Infliximab Treatment of Rheumatoid Arthritis Patients Simultaneously Increases TNF-α Protein Levels and Reduces mRNA Expression in the Blood: Abstracts

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  Objective:  Tumour necrosis factor-α (TNF-α) is an important mediator in the pathogenesis of rheumatoid arthritis (RA). We have investigated long-term anti-TNF-α treatment with infliximab with respect to TNF-α gene activity and protein levels in the
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  AbstractsScandinavian Society for Immunology35th Annual Meeting and 20th Summer SchoolAarhus, Denmark, June 13–16, 2004 The followingworkshops willbe runningat the35thAnnualmeeting of TheScandinavian Society forImmunology in Aarhus, Denmark, June 13–16, 2004. The number given to the abstracts in eachworkshop does not reflect the order of presentation. Monday  : AutoimmunityInfection and immunityStimulus and response Tuesday  : HypersensitivityCommensals and immunityComplement Wednesday  : TumourimmunologyImmunotechnology Abstract Editors Steffen ThielRalf AggerJesper ReinholdtHans Ju¨rgen Hoffmann # 2004 Blackwell Publishing Ltd.  Scandinavian Journal of Immunology   59, 609–637   A  UTOIMMUNITY   1 Autoantibodies in Patients withRheumatoid Arthritis A. Astrinidou-Vakaloudi, I. Diamanti, S. Xytsas,D. Xatzidimitriou & E. Georgakopoulou Department of Microbiology, General Hospital of Thessaloniki ‘Agios Pavlos’, Thessaloniki, Greece. E-mail: stasa@hol.gr  Aim:  The aim of this study is to examine the diagnosticvalue of autoanitbodies in patients suffering from rheuma-toid arthritis. We evaluated the presence of the following autoantibodies: rheumatoid factor (RF), antinuclear anti-bodies (ANAs), antibodies against cadiolipin (a-CL) andantibodies against cyclic citrullinated peptide (anti-CCP). Methods:  We studied the presence of RF, ANA, a-CL andanti-CCP in 40 patients with rheumatoid arthritis. Rheuma-toid factor was measured using nephelometric method, while ANAs were examined by indirect immunofluorescence tech-nique using Hep-2 cells as substrate. Sera that reacted at 1/80dilution were classified as ANA positive. Positive sera werestudied up to 1/1280 dilution. A-CL and anti-CCP weremeasured by enzyme-linked immunosorbent assay. Results:  RF was positive in 30 patients (75%), ANA in 15(37%), a-CL in 10 (25%) and anti-CCP in 36 (90%).Predominant pattern of nuclear staining of ANA-positivesera was homogenous and speckled type. ANA titres wereparticularly low; most patients (6) had ANA titre equal to1/80, and five patients had a titre of 1/160, while only fourout of 40 had an ANA titre of 1/320. Conclusions:  Autoimmune disorders such as RA arecharacterized by various autoantibodies that usually arenot specific, as they are present in many other diseases.However, RF and especially anti-CCP are very often andshow higher specificity for RA, being useful diagnosticserological markers. On the other hand, ANA and a-CLare less common in RA paitents; they may be useful interms of prognosis and treatment, but they always shouldbe evaluated in correlation with the clinical features andthe rest of the laboratory findings of each patient.  A  UTOIMMUNITY   2 Plasma TNF-Binding Capacity and SolubleTNF Receptors in Patients with JuvenileIdiopathic Arthritis B. Bjoernhart, 1 P. Svenningsen, 2 S. Gudbrandsdottir, 1 M. Zak, 2 S. Nielsen, 2 K. Bentzen 1 & K. Mu¨ller 1,2 1 Institute for Inflammation Research, Rigshospitalet, and   2 Pediatric Department, Rigshospitalet, Copenhagen, Denmark. E-mail: birgittebj@m6.ku.dk  Background:  Unbalanced production of proinflammatory cytokines may be related to disease progression in rheu-matoid arthritis and juvenile idiopathic arthritis (JIA). Within the TNF system, the two agonists, TNF- a  andTNF- b , also called lymphotoxin- a  (LT), are bound by soluble TNF receptors (sTNFR-I and -II) that act asnatural inhibitors of TNF-induced inflammation. Weinvestigated the plasma levels of sTNFR-I in parallel withLT-binding capacity (LTBC) in patients with JIA. Methods:  The levels of sTNFR-I were measured by ELISA (R&D). LTBC was determined by spiking dilutedplasma samples with recombinant LT. Detectable LT wasmeasured by an in-house ELISA measuring unbound LTonly. LTBC was expressed in arbitrary units (AUs) as thepercentage value of bound LT to added LT. Result:  In contrast to previous findings of elevatedsTNFR levels in patients with various chronic inflamma-tory diseases, we found slightly reduced sTNFR-I levels in JIA patients ( n  ¼ 123) compared with age-matchedhealthy controls ( n  ¼ 37): 1077pg/ml (819–2280) versus1185pg/ml (625–2303) [median (range)],  P  ¼ 0015.However, the sTNFR-I levels correlated positively withthe number of active joints, physicians’ global assessmentand CRP. In contrast, patient LTBC values were elevatedcompared to healthy controls: 44AU (36–52) versus31AU (13–41),  P  < 0.0001. Conclusion:  Despite overall slightly reduced plasma levelsof sTNFR-I, the capacity to bind TNF was increased inplasma samples from JIA patients. Studies to identify theTNF-binding substances in plasma are in progress.  A  UTOIMMUNITY   3 Infliximab Treatment of RheumatoidArthritis Patients SimultaneouslyIncreases TNF- a  Protein Levels andReduces mRNA Expression in the Blood T. O. Hjelmevik, 1 A. G. Kvalvik, 2 P. M. Knappskog, 1 L. Lefsaker, 2 A. S. Kleiven, 2 S. Dyvik, 2 J. G. Brun, 1 H. Østergaard & H. G. Eiken 1 1 Haukeland University Hospital,  2 Haugesund Sanitetsforening Revmatis-mesykehus, and   3 Department Laboratory Haugesund Hospital, Bergen,Norway. E-mail: hans.ostergaard@helse-fonna.no  Objective:  Tumour necrosis factor- a  (TNF- a ) is animportant mediator in the pathogenesis of rheumatoidarthritis (RA). We have investigated long-term anti-TNF- a  treatment with infliximab with respect to TNF- a  geneactivity and protein levels in the blood of RA patients anddisease activity score (DAS). Methods:  TNF- a  mRNA and plasma protein in RA patients ( n  ¼ 29) and healthy controls ( n  ¼ 24) was deter-mined before and during treatment with infliximab (3mg/kg)610  Abstracts .................................................................................................................................................................................................. # 2004 Blackwell Publishing Ltd.  Scandinavian Journal of Immunology   59, 609–637  using real-time quantitative reverse transcription-polymerasechain reaction (RT-PCR) and high sensitivity enzyme-linkedimmunosorbent assay (ELISA), respectively. The diseaseactivity of the patients was assessed as DAS value. Results:  The TNF- a  mRNA levels of RA patients at base-line were higher than that of the control group ( P  ¼ 0.0135)but were significantly reduced after initiation of treatment( P  < 0.001). Low mRNA levels were sustained throughoutthe 54 weeks of the study. Baseline protein levels of RA patients were similar to the control group. After 2 weeks of treatment, the protein levels were significantly elevated frombaseline ( P  ¼ 0.0353) and increased throughout week 14.Clinical improvement for all RA patients was found uponinfliximab treatment, as a reduction in DAS values( P  < 0.001). The increase in protein and reduction in DASvalue from week 2–14 was also correlated ( P  ¼ 0.0374). Conclusion:  During infliximab treatment of RA patients,there is an accumulation in immune-reactive TNF- a  pro-tein in blood plasma and simultaneously a reduction inTNF- a  gene expression in PBMC, which may in partexplain the beneficial course of RA symptoms.  