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1.  Characterisation of a dendritic cell subset in synovial tissue which strongly expresses Jak/STAT transcription factors from patients with rheumatoid arthritis 
Annals of the Rheumatic Diseases  2007;66(8):992-999.
To characterise the phenotype of the putative dendritic cells strongly expressing Jak3 and STAT4, which have been previously identified in the synovial tissue of patients with active rheumatoid arthritis (RA).
Synovial biopsy specimens were obtained at arthroscopy from 30 patients with active RA (42 synovial biopsies). Immunohistological analysis was performed using monoclonal antibodies to detect dendritic cell subsets, including activation markers and cytokines relevant to dendritic cell function. Co‐localisation of cell surface markers and cytokines was assessed primarily using sequential sections, with results confirmed by dual immunohistochemistry and immunofluorescence with confocal microscopy.
The dendritic cells identified in RA synovial tissue that strongly express Jak3 also strongly express STAT4 and STAT 6 and are correlated with the presence of serum rheumatoid factor. These cells are not confined to a single dendritic cell subset, with cells having phenotypes consistent with both myeloid‐ and plasmacytoid‐type dendritic cells. The activation status of these dendritic cells suggests that they are maturing or mature dendritic cells. These dendritic cells produce IL12 as well as interferon α and γ.
The close correlation of these dendritic cells with the presence of serum rheumatoid factor, a prognostic factor for worse disease outcome, and the strong expression by these cells of components of the Jak/STAT transcription factor pathway suggest a potential therapeutic target for the treatment of RA.
PMCID: PMC1954703  PMID: 17223651
rheumatoid arthritis; myeloid dendritic cells; plasmacytoid dendritic cells; IL12; interferon alpha; interferon gamma
2.  Changes in synovial tissue Jak‐STAT expression in rheumatoid arthritis in response to successful DMARD treatment 
Annals of the Rheumatic Diseases  2006;65(12):1558-1564.
Modulation of Jak‐STAT signalling may provide an effective therapeutic strategy in inflammatory arthritis (IA).
To examine the effect of successful disease‐modifying antirheumatic drug (DMARD) treatment on the expression of Jak‐STAT in a cohort of patients with active rheumatoid arthritis.
Synovial tissue biopsy specimens from 16 patients with active rheumatoid arthritis, taken before and after initiation of DMARD treatment, were examined for the presence of janus kinase (Jak)3, signal transducer and activator of transcription (STAT)1, STAT4 and STAT6 expression using immunohistochemistry.
Successful treatment with DMARDs results in reduction in STAT1 expression in the lining, and STAT1 and STAT6 in the sublining of rheumatoid arthritis synovial tissue. Although the overall expression of STAT4 and Jak3 was not significantly altered by DMARD treatment, there was a significant reduction in the expression of the STAT4 and Jak3 bright cells, thought to be an activated dendritic cell subpopulation.
Results show that Jak3, STAT1, STAT4 expression and STAT6 sublining expression decrease in response to successful treatment of rheumatoid arthritis with standard DMARDs. Therefore, altering the expression of these pathways may represent an alternative treatment option, either through promoting up‐regulation of inhibitory pathways, or suppressing inflammatory paths.
PMCID: PMC1798468  PMID: 16760256
3.  Expression of Jak3, STAT1, STAT4, and STAT6 in inflammatory arthritis: unique Jak3 and STAT4 expression in dendritic cells in seropositive rheumatoid arthritis 
Annals of the Rheumatic Diseases  2005;65(2):149-156.
Modulation of Jak‐STAT signalling may provide an effective therapeutic strategy in inflammatory arthritis.
To document Jak‐STAT expression in a cohort of patients with active rheumatoid arthritis (RA), spondyloarthritis (SpA), and osteoarthritis (OA) and compare these subsets with normal synovial tissue.
