[Future treatment of rheumatism. A compromise in the game between inflammation and infections].
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Humans↗
Biomedical subjects
L Klareskog
Publications and source records attributed to L Klareskog.
Increased number of interleukin-10-producing cells in systemic lupus erythematosus patients and their first-degree relatives and spouses in Icelandic multicase families.
OBJECTIVE: To evaluate the production of interleukin-10 (IL-10) as well as levels of IgG and antinuclear antibodies (ANA) in systemic lupus erythematosus (SLE) patients and their first-degree relatives and spouses in Icelandic SLE multicase families. METHODS: IL-10 production was studied by enzyme-linked immunospot assay of freshly isolated peripheral blood mononuclear cells. Total IgG and ANA were also investigated. Subjects consisted of 23 SLE patients and 47 of their first-degree relatives in 9 Icelandic multicase families. Subjects were ethnically matched by a group of healthy controls. A separate study investigated 12 SLE patients (also from SLE multicase families) and their spouses and a matched group of healthy controls. A predefined protocol was used to obtain both clinical and laboratory data, including information about SLE and other autoimmune disorders. RESULTS: The SLE patients had a significantly higher number of IL-10-producing cells compared with both first-degree relatives and healthy controls (P = 0.0005 and P < 0.0001, respectively). First-degree relatives also had a significantly higher number of IL-10-producing cells compared with healthy controls (P = 0.01). This was also true for the spouses of SLE patients, who had a higher number of IL-10-producing cells compared with matched healthy controls (P = 0.02). CONCLUSION: SLE patients and their first-degree relatives, as well as a limited number of healthy spouses of SLE patients, had increased numbers of spontaneous IL-10-producing cells. These data support the hypothesis that IL-10 production may be genetically determined, and may predispose one toward development of SLE. This has previously been suggested by studies of SLE patients and their relatives in another ethnic population, using another method for measuring IL-10 production. Although these data are based on a small number of observations, they suggest that not only genetic but also environmental factors may be of importance in determining IL-10 production, since the spouses of SLE patients also had an increased number of IL-10-producing cells.
Autoantibodies↗
A comparison of genome-scans performed in multicase families with systemic lupus erythematosus from different population groups.
Systemic lupus erythematosus is a disease of unknown etiology. Multiple genetic factors are believed to be involved in its pathogenesis. In addition, and due to genetic heterogeneity, these factors and/or their combinations may be different in different ethnic groups, while some might be shared between populations. We have performed genome scans in multicase families from three different population groups, two from Northern Europe, with a high degree of homogeneity, and the third from a recently admixed population of Mexican Mestizos. Although our family material is relatively small, the results presented here show that using family sets from well defined populations are sufficient to detect susceptibility loci for SLE. Our results also reveal the chromosomal regions most likely to contain susceptibility genes for SLE.
Ethnicity↗
Susceptibility of rats to homologous collagen-induced arthritis depends on MHC genes in the class II region.
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Animals↗
Rheumatoid arthritis and its animal models: the role of TNF-alpha and the possible absence of specific immune reactions.
Rheumatoid arthritis is an organ-specific inflammatory disease of humans. Recent studies have focused on associations with non-MHC genes, new autoantigens and the role of innate immune responses. The success of anti-TNF-alpha in the majority (but, interestingly, not all) of patients has implications for disease mechanisms but the dangers of long-term therapy are becoming clearer. A number of new models of arthritis have been defined and emphasize the importance of the genetic make-up of the host. Attention has also focused on why the joint is a particularly vulnerable site for inflammatory responses.
Animals↗
Anti-inflammatory effects of a new tumour necrosis factor-alpha (TNF-alpha) inhibitor (CNI-1493) in collagen-induced arthritis (CIA) in rats.
A recently developed compound, a multivalent guanylhydrazone (CNI-1493) that inhibits TNF-alpha production by suppressing TNF-alpha translational efficiency, was administered in an experimental model of collagen type II-induced arthritis in DA rats. CNI-1493 was injected daily intraperitoneally either before the onset of arthritis or after the establishment of clinical disease. Prophylactic treatment with CNI-1493 significantly prevented or delayed the onset and suppressed the severity of arthritis in a dose-dependent manner. Therapeutic intervention with CNI-1493 in established joint disease also resulted in a significant reduction of clinical signs of arthritis in treated animals. No severe side-effects were noted when animals were treated with daily CNI-1493 doses up to 5 mg/kg. An immunohistochemical study was performed which demonstrated that CNI-1493 led to a reduced expression of TNF-alpha at the site of disease activity. Thus, CNI-1493 with documented inhibitory effects on TNF-alpha synthesis, has proven successful in ameliorating the course of arthritis in CIA. We believe that the use of a compound such as CNI-1493 with a defined mode of action provides a useful tool for dissecting and understanding important pathogenic mechanisms operating in the development of chronic arthritis.