A  UTOIMMUNITY   4 Anti-Inflammatory Liver X Receptors andRelated Molecules in Multiple SclerosisPatients from Sardinia and Sweden Y.-M. Huang, 1 X. Liu, 1 K. Steffensen, 2 A. Sanna, 3 G. Arru, 3 A. Sominanda, 1 S. Sotgiu, 3 G. Rosati, 3 J.-A˚. Gustafsson 2 & H. Link 1 1 Division of Neuroimmunology, Neurotec Department, Karolinska Institute,Stockholm,  2 Department of Biosciences, Karolinska Institutet at NOVUM,Huddinge, Sweden, and   3 Institute of Clinical Neurology, University of Sassari, Sassari, Italy. E-mail: yu-min.huang@neurotec.ki.se  The nuclear receptor heterodimers of liver X receptors(LXRs) are recently identified as key transcriptional regu-lators of genes involved in lipid homeostasis and inflam-mation. LXRs and their ligands are negative regulators of macrophage inflammatory gene expression. Multiplesclerosis (MS), a demyelinating disease of the central ner-vous system of unknown cause, is characterized by recur-rent inflammation involving macrophages and theirinflammatory mediators. Sweden belongs to the countrieswith a high MS incidence. In Italy, incidence is lower, withan exception for Sardinia where the incidence is evenhigher than that in Sweden. Subjects from Sardinia areethnically more homogeneous and differ from Swedes,also regarding genetic background and environment. Westudied LXRs and their related molecules of bloodmononuclear cells (MNCs) from female patients withuntreated relapsing-remitting MS from Sassari, Sardinia and Stockholm, Sweden. Sex- and age-matched healthy controls (HCs) were from both areas. mRNA expressionwas evaluated by real-time PCR. LXR- a  was lower( P  < 0.05) in MS (mean  SEM: 3.1  0.2;  n  ¼ 37) com-pared to HC (3.6  0.1;  n  ¼ 37). LXR- a  was lower in MSfrom Stockholm (2.6  0.2;  n  ¼ 22) compared to corre-sponding HC (3.4  0.1;  n  ¼ 22;  P  < 0.01) and comparedto MS (3.8  0.2;  n  ¼ 15;  P  < 0.001) and HC (4  0.2; n  ¼ 15;  P  < 0.001) from Sardinia. MS patients fromStockholm, but not from Sassari, also expressed lower( P  < 0.05) LXR- b  (  4.1  0.4) compared to correspond-ing HC (  2.9  0.3). MS from Stockholm was associatedwith higher ABCA-1 (6.1  0.4 versus 5.0  0.3; P  < 0.05) and higher estrogen receptor- b -Cx (2.4  0.4versus 0.8  0.4;  P  < 0.01) compared to corresponding HC. The HC from Sassari had higher androgen receptor(2.9  0.2) compared to MS from Sassari (1.4  0.3; P  < 0.01), MS (1.3  0.4;  P  < 0.01) and HC fromStockholm (1.2  0.3;  P  < 0.01). MS from Sassari hadlower cyclooxygenase-1 compared to corresponding HC(5.1  0.4 versus 6.6  0.3;  P  < 0.01) and lower prosta-glandin-E (  0.03  0.5) compared to the HC (1.4  0.5; P  < 0.05) and MS (2.7  0.4;  P  < 0.05) and HC fromStockholm (1.9  0.4,  P  < 0.001). Our findings identify LXRs and their related molecules as being involved in MSfrom Stockholm but not from Sassari, while sex hormonereceptors seem to be involved in MS in Sassari.  A  UTOIMMUNITY   5 Multiple Sclerosis: IFN- b  InducesCD123  + BDCA2 – Dendritic Cells thatProduce IL-6 and IL-10 and have NoEnhanced Type I Interferon Production Y. M. Huang, 1 S. Adikari, 1 U. Ba˚ve, 2 A. Sanna 1,3 &G. Alm 4 1 Division of Neuroimmunology, Neurotec Department, Karolinska Institute,Stockholm,  2 Department of Medical Sciences, Uppsala University, Uppsala,Sweden,  3 Institute of Clinical Neurology, University of Sassari, Sassari,Italy, and   4 Division of Veterinary Immunology and Virology, Department of Molecular Biosciences, Biomedical Center, Uppsala, Sweden. E-mail: yu-min.huang@neurotec.ki.se  IFN- b , an approved drug for multiple sclerosis (MS), acts ondendritic cell (DC) by suppressing their production of IL-12p40 and increasing IL-10. This results in Th2-biasedimmune responses. The nature of IFN- b -modulated DCremains elusive. Previously, we observed that IFN- b  dosedependently induces expression of CD123, i.e. a classicalmarker for plasmacytoid DC, on human blood monocyte-derived myeloid DC. Such IFN- b -modulated DC producepredominantly IL-10 but are IL-12 deficient, with potentTh2 promotion. In the present study, we further characterizeIFN- b -modulated DC by using recently identified blood Abstracts  611 .................................................................................................................................................................................................. #  2004 Blackwell Publishing Ltd.  