Synovial tissue biopsy specimens from patients with RA, OA, and SpA and histologically normal tissue (n = 10 in each arthritis group) were examined for the presence of Jak3, STAT1, STAT4, and STAT6 expression using immunohistochemistry. Phenotyping was performed using immunohistochemistry and immunofluorescence. Clinical and serological characteristics of patients with RA expressing Jak3‐STAT4 were assessed.
STAT1, STAT4, and Jak3 protein expression was generally increased in inflammatory arthritis. In contrast, STAT6 expression was relatively heterogeneous. A subpopulation of CD1a positive dendritic cells unique to seropositive patients with RA was detected. These cells showed intense protein expression for Jak3, STAT4, and STAT6.
CD1a positive dendritic cells intensely express Jak3, STAT4, and STAT6 in seropositive RA tissue and may be an alternative marker for dendritic cells in their early stages of activation as well as providing a tool for identifying RA at the level of the synovium. Jak3 inhibition may be a potential therapeutic target to prevent dendritic cell maturation in RA. STAT1 expression is increased in inflammatory arthritis, suggesting that its pro‐apoptotic and anti‐inflammatory effects cannot effectively counteract inflammation. STAT6 expression is heterogeneous in synovium, suggesting a possible homoeostatic role in addition to any anti‐inflammatory effects.
PMCID: PMC1798020  PMID: 16096332
dendritic cells; rheumatoid arthritis; transcription factors
4.  Does steroid pulsing influence the efficacy and toxicity of chrysotherapy? A double blind, placebo controlled study. 
Annals of the Rheumatic Diseases  1990;49(6):370-372.
To test the hypothesis that early steroid pulsing augments the efficacy and decreases the toxicity of chrysotherapy 40 patients with rheumatoid arthritis were studied in a double blind, placebo controlled study. During the first three months of gold treatment group 1 received monthly intravenous methylprednisolone pulsing (steroid group) while group 2 received placebo (placebo group). All patients were assessed clinically and serologically over a 24 week period. Twelve patients were withdrawn before completion of the study and all but one of the remaining 28 patients reported clinical and serological improvements. Two patients in the steroid group were withdrawn owing to gold induced side effects while four were withdrawn in the placebo group. These small numbers were not significantly different. Minor side effects occurred more commonly in the placebo group. The clinical response was clearly better in the steroid group with statistical significance almost being achieved. In an endeavour to obtain a significant conclusion further patients will now be entered into this study.
PMCID: PMC1004102  PMID: 2116773
5.  Low molecular weight IgM in primary biliary cirrhosis. 
Gut  1990;31(1):88-91.
Low molecular weight IgM is the monomeric subunit of pentameric IgM and is not generally found in the blood of healthy individuals. Using a sensitive immunoblotting technique, low molecular weight IgM was detected in all 17 patients with primary biliary cirrhosis and constituted up to 5% of the total circulating IgM. This low molecular weight IgM moiety correlated significantly with total IgM (p less than 0.01) but not with the specific biliary cirrhosis mitochondrial autoantibody anti-M2. Furthermore it was not possible to show that a partially purified sample of low molecular weight IgM contained M2 binding activity. Mitogen stimulated peripheral blood mononuclear cells from two of four patients were observed to secrete low molecular weight IgM in vitro, a finding seen in only one of six healthy subjects. Immunoblot analysis of patients sera revealed the presence of other oligomers of IgM in addition to low molecular weight IgM. In conclusion this study suggests that during the enhanced IgM synthesis observed in primary biliary cirrhosis a defect occurs in the assembly of the IgM pentamer with release of monomeric and oligomeric IgM into the circulation. The pathogenic significance of these circulating low molecular weight IgM species is unknown.
PMCID: PMC1378346  PMID: 2318435
6.  Illness behaviour in patients with arthritis. 
Annals of the Rheumatic Diseases  1995;54(4):245-250.
