Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
| ID | PMID | Title | PublicationDate | abstract |
|---|---|---|---|---|
| 2587935 | Synovial fluid from rheumatoid arthritis patients induces polyclonal antibody formation in | 1989 Nov | Our previous studies demonstrated the presence of a T-cell replacing factor in the synovial fluid (SF) of patients with rheumatoid arthritis (RA) and that RA-SF can activate, selectively, the induction of IgG2b antibody secreting cells in lipopolysaccharide (LPS)-pretreated mouse spleen cell cultures. In the present study the effect of RA-SF was tested in vivo in mice. Injection of the polyclonal activator LPS induced the production of IgM and IgG3 secreting cells in normal mice. However, the addition of RA-SF led to a selective increase in the production of IgG2b with a peak response on day 5 and IgG1 plaque-forming cells (PFC) with a peak on day 7. Neither the IgG2b nor IgG1 responses were caused by specific immunity against heterologous proteins present in RA-SF, as injection of in vitro inactive RA-SF samples did not induce PFC. The effect on B cells of RA-SF was further evaluated by injection of RA-SF in combination with LPS to the Xid B-cell deficient CBA/N mice. RA-SF had identical effects in CBA/N as in normal mice. The biological implication of these findings is discussed. Our earlier results support the idea that B cells are endogenously activated in RA patients. We have speculated that this activation is caused by the B-cell differentiation factor which is present in SF. Therefore, we also tested whether RA-SF could influence antibody-forming cells in mice that spontaneously develop autoimmunity. We found that injection of RA-SF alone, in the absence of any other activating substance, induced a very marked increase of IgG producing cells in (NZW x NZB) F1 hybrid mice. From a relatively high background level the RA-SF could still induce an up to 100-fold increase in the numbers of PFC in spleens of such mice. | |
| 3147827 | Production of interferon gamma by peripheral blood mononuclear cells from normal subjects | 1988 Oct | A radioimmunoassay for human interferon gamma (IFN-gamma) has been carried out using a recombinant glycosylated interferon (Hu IFN-gamma) as tracer, the N.I.H. reference preparation (Gg 23-901-530) and a polyclonal rabbit antiserum. The assay is highly specific for IFN-gamma: there is no cross-reaction either with interferons alpha and beta, Interleukins 1 and 2, tumor necrosis factor alpha and beta or with various brain peptides. The sequential saturation procedure allowed a sensitivity of 0.4 U/ml with intra and between assay coefficients of variation less than 8 and 12%, respectively. The in-vitro production of IFN-gamma by peripheral blood mononuclear cells (P.B.M.C.) was also measured. In unstimulated cultures, IFN-gamma production remained undetectable, i.e. below the 0.4 U/ml sensitivity level. After stimulation of P.B.M.C. from normal subjects with increasing amounts of PHA, both the 3H-thymidine incorporation and IFN-gamma release followed bell-shaped curves. There was no significant difference of 3H-thymidine incorporation between PHA stimulated cultures (0.2 and 2.5 ug/ml) from normal subjects (36 cases) and those with active (16 cases) or non-active (14 cases) rheumatoid arthritis. At two PHA concentrations of 0.2 and 2.5 ug/ml, mononuclear cells from patients with active disease produced significantly less IFN-gamma than those from either controls or cases with non-active disease. | |
| 3213263 | [Defects in opsonization activity of the serum of patients with chronic arthritis]. | 1988 May | The opsonizing capacity of sera from 22 patients with rheumatoid arthritis (RA), from 14 with psoriatic arthritis (AP), from seven with ankylosing spondylitis, and from healthy control persons was investigated by luminol-dependent chemiluminescence, induced during yeast phagocytosis of normal polymorphonuclear leukocytes. The chemiluminescence response using opsonizing sera was compared to that induced by no-opsonized yeast and the opsonizing capacity was expressed as a percentage. For the opsonization, fresh native serum, in some experiments Mg2+-EGTA and EDTA-treated serum, was used. In RA and AP sera, a significantly diminished opsonizing capacity (p less than 0.005) was observed. In healthy controls and in SPA patients, the opsonizing capacity of their sera was over 200%, while in seronegative RA patients, it was only 175%, in seropositive RA 125%, and in AP 150% was measured. There was no correlation between opsonizing capacity and complement or immunoglobulin content of the investigated sera. The amount of C3b, IgG and IgM covalently bound to yeast particles was determined, too. Yeast particles bind significantly less (p less than 0.01) IgG when opsonized with RA and AP sera, while a higher relative amount of IgM (p less than 0.01) was bound to yeast incubated in the sera of seropositive RA patients. No significant differences in the C3b binding were observed. | |
