bromochloroacetic-acid and Arthritis

Peptides derived from amino acid sequence 60-80 of HLA-B27 (B27PA, aa 60-72 and B2702PA, aa 60-80) mimic cytokeratin and are able to induce in vitro proliferation of human peripheral blood lymphocytes as well as arthritis in Lewis rats. Here we show that the pathogenic epitope recognized by autoaggressive rat T cells is located at the N-terminus of the sequence, between aa 60 and 72. A C-terminally elongated 25mer peptide (B2702.60-84) showed increased pathogenicity, indicating either a second arthritogenic epitope or an immunomodulatory region within this peptide. B2702.60-84 has been described to inhibit murine and human CD8 + cytotoxic T cells (CTL) and was even successfully used for the treatment of allograft rejection. In addition to pathogenicity we have investigated the immunomodulatory effect of peptide B2702.60-84 in our rat model of experimental autoimmune uveitis (EAU), induced with retinal S-Antigen peptide PDSAg. We found that disease exacerbated following coimmunization of PDSAg with B2702.60-84. In vitro, the B27-peptide enhanced the proliferation of CD4+ T cell lines specific for retinal autoantigen peptides during coincubation of B2702.60-84 with the respective antigen. Oral tolerance induction, an effective mechanism to prevent uveitis in Lewis rats, is abrogated by cofeeding peptide B2702.60-84 with the tolerogen PDSAg. In rat EAU, naturally occurring regulatory T cells and orally induced gamma deltaTCR+ suppressor cells are CD8+ which might be impeded by peptide B2702.60-84. As a consequence of their abrogated suppressive capacity disease was exacerbated. We propose a similar role of HLA-B27 in man: disturbing the mechanisms down-regulating self-responses might lead to autoimmune diseases. This could explain the high association of HLA-B27 with a variety of autoimmune diseases targeting different organs or tissues.

Topics: Amino Acid Sequence; Animals; Arthritis; Autoimmune Diseases; Cell Proliferation; Disease Models, Animal; Female; HLA-B27 Antigen; Immune Tolerance; Keratins; Male; Molecular Sequence Data; Peptide Fragments; Rats; Rats, Inbred Lew; T-Lymphocytes; Uveitis

Chronic hepatitis C virus (HCV) has been linked to extrahepatic autoimmune phenomena. In addition a variety of autoantibodies were found in patients with HCV. This study was performed to assesss the clinical relevance of antikeratin antibodies in rheumatoid arthritis (RA) and in patients with symmetric polyarthritis associated with hepatitis C infection. Serum antikeratin antibodies were evaluated in 3 different groups of patients; all were rheumatoid factor (RF) seropositive: Group 1: 31 patients with HCV associated symmetric polyarthralgia or arthritis. Group 2: 28 patients with RA (modified ACR criteria for probable RA). Group 3: 16 patients with autoimmune disorders other than RA. Seventeen healthy individuals matched for age and sex served as controls. In our study, 75 patients who were rheumatoid factor positive (measured by ELISA, the cutoff was established to 20 U/mL) were tested for antikeratin antibodies using an indirect immunofluorescence technique with 1:10 serum dilution. Antikeratin antibodies were detected in 18/28 (64%) patients with true RA and only 3/31 (9%) patients with HCV-related arthritis (p < 0.0001). Antikeratin antibodies were observed in 3/16 (18%) patients of group 3 (p < 0.05). Antikeratin antibodies were not found in the sera of the healthy controls.