Animals↗
Cytokine-producing cells in peripheral blood of children with coeliac disease secrete cytokines with a type 1 profile.
Coeliac disease (CoD) is a small intestinal disorder characterized by crypt cell hyperplasia and villous atrophy, and the production of cytokines from T cells and macrophages are of importance for the histological changes seen in CoD. A peroral immunization with an antigen, which gives rise to a mucosal immune response, may increase the levels of circulating cytokine-producing cells, and we wanted to obtain a better picture of an eventual emergence of activated circulating T cells in the peripheral blood in children with CoD. The cytokine expression of interferon-gamma (IFN-gamma), IL-4, IL-6 and IL-10 was measured at the single-cell level by an ELISPOT method in 38 children with CoD. The numbers of IFN-gamma-producing cells in the peripheral blood was increased in children with untreated CoD (P < 0.01) and after gluten challenge (P < 0.05) compared with healthy controls. Also, the numbers of IL-6-producing cells were increased (P < 0.05) after gluten challenge compared with the healthy controls. A paired comparison showed that the numbers of IFN-gamma-producing cells increased after gluten challenge (P < 0.05), whereas no such change was seen for IL-4- or IL-10-producing cells. There were no differences in the numbers of IFN-gamma-producing cells between the group of children with treated CoD and the groups of untreated or challenged CoD children. IL-4 production correlated with serum levels of total IgE. These results show that circulating mononuclear cells in children with active CoD secrete cytokines compatible with a type 1 response.
Adolescent↗
Celiac disease in relation to immunologic serum markers, trace elements, and HLA-DR and DQ antigens in Swedish children with Down syndrome.
BACKGROUND: An association between Down syndrome and celiac disease has been reported. This study was conducted to determine the association between childhood celiac disease and Down syndrome in the county of Uppsala, Sweden. METHODS: All 76 children with Down syndrome (1-18 years) were screened for the occurrence of anti-gliadin antibodies (AGA) and anti-endomysium antibodies (EMA). Twelve children with suspected celiac disease were investigated further. RESULTS: Increased levels of both IgA and IgG AGA were found in 26% of the children and of EMA in and 5 of 76. Celiac disease was diagnosed in at least three of the children (3.9%; 95% confidence interval 0%-8.3%), and it could have been present in as many as eight. Three of the five EMA-positive children with suspected celiac disease had the HLA phenotype DR3, DQ2. CONCLUSIONS: The results show that determination of EMA is more useful as a screening test for celiac disease and for follow-up than is AGA in children with Down syndrome. The present study also confirms that celiac disease is overrepresented among Swedish children with Down syndrome and that celiac disease should be considered in all persons with Down syndrome.
Adolescent↗
Genetic analysis of the contribution of IL10 to systemic lupus erythematosus.
OBJECTIVE: To study the contribution of the IL10 gene to the susceptibility to systemic lupus erythematosus (SLE). METHODS: Analysis by fluorescent-semiautomated genotyping of a dinucleotide repeat located in the promoter region of the IL10 locus (microsatellite G). RESULTS: No significant difference was found in the frequencies of the microsatellite alleles of 330 Mexican patients with SLE compared to 368 controls from the same population. Two-point linkage analyses were carried out using 13 Mexican, 13 Swedish, and 8 Icelandic families with 2 or more cases with SLE. No linkage was revealed between IL10 and SLE, using a variety of parameter settings. CONCLUSION: Our results do not support that the IL10 gene contributes to the susceptibility to SLE in the populations we studied.
Dinucleotide Repeats↗
Disease activity and risk of lymphoma in patients with rheumatoid arthritis: nested case-control study.
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Arthritis, Rheumatoid↗
Identification of rat susceptibility loci for adjuvant-oil-induced arthritis.