OBJECTIVES--To determine if there are specific patterns of illness behaviour in patients with arthritis, and if abnormal patterns of illness behaviour are associated with withdrawal from trials of anti-inflammatory drugs, and to examine which aspects of illness behaviour are perceived by rheumatologist to be related to the disease process. METHODS--The illness behaviour questionnaire (IBQ) was administered to 211 patients with rheumatoid arthritis (RA) and 107 patients with osteoarthritis (OA) participating in five drug trials of NSAIDs at the beginning of the studies, and was commented upon by 17 clinical rheumatologists. RESULTS--Factor analysis of 211 patients with RA produced a unique factor solution. RA patients were more preoccupied with their illness and its effects and worried more about their health than patients with OA. Patients who withdrew from drug trials showed behaviour patterns similar to those of chronic pain patients, and different from those of patients who completed the studies. When asked to account for a rheumatoid patient's response to the IBQ, rheumatologists focused on physical symptoms and did not recognise some of the psychological issues which patients saw as being relevant. CONCLUSIONS--We have demonstrated differences in illness behaviour between patients with OA and with RA. Patients withdrawing from drug trials of NSAIDs showed differences in illness behaviour compared with those successfully completing the trials. Rheumatologists underestimated the impact of the disease on their RA patients' psychological well being.
PMCID: PMC1005568  PMID: 7763099
7.  Autoantibodies in patients with juvenile chronic arthritis and their immediate family relatives. 
Annals of the Rheumatic Diseases  1990;49(12):968-972.
Antibodies to nuclear antigens were assessed in 23 children with juvenile chronic arthritis (JCA) and 66 of their first degree relatives. Serum samples from 16 patients with JCA (70%) and nine relatives (14%) had antinuclear antibodies by indirect immunofluorescence. Antibodies against nuclear antigens in rabbit thymus extract or an erythroblastoid cell line (K562) were detected by countercurrent immunoelectrophoresis and immunoblotting in 16 patients (70%) and 39 family relatives (59%). Immunoblotting did not show any banding patterns common to all patients with JCA, though bands in the 43-45 kD range were detected in 5/23 patients. Anticardiolipin antibodies were found in 7/23 patients. In total, 18/20 families (90%) had members other than the probands with detectable autoantibodies. In five families immunoblotting showed common banding patterns between the probands and other members. This suggests that there might be an inherited trend towards autoimmune responses in some families of patients with JCA.
PMCID: PMC1004288  PMID: 2270968
9.  Phenotypic and genotypic analysis of mononuclear cells from patients with Felty's syndrome. 
Annals of the Rheumatic Diseases  1990;49(2):103-106.
Phenotypic and genotypic characteristics of the peripheral blood mononuclear cells in nine patients with Felty's syndrome have been examined. One patient had an increased number and percentage of peripheral blood mononuclear cells with the phenotype CD3+ Leu-7+ CD16+ and showed a clonal rearrangement of the T cell receptor B chain gene. The remaining eight patients all showed a germline configuration of the T cell receptor B chain gene. In two patients an increased proportion of CD3+ Leu-7+ CD16- peripheral blood mononuclear cells (45 (SD 11)% of peripheral blood mononuclear cells) were found, while the remaining six patients had proportions of CD3+ Leu-7+ cells similar to those of patients with uncomplicated rheumatoid arthritis. These data confirm that patients with Felty's syndrome are heterogeneous, with at least three different peripheral blood mononuclear cell phenotypic subsets. One subset is characterised by a clonal expansion of an unusual lymphocyte subpopulation, another by polyclonal expansion, and the third subset has the same proportions of peripheral blood mononuclear cells as patients with uncomplicated rheumatoid arthritis.
PMCID: PMC1003987  PMID: 2317110
10.  Large quantities of low molecular weight IgM in mixed cryoglobulinaemia. 
Annals of the Rheumatic Diseases  1988;47(2):105-109.
