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Summary: Psoriasis (Ps), psoriatic arthritis (PsA) and rheumatoid arthritis (RA) are common diseases dependent on environmental factors that activate the immune system in unknown ways. Mannan is a group of polysaccharides common in the environment; they are potentially pathogenic, because at least some of them induce Ps‐, PsA‐ and RA‐like inflammation in mice. Here, we used positron emission tomography/computed tomography to examine in‐vivo transport and spread of mannan labelled with fluorine‐18 [18F]. The results showed that mannan was transported to joints (knee) and bone marrow (tibia) of mice within 6 h after intraperitoneal injection. The time it took to transport mannan, and its presence in blood, indicated cellular transport of mannan within the circulatory system. In addition, mannan was filtered mainly through the spleen and liver. [18F]fluoromannan was excreted via kidneys, small intestine and, to some extent, the mouth. In conclusion, mannan reaches joints rapidly after injection, which may explain why mannan‐induced inflammatory disease is targeted to these tissues. [ABSTRACT FROM AUTHOR]

Oestradiol and the selective oestrogen receptor modulator (SERM) raloxifene have been shown to ameliorate collagen-induced arthritis (CIA) in rats and in mice. One aim was to investigate if raloxifene exerts its anti-arthritic and anti-osteoporotic effects during the induction or effector phase of arthritis. A second aim was to analyse if raloxifene activates the oestrogen response element (ERE) to produce its immune-modulator effects. CIA or collagen-antibody-induced arthritis (CAIA) was induced in ovariectomized DBA/1-mice. CIA was used for evaluation of treatment during the induction, and CAIA for the effector phase of arthritis and osteoporosis development. Raloxifene, oestradiol or vehicle was administered 5 days/week. The clinical disease was evaluated continuously. Bone marrow density (BMD) was analysed with peripheral quantitative computer tomography, paws were collected for histological examination, and sera were analysed for markers of bone and cartilage turnover and proinflammatory cytokines. Transgenic luciferase (Luc)-ERE mice were immunized with collagen (CII), and after 10 days injected once with raloxifene, oestradiol or vehicle before termination. Spleens were analysed for luciferase activity to measure ERE activation. Treatment with oestradiol or raloxifene during the induction phase of CIA failed to affect arthritis. Raloxifene did not hamper disease activity in CAIA, whereas oestradiol delayed the onset and ameliorated the severity. Both raloxifene and oestradiol preserved BMD in CAIA. CII-immunization increased the oestradiol-induced ERE activation in spleen, and raloxifene activated the ERE at about 25% the intensity of oestradiol. Further experiments are needed to elucidate the exact mechanisms behind this finding. [ABSTRACT FROM AUTHOR]

SUMMARY The high number of γ /δ -expressing T cells found in the epithelial lining layer suggests that they form a first line of defence against invading pathogens. To evaluate the role of γ /δ T cell-receptor (TCR)-expressing cells in cutaneous infection caused by Staphylococcus aureus , mice lacking γ /δ -expressing T cells (TCRδ-/- ) were inoculated intradermally with S. aureus, and compared with S. aureus -infected congeneic TCRδ+/- control mice. The number of bacteria recovered from the skin of TCRδ-/- mice was significantly higher (P = 0·0071) at early time-points after inoculation compared to the number of bacteria isolated from infected TCRδ+/ - congeneic controls. Nevertheless, inflammatory responses measured as serum IL-6 levels, were significantly lower in TCRδ-/- mice than in the control group. A possible explanation for this discrepancy was the observation of significantly decreased overall numbers of infiltrating cutaneous T lymphocytes, which are important producers of IL-6. These results support the notion that the γ /δ -expressing T cells that reside at the epithelial lining layer of the skin is of importance for early containment of the bacteria, thereby limiting their replication and spread. [ABSTRACT FROM AUTHOR]