| 2925120 | [Arthrodesis of the metacarpophalangeal joint of the thumb. Indications, technic, arthrode | 1989 Jan | The metacarpophalangeal joint of the thumb has less range of motion than any other digital joint. Its stability is more important than its mobility. Thus, arthrodesis of this joint causes relatively little loss of function, provided only that the joint is fused in the correct position. The authors reviewed all MP joint fusions of the thumb which were done at their hospital between 1974 and 1985. They examined individually forty-one of the fifty patients and studied the indications, surgical techniques and difficulties, and the complications. Furthermore, they measured all angles of fusion and concluded that the optimal position is fifteen degrees of flexion and ten degrees of pronation. The use of tension band wiring facilitates the achievement and maintenance of the desired position. The stability of the fusion permits exercise immediately after the operation; this helps to avoid a tenodesis of the long extensor tendon of the thumb. | |
| 3135959 | A competitive enzyme-linked immunosorbent assay for alpha 1-acid glycoprotein in serum and | 1988 Aug | In this solid-phase competitive enzyme-linked immunosorbent assay for alpha 1-acid glycoprotein in serum or urine, antiserum to human alpha 1-acid glycoprotein is incubated with solid-phase-bound alpha 1-acid glycoprotein in the presence of standard or sample. Incubation with second antibody labeled with alkaline phosphatase then follows, before development with substrate. Results obtained correlate well with a fluorescent assay involving the dye Auramine O (r = 0.953) and with radial immunodiffusion (r = 0.921). The present assay covers the range 0.2 to 5 mg/L and 16 samples take 2.5 h to complete. This assay is useful for measuring concentrations of alpha 1-acid glycoprotein in serum and also in urine, for which other assay methods are not sufficiently sensitive. | |
| 2833184 | Effects of altering dietary essential fatty acids on requirements for non-steroidal anti-i | 1988 Feb | In rheumatoid arthritis (RA) benefit from non-steroidal anti-inflammatory drugs (NSAIDs) is mediated through inhibition of the cyclo-oxygenase enzyme, thereby decreasing production of the 2 series prostaglandins (PGs). The lipoxygenase enzyme is intact, however, allowing leucotriene (LT) production, e.g., LTB4 (an inflammatory mediator). Treatment with evening primrose oil (EPO) which contains gamma-linolenic acid (GLA) leads to production of the 1 series PGs, e.g., PGE1, which has less inflammatory effects. Also LT production is inhibited. Eicosapentaenoic acid (EPA, fish oil) treatment provides a substrate for PGs and LTs, which are also less inflammatory. In this study 16 patients with RA were given 540 mg GLA/day (EPO), 15 patients 240 mg EPA and 450 mg GLA/day (EPO/fish oil), and 18 patients an inert oil (placebo). The aim of this study was to determine if EPO or EPO/fish oil could replace NSAID treatment in RA. The initial 12 month treatment period was followed by three months of placebo for all groups. Results at 12 months showed a significant subjective improvement for EPO and EPO/fish oil compared with placebo. In addition, by 12 months the patients receiving EPO and EPO/fish oil had significantly reduced their NSAIDs. After 3 months of placebo those receiving active treatment had relapsed. Despite the decrease in NSAIDs, measures of disease activity did not worsen. It is suggested that EPO and EPO/fish oil produce a subjective improvement and allow some patients to reduce or stop treatment with NSAIDs. There is, however, no evidence that they act as disease modifying agents. | |
