of synovial inflammation due to sampling of non-inflamed parts of the tissue. Removing these biopsies reduced the average number of differentially expressed genes between the orthopedic biopsies from 455 to 171, in comparison with 143 for the arthroscopic biopsies. Hierarchical clustering analysis showed that the remaining orthopedic and arthroscopic biopsies had gene expression signatures that were unique for each patient, apparently reflecting patient variation rather than tissue heterogeneity. Subsets of genes found to vary between biopsies were investigated for overrepresentation of biological processes by using gene ontology. This revealed representative 'themes' likely to vary between synovial biopsies affected by inflammatory disease.

  • 9.
    Lindberg, Johan
    et al.
    KTH, School of Biotechnology (BIO), Gene Technology.
    Lundeberg, Joakim
    KTH, School of Biotechnology (BIO), Gene Technology.
    The plasticity of the mammalian transcriptome2010In: Genomics, ISSN 0888-7543, E-ISSN 1089-8646, Vol. 95, no 1, p. 1-6Article, review/survey (Refereed)
    Abstract [en]

    The dogmatic view of RNA as a mere necessity in the transfer of information between DNA and proteins has during recent years come into question. Novel approaches and new technology has revealed an unprecedented level of inherent complexity in the mammalian transcriptome. Here, the majority of nucleotides are expressed, in sharp contrast to the similar to 1.2% of the human genome harboring protein coding information. Also, >50% of genomic loci contain antisense and interleaved transcription, a conservative estimate since non-coding RNA is highly regulated between tissues and developmental stages, which has only been investigated to a limited extent. Subsequent focus on RNA with no coding potential has revealed numerous species with novel functions, and deep sequencing studies imply that many remain to be discovered. This review gives an overview of the plasticity and dynamics of the mammalian transcriptome and the prevailing interpretation of its effect on the complexity of species.

  • 10.
    Lindberg, Johan
    et al.
    KTH, School of Biotechnology (BIO), Gene Technology.
    Wijbrandts, Carla A.
    Univ Amsterdam, Acad Med Ctr, Div Clin Immunol & Rheumatol.
    van Baarsen, Lisa G.
    Univ Amsterdam, Acad Med Ctr, Div Clin Immunol & Rheumatol.
    Nader, Gustavo
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Rheumatol Unit.
    Klareskog, Lars
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Rheumatol Unit.
    Catrina, Anca Irinel
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Rheumatol Unit.
    Thurlings, Rogier
    Univ Amsterdam, Acad Med Ctr, Div Clin Immunol & Rheumatol.
    Vervoordeldonk, Margriet
    Univ Amsterdam, Acad Med Ctr, Div Clin Immunol & Rheumatol.
    Lundeberg, Joakim
    KTH, School of Biotechnology (BIO), Gene Technology.
    Tak, Paul P.
    Univ Amsterdam, Acad Med Ctr, Div Clin Immunol & Rheumatol.
    Gene expression analysis of synovial tissue biopsies obtained from rheumatoid arthritis patients prior to infliximab treatmentManuscript (Other academic)
  • 11.
    Lindberg, Johan
    et al.
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Wijbrandts, Carla A.
    van Baarsen, Lisa G.
    Nader, Gustavo
    Klareskog, Lars
    Catrina, Anca
    Thurlings, Rogier
    Vervoordeldonk, Margriet
    Lundeberg, Joakim
    KTH, School of Biotechnology (BIO), Gene Technology.
    Tak, Paul P.
    The Gene Expression Profile in the Synovium as a Predictor of the Clinical Response to Infliximab Treatment in Rheumatoid Arthritis2010In: PLOS ONE, ISSN 1932-6203, Vol. 5, no 6, p. e11310-Article in journal (Refereed)
    Abstract [en]

    Background: Although the use of TNF inhibitors has fundamentally changed the way rheumatoid arthritis (RA) is treated, not all patients respond well. It is desirable to facilitate the identification of responding and non-responding patients prior to treatment, not only to avoid unnecessary treatment but also for financial reasons. In this work we have investigated the transcriptional profile of synovial tissue sampled from RA patients before anti-TNF treatment with the aim to identify biomarkers predictive of response. Methodology/Principal Findings: Synovial tissue samples were obtained by arthroscopy from 62 RA patients before the initiation of infliximab treatment. RNA was extracted and gene expression profiling was performed using an in-house spotted long oligonucleotide array covering 17972 unique genes. Tissue sections were also analyzed by immunohistochemistry to evaluate cell infiltrates. Response to infliximab treatment was assessed according to the EULAR response criteria. The presence of lymphocyte aggregates dominated the expression profiles and a significant overrepresentation of lymphocyte aggregates in good responding patients confounded the analyses. A statistical model was set up to control for the effect of aggregates, but no differences could be identified between responders and non-responders. Subsequently, the patients were split into lymphocyte aggregate positive-and negative patients. No statistically significant differences could be identified except for 38 transcripts associated with differences between good- and non-responders in aggregate positive patients. A profile was identified in these genes that indicated a higher level of metabolism in good responding patients, which indirectly can be connected to increased inflammation. Conclusions/Significance: It is pivotal to account for the presence of lymphoid aggregates when studying gene expression patterns in rheumatoid synovial tissue. In spite of our original hypothesis, the data do not support the notion that microarray analysis of whole synovial biopsy specimens can be used in the context of personalized medicine to identify non-responders to anti-TNF therapy before the initiation of treatment.