SUMMARY Rheumatoid arthritis (RA) is a chronic inflammatory disease primarily affecting cartilaginous joints but also extra-articular tissues such as the nose and upper respiratory tract. We have investigated extra-articular cartilage involvement in two commonly used animal models for RA, collagen-induced and pristane-induced arthritis, by immunizing rats with different susceptibility to disease (LEW.1 A, LEW.1F and DA rats). We found that nasal and tracheolaryngeal cartilage is affected in LEW.1 A and DA rats to varying degrees in collagen-induced arthritis but not in any strain in the pristane-induced model. Antibodies to matrilin-1, a cartilage-specific protein expressed mainly in tracheolaryngeal and nasal cartilage but not in joints, were positively associated with the presence of inflammation in nasal cartilage. In contrast, no antibody response to matrilin-1 could be detected in pristane-induced arthritis. In addition, nasal vaccination with collagen type II prior to immunization in DA rats significantly decreased the antibody response to matrilin-1 at day 56, but not at earlier time points, indicating a late protective effect on extra-articular cartilage. We conclude that pristane-induced arthritis is a joint-specific model whereas collagen-induced arthritis affect joints as well as extra-articular cartilage. Furthermore, collagen immunization induces an antibody response to matrilin-1. [ABSTRACT FROM AUTHOR]

Protein energy malnutrition decreased the number of rosette forming T lymphocytes, of T4 positive cells and their ability to provide help to B cells in antibody synthesis. There was a reduction in serum thymic hormone activity and an elevation of leucocyte terminal transferase and plasma cortisol levels. The numerical and functional deficiency of T4+ helper cells may be important in the pathogenesis of some of the clinical and immunological manifestations of protein energy malnutrition. [ABSTRACT FROM AUTHOR]

Susceptibility lo collagen-induced arthritis (CIA) in mice is associated with a class II gene in MHC (A9) but also with unknown genes outside MHC. Investigated here is the influence of genes on the X chromosome as well as the role of the X-linked immunodeficiency (xid) mutation. Reciprocal male F1 hybrids, bred to be heterozygous or homozygous for A9, showed a genetic influence in their susceptibility to develop CIA. Crosses were made between B 10, G, B10, Q, DBA/I, SWR/J, C3H, Q and CBA/Ca, and all F1 mice were castrated to avoid sex hormone modulation of the susceptibility. A differential timing of arthritis onset and severity were seen in the reciprocal F1 males. An exception was the reciprocal F1 male offspring from SWR/J and DBA/1 crosses which differed only in disease severity late in the course of the disease. The female F1 crosses did not show the same pattern of differential susceptibility to CIA as the F1 males. To exclude the possible influence of the Y chromosome, F1 males of reciprocal crosses were hack-crossed lo the parental strains creating offspring with equal X chromosomes but divergent Y chromosomes. No difference in development of arthritis was observed in these. The influence of the xid mutation was investigated next. The xid loci from the CBA/N mouse was bred into DBA/1 strain which is highly susceptible to CIA, The resulting congenic DBA/l-xid strain was resistant to induction of CIA and did not develop an antibody response to type II collagen. We conclude that polymorphic genes on the X chromosome modulate susceptibility to CIA. The results from the experiments with mice carrying xid mutations confirm that such immune modulating genes exist on the sex chromosomes. [ABSTRACT FROM AUTHOR]

To extend our previous findings that exposure to constant darkness (stimulation of endogenous melatonin release) as well as treatment with exogenous melatonin magnifies the severity of collagen-induced arthritis in mice, we have examined the effects of melatonin cutback by removing the pineal gland. Two strains of mice, DBA/1 and NFR/N, were subjected to surgical pinealectomy. The melatonin levels in sera were reduced by approximately 70% by the pinealeetomy compared with the corresponding sham-operated controls. After 3-4 weeks of rest the mice were immunized with rat type II collagen to induce autoimmune arthritis, and the animals were kept in constant darkness during the experiments. In comparison with the controls, all groups of pinealectomized mice showed reduced severity of the arthritis by means of (i) a slower onset of the disease, (ii) a less severe course of the disease (reduced clinical scores), and (iii) reduced serum levels of anti-collagen II antibodies. These effects were not significant in all experiments, but the trends were always the same. Thus, the present results strengthen the hypothesis that high physiological levels of melatonin (which can be induced by exposure to darkness) stimulate the immune system and cause exacerbation of autoimmune collagen II arthritis, while inhibition of melatonin release (pinealectomy or exposure to light) has a beneficial effect. [ABSTRACT FROM AUTHOR]