Scandinavian Journal of Immunology   59, 609–637  DC antigens (BDCA) and investigate their ability to produceType I IFN in response to virus stimulation. We show thatIFN- b  induces development of CD123 þ DC from humanblood monocytes, which coexpress BDCA4 þ but are nega-tive for BDCA2 – , a specific marker for plasmacytoid DC.Such IFN- b -modulated DC produce large amounts of IL-6and IL-10, but no IL-12p40 and have no enhanced IFN- b and IFN- b  production. The findings indicate that IFN- b -modulated DC represent a myeloid DC subset with dimin-ished CD11c, BDCA-1 and CD1a expression, having potentTh2-promoting function but lacking antiviral capacity.  A  UTOIMMUNITY   6 Peripheral Blood T-Cell Responses toKeratin Peptides that Share Sequenceswith M Proteins are Largely Restricted toSkin-Homing CD8  + T Cells A. Johnston, J. E. Gudjo´nsson, H. Sigmundsdo´ttir,T. H. Lo¨ve & H. Valdimarsson Department of Immunology, Landspitali-University Hospital, Reykjavik,Iceland. E-mail: andrewj@landspitali.is  The association of psoriasis with throat infections by strep-tococcus pyogenes suggests a potential antigenic target forthe T cells that are known to infiltrate dermis and epider-mis of psoriatic skin. Streptococcal M protein shares anextensive sequence homology with human epidermal kera-tins. Keratins 16 (K16) and 17 (K17) are mostly absentfrom uninvolved skin but are upregulated in psoriaticlesions. There is increasing evidence that CD8 þ T cellsplay an important effector role in psoriasis and M protein-primed T cells may recognize these shared epitopes in skinvia molecular mimicry. To identify candidate epitopes,peptides with sequences from K17 were selected on thebasis of predicted binding to HLA-Cw6 and sequencesimilarities with M6 protein. Matched peptides from thesequence of M6 protein and a set of peptides with poorpredicted binding were also selected. Cw6 þ individualswith psoriasis and Cw6 þ healthy controls, having a family history of psoriasis, were recruited. PBMCs were incubatedwith the peptide antigens. T-cell activation in the CD4 þ ,CD8 þ and later the skin-homing cutaneous lymphocyte-associated antigen (CLA)-expressing subset of CD8 þ Tcells was evaluated by CD69 expression and intracellularIFN- g  accumulation using flow cytometry. We demon-strate that Cw6 þ psoriasis patients had significant CD8 þ T-cell IFN- g  responses to peptides from K17 and M6protein selected on the basis of sequence homology andpredicted HLA-Cw*0602 binding. These responses wereabout 10 times more frequent in the skin-homing cuta-neous lymphocyte-associated antigen-expressing (CLA  þ )subset of CD8 þ T cells. CD4 þ T cells showed only borderline responses. CD8 þ T cells from Cw6 þ nonpsoriatic individuals responded to some M6 peptidesbut very rarely to K17 peptides, and this also applied tothe CLA  þ CD8 þ subset. These findings indicate that psori-atic individuals have CD8 þ T cells that recognize keratinself-antigens and that epitopes shared by streptococcal Mprotein and human keratin may be targets for the CD8 þ Tcells that infiltrate psoriatic skin lesions.  