Low molecular weight (LMW) IgM is the monomeric subunit of pentameric IgM. It was not found in the sera of 20 healthy subjects but was detected in all six patients with mixed cryoglobulinaemia with a mean value of 1.4 g/l, representing 34% of the total IgM. In three of four patients studied LMW IgM was monoclonal and of the same light chain type (kappa) as the pentameric monoclonal IgM rheumatoid factor (RF) observed in the cryoprecipitate. LMW IgM was proportionately under-represented, however, in the cryoprecipitate compared with the corresponding serum, possibly because of the lower valency of the LMW molecule. Immunoblot analysis of sera showed the presence of other oligomers of IgM in addition to monomeric IgM, suggesting that a disorder of IgM assembly was responsible for its occurrence, and this was supported by the secretion of large proportions of LMW IgM in vitro by peripheral blood mononuclear cells (PBMC) from one patient with this disorder but not from healthy controls. In conclusion, the occurrence of large quantities of monoclonal LMW IgM in mixed cryoglobulinaemia was observed, and it is suggested that this is unlikely to have a direct pathogenic significance. It is postulated that its presence reflects a disturbance of assembly of the monomeric IgM subunits that occurs during the polymerization of the pentameric molecule.
PMCID: PMC1003461  PMID: 3355247
11.  Effects of chrysotherapy on circulating lymphocyte numbers and subsets. 
In a prospective 24 week study of 25 patients with rheumatoid arthritis (RA) weekly intramuscular (IM) sodium aurothiomalate resulted in a small but significant reduction in the circulating lymphocyte count. Analysis of absolute levels of pan T cells, T4 helper cells, T8 suppressor cells, T4/8 ratio, B cells, and major histocompatibility complex (MHC) class II positive cells showed reductions in these subsets, though these changes did not reach significance. At entry there was no association between circulating lymphocyte counts and subsets and clinical and laboratory indices which reflected disease activity, and during the study gold responders could not be differentiated from non-responders with regard to changes in lymphocyte counts and subsets. Thus this study suggests that weekly IM gold leads to a modest reduction in circulating lymphocyte numbers which involves most subsets. This effect appears to be independent of the clinical efficacy of this drug.
PMCID: PMC1003436  PMID: 3125797
12.  SEAPAL quality control analysis of rheumatoid factor measurement in 29 diagnostic laboratories. 
Annals of the Rheumatic Diseases  1987;46(5):417-420.
A programme for rheumatoid factor (RF) measurement was sponsored by the South East Asian Pacific League against Rheumatism (SEAPAL) and the Clinical Immunology Group (CIG) of the Australian Society for Immunology. Measurements in 29 laboratories in 12 countries showed: a large variety of methods were being used to measure RF, most using semiquantitative agglutination techniques; some laboratories have invalid techniques; the quoted upper normal limit varied considerably between assays, and false positives were identified in three laboratories; a wide range of intralaboratory precision within and between assays; and a reduction in discordance between laboratories by the inclusion of local standards. Before international standardisation of RF measurement can be achieved attention to many of these problems is required. In particular we recommend the wider use of reference standards and the regular participation in quality control programmes in order to monitor performance.
PMCID: PMC1002152  PMID: 3592802
13.  Lack of correlation between in vitro and in vivo effects of low density lipoprotein on the inflammatory activity of monosodium urate crystals. 
Annals of the Rheumatic Diseases  1986;45(8):673-676.
The effect of coating monosodium urate crystals (MSU) with low density lipoprotein (LDL), postulated previously as a major regulator of gouty inflammation, was studied in a neutrophil chemiluminescence (CL) assay and an air pouch model of inflammation induced by MSU. LDL crystalline coating abrogated the neutrophil CL response but, in contrast, had no inhibitory effect on leucocyte accumulation, levels of the prostaglandin (PG) metabolite 6-keto-PGF1 alpha, and exudation of plasma proteins in the in vivo model. This latter observation raises doubts about the postulated physiological role of LDL in terminating the acute gouty attack.