| 2790396 | The relationship of anticardiolipin antibodies to disease activity in systemic lupus eryth | 1989 Oct | Sera from 124 blood donors, 60 rheumatoid arthritis (RA) and 57 SLE patients were measured for anticardiolipin antibodies by ELISA. Significantly raised IgG (aCLG) and IgM (aCLM) anticardiolipin antibody levels were found in RA and SLE (p less than 0.0005). However, in SLE both aCLG and aCLM levels were significantly higher than in RA (p less than 0.0025). We then conducted a transectional study to evaluate aCL levels and disease activity in SLE. There was a good positive predictive value (70%) between aCL and overall disease activity, but not for individual systems. A strong association between aCL and renal involvement irrespective of activity was also found (80%). Nine SLE patients fulfilled both the clinical and serological criteria for the antiphospholipid syndrome (APS) and a further 18 patients fulfilled the serological criteria for APS. Results indicate that aCL levels are of value in predicting overall disease activity in SLE and in monitoring those patients who fulfil or partially fulfil the criteria for APS. | |
| 3530585 | Renal safety of two analgesics used over the counter: ibuprofen and aspirin. | 1986 Oct | The incidence of potentially serious drug-related elevations of BUN or serum creatinine was examined among 1468 patients with rheumatoid arthritis or osteoarthritis who took daily therapeutic doses of aspirin, ibuprofen, or oxaprozin, an investigational nonsteroidal antiinflammatory drug (NSAID), in multicenter clinical trials. Algorithms were developed to identify patients with potentially important elevations of these renal laboratory parameters and to assess the possible relation between these elevations and the study drugs. All three drugs were associated with a low (4% to 6%) incidence of potentially significant elevations in renal function parameters. Changes considered serious occurred in only three (less than 1%) patients (one treated with oxaprozin and two with ibuprofen), all of whom were receiving concomitant diuretic therapy. None of the changes led to adverse clinical consequences. Thus despite recent controversy regarding the renal safety of NSAIDs, all three drugs proved safe in these studies, despite the fact that aspirin and ibuprofen were given in doses equal to or higher than those used for over-the-counter indications. | |
| 1689580 | Antibodies from patients with rheumatoid arthritis and systemic lupus erythematosus recogn | 1990 Feb | Antibodies to recombinant heterogeneous nuclear RNP core protein A1 were detected in sera from 27 of 58 patients with rheumatoid arthritis (RA) and from 7 of 31 patients with systemic lupus erythematosus, by immunoblotting and enzyme-linked immunosorbent assay. Protein A1 consists of 2 distinct domains: The N-terminal sequence is identical to a single-stranded DNA binding protein termed UP1, and the C-terminal domain shows a partial homology with keratin. All 7 A1-positive systemic lupus erythematosus sera reacted with UP1, whereas 9 of the 27 A1-positive RA sera did not. In RA, anti-A1 activity was significantly associated with antikeratin antibodies (AKA); these antibodies were present in 23 of 27 A1-positive sera and 10 of 31 A1-negative sera (P less than 0.01). Immunoabsorption with recombinant protein A1 resulted in a significant reduction of AKA titers in 6 of 10 RA sera tested, suggesting that AKA from RA patients may cross-react with the C-terminal portion of the heterogeneous nuclear RNP protein A1. | |
| 2969784 | Reactivity of T-cells from patients with rheumatoid arthritis to anti-CD3 antibody. | 1988 Sep | The ability of an anti-CD3 monoclonal antibody (OKT3) to induce proliferation was examined in peripheral blood mononuclear cells (PBM) from 30 patients with rheumatoid arthritis (RA). Controls consisted of 10 patients with osteoarthritis, 12 patients with psoriatic arthritis, and 12 healthy subjects. The results revealed enhanced PBM reactivity in patients with active RA relative to inactive RA patients and all control groups. PBM of patients with mild/moderate clinical disease activity exhibited augmented anti-CD3 reactivity while those with severe disease demonstrated impaired reactivity. Enhanced reactivity was also observed in the active RA group using another anti-CD3 monoclonal antibody (Leu-4). Differences in anti-CD3 dose-response or time kinetics could not account for the results. Studies of enriched T-cell preparations revealed a markedly enhanced anti-CD3 reactivity of RA T-cells relative to normal control T-cells. Monocyte/T-cell mixing experiments revealed no enhanced reactivity of RA monocytes in the anti-CD3 response. RA T-cell preparations depleted of monocytes by limiting dilution reacted significantly more to anti-CD3 in the presence of IL-2 relative to controls. The enhanced reactivity could be accounted for in part by hyperreactivity of the OKT8-bearing subpopulation of T-cells. | |