The F1 hybrid mouse strain, from B10Q and DBA/1 parentals (the QD strain), is highly susceptible to induction of type II collagen-induced arthritis, an experimental model for rheumatoid arthritis. Males are more susceptible than females. Oophorectomy enhances susceptibility to arthritis and treatment with physiological doses of 17β-oestradiol (E2) suppresses disease. E2 treatment lowers the incidence of arthritis also in non-castrated and castrated males, showing that the anti-arthritic effect by oestrogen is not dependent on either sex hormone imprinting effects or interference with male sex hormones. Testosterone treatment of normal females, but not of castrated females, exaggerated development of the disease. In the testosterone-treated normal females, the oestrogen effect on vaginal smear was abolished and ovarian weight decreased, suggesting that the testosterone-mediated enhancing effect is caused by inhibition of ovarian oestrogen production. The crucial importance of oestrogens for the development of arthritis is focused on the effectiveness of treatment with gestation-related doses of E2 of normal, non-castrated females. [ABSTRACT FROM AUTHOR]

DBA/1 male mice develop arthritis spontaneously al the age of 4 months. The affected joints show cell-rich pannus formation without T cell infiltration and only limited MHC class II expression. Specific pathogen-tree DBA/1 mice from different sources developed the same disease. Analyses of inbred mouse strains with various genetic backgrounds and Fl hybrids revealed that the disease is genetically dependent of DBA/I recessive genes. However. Fl hybrids between DBA/1 and BXSB spontaneously developed arthritis with earlier onset than DBA/I mice, suggesting that the BXSB autoimmune gene background had both permissive and contributing effects on the development of arthritis. The complete male preponderance for disease susceptibility was investigated by castration and testosterone treatment of DBA/1 males. No arthritis developed after castration and disease susceptibility was restored by testosterone treatment. Arthritis developed only where more than two males were kept in cages, suggesting an influence by aggressive behaviour. Thus, the spontaneous development of arthritis is dependent on hormonal and behavioural mediated effects and differs from experimental models for rheumatoid arthritis such as type II collagen-induced arthritis and pristine induced arthritis. We conclude that the spontaneously developing arthritis in the normal DBA/I strain may be more useful as a disease model for osteoarthritis than for rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

The DA rat is highly susceptible to induction of arthritis after immunization with homologous type 11 collagen (CIA) emulsified in Freund's incomplete adjuvant (FIA), resulting in collagen-induced arthritis (CIA). The DA rat also develops arthritis after injection of FIA alone (oil-induced arthritis (OIA)). This finding allows a direct comparison of two different models for rheumatoid arthritis; one induced with a defined auto-immunogen and one with a pure adjuvant. Both CIA and OIA develop approximately 2 weeks after induction but OIA is a self-limited acute disease whereas CIA induced with homologous CII follows a chronic disease course. Immunization with CII leads to a strong autoantibody response to CM while injection of FIA leads to no or very limited anti-CII antibody response. The Lewis rat develops neither CIA nor OIA while F1(DA × Lewis) rats develop CIA but not OIA-Olive oil or CII emulsified in olive oil docs not induce arthritis in DA rats. Pretreatment with CII in olive oil vaccinates against CIA but not OIA whereas pretreatment with FIA vaccinates against OIA but not CIA. These findings demonstrate that inclusion of CII in the adjuvant leads to a disease distinct from OIA which is characterized by a CII autoimmune response and chronicity of the disease course. [ABSTRACT FROM AUTHOR]

Experimental animal models can be used to help understand how oestrogen modulates autoimmune arthritis. We have previously shown that castration of female DBA/1 mice exaggerates arthritis induced with type II collagen. This report shows that treatment of castrated DBA/1 mice with low doses (0.2 μg twice a week) of β-oestradiol reduces the incidence (37%, vs78% in controls) and severity (3.9 vs 5.6 mean scores) of arthritis. Levels of IgG anti type II collagen antibodies are decreased whereas levels of IgM antibodies are increased in the β-oestradiol treated mice. The T cell response, as measured by a ³H-thymidine assay,, is reduced in the β-oestradiol treated mice. The results suggest that treatment with low doses of β-oestradiol exerts a suppressive effect on both development of collagen arthritis as well as T cell dependent immune reactivity towards type II collagen. [ABSTRACT FROM AUTHOR]

