1.
Roström, Björn, et al.
(författare)
Oligoclonal IgG bands synthesized in the central nervous system are present in rats with experimental autoimmune encephalomyelitis.
2004
Ingår i: Acta Neurologica Scandinavica. - : Hindawi Limited. - 1600-0404 .- 0001-6314. ; 109:2, s. 106-112
Tidskriftsartikel (refereegranskat) abstract
Objective: Oligoclonal bands (OBs) in electrophoresis of cerebrospinal fluid (CSF) are present in multiple sclerosis and here is investigated whether these also occur in experimental autoimmune encephalomyelitis (EAE). Material and methods: Experimental autoimmune encephalomyelitis was induced in 42 DA rats after immunization with rat spinal chord homogenate and the occurrence of OBs were detected by electrophoresis of both sera and CSF. The relationship between disease symptoms, antibody response against myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG) and appearance of OBs was studied. Results: Development of CSF-specific OB was found to occur, 6 weeks after immunization, in seven of 42 rats. OB was detected in rats with an antibody response against MBP, whereas as a role no such bands were present in rats with an antibody response against MOG. Initially severe disease symptoms were correlated to a concomitant intense oligoclonal antibody response. Conclusion: Cerebrospinal fluid-specific OB occurs in EAE. It is present in rats with an anti-MBP, but not in rats with an anti-MOG antibody response. A severe disease results in an intense oligoclonal antibody response, which might have an anti-inflammatory effect.
2.
Kutty Selva, Nandakumar, et al.
(författare)
A recombinant vaccine effectively induces c5a-specific neutralizing antibodies and prevents arthritis.
2010
Ingår i: PLoS ONE. - San Francisco, CA : Public Library of Science (PLoS). - 1932-6203. ; 5:10
Tidskriftsartikel (refereegranskat) abstract
OBJECTIVES: To develop and validate a recombinant vaccine to attenuate inflammation in arthritis by sustained neutralization of the anaphylatoxin C5a. METHODS: We constructed and expressed fusion protein of C5a and maltose binding protein. Efficacy of specific C5a neutralization was tested using the fusion protein as vaccine in three different arthritis mouse models: collagen induced arthritis (CIA), chronic relapsing CIA and collagen antibody induced arthritis (CAIA). Levels of anti-C5a antibodies and anti-collagen type II were measured by ELISA. C5a neutralization assay was done using a rat basophilic leukemia cell-line transfected with the human C5aR. Complement activity was determined using a hemolytic assay and joint morphology was assessed by histology. RESULTS: Vaccination of mice with MBP-C5a led to significant reduction of arthritis incidence and severity but not anti-collagen antibody synthesis. Histology of the MBP-C5a and control (MBP or PBS) vaccinated mice paws confirmed the vaccination effect. Sera from the vaccinated mice developed C5a-specific neutralizing antibodies, however C5 activation and formation of the membrane attack complex by C5b were not significantly altered. CONCLUSIONS: Exploitation of host immune response to generate sustained C5a neutralizing antibodies without significantly compromising C5/C5b activity is a useful strategy for developing an effective vaccine for antibody mediated and C5a dependent inflammatory diseases. Further developing of such a therapeutic vaccine would be more optimal and cost effective to attenuate inflammation without affecting host immunity.
3.
Bersellini Farinotti, Alex, et al.
(författare)
Cartilage-binding antibodies induce pain through immune complex-mediated activation of neurons
2019
Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 216:8, s. 1904-1924
Tidskriftsartikel (refereegranskat) abstract
Rheumatoid arthritis-associated joint pain is frequently observed independent of disease activity, suggesting unidentified pain mechanisms. We demonstrate that antibodies binding to cartilage, specific for collagen type II (CII) or cartilage oligomeric matrix protein (COMP), elicit mechanical hypersensitivity in mice, uncoupled from visual, histological and molecular indications of inflammation. Cartilage antibody-induced pain-like behavior does not depend on complement activation or joint inflammation, but instead on tissue antigen recognition and local immune complex (IC) formation. smFISH and IHC suggest that neuronal Fcgr1 and Fcgr2b mRNA are transported to peripheral ends of primary afferents. CII-ICs directly activate cultured WT but not FcRγ chain-deficient DRG neurons. In line with this observation, CII-IC does not induce mechanical hypersensitivity in FcRγ chain-deficient mice. Furthermore, injection of CII antibodies does not generate pain-like behavior in FcRγ chain-deficient mice or mice lacking activating FcγRs in neurons. In summary, this study defines functional coupling between autoantibodies and pain transmission that may facilitate the development of new disease-relevant pain therapeutics.
4.
Liu, Yawei, et al.