PMCID: PMC1001966  PMID: 3755584
14.  Routine quantification of rheumatoid factor by rate nephelometry. 
Annals of the Rheumatic Diseases  1985;44(6):379-383.
In a cross-sectional study of over 3000 consecutive serum specimens the levels of rheumatoid factor (RF) measured by rate nephelometry (Beckman ICS II) were compared with values obtained by the more traditional methods of sheep cell agglutination (Rose-Waaler) and latex agglutination. Similar values for sensitivity and specificity were found for all three methods for rheumatoid arthritis, with nephelometry giving slightly higher levels of sensitivity for other rheumatic disorders. A significant correlation (r = 0.46, p less than 0.01) was found between the nephelometric and Rose-Waaler method for 147 consecutive seropositive specimens. Of interest, however, several disparate results were observed, and explanations for these were sought. Longitudinal studies of RF were performed in 49 seropositive patients over a two-year period. The nephelometric method was considered superior compared with the other techniques because of its ability to detect changes in absolute levels at earlier stages and its low interassay coefficient of variance (11%). We conclude that the nephelometric technique appears suitable for routine diagnostic use, offers several advantages compared with more traditional methods, and is no more expensive per test specimen than the Rose-Waaler technique.
PMCID: PMC1001656  PMID: 4015199
15.  Quantitation and evaluation of low molecular weight IgM in rheumatoid arthritis. 
Annals of the Rheumatic Diseases  1980;39(4):349-353.
Laser nephelometric estimation of IgM in the eluate fractions following Sepharose 6B chromatography has enabled the calculation of the proportion of low molecular weight IgM (7S IgM) in normal and pathological sera. This figure has then been used to determine the absolute amount of 7S IgM. Twenty-seven of 36 (75%) patients with rheumatoid arthritis had 7S IgM with a mean value of 17 mg/100 ml (170 mg/l) (range 2.5-59 mg/100 ml). No sera from 10 healthy controls were found to contain 7S IgM. Patients with active rheumatoid arthritis had significantly more 7S IgM than those with inactive disease, but there was no significant difference between those patients with and without rheumatoid vasculitis. Significant correlations occurred between 7S IgM and the absolute IgM level (P < 0.01), the Rose-Waaler titre (P < 0.01), and the erythrocyte sedimentation rate (P = 0.01). However, there was no significant correlation with the age of the patient, the duration of the disease, or the level of circulating immune complexes as measured by the Clq binding assay. It is concluded that 7S IgM commonly occurs in rheumatoid arthritis, and it is postulated that a common immunological stimulus is responsible for the production of 7S IgM and rheumatoid factors, serological abnormalities that characterise this disease.
PMCID: PMC1000555  PMID: 6893651
16.  Factors relating to circulating immune complexes in rheumatoid arthirits. 
Annals of the Rheumatic Diseases  1976;35(4):314-320.
Evidence has been presented suggesting that circulating immune complexes occur in over half of the sera of patients with rheumatoid arthritis. These IgG-containing complexes were small, eluting between IgG and IgM on gel filtration on Sepharose 6B and were not seen in the sera of healthy control subjects. These complexes were detected in the sera of both seronegative and seropositive patients and their quantity did not correlate with IgM rheumatoid factor titre. The quantity of complexed IgG was estimated from a ratio derived from the IgG profile obtained by gel filtration of the serum. This quantity correlated significantly with the degree of inhibition by the rheumatoid sera of cytolysis in vitro of IgG sensitized target cells by K cells from human peripheral blood. A significant inverse correlation was observed between the quantity of serum complexes and the chemotactic index of the circulating polymorphonuclear leucocytes obtained from the same rheumatoid patient. It is suggested that ingestion of these complexes may be implicated in the reduction in chemotaxis observed in patients with rheumatoid arthritis. There was no correlation between the quantity of the complexes in the sera and the clinica, haematological, and biochemical measurements.
PMCID: PMC1007388  PMID: 970988
17.  Cerebrospinal fluid immunoglobulin quotients, kappa/lambda ratios, and viral antibody titres in neurological disease. 