The kinetics and mechanisms for secretion of antibodies against native and denatured collagen type II have been studied in spontaneously arthritic MRL/l mice. Circulating antibodies were quantified by an ELISA assay and frequencies of specific antibody secreting spleen cells by an ELISPOT assay. The degree of humoral immunity to collagen type II increased at late stages of the disease (6 months of age) whereas severe synovitis was seen earlier (5 months of age). Both the appearance of anti-collagen II producing cells and development of synovitis was preceded by and not correlated with a general state of polyclonal B cell activation. In MRL/l mice, collagen II specific antibodies appeared spontaneously and titres were largely unaffected by collagen II immunization. The levels of circulating anti-collagen II antibodies in MRL/l mice were lower, and the antibodies displayed lower avidities and different specificities as compared with the antibodies generated in collagen II high responder DBA/l mice after immunization with collagen II. It is suggested that the antibody response in MRL/l mice against collagen type II docs not need MHC-restricted T cell help and that induction of antibody production to collagen II in MRL/l mice is triggered by joint cartilage destruction and subsequent collagen II release. [ABSTRACT FROM AUTHOR]

Native type II collagens of rat, chick, bovine, human and murine origin have been used for immunization of male and female DBA/1 mice of different ages. The four heterologous collagens were able to induce arthritis in both male and female mice although the incidence of arthritis was higher in males. The onset of arthritis was sudden with severe lesions starting to appear 5- to 6-weeks after immunization. Mouse collagen II, on the other hand, caused arthritis exclusively in males. The onset of arthritis was in the latter case less dramatic and usually delayed until 12- to 14-weeks post immunization. Antibody production against both the immunogen and other type II collagens, including mouse collagen was seen in both arthritic and non-arthritic animals, and antibody titres against both the collagen used for immunization and mouse collagen were higher in the sera from arthritic than in identically immunized non-arthritic animals. Total amounts of auto-anti- collagen II antibodies were, however, more dependent on which collagen preparation was used for immunization than on whether the immunized mice developed arthritis or not. These results indicate that arthritis induction in mice is not dependent solely on the levels of auto reactive anti-collagen II antibodies. [ABSTRACT FROM AUTHOR]

The purpose of the study was to map the dominant T ceil epitope of the CBIl sequence of CII in RTIu huplotype rats and lo determine if, when used as a synthetic peptide, it would induce tolerance to protect against CIA. A dominant epitope corresponding to residues 184-198 included in the sequence of the CBII fragment of bovine CII was identified in proliferation assay using peptides in an epitope scanning system using synthetic peptides of 15 amino acids, overlapping by 12 amino acids. This epitope is bovine-specific, but cross-reacts with the corresponding rat peptide. Minor epitopes in the bovine CBII sequence were also autoantigenic. Use of independently synthesized and purified 184-198 peptide confirmed its dominance in the T cell responses of arthritic rats. The peptide itself was not arthritogenic. Cells from lymph nodes draining arthritic feel were particularly responsive to the dominant peptide sequence, and showed evidence of epitope spreading to include reactions to at least four subdominant epitopes. Mucosal tolerance was successfully induced by instilling CII into the nose of rats before induction of CIA; this was found to delay the onset of disease, reduce mean disease severity, shift the anti-CII antibody response to favour antibodies of the IgGl, rather than the lgG2b isiotype, and to reduce T cell reactivity to both CII and to the 184-198 peptide. The dominant 184-198 peptide itself had the same tolerogenic effects when given nasally lo rats daily, on the 4 days immediately preceding the induction of CIA. Two forms of CIA with acute and delayed disease onset were each modified by pre-treatment with the peptide. This study demonstrates that mucosal tolerance to CII can be induced by delivering it nasally in a way similar to that achieved previously by oral delivery, and that the use of an imnunodominanl epitope contained in a synthetic peptide will also suppress the immunologic and arthritic responses to collagen. [ABSTRACT FROM AUTHOR]