One intradermal injection of incomplete Freund's adjuvant-oil induces a T cell-mediated inflammatory joint disease in DA rats. Susceptibility genes for oil-induced arthritis (OIA) are located both within and outside the major histocompatibility complex (MHC, Oia1). We have searched for disease-linked non-MHC loci in an F2 intercross between DA rats and MHC-identical but arthritis-resistant LEW.1AV1 rats. A genome-wide scan with microsatellite markers revealed two major chromosome regions that control disease incidence and severity: Oia2 on chromosome 4 (P = 4 x 10(-13)) and Oia3 on chromosome 10 (P = 1 x 10(-6)). All animals homozygous for DA alleles at both loci developed severe arthritis, whereas all those homozygous for LEW.1AV1 alleles were resistant. These results have general implications for situations where nonspecific activation of the immune system (e.g., incomplete Freund's adjuvant-oil) causes inflammation and disease, either alone or in conjunction with specific antigens. They may also provide clues to the etiology of inflammatory diseases in humans, including rheumatoid arthritis.
Animals↗
A vitamin D analogue (MC 1288) has immunomodulatory properties and suppresses collagen-induced arthritis (CIA) without causing hypercalcaemia.
The immunomodulatory properties of the vitamin D analogue MC 1288 (20-epi-1alpha,25-dihydroxycholecalciferol) were investigated in CIA in rats. The analogue was administered systemically at three different time points; (i) for 10 consecutive days before collagen (CII) immunization; (ii) for 10 consecutive days after CII immunization; or (iii) for 7 consecutive days from disease onset. Treatment initiated either 10 days before CII immunization or at the day of collagen immunization effectively suppressed the development of arthritis. Treatment initiated at the day of the onset of arthritis reduced the severity of joint inflammation. Significantly, doses which did not induce hypercalcaemia decreased the incidence and severity of arthritis. In vivo treatment with the 20-epi analogue of 1alpha,25-dihydroxycholecalciferol diminished the serum levels of antibodies to rat CII. Similarly, mitogen-induced proliferation of lymph node cells from rat CII-immunized animals was reduced. The experiments demonstrate that the vitamin D analogue MC 1288 has the ability to prevent, and furthermore to suppress, already established CIA by its immunomodulatory properties without inducing hypercalcaemia.
Adjuvants, Immunologic↗
Decreased expression of signal-transducing CD3 zeta chains in T cells from the joints and peripheral blood of rheumatoid arthritis patients.
Although T cells from patients with rheumatoid arthritis (RA) have previously been determined to have poor proliferative responses to a variety of stimuli, the underlying mechanism is not known. We have investigated the expression of the signal-transducing zeta molecule in subsets of T cells and natural killer (NK) cells derived from the peripheral blood mononuclear cells (PBMC) and synovial fluid mononuclear cells (SFMC) of RA patients using quantitative flow cytometry, Western blot analysis and immunohistochemistry. A decrease of zeta expression was apparent in all investigated lymphocyte subsets from the PBMC and SFMC of RA patients, as compared to the corresponding subsets from healthy age- and sex-matched controls. A less pronounced reduction of cell surface-located CD3 epsilon, CD4 and CD8 was also located in T cells from SFMC as compared to PBMC from RA patients. Biochemical demonstration of the low or absent CD3 zeta in PBMC from patients with RA was achieved by Western blot analysis. Immunohistochemical staining and image analysis also confirmed the low expression of zeta chains in synovial tissue of RA patients. The possibility that the decreased expression of zeta and of immune functions of T cells from RA patients may be related to the presence of free oxygen radicals, as we have previously reported in cancer patients, should be considered.
Arthritis, Rheumatoid↗
Production of T-cell cytokines at the single-cell level in patients with inflammatory arthritides: enhanced activity in synovial fluid compared to blood.
We used a newly developed, sensitive ELISPOT technique in order to estimate the number of cells producing interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) in synovial fluid mononuclear cells (SFMC) and peripheral blood mononuclear cells (PBMC) in patients with rheumatoid arthritis (RA) and other inflammatory arthritides, and to correlate the results with clinical and laboratory parameters of disease activity. SFMC and PBMC were cultured either without stimuli or with a standardized dose of phytohaemagglutinin (PHA) for 6 h. Twenty-nine patients, 16 with RA and 13 with other inflammatory joint diseases, were investigated and compared to PBMC from 25 healthy controls. The mean number of IFN-gamma-producing cells was 37.1/10(5) plated SFMC (range 0-121.5). The corresponding value for PBMC was 5.1 (0-39). The difference was highly significant (P = 0.0033 for RA patients, P = 0.0050 for non-RA patients and P < 0.0001 for all patients). Forty-five per cent of SFMC samples (range for all samples 0-38.5 SFC/10(5) MNC) and 25% of PBMC samples (0-20.5) exhibited spontaneous IL-4 production, yielding a significant difference for all patients treated collectively (P = 0.021). Although the cells that spontaneously secrete these cytokines are relatively few, quantification of these cells thus shows increased functional T-cell activation and decreased ratio of cells spontaneously producing IL-4 vs IFN-gamma in the joint fluid as compared to blood of arthritis patients.