| 2272188 | Controlled-release indomethacin and sustained-release diclofenac sodium in the treatment o | 1990 | The efficacy and tolerability of a new, controlled-release indomethacin (75 mg) tablet was compared to that of a sustained-release diclofenac sodium (100 mg) tablet in 84 patients with rheumatoid arthritis. The study was designed as a double-blind, double-dummy crossover trial, patients being allocated at random to receive 1 active tablet and 1 placebo tablet of the alternative medication at night for 4 weeks before being crossed over to the alternative treatment for a further 4 weeks. Patient and clinical assessments on entry and at the end of each treatment period showed that pain scores for day and night, duration of morning stiffness, requirement for escape analgesia (paracetamol) and treatment preference were similar for both treatments. Both preparations also significantly improved the degree of joint tenderness compared to baseline (p less than 0.001), as measured by a modified Ritchie Articular Index. Incidence and severity of side-effects were comparable, with a significant improvement in degree of constipation reported for both treatments compared to baseline (p less than 0.05). The incidence and severity of headache was statistically significantly worse (p less than 0.05) for controlled-release indomethacin; however, there was no difference in any other parameter of tolerability. It was concluded that controlled-release indomethacin tablets (75 mg) given as a single night-time dose were as efficacious and well tolerated as sustained-release diclofenac sodium (100 mg). | |
| 2157776 | Erythropoietin: receptors and clinical use in rheumatoid arthritis. | 1990 Jan | Erythropoietin (Epo) receptors have been delineated using radioiodinated recombinant erythropoietin (rEpo) and highly purified murine and human erythroid colony-forming units (CFU-e). The murine CFU-e had 950 receptors/cell. One-third had a Kd of 0.09 nM while two-thirds had a Kd of 0.57 nM. Human CFU-e had 1,050 receptors/cell. Two hundred had a Kd of 0.10 nM and 850 had a Kd of 0.57 nM. 125I-rEpo was rapidly internalized and degraded by the CFU-e. Cross-linking of 125I-rEpo to human Epo receptors demonstrated two proteins of 100 and 90 kDa and proteolytic peptide mapping of each protein showed identical fragments indicating that they are very similar. rEpo was also used to treat patients with the anemia of rheumatoid arthritis, and one case is presented in which the patient's hematocrit rose from 32.5% to 44% in eight weeks. When the rEpo was discontinued, the hematocrit fell back to 33%. | |
| 1895954 | Evidence for peripheral impaired glucose handling in patients with connective tissue disea | 1991 Sep | Sixteen patients suffering from rheumatoid arthritis (RA) (n = 8), systemic lupus erythematosus (SLE) (n = 5), and systemic sclerosis (SSc) (n = 3), and 10 healthy subjects matched for age, sex, and body mass index, were submitted to an intravenous (IV) glucose tolerance test (GTT) (0.33 g/kg of body weight in 3 minutes) and to a euglycemic hyperinsulinemic glucose clamp to study insulin response and action. In the euglycemic clamp, along with the two insulin infusion rates (0.5 mU/kg.min from 0 to 120 minutes and 1 mU/kg.min from 121 to 240 minutes), a primed (20 microCi) continuous (0.2 microCi/min) infusion of 3H-glucose allowed determination of glucose kinetics. Our data show that patients versus controls have (1) a significant increase in basal plasma insulin levels (87.2 +/- 14.8 v 41.3 +/- 6.0 pmol/L, P less than .05); (2) similar glucose-induced acute insulin response; and (3) a lower glucose disappearance rate (Rd), glucose metabolic clearance rate (gMCR), and glucose infusion rate (GIR) when the lowest insulin infusion rate was delivered. These differences disappeared when the insulin infusion rate was doubled. Furthermore, basal plasma insulin levels and glucose disappearance rate significantly correlated with the main inflammatory indices of each disease studied. We conclude that in our patients impaired glucose handling is mainly due to peripheral insulin resistance. | |