Journal of Clinical Pathology  1976;29(12):1105-1115.
A description has been given of cerebrospinal fluid (CSF) immunoglobulins in 355 patients with demyelinating, infectious, neuropathic, and other neurological disorders. An increase in the CSF IgG/albumin quotient was observed in 19/36 (53%) cases of definite multiple sclerosis (MS), in 13/47 (28%) cases of probable or possible MS, in 6/9 (67%) cases of proven herpes simplex viral encephalitis (HSVE), in 3/4 (75%) cases of neurosyphilis, in 1/1 case of subacute sclerosing panencephalitis (SSPE), in 2/9 )22%) cases of other central nervous system infections, and in 2/12 (17%) cases of polyneuritis when compared with a group of 236 patients having other neurological disorders. In constrast, a relative increase in the CSF IgA of IgM was seen only in some of the patients with central nervous system infections. It was also found that the quotient CSF/serum IgG, expressed as a percentage of the CSF/serum albumin, was better in distinguishing patients with definite or suspected MS from those with other neurological disorders than the quotients IgG/albumin or IgG/total protein. The CSF K/lambda ratio and the CSF and serum complement-fixing antibody titre to measles and herpes simplex virus were measured in many of the patients. In general, abnormalities of these measurements were associated with raised IgG/albumin quotients. However, in eight patients with definite or suspected MS, a normal IgG/albumin quotient was found with abnormal CSF K/lambda ratios (6 cases) or abnormal CSF titres of measles antibody (7 cases). In addition, two patients, with HSVE had normal IgG/albumin ratios but detectable herpes antibody in the CSF. These findings suggest that the measurement of the relative concentration of CSF immunoglobulin in combination with the K/lambda ratio and antibody titre to various viruses may supplement each other in the endeavour to detect central nervous system immunglobulin sysnthesis in neurological diseases.
PMCID: PMC476313  PMID: 188871
18.  Neutrophil activation by immune complexes and the role of rheumatoid factor. 
Membrane activation of human neutrophils by preformed immune complexes and heat aggregated human gammaglobulins was studied by chemiluminescence. Strong neutrophil activation was found with human-albumin rabbit-antialbumin complexes prepared at equivalence, with maximal activation occurring in slight antigen excess. Furthermore different preparations of heat aggregated gammaglobulin which were of large size also showed similar activity. In contrast, heat aggregates of small size were inactive and blocked the chemiluminescent response found with larger active aggregates. A purified monoclonal rheumatoid factor with specificity for IgG modulated these responses when preincubated with preformed complexes or aggregates. Both enhancement of the neutrophil chemiluminescence response with inactive preparations and suppression of the response with highly active preparations were observed. Kinetic studies of the neutrophil chemiluminescent response varied with respect to the activating preparation, but were generally biphasic. This observation suggested an initial direct membrane activation followed by a more delayed response reflecting phagocytosis of complexes. We have demonstrated the direct activation of neutrophil chemiluminescence by laboratory preparations of immune complexes. The chemiluminescent responses observed were influenced by both the size and immunochemical properties of the activating complexes and by the presence of rheumatoid factor. These observations may have important implications in the immunopathogenesis of immune-complex-mediated diseases.
PMCID: PMC1001214  PMID: 6696514
19.  Low molecular weight IgM and CD5 B lymphocytes in rheumatoid arthritis. 
Annals of the Rheumatic Diseases  1994;53(6):383-390.