Topics: Arthritis; Arthritis, Rheumatoid; Autoantibodies; Biomarkers; Case-Control Studies; Female; Fluorescent Antibody Technique, Indirect; Hepatitis C, Chronic; Humans; Immunoglobulin G; Keratins; Male; Rheumatoid Factor

We analysed the presence of anti-cyclic citrullinated peptide (anti-CCP) and anti-keratin (AKA) antibodies of the IgG class in sera of patients with defined juvenile idiopathic arthritis (JIA) of various subgroups with more than one year duration of the disease. Enzyme-linked immunosorbent assay (Immunoscan RA, Eurodiagnostica, The Netherlands) and an indirect immunofluorescence (IIF) test on rat oesophagus substrate (ImmuGloTM, Immco Diagnostics, Buffalo, USA) were used for the detection and quantification of anti-CCP and AKA antibodies in 140 patients with JIA (64 male and 76 female) aged 2-47 years (median 16.5 years). Overall, anti-CCP were found in 7/140 (5.0%) patients including 3/52 RF negative polyarthritis, 2/18 RF positive polyarthritis, 1/15 enthesitis related arthritis and 1/5 unclassifiable arthritis. AKA were detected in 40/140 patients (28.6%, p = 0.04) including 2/11 systemic arthritis, 2/32 oligoarthritis, 18/52 patients with RF negative polyarthritis (34.6%, p = 0.01), 14/18 RF positive polyarthritis (77.8%, p = 0.000002), 2/15 enthesitis related arthritis and 2/3 psoriatic arthritis. While simultaneous negativity for AKA and anti-CCP occurred in most (97/140; 69.3%) studied cases, simultaneous antibody positivity was found only in few (4/140; 2.9%) studied samples. We conclude that while AKA measured using IIF on rat esophagus can be detected approximately in one third of patients with definite JIA with more than 1 year duration of the disease, only rare occurrence of anti-CCP was observed. We conclude that AKA seem to be partly useful to confirm JIA diagnosis, however, useless to follow-up severity or activity in JIA patients. Anti-CCP do not have any additional value in MA cohort in comparison to RA where their diagnostic and prognostic importance was reported.

Topics: Adolescent; Adult; Arthritis; Child; Child, Preschool; Citrulline; Female; Humans; Immunoglobulin G; Keratins; Male; Middle Aged; Peptides, Cyclic

Ankylosing spondylitis (AS) is highly associated with HLA-B27. We have previously shown that peripheral blood lymphocytes from AS patients respond to stimulation with a peptide from the sequence of HLA-B27. Here we report on molecular mimicry of peptides from HLA-B27 and cytokeratin, the latter being specifically expressed in synovial membranes and eyes, the main targets of the autoaggressive immune response in AS patients. Immunization of rats with these peptides induced an inflammatory response in joints, spine and eyes, resembling the symptoms in AS. Furthermore, both HLA-B27- and cytokeratin-derived peptides, are effective oral tolerogens: feeding these peptides ameliorated arthritis and uveitis induced with the cytokeratin peptide. Our model might elucidate the role of peptides from the sequence of HLA-B27 as an antigen of the immune response in AS, introducing a new aspect of antigenic mimicry between HLA-B27 and tissue-specific antigens. We propose this as a mechanism directing a systemic autoimmune response to specific target organs by antigenic mimicry of T cell epitopes.

Topics: Amino Acid Sequence; Animals; Arthritis; Cross Reactions; Female; HLA-B27 Antigen; Immune Tolerance; Keratins; Male; Molecular Mimicry; Molecular Sequence Data; Peptides; Rats; Rats, Inbred Lew; T-Lymphocytes; Uveitis

To investigate whether antikeratin antibodies (AKA) could be useful in the differential diagnosis of patients with rheumatoid arthritis (RA) compared to patients with hepatitis C virus (HCV) associated polyarthritis, who are seropositive for rheumatoid factor (RF).. AKA were assayed in 3 different groups of patients; all were RF seropositive: Group 1: 25 patients with HCV associated polyarthralgia or arthritis. Group 2: 33 patients with RA. Group 3: 13 patients with autoimmune disorders other than RA. Fifteen healthy individuals served as controls.. AKA were detected in 20/33 patients with RA (60.6%) compared to only 2/25 patients (8%) with HCV associated arthritis (p < 0.0001). AKA were observed in 2/13 patients of Group 3 (15.3%). These results were also statistically different from those of patients with RA (p = 0.008). AKA were not found in the sera of the healthy controls.. AKA is a useful marker to differentiate patients with RA from those with hepatitis C arthritis.