| 2081491 | German drug monitoring studies with nabumetone. | 1990 | Although randomised controlled comparative trials concerning the efficacy of the drug tested can produce reliable results in a limited number of selected patient groups, drug monitoring studies involving 10,000 patients or more are the methods of choice to detect rare adverse events. The aim of this drug monitoring study was to evaluate the efficacy and safety of dispersible nabumetone tablets. 8865 patients (46.2% male, 53.5% female, mean age 55 years, range 14.95) were involved in the investigation carried out by 1172 general practitioners. The disease indications comprised osteoarthritis (69.8%), soft-tissue rheumatism (11.3%), rheumatoid arthritis (9.9%) and soft tissue injuries (7.7%). Most of the patients (67.3%) received a daily dose of nabumetone 1 g for up to 6 weeks. Efficacy was evaluated at baseline, and after 1 week, 3 weeks and 6 weeks of treatment. With regard to global efficacy, overall improvement (symptoms resolved or markedly improved) was assessed in 82% of the patients. Elimination or at least significant improvement of pain on movement occurred in 95%, pain on pressure in 90% and pain at rest in 89% of the patients with symptoms. In relation to swelling, morning stiffness and joint mobility, elimination or at least significant improvement occurred in 79%, 80% and 82% of patients, respectively. 1846 patients (20.8%) had frequent periods of NSAID-related symptoms before treatment with nabumetone. A total of 1174 adverse events occurred in 850 patients (9.6%), most comprising minor gastrointestinal complaints. Considering that at least 25,000 patients have been documented in 2 German drug monitoring studies, it is therefore unlikely that any unexpected side effects will occur in the future. Consequently, nabumetone can be classified as an effective and safe NSAID. | |
| 2897645 | Co-localization of proenkephalin- and prodynorphin-derived opioid peptides in laminae IV/V | 1988 Feb 29 | By the use of highly selective antisera and an immunohistochemical technique the possible coexistence of proenkephalin- (PRO-ENK)- and prodynorphin (PRO-DYN)-derived peptides was examined in 4- to 6-micron thick serial sections of the L4-L5 segments of the spinal cord of non-colchicine-treated polyarthritic rats. In control, non-colchicine treated animals, virtually no cell bodies stained for the PRO-ENK-derived peptides, heptapeptide (MRF) and octapeptide (MRGL), nor for the PRO-DYN-derived peptides, dynorphin A (DYN) and alpha-neoendorphin (NEO). In contrast, in polyarthritic rats, numerous large (15-30 micron) multipolar neurons could be visualized with each antiserum in laminae IV/V. Alternate staining of adjacent sections with either anti-MRF or anti-MRGL antisera, followed by either anti-DYN or anti-NEO antisera, revealed a clear coexistence of PRO-ENK and PRO-DYN peptides. It was possible to demonstrate co-localization of all 4 opioids in a single cell. It appeared that all cells staining for PRO-ENK peptides in laminae IV/V also stained for PRO-DYN peptides. | |
| 2198352 | Synovial fluid tests. What should be ordered? | 1990 Aug 22 | To determine which synovial fluid tests are most useful, we prospectively analyzed the synovial fluid test results of 100 consecutive patients undergoing diagnostic arthrocentesis. Each patient's diagnosis was established independently of synovial fluid laboratory test results; in 69 patients a definite inflammatory or noninflammatory categorization could be made. Sensitivity and specificity were estimated for synovial fluid white blood cell count (sensitivity, 0.84; specificity, 0.84), percentage of polymorphonuclear cells (sensitivity, 0.75; specificity, 0.92), glucose (sensitivity, 0.20; specificity, 0.84), protein (sensitivity, 0.52; specificity, 0.56), and lactate dehydrogenase (sensitivity, 0.83; specificity 0.71). Receiver operating characteristic regression analysis indicated that both white blood cell count and percentage of polymorphonuclear cells were found to contribute independent diagnostic information but lactate dehydrogenase did not. In a separate, retrospective analysis of 19 patients with definite septic arthritis, similar results were observed. We conclude that synovial fluid white blood cell count and percentage of polymorphonuclear cells perform well as discriminators between inflammatory and noninflammatory disease. Ordering chemistry studies of synovial fluid should be discouraged because they are likely to provide misleading or redundant information. | |
| 2141140 | [Hyaluronic acid. Usefulness and perspectives of its serum assay]. | 1990 May 26 | Hyaluronic acid (hyaluronan or HA) is a major component of connective tissue synthesized by fibroblasts. Some progress has been made in recent years in the understanding of its metabolism, regulation and physiological role. The development of specific and sensitive assay methods has shown that the HA plasma level is increased in a wide variety of disorders. This increase may be due to decrease hepatic clearance, excessive synthesis (systemic sclerosis, inflammatory arthropathies, psoriasis, cancers, etc.), or even to an increased hyaluronidase activity in certain cancers. The major use of HA assays at the moment is in the evaluation of the evolutivity of those diseases where the HA increase relates to their activity. It seems to be of no diagnostic activity, at least for the time being. | |