  • 12. Lindqvist, Christina
    et al.
    Janczak, Andrew M.
    Natt, Daniel
    Baranowska, Izabella
    Lindqvist, Niclas
    Wichman, Anette
    Lundeberg, Joakim
    KTH, School of Biotechnology (BIO), Gene Technology.
    Lindberg, Johan
    KTH, School of Biotechnology (BIO), Gene Technology.
    Torjesen, Peter A.
    Jensen, Per
    Transmission of Stress-Induced Learning Impairment and Associated Brain Gene Expression from Parents to Offspring in Chickens2007In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 2, no 4, p. e364-Article in journal (Refereed)
    Abstract [en]

    Background. Stress influences many aspects of animal behaviour and is a major factor driving populations to adapt to changing living conditions, such as during domestication. Stress can affect offspring through non-genetic mechanisms, but recent research indicates that inherited epigenetic modifications of the genome could possibly also be involved. Methodology/Principal Findings. Red junglefowl (RJF, ancestors of modern chickens) and domesticated White Leghorn (WL) chickens were raised in a stressful environment (unpredictable light-dark rhythm) and control animals in similar pens, but on a 12/12 h light-dark rhythm. WL in both treatments had poorer spatial learning ability than RJF, and in both populations, stress caused a reduced ability to solve a spatial learning task. Offspring of stressed WL, but not RJF, raised without parental contact, had a reduced spatial learning ability compared to offspring of non-stressed animals in a similar test as that used for their parents. Offspring of stressed WL were also more competitive and grew faster than offspring of non-stressed parents. Using a whole-genome cDNA microarray, we found that in WL, the same changes in hypothalamic gene expression profile caused by stress in the parents were also found in the offspring. In offspring of stressed WL, at least 31 genes were up- or down-regulated in the hypothalamus and pituitary compared to offspring of non-stressed parents. Conclusions/Significance. Our results suggest that, in WL the gene expression response to stress, as well as some behavioural stress responses, were transmitted across generations. The ability to transmit epigenetic information and behaviour modifications between generations may therefore have been favoured by domestication. The mechanisms involved remain to be investigated; epigenetic modifications could either have been inherited or acquired de novo in the specific egg environment. In both cases, this would offer a novel explanation to rapid evolutionary adaptation of a population.

  • 13. Snir, O.
    et al.
    Widhe, M.
    von Spee, C.
    Lindberg, Johan
    KTH, School of Biotechnology (BIO), Gene Technology.
    Padyukov, L.
    Lundberg, K.
    Engstrom, A.
    Venables, P. J.
    Lundeberg, Joakim
    KTH, School of Biotechnology (BIO), Gene Technology.
    Holmdahl, R.
    Klareskog, L.
    Malmstrom, V.
    Multiple antibody reactivities to citrullinated antigens in sera from patients with rheumatoid arthritis: association with HLA-DRB1 alleles2009In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 68, no 5, p. 736-743Article in journal (Refereed)
    Abstract [en]

    Background: Autoantibodies to cyclic citrullinated peptides (anti-CCP) are present in most patients with rheumatoid arthritis ( RA), and associate with HLA-DRB1 shared epitope (SE) alleles. Objective: To investigate reactivities of anti-CCP to various citrullinated proteins/peptides, which represent potential autoantigens in RA, and to examine the relationship between such antibodies, and their association with genetic variants within HLA-DRB1 SE alleles. Methods: Serum samples from 291 patients with established RA and 100 sex- and age-matched healthy subjects were included in this study. Sera were first analysed for presence of anti-CCP antibodies and further for IgG and IgA antibodies towards candidate autoantigens in both their native and citrullinated form including: fibrinogen, alpha-enolase peptide-1 and the C1-epitope of type II collagen (C1(III)). Antibody specificity was confirmed by cross-reactivity tests. HLA-DR genotyping was performed. Results: 72% of patients with RA were anti-CCP positive. Among the candidate autoantigens examined, IgG antibodies to citrullinated fibrinogen were found in 66% of patients' sera and in 41% for both citrullinated alpha-enolase peptide-1 and citrullinated C1(III). These antibodies were mainly seen in the anti-CCP-positive patient group; they were specific for their respective antigen and displayed limited cross reactivity. IgA responses were also detected, but less frequently than IgG. Anti-CCP and anti-citrullinated protein antibodies were associated with HLA-DRB1*04 rather than with HLA-DRB1*01 alleles. Conclusions: Antibodies directed against several citrullinated antigens are present in CCP-positive RA, with many patients displaying multireactivity. All specific reactivities were primarily associated with the HLA-DRB1*04 alleles, suggesting common pathways of anti-citrulline immunity.