Topics: Adult; Aged; Antibodies; Arthritis; Arthritis, Rheumatoid; Autoimmune Diseases; Diagnosis, Differential; Female; Hepatitis C; Humans; Immunologic Tests; Keratins; Male; Middle Aged

The goal of this prospective longitudinal study was to determine the serological profile of early rheumatoid arthritis (RA), and to test whether antikeratin antibody (AKA), antiperinuclear factor (APF), anti-RA33 antibody and antinuclear antibodies (ANA) had an additional diagnostic value when prescribed after rheumatoid factor (RF)-detecting methods. Sixty-nine patients with early polyarthritis suggestive of RA, seen between 1991 and 1993, were included. Five autoantibodies (i.e. RF, AKA, APF, RA33, ANA) were looked for at regular intervals. After 24 months follow-up, patients were classified as having RA (n = 49), unclassified polyarthritis (UP; n = 15) or other rheumatic diseases. Among patients with early RA, the sensitivity of these markers was 40.8% for RF, 36.7% for AKA, 28.6% for APF and 28.6% for anti-RA33. Among RF-negative RA patients, 51.7% were positive for AKA, APF, anti-RA33 antibodies and/or ANA. Positivity of the three recent markers usually persisted throughout follow-up, whereas RF was lost by 58% of patients with early, RF-positive, treated RA. Using multivariate analysis, only latex, RF test and AKA or APF had an independent and statistically significant diagnostic value for early RA. Our data suggest that RF and AKA (or APF) should be concomitantly determined for diagnosis in patients with suspected early RA.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Antinuclear; Arthritis; Arthritis, Rheumatoid; Autoantibodies; Female; Follow-Up Studies; Humans; Immunologic Tests; Keratins; Longitudinal Studies; Male; Middle Aged; Prospective Studies; Rheumatoid Factor; Sensitivity and Specificity

Immunocytochemical studies with a monoclonal anti-HLA-DR antibody were performed on skin sections and keratinocyte (KTC) suspensions obtained from suction blisters of active psoriatic plaques. HLA-DR+ KTCs were found in the plaques of 23 of 38 patients with active psoriasis. Of these 23, 16 had clinical findings typical of psoriatic arthritis (PA); none of the 15 patients who lacked HLA-DR+ KTCs had PA. Although KTC HLA-DR expression was more prevalent in patients with severe skin disease, 7 of the 23 patients with HLA-DR+ KTCs in active psoriatic plaques had mild skin disease; 4 of these 7 had PA. Nail pitting or duration of skin disease did not account for increased incidence of PA in patients with HLA-DR+ KTCs. All psoriasis patients with arthritis received nonsteroidal antiinflammatory drug therapy; 14 received additional therapy directed primarily to the cutaneous manifestations of psoriasis. Nine of these noted arthritis improvement with concurrent skin response; however, in 5 patients, arthritis activity increased, despite improvement of the cutaneous disease. Two other patients, treated with methotrexate, also had concurrent skin and joint improvement. These data suggest that psoriasis patients with HLA-DR+ KTCs are at increased risk for the development of associated arthritis.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Arthritis; Epidermis; Histocytochemistry; HLA-D Antigens; HLA-DR Antigens; Humans; Immunochemistry; Keratins; Psoriasis

Topics: Antibodies; Arthritis; Humans; Keratins

We report an interesting case of generalized papular and nodular lesions with central keratinous plugs and severe hyperkeratotic-acanthotic histopathology with arthritis in a 19-year-old male patient who had suffered from a similar disease 2 years earlier. Papules and nodules erupted a few days after the arthritis and this was noticed during both episodes. On healing, nodules fell spontaneously leaving behind insignificant hyperpigmented scars.

Topics: Adult; Arthritis; Humans; Keratins; Keratoacanthoma; Keratosis; Male; Skin; Skin Diseases