(författare)
Endogenous collagen peptide activation of CD1d-restricted NKT cells ameliorates tissue-specific inflammation in mice
2011
Ingår i: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 121:1, s. 249-264
Tidskriftsartikel (refereegranskat) abstract
NKT cells m the mouse recognize antigen in the context of the MHC class I-like molecule CD1d and play an important role in peripheral tolerance and protection against autoimmune and other diseases NKT cells are usually activated by CD1d-presented lipid antigens However, peptide recognition m the context of CD 1 has also been documented, although no self-peptide ligands have been reported to date Here, we have identified an endogenous peptide that is presented by CD1d to activate mouse NKT cells This peptide, the immunodominant epitope from mouse collagen type II (mCII(707-721)), was not associated with either MHC class I or II Activation of CD1d-restricted mCII(707-721)-specific NKT cells was induced via TCR signaling and classical costimulation hi addition, mCII(707-721)-specific NKT cells induced T cell death through Fas/FasL, man IL-17A-independent fashion Moreover, mCII(707-721)-specific NKT cells suppressed a range of in vivo inflammatory conditions, including delayed-type hypersensitivity, antigen-induced airway inflammation, collagen-induced arthritis, and EAE, which were all ameliorated by mCII(707) (721) vaccination The findings presented here offer new insight into the intrinsic roles of NKT cells in health and disease Given the results, endogenous collagen peptide activators of NKT cells may offer promise as novel therapeutics in tissue-specific autoimmune and inflammatory diseases
5.
Nandakumar, Kutty Selva, 1965-, et al.
(författare)
A genetic contamination in MHC-congenic mouse strains reveals a locus on chromosome 10 that determines autoimmunity and arthritis susceptibility
2005
Ingår i: European Journal of Immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 35:4, s. 1275-1282
Tidskriftsartikel (refereegranskat) abstract
Among the arthritis-susceptible MHC (H-2)-congenic mouse strains, B10.RIII mice are highly susceptible to collagen-induced arthritis. Surprisingly, the B10.RIII strain was also more susceptible to the T cell independent model CAIA (collagen-antibody-induced arthritis). Through genome-wide genotyping, we found that the B10.RIII and B10.Q strains differed not only in chromosome 17 (MHC) but also in a region on chromosome 10, which contained a fragment from the MHC donor RIIIS/J. We isolated the chromosome 10 as well as the chromosome 17 segments on the B10.RIII and B10.Q backgrounds. Congenic mice containing the RIIIS/J-derived chromosome 10 segment showed significantly higher susceptibility and severity of arthritis with an enhanced autoimmune response to type II collagen. Furthermore, this chromosomal segment significantly promoted CAIA. Similarly, the RIIIS/J segment in chromosome 17 also promoted CAIA independently of other gene segments. These data show that other gene regions, apart from MHC class II, may explain effects both at the priming and effector level of arthritis observed in widely used MHC congenic strains. These new congenic fragments, on both chromosome 10 and 17, provide new mouse strains suitable for studies aiming at positional cloning of new genes associated with arthritis.
6.
Olofsson, Peter, et al.
(författare)
Arthritis suppression by NADPH activation operates through an interferon-beta pathway
2007
Ingår i: BMC Biology. - : Springer Science and Business Media LLC. - 1741-7007. ; 5
Tidskriftsartikel (refereegranskat) abstract
Background: A polymorphism in the activating component of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex, neutrophil cytosolic factor 1 (NCFI), has previously been identified as a regulator of arthritis severity in mice and rats. This discovery resulted in a search for NADPH oxidase- activating substances as a potential new approach to treat autoimmune disorders such as rheumatoid arthritis (RA). We have recently shown that compounds inducing NCFI- dependent oxidative burst, e. g. phytol, have a strong ameliorating effect on arthritis in rats. However, the underlying molecular mechanism is still not clearly understood. The aim of this study was to use gene- expression profiling to understand the protective effect against arthritis of activation of NADPH oxidase in the immune system. Results: Subcutaneous administration of phytol leads to an accumulation of the compound in the inguinal lymph nodes, with peak levels being reached approximately 10 days after administration. Hence, global gene- expression profiling on inguinal lymph nodes was performed 10 days after the induction of pristane-induced arthritis (PIA) and phytol administration. The differentially expressed genes could be divided into two pathways, consisting of genes regulated by different interferons. IFN-gamma regulated the pathway associated with arthritis development, whereas IFN-beta regulated the pathway associated with disease protection through phytol. Importantly, these two molecular pathways were also confirmed to differentiate between the arthritis-susceptible dark agouti (DA) rat, (with an Ncf-/(DA) allele that allows only low oxidative burst), and the arthritis-protected DA.Ncf-/(E3) rat (with an Ncf/(E3) allele that allows a stronger oxidative burst). Conclusion: Naturally occurring genetic polymorphisms in the Ncf-/ gene modulate the activity of the NADPH oxidase complex, which strongly regulates the severity of arthritis. We now show that the Ncf-/ allele that enhances oxidative burst and protects against arthritis is operating through an IFN-gamma-associated pathway, whereas the arthritis-driving allele operates through an IFN-gamma-associated pathway. Treatment of arthritis- susceptible rats with an NADPH oxidase- activating substance, phytol, protects against arthritis. Interestingly, the treatment led to a restoration of the oxidative- burst effect and induction of a strikingly similar IFN-beta-dependent pathway, as seen with the disease-protective Ncfl polymorphism.