  • 14. Snir, Omri
    et al.
    Widhe, Mona
    Hermansson, Monika
    von Spee, Caroline
    Lindberg, Johan
    KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Hensen, Sanne
    Lundberg, Karin
    Engstrom, Ake
    Venables, Patrick J. W.
    Toes, Rene E. M.
    Holmdahl, Rikard
    Klareskog, Lars
    Malmstrom, Vivianne
    Antibodies to Several Citrullinated Antigens Are Enriched in the Joints of Rheumatoid Arthritis Patients2010In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 62, no 1, p. 44-52Article in journal (Refereed)
    Abstract [en]

    Objective. High titers of specific anti-citrullinated protein antibodies (ACPAs) are frequently present in the serum of rheumatoid arthritis (RA) patients, but their presence in synovial fluid is less well characterized. The purpose of this study was to compare the levels of antibody to 4 well-defined citrullinated candidate RA autoantigens in serum and synovial fluid and to determine whether antibodies to one citrullinated antigen are dominant over another. Furthermore, we studied their relationships with mutated citrullinated vimentin (MCV), a newly identified RA-specific serum assay, and the classic cyclic citrullinated peptide (CCP) in the synovial fluid of well-defined HLA-DR groups. Methods. Paired serum and synovial fluid samples from 290 RA patients and serum samples from 100 age-and sex-matched healthy controls were analyzed for the presence of anti-MCV and anti-CCP antibodies and for reactivity to citrullinated fibrinogen, alpha-enolase, type II collagen, and vimentin. A total of 219 of the 290 patients were genotyped for the HLA-DR shared epitope alleles. Results. Significantly higher proportions of antibodies against all RA-associated citrullinated antigens were found in synovial fluid as compared with serum. This was also true for the MCV and CCP responses but not for non-RA-associated anti-tetanus toxoid antibodies. As expected, we found a high correlation between citrullinated vimentin and MCV responses. All synovial fluid ACPAs were predominantly associated with HLA-DRB1*04 alleles and were confined to the CCP+/MCV+ subset of patients. Conclusion. MCV and CCP positivity represent a similar subset of RA patients, whereas ACPAs with different fine specificities fall into subgroups of anti-CCP+/anti-MCV+ patients. The levels of all specific ACPAs were elevated in synovial fluid, suggesting that there is local antibody production and/or retention of ACPAs at the site of inflammation governed by RA-predisposing genes.

  • 15. Sundberg, Erik
    et al.
    Grundtman, Cecilia
    Klint, Erik A. F.
    Lindberg, Johan
    KTH, School of Biotechnology (BIO), Gene Technology.
    Ernestam, Sofia
    Ulfgren, Ann-Kristin
    Erlandsson Harris, Helena
    Andersson, Ulf
    Systemic TNF blockade does not modulate synovial expression of the pro-inflammatory mediator HMGB1 in rheumatoid arthritis patients: a prospective clinical study2008In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 10, no 2, p. R33-Article in journal (Refereed)
    Abstract [en]

    Introduction High-mobility group box chromosomal protein 1 (HMGB1) has recently been identified as an endogenous mediator of arthritis. TNF and IL-1 beta, pivotal cytokines in arthritis pathogenesis, both have the ability to induce the release of HMGB1 from myeloid and dendritic cells. It was, therefore, decided to investigate whether treatment based on TNF blockade in rheumatoid arthritis (RA) affects the expression of synovial HMGB1. Methods Repeated arthroscopy-guided sampling of synovial tissue was performed in nine patients with RA before and nine weeks after initiation of anti-TNF mAb (infliximab) therapy. Synovial biopsy specimens were analysed for HMGB1 protein by immunohistochemical staining and for HMGB1 mRNA expression by real-time reverse transcriptase PCR (RT-PCR). Statistical evaluations were based on Wilcoxon's signed rank tests or Spearman rank sum tests. Results Aberrant, extranuclear HMGB1 and constitutive nuclear HMGB1 expression, with histological signs of inflammation, were evident in all biopsies obtained before infliximab therapy. Signs of inflammation were still evident in the second biopsies obtained nine weeks after initiation of infliximab therapy. The cytoplasmic and extracellular expression of HMGB1 decreased in five patients, remained unchanged in one patient and increased in three patients, making the overall change in HMGB1 protein expression not significant. No correlation between the clinical response, as measured by disease activity score calculated for 28 joints (DAS28) or the American College of Rheumatology response criteria (ACR 20, 50, and 70), and the direction of change of HMGB1 expression in individual patients could be discerned. In addition, infliximab therapy did not alter HMGB1 mRNA synthesis. Conclusion Pro-inflammatory HMGB1 expression during rheumatoid synovitis was not consistently influenced by TNF-blocking therapy with infliximab. This suggests that TNF is not the main inducer of extranuclear HMGB1 during synovitis and that HMGB1 may represent a TNF-independent molecule that could be considered as a possible target for future therapeutic intervention in RA.

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