OBJECTIVES--To evaluate the role of low molecular weight (LMW) IgM and CD5 B cells in rheumatoid arthritis (RA) and to explore the possibility that LMW IgM is derived selectively from this subset of B cells. METHODS--LMW IgM in sera and culture supernatants was detected by a sensitive immunoblot technique with an enhanced chemiluminescence detection system. CD5 B cells were determined by FACScan cytometry. In vitro studies were established in culture plates containing pokeweed mitogen with or without 2-mercaptoethanol (2-ME). Supernatants were obtained from CD5 positive hybridomas and CD5 negative hybridomas. Other immunological indices were measured by laser nephelometry. RESULTS--Circulating LMW IgM was detected in all rheumatoid patients with significantly higher levels being observed in sero-positive patients. LMW IgM correlated significantly with total IgM and RF. Peripheral blood mononuclear cells (PBMC) from the majority of the patients with RA secreted LMW IgM in vitro as did mononuclear cells from a synovial fluid sample. The addition of low concentrations of 2-ME to the culture medium enhanced the proportions of secreted monomeric IgM. In contrast, PBMC from healthy subjects secreted only trace quantities of LMW IgM. In RA no significant correlations were observed between CD5 B cells and LMW IgM and RF. LMW IgM could be detected in the supernatants from both CD5+ and CD5- B cell lines. Finally, CD5 B cells were not significantly elevated in RA and levels remained constant over time. CONCLUSION--LMW IgM exists in high concentrations in RA sera and synovial fluid. Serum level correlates with RF and IgM. In vitro studies have suggested that the occurrence of LMW IgM may be due to an intrinsic defect(s) in the assembly of the IgM pentameric molecule. LMW IgM is unlikely to be derived solely from CD5 B cells.
PMCID: PMC1005353  PMID: 7518662
20.  Lymphocyte surface marker expression in rheumatic diseases: evidence for prior activation of lymphocytes in vivo. 
Expression of major histocompatibility complex (MHC) class II and other lymphocyte activation markers on peripheral blood and synovial fluid T lymphocytes from patients with rheumatoid arthritis (RA), psoriatic arthritis, and Reiter's syndrome were measured and the mean fluorescence intensities of these antigens were assessed. Increased expression of MHC class II antigens of synovial fluid T lymphocytes is not unique to RA, though it is quantitatively greater on RA synovial fluid T cells. There was less expression of other lymphocyte activation markers (4F2, transferin receptor) and a marked discordance between the expression of these markers and the interleukin 2 receptor (IL2r). Synovial fluid T lymphocytes contain a subpopulation of larger cells expressing MHC class II and other lymphocyte activation antigens with the exception of the IL2r. Mean fluorescence intensity of CD3 and CD4 antigens on synovial fluid T lymphocytes was decreased in all three patient groups, suggesting prior in vivo exposure of synovial fluid T lymphocytes to an unknown antigen.
PMCID: PMC1003983  PMID: 2138450
22.  Low molecular weight IgM in juvenile chronic arthritis. 
Archives of Disease in Childhood  1988;63(12):1453-1456.
Low molecular weight IgM, the monomeric subunit of pentameric IgM, was clearly detected by immunoblotting and filtration chromatographic techniques in six patients with juvenile chronic arthritis and in trace quantities in a further eight of 24 patients studied. This low molecular weight IgM moiety contributed up to 33% of the total circulating IgM and was strongly associated with raised serum concentrations of IgM and the presence of antinuclear antibodies, extractable antinuclear antibodies, and rheumatoid factor. Immunoblot analysis of positive serum samples showed small quantities of other low molecular weight oligomers of IgM in addition to monomeric IgM. It is postulated that the presence of low molecular weight IgM in the serum of patients with juvenile chronic arthritis reflects a disorder of the intracellular assembly of IgM subunits during a stimulated IgM immune response. The pathogenetic role of low molecular weight IgM remains uncertain.
PMCID: PMC1779214  PMID: 3266068
23.  Studies on the interaction of rheumatoid factor with monosodium urate crystals and case report of coexistent tophaceous gout and rheumatoid arthritis. 
Annals of the Rheumatic Diseases  1985;44(6):384-389.