Adult↗
Common commercial cosmetic products induce arthritis in the DA rat.
Many different agents, including mineral oil and silicone, have the capacity to act as immunological adjuvants, i.e., they can contribute to the activation of the immune system. Some adjuvants, including mineral oil, are known to induce arthritis in certain strains of rats after intradermal injection or percutaneous application. The aim of this study was to determine if common commercial cosmetic products containing mineral oil could induce arthritis in the highly susceptible DA (Dark Agouti) rat. Intradermal injection of five out of eight assayed cosmetic products without further additives resulted in arthritis with synovitis. One of the products induced a very aggressive arthritis, which had declined after 5-9 weeks. When this product was also assayed for arthritogenicity upon percutaneous administration, it induced a mild and transient arthritis in 5 out of 10 DA rats, whereas control animals showed no clinical signs of joint involvement. No arthritic reaction was seen in rats after peroral feeding with the most arthritogenic product or by intravaginal application of Freund's adjuvants. Silicone gel implants in DA rats did not cause arthritis. We conclude that mineral oils included in common commercially available products retain their adjuvant properties and are arthritogenic in the presently investigated arthritis-prone rat strain. There is yet no evidence that mineral oils present in cosmetics may contribute to arthritis in humans, but we suggest that this question should be subject to further investigation.
Administration, Oral↗
Major histocompatibility complex class II expression and parathyroid autoantibodies in primary hyperparathyroidism.
BACKGROUND: Autoimmune diseases are characterized by induced parenchymal expression of major histocompatibility complex (MHC) class II antigens and circulating autoantibodies directed toward surface structures on the target cells. MHC class II expressions can be modified by viral infections of potential pathogenic importance in autoimmune reactions. Primary hyperparathyroidism exhibits incompletely clarified cause. METHODS: With cryosections, human parathyroid glands were stained with monoclonal antibodies to MHC class II antigens according to a peroxidase-antiperoxidase technique. Human parathyroid adenoma tissue transplanted to nude mice and rat parathyroid glands was tested with serum from patients with hyperparathyroidism and control subjects. RESULTS: Induced MHC class II expression was demonstrated on parathyroid parenchymal cells in 13 of 54 adenomatous and eight of 23 hyperplastic glands of patients with primary hyperparathyroidism. This reactivity was absent in 12 normal glands, nine normal-sized glands associated with the adenomas, and 17 enlarged glands of patients with hyperparathyroidism caused by uremia. Staining of parathyroid tissue was found with serum from 27 of 38 patients with primary hyperparathyroidism, whereas this reactivity was absent on rat thyroid and pancreatic tissue, as well as with control sera. CONCLUSION: The concurrent induction of MHC class II antigen expression and c circulating antiparathyroid autoantibodies in 16 or 38 patients with primary hyperparathyroidism suggests hitherto unrecognized immunologic involvement in this disease.
Adenoma↗
A comparison between ELISPOT methods for the detection of cytokine producing cells: greater sensitivity and specificity using ELISA plates as compared to nitrocellulose membranes.
We have used the ELISPOT method employing plastic ELISA plates without substrate in agar for the detection of single cells producing interferon-gamma (IFN-gamma) and interleukin-4 (IL-4). When using PBMC directly stimulated in the assay wells with T cell mitogens it was possible to measure production of human IFN-gamma at an earlier time point and with a higher sensitivity compared to conventional nitrocellulose plates. The plastic surface was not autostimulatory for IFN-gamma production, as seems to be the case for nitrocellulose surfaces. Compared to the use of nitrocellulose plates, the use of plastic ELISA plates is considerably cheaper and easier to perform. The increased sensitivity for cytokine detection, together with minimal autostimulatory properties of the detection surface, makes this method suitable for the detection of spontaneous low grade cytokine production from cells obtained in vivo.
Cells, Cultured↗
[New perspectives on rheumatoid arthritis].
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Arthritis, Rheumatoid↗