| 1918267 | Analysis of function-associated receptor molecules on peripheral blood and synovial fluid | 1991 Jul | In this study we report the expression pattern of 13 different function-associated surface molecules on synovial fluid and peripheral blood granulocytes from rheumatoid and reactive arthritis patients. We found increased expression of the complement receptors 1 (CD35) and 3 (CD11b) and of the activation-associated antigens CD67, CD24, and M5 on synovial fluid granulocytes from rheumatoid and/or reactive arthritis patients compared to autologous peripheral blood granulocytes. In addition, synovial fluid granulocytes expressed IgG Fc receptor 1 (CD64) and complement receptor 4 (CD11c), neither of which can be found on peripheral blood granulocytes. Peripheral blood granulocytes from rheumatoid and reactive arthritis patients expressed higher levels of leucocyte function-associated antigen 1 (CD11a) and of the membrane proteins CD31, CD24, M5, and M6 compared to peripheral blood granulocytes from healthy controls and patients with degenerative joint disease. No significant differences in the expression of any of the molecules studied could be observed between cells from rheumatoid and cells from reactive arthritis patients, suggesting a similar activation process for granulocytes in these two diseases. | |
| 2209691 | Autoantibody production by severe combined immunodeficient mice reconstituted with synovia | 1990 Aug | In an attempt to characterize the heterogeneity of the human autoantibody response, mice with severe combined immunodeficiency were reconstituted with synovial or blood lymphocytes from patients with rheumatoid arthritis (RA). Mononuclear cells extracted from synovial fluid or tissue (SMC) were a greatly enriched source of IgM rheumatoid factor (RF)-producing cells compared to the peripheral blood mononuclear cells (PBMC) of rheumatoid arthritis patients or normal donors. Six to nine weeks after reconstitution of mice with synovial mononuclear cells, 0%-39.3% (mean = 11.4%) of total IgM consisted of IgM RF compared to 0%-0.15% (mean = 0.02%) in mice given RA PBMC and 0%-1.2% (mean = 0.34%) in mice given normal PBMC. Detectable levels of IgM RF were maintained in some mice for as long as 20 weeks after transfer. Mice reconstituted with synovial membrane or synovial fluid lymphocytes produced a heterogeneous mixture of immunoglobulins. These included other autoantibodies, such as anti-nuclear and anti-cytoplasmic antibodies, and antibodies to exogenous antigens such as the Epstein-Barr virus nuclear antigen-1 (EBNA-1). This heterogeneity is further illustrated by the demonstration that the sera from mice given synovial cells also contained IgG antibodies possessing all three major VH families (VH1, VH3 and VH4) and the four major V kappa families (V kappa 1 to V kappa 4). Autoantibody production gradually decreased with time even under circumstances where total immunoglobulin levels increased, and elevated production could not be induced by antigenic stimulation. These findings describe a new model for the analysis of human autoantibody production. | |
| 2512629 | [The value of using HEP/2 cells as compared to sections of rat liver in the detection of a | 1989 Oct | 1,400 sera taken from patients suspected of having autoimmune diseases and sent to the laboratory for determination of antinuclear antibodies, are tested by comparative indirect immunofluorescence on 2 subtrata; rat liver section and HEP/2 cells. The 143 positive sera on rat liver sections are also positive on HEP-2. In the 1,010 sera which are negative on rat liver sections, 165 are positive on HEP-2, 113 give a nuclear fluorescence, 26 give a cytoplasmic fluorescence and 26 give a nuclear and cytoplasmic fluorescence. Three positive sera were also used in immunofluorescence on another cells: VERO and MRC 5, as well as dual immunodiffusion versus thymic and splenic cell extracts and 76 p. cent of these sera were found positive with these techniques. This confirms the advantage of the use of HEP/2 cells in demonstrating autoantibodies, especially when they are not detected on rat liver sections, like the anticentromer antibodies. This substratum offers the advantage of detecting not only antibodies directed against nuclear antigens, but also those directed against cytoplasmic antigens. |