A protracted and relapsing form of experimental allergic encephalomyelitis (EAE) develops in the DA rat after immunization with rat spinal cord homogenate (SCH) emulsified in incomplete Freund's adjuvant (IFA). The genetic influence on this model has been analyzed by immunizing MHC congenic strains on both LEW and DA genetic backgrounds, and recombinant inbred strains between DA and E3 rats. An in situ hybridization assay was used to examine the expression of mRNA for IFN-γ, IL-4, IL-10 and transforming growth factor (TGF)-β both in sections of spinal cords and the antigen-induced expression for these cytokines by splenotcytes after in vitro stimulation with encephalitogenic MBP peptides. The susceptibility of relapsing EAT after immunization with SCH in IFA in the DA strain, but not the E3 strain, was correlated with a lack of expression for TGF-β in the spinal cord. The recombinant inbred DXEB rats developed a severe EAE while surprisingly no signs of disease were observed in the DXEA strain, which shares the MHC region with the DXEB strain, after immunization with the MBP 63-87 peptide. Resistance to relapsing EAE in the DXEA strain correlated with increased non-MHC controlled expression for TGF-β and lack of IFN-γ in the spinal cord. The same pattern of cytokine expression was seen in splenocytes after restimulation in vitro with the MBP 63-87 peptide. A spreading of the immune response to the MBP 87-100 peptide was seen. Non-MHC genes controlled the quality of this response: splenocytes from MBP 73-87 immunized DXEB rats responded in vitro towards the MBP 87-110 peptide by expressing mRNA for IFN-γ, IL-10 and IL-4, whereas in the DXEA strain the corresponding response involved IL-4 and TGF-β. Taken together these data show that non-MHC controlled expression of mRNA for TGF-β is associated with resistance to EAE. [ABSTRACT FROM PUBLISHER]

Type II collagen (CII) is of immunological interest because of its repetitive structure and properties as an autoantigen. The mouse gene has recently been cloned, thus enabling T cell-defined epitopes to be identified. Multiple novel epitopes on mouse CII are here detected in the autoreactive T cell response. The major response is directed to an epitope with residues 707-721 located on the CB10 fragment. Some 25 other epitopes are also recognized, including the autologous homologue of the 256-270 epitope which dominates in the response to foreign collagen. The cells reactive with mouse collagen peptides were of Th1 type, as judged by release of IFN-gamma. No significant reactivity was detected to mouse CII peptides during ongoing disease. Alignment of the mouse epitopes revealed a sequence motif with characteristic side chains at residues P1, P4 and P7, and to a lesser extent at P5, within a nonamer core sequence. Binding of these epitopes was simulated in a computer model of the I-Aq molecule, where peptides with anchor residues at P1, P4 and P7 were indeed found to fit the binding groove best. The spacing of pockets and the fine structure of the binding surface of the I-Aq molecule meshes with the repetitive structure of the collagen (X-Y-Gly), thus providing a likely explanation for the occurrence of multiple epitopes. Comparison with human DR binding motifs showed that the I-Aq motif resembles most closely that of the DR4 subtypes which predispose for rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

Pregnancy is known to influence the course of rheumatoid arthritis (RA) in women, as well as type II collagen-Induced arihritis (CIA) in DBA/I mice. A characteristic feature is the remission during gestation and the exacerbation of the diseases during the post-partum period. In the case of CIA in DBA/1 mice, two hormonal changes have been assumed to be critical for the induction of the postpartum flare: (i) the fall in steroid hormone levels from those present during pregnancy; and (ii) surges of prolactin (PRL) release at and after delivery. Our results show that treatment with oestradiol during a short period immediately after parturition protects the mouse from a post-partum flare of the disease, and that treatment with broniocriptine, a drug known to inhibit the endogenous PRL release, has a significant though less marked effect. Studies of lactating (i.e. animals with physiological stimulation of endogenous PRL release) and non-lactating arthritic mice revealed no clear-cut differences. Indicating that PRL is of minor importance for the induction of the post-partum flare. Some steroids other than oestradiol, which may be implicated in the exacerbation of arthritis, namely progesterone and hydrocortisone. had no clinical effect. Analyses of agalactosyl IgG levels in mice with CIA, and anti-collagen II antibodies in sera collected at the end of the experiments revealed no significant differences between the oestradiol and the control groups. The successful oestradiol treatment of the mice indicates that the drop in endogenous oestradiol levels prior to delivery ends the oestrogen-mediated protection against arthritis during pregnancy. [ABSTRACT FROM AUTHOR]