7.
8.
Hansson, Ann-Sofie, et al.
(författare)
Relapsing polychondritis, induced in mice with matrilin 1, is an antibody- and complement-dependent disease
2004
Ingår i: American Journal of Pathology. - New York, NY : Elsevier. - 0002-9440 .- 1525-2191. ; 164:3, s. 959-966
Tidskriftsartikel (refereegranskat) abstract
Relapsing polychondritis is an autoimmune disease that affects cartilage in the ear, nose, and respiratory tract. A pathogenic immune response has been proposed and antibodies to several cartilage proteins are detected in sera from these patients. To investigate the role of the humoral immune response in relapsing polychondritis, we used the matrilin-1-induced relapsing polychondritis model. Mice deficient of B cells (muMT) and mice congenic at the complement factor 5, were immunized with matrilin-1, a cartilage-specific protein mainly detected in the tracheal cartilage. To investigate the binding properties and tissue selection of matrilin-1-specific antibodies we produced matrilin-1-specific B-cell hybridomas. Although 83% of the micro MT heterozygous mice developed respiratory distress and erosive chondritis in the respiratory tract, none of the B-cell-deficient mice were susceptible to disease. In addition, we show that complement factor 5 is important for the induction of matrilin-1-induced relapsing polychondritis. Monoclonal matrilin-1-specific antibodies injected into neonatal mice bound specifically to cartilage of the respiratory tract and adult B-cell-deficient mice injected with the same antibodies developed erosive chondritis in the respiratory tract. We conclude that relapsing polychondritis can be mediated by a pathway involving tissue-specific antibodies and complement activation.
9.
Khmaladze, Ia, et al.
(författare)
Mannan induces ROS-regulated, IL-17A-dependent psoriasis arthritis-like disease in mice
2014
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - Washington, DC : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 111:35, s. E3669-E3678
Tidskriftsartikel (refereegranskat) abstract
Psoriasis (Ps) and psoriasis arthritis (PsA) are poorly understood common diseases, induced by unknown environmental factors, affecting skin and articular joints. A single i.p. exposure to mannan from Saccharomyces cerevisiae induced an acute inflammation in inbred mouse strains resembling human Ps and PsA-like disease, whereas multiple injections induced a relapsing disease. Exacerbation of disease severity was observed in mice deficient for generation of reactive oxygen species (ROS). Interestingly, restoration of ROS production, specifically in macrophages, ameliorated both skin and joint disease. Neutralization of IL-17A, mainly produced by gammadelta T cells, completely blocked disease symptoms. Furthermore, mice depleted of granulocytes were resistant to disease development. In contrast, certain acute inflammatory mediators (C5, Fcgamma receptor III, mast cells, and histamine) and adaptive immune players (alphabeta T and B cells) were redundant in disease induction. Hence, we propose that mannan-induced activation of macrophages leads to TNF-alpha secretion and stimulation of local gammadelta T cells secreting IL-17A. The combined action of activated macrophages and IL-17A produced in situ drives neutrophil infiltration in the epidermis and dermis of the skin, leading to disease manifestations. Thus, our finding suggests a new mechanism triggered by exposure to exogenous microbial components, such as mannan, that can induce and exacerbate Ps and PsA.
10.
Li, Jinan, et al.
(författare)
The plasminogen activator/plasmin system is essential for development of the joint inflammatory phase of collagen type II-induced arthritis.
2005
Ingår i: American Journal of Pathology. - New York : Elsevier. - 0002-9440 .- 1525-2191. ; 166:3, s. 783-792
Tidskriftsartikel (refereegranskat) abstract
The plasminogen activator (PA) system has been proposed to have important roles in rheumatoid arthritis. Here we have used the autoimmune collagen type II (CII)-induced arthritis (CIA) model and mice deficient for urokinase-type PA (uPA) or plasminogen to investigate the role of the PA system for development of arthritis. Our data revealed that uPA-deficient mice have a lower severity and incidence of CIA than wild-type mice. Furthermore, although >80% of wild-type control mice developed CIA, we found that none of the 50 plasminogen-deficient littermates that were tested developed CIA within a 40-day period. Antibody generation after CII immunization as well as the binding of labeled anti-CII antibodies to the surface of cartilage were similar in wild-type and plasminogen-deficient mice. No sign of inflammation was seen when plasminogen-deficient mice were injected with a mixture of monoclonal antibodies against CII. However, after daily injections of human plasminogen, these mice developed arthritis within 5 days. Our finding that infiltration of inflammatory cells into the synovial joints was impaired in plasminogen-deficient mice suggests that uPA and plasminogen are important mediators of joint inflammation. Active plasmin is therefore essential for the induction of pathological inflammatory joint destruction in CIA.