A  UTOIMMUNITY   7 Citrullinated Proteins in Arthritis; theirPresence in Joints and Effects onImmunogenicity K. Lundberg, 1 S. Nijenhuis, 2 E. Vossenaar, 2 W. J. Venrooij, 2 L. Klareskog 1 & H. E. Harris 1 1 Rheumatology Unit, Department of Medicine, Karolinska Institutet,Stockholm, Sweden, and   2 Department of Biochemistry, University of Nijmegen, Nijmegen, The Netherlands. E-mail: karin.lundberg@cmm.ki.se   Autoantibodies directed against citrulline-containing pro-teins have an impressive specificity of nearly 100% in RA patients and a suggestive involvement in the pathogenesis.The targeted epitopes are generated by a post-translationalmodification catalysed by the calcium-dependent enzymepeptidyl arginine deaminase that converts the positively charged arginine to polar but uncharged citrullin. The aimof this study was to analyse the presence of citrulline in the joints at different time points of collagen-induced arthritisin DA rats by immunohistochemistry and to investigatehow immunogenicity and arthritogenicity was affected by citrullination of rat serum albumin (RSA) and collagen typeII (CII). Our results indicate that citrulline could bedetected in joints of arthritic animals, first appearance atthe onset of disease and increasing as disease progressed intoa chronic state. Unimmunized animals or time points beforeclinical signs of arthritis were negative. By morphology, westate that some infiltrating macrophages as well as thecartilage surface stain positive for citrulline, while themajor source of citrullinated proteins appears to be fibrindepositions. A specific Cit-RSA T-cell response wasobserved in animals challenged by citrullinated RSA, noresponse was recorded when RSA was used as a stimulus.The IgG analysis reveals not only a response towards themodified protein but also cross-reactivity to native RSA. NoT-cell or B-cell response was noted in animals injected withunmodified RSA. Cit-CII induced a disease with higherincidence and earlier onset than did the native counterpart. We conclude that, in contrast to the human disease, citrul-line does not seem to appear before clinical signs. Asinflammation proceeds, citrulline is detected specifically inthe joints. All other organs investigated were negative. We612  Abstracts .................................................................................................................................................................................................. # 2004 Blackwell Publishing Ltd.  Scandinavian Journal of Immunology   59, 609–637  also conclude that citrullination of a protein can break tolerance and increase its arthritogenic properties.  A  UTOIMMUNITY   8 Germinal Centres in Primary Sjo¨gren’sSyndrome Indicate a Certain ClinicalImmunological Phenotype M. V. Jonsson, 1 J. G. Brun, 2 K. Skarstein 1 &R. Jonsson 1,2,3 1 Department of Oral Pathology, Institute of Odontology, University of Bergen,  2 Department of Rheumatology, Haukeland University Hospital, 3 Broegelmann Research Laboratory, The Gade Institute, University of Bergen, and   4 Department of Oto-Rhino-Laryngology/Head and Neck Surgery, Haukeland University Hospital, Bergen, Norway. E-mail: malin. jonsson@odont.uib.no  Ectopic germinal centers (GCs) can be detected in thesalivary glands of approximately 1/5 of patients withSjo¨gren’s syndrome (SS) and appear in both primary andsecondary SS. Previously, ectopic GC have been associatedwith increased local autoantibody production. The aim of this study was to determine whether GC in primary Sjo¨gren’ssyndrome (pSS) defines a distinct seroimmunological pheno-type. Retrospectively, a material of 130 haematoxylin andeosin-stained paraffin-embedded tissue sections of minorsalivary gland tissue from patients with pSS was morpholo-gically screened for the presence of ectopic GC. GC-likelesions were detected in 33/130 (25%) of the pSS patients.Seventy-two pSS patients lacking these structures (GC-) wererandomly selected for comparison. Focus score was signifi-cantly increased in