Gout and classical rheumatoid arthritis rarely coexist. We report a patient with strong evidence for both these diseases. Possible reasons for the negative correlation between these diseases are summarised. One hypothesis suggests inhibition of surface activity of monosodium urate crystals (MSU) by binding of rheumatoid factor (RF). This was studied with a purified monoclonal rheumatoid factor (mRF) with specificity for IgG. The mRF bound preferentially to MSU coated with IgG in contrast with the IgM control. Inhibition of the neutrophil chemiluminescence (CL) response to IgG-coated MSU was observed at concentrations of mRF that had no effect on the CL response to uncoated crystals. Neutrophil activation was not altered by coating crystals with an IgM control at the same concentration. These data suggest that RF may bind to antigenic determinants on exposed Fc of adsorbed IgG and block the interaction of crystal-bound IgG with Fc receptors. Although crystal coating by RF may modify the expression of gouty arthritis, it is unlikely to be the sole explanation for the dissociation between gout and RA.
PMCID: PMC1001657  PMID: 4015200
24.  Direct activation of neutrophil chemiluminescence by rheumatoid sera and synovial fluid. 
Annals of the Rheumatic Diseases  1983;42(2):158-162.
The majority of paired sera and synovial fluids from 21 patients with rheumatoid arthritis produced a rapid chemiluminescent response when incubated with human neutrophils. Synovial fluid gave considerably higher responses than the paired serum specimen. In contrast little or no response was found with paired sera and joint fluid taken from patients with gout, psoriasis, and osteoarthritis and with sera from healthy donors. A similar chemiluminescent response was observed when neutrophils were preincubated with large aggregates of heated human gammaglobulin (HAGG), which were used as a model of immune complexes. Smaller nonreactive aggregates of gammaglobulin became reactive after preincubation with a purified monoclonal rheumatoid factor (mRF) which had a high avidity for aggregated IgG. The addition of this monoclonal rheumatoid factor also caused enhancement of chemiluminescence by rheumatoid sera. Further evidence suggesting that the active material found in these rheumatoid specimens contained complexed immunoglobulin was obtained by indirect immunofluorescence. Neutrophils developed intracellular immunoglobulin inclusions after preincubation in reactive rheumatoid sera but not with nonreactive or normal sera. However, activation of neutrophil chemiluminescence by rheumatoid specimens did not correlate significantly with levels of rheumatoid factor or immune complexes suggesting that the activating complexes were of a particular type. In conclusion we have shown the direct activation of neutrophil chemiluminescence by rheumatoid sera synovial fluid and suggest that the activation is caused by large IgG-containing immune complexes. It is possible that this activation may have important implications in the immunopathogenesis of the rheumatoid inflammatory process.
PMCID: PMC1001091  PMID: 6847260
25.  Circulating and intra-articular immune complexes in rheumatoid arthritis: a comparative study of the C1q binding and monoclonal rheumatoid factor assays. 
Annals of the Rheumatic Diseases  1980;39(5):438-444.
The C1q binding assay and the nephelometric monoclonal rheumatoid factor assay were able to discriminate 79% and 57% respectively of rheumatoid arthritis (RA) patients from healthy blood donors. In addition these assays could distinguish those patients with active arthritis from those with inactive disease, and the C1q binding assay correlated significantly with other laboratory indices of the rheumatoid process, including the erythrocyte sedimentation rate, low molecular weight or 7S IgM, and the rheumatoid factor titre. High levels of C1q binding were also seen in rheumatoid vasculitis. Both assays gave higher mean values in synovial fluid compared with the corresponding serum, but it appeared from ultracentrifugal analysis and from a lack of a consistent correlation between these assays that each assay was measuring different forms of immunecomplex-like material which may be involved in the immunopathogenesis of this disease. The C1q binding assay is of some value in the laboratory assessment of rheumatoid arthritis and appears to offer greater advantages than the monoclonal rheumatoid factor assay, although the usefulness of this latter assay may be very dependent on the monoclonal rheumatoid factor used.
PMCID: PMC1000581  PMID: 7436574

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