The influence of oestrogen on the lupus disease in MRL/I mice has been investigated. Adult, castrated male and female MRL/I mice were administered with s.c. injections of 3.2 μg of 17&bea;-oestradiol twice a week. The results clearly demonstrate that a relatively small dose of oestrogen is a potent accelerator of the lupus disease in this mouse strain. Thus, administration of oestrogen accelerates glomerulonephritis. lymphoproliferation and mortality. Our results also indicate that oestrogen exerts a dual effect on the immune system of MRL/l mice by depression of antigen-specific and mitogen-induced I cell responses as well as enhancement of polyclonal B cell activation and autoantibody formation. In addition, even short-term administration of oestrogen in the preclinical phase oft he disease resulted in long-lasting effects as evaluated by reduced longevity and aggravation of renal disease. [ABSTRACT FROM AUTHOR]

The effects of the immunomodulatory drug Linomide (LS-2616) have been investigated on two variants of collagen-induced arthritis (CIA) in Lewis rats. i.e. arthritis induced cither with heterologous (bovine) or with homologous (rat) collagen type II (CM). Treatment with Linomide from the day of immunization (prophylactic) had a mild ameliorative effect on the severity of arthritis in the heterologous CIA, while the homologous CIA was strongly augmented. In both models, Linomide treatment caused a more severe arthritis when given from onset of clinical signs of disease and onwards (therapeutic). Serum antibody levels to CII were significantly decreased by prophylactic Linomide treatment in rats immunized with heterologous CII, while elevated levels of anti-rat CII antibodies were seen in the homologous model. No effect on antibody levels was seen with the therapeutic treatment regime. The opposing effects of prophylactic treatment with Linomide in heterologous and homologous CIA indicate that the immune response to an autoantigen may be regulated differently from that to a foreign antigen. These results further strengthen the view that heterologous and homologous CIA should be regarded as separate experimental models, and that the studies on homologous CIA may represent a novel approach for future studies of autoimmune responses and evaluation of anti-rheumatic drugs. [ABSTRACT FROM AUTHOR]

During the delayed type of hypersensitivity (DTH) reaction in the skin, class II transplantation antigens are expressed on the keratinocytes. This induction is attributed to the action of y-interferon (IFN-γ). We have now studied the influence of antibodies against IFN-γ on the DTH-reaction. Lewis rats were sensitized to 2,4-dinitro-1-fluorobenzene (DNFB) and challenged 5 days later with DNFB on the ears. Immediately before challenge each animal in one group (n = 16) was given I mg of mouse monoclonal antibodies (MoAb) against rats IFN-γ, denoted DB-l, intraperitoneally (i.p.). another group (n = 15), 1 mg of an irrelevant MoAb and a third group (n = 11) was left untreated. The ear thickness was measured with a micrometer, before challenge and after 24, 48 and 72 h. At 72 h all rats were killed, the ears cut off, snap frozen and stained with immunoperoxidase using MoAbs OX 6 and OX 17, directed against rat class II antigens. The DB-1 treated group was found to have a larger ear swelling that was statistically significant at each time point compared with the other two groups. Furthermore, the animals given DB-1 showed class II antigen expression on Langerhans' cells, but almost none on keratinocytes. In contrast, the rats in the two other groups displayed a moderate to strong expression of class H antigens on keratinocytes as well as on Langerhans' cells. It is concluded that DB-l can inhibit class II antigen expression on keratinocytes during the DTH- reaction and also enhance the local response. [ABSTRACT FROM AUTHOR]