the GC þ patients compared to the GC – patients ( P  ¼ 0.035). In the GC þ group, 54.5% of thepatients presented with anti-Ro/SSA compared to 43.7% inthe GC – group. Anti-La/SSB was detected in 31.3% of theGC þ patients compared to 25.7% of the GC – patients.Sixty-one percentage of GC þ patients presented withincreased levels of IgG, a nonsignificant difference whencompared to 39.4% in the GC – patients ( P  ¼ 0.089). Levelsof RF, ANA, ENA, IgM and IgA were similar in both patientgroups, as were ESR and CRP. In conclusion, patients withectopic GC have a higher focus score and more often presentwith autoantibodies and increased levels of IgG comparedto pSS patients with regular focal infiltration (GC – ). Ourfindings may indicate a certain seroimmunological phenotypeand warrant for further prospective studies.  A  UTOIMMUNITY   9 Association between Mannose-BindingLectin and Vascular Complications in Type1 Diabetes T. K. Hansen, 1 L. Tarnow, 2 S. Thiel, 3 R. Steffensen, 4 H.-H. Parving 2 & A. Flyvbjerg 1 1 Immunoendocrine Research Unit, Medical Department M, Aarhus Uni-versity Hospital, Aarhus,  2 Steno Diabetes Center, Gentofte,  3 Department of Medical Microbiology and Immunology, University of Aarhus, Aarhus, and  4 Regional Centre for Blood Transfusion and Clinical Immunology, Aalborg Hospital, Aalborg, Denmark. E-mail: tkh@dadlnet.dk  Complement activation and inflammation have been sug-gested in the pathogenesis of diabetic vascular lesions. Weinvestigated serum mannose-binding lectin (MBL) levelsand polymorphisms in the  MBL   gene in type 1 diabetic(T1DM) patients with and without diabetic nephropathy and associated macrovascular complications. Polymorph-isms in the  MBL   gene and serum MBL levels were deter-mined in 199 T1DM patients with overt nephropathy and192 T1DM patients with persistent normoalbuminuria matched for age, sex and duration of diabetes as wellas in 100 healthy control subjects. The frequencies of high and low expression MBL genotypes were similar inpatients with T1DM and healthy controls. High MBLgenotypes were significantly more frequent in diabeticpatients with nephropathy than in the normoalbuminuricgroup, and the risk of having nephropathy, given a high MBL genotype, assessed by odds ratio was 1.52(1.02–2.27),  P  ¼ 0.04. Median serum MBL concentrationswere significantly higher in patients with nephropathy than in patients with normoalbuminuria [2306 m g/l (IQR 753–4867 m g/l) versus 1491 m g/l (IQR 577–2944), P  ¼ 0.0003], and even when comparing patients withidentical genotypes, serum MBL levels were higher in thenephropathy group than in the normoalbuminuric group.Patients with a history of cardiovascular disease had sig-nificantly elevated MBL levels independently of nephro-pathy status [3178 m g/l(IQR 636–5231 m g/l) versus 1741 m g/l(IQR 656–3149 m g/l),  P  ¼ 0.02]. The differences in MBLlevels between patients with and without vascular complica-tions were driven primarily by pronounced differencesamong carriers of high MBL genotypes ( P  < 0.0001). Ourfindings suggest that MBL may be involved in the patho-genesis of microvascular and macrovascular complicationsin type 1 diabetes and that determination of MBL statusmight be used to identify patients at increased risk of developing these complications.  A  UTOIMMUNITY   10 Protective DNA Vaccination AgainstMOG 91-108 -Induced ExperimentalAutoimmune Encephalomyelitis InvolvesInduction of IFN b J. Wefer, R. A. Harris & A. Lobell Abstracts  613 .................................................................................................................................................................................................. #  2004 Blackwell Publishing Ltd.  Scandinavian Journal of Immunology   59, 609–637
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