Appearance of anti-DNA antibodies in patients treated with interferon-alpha.
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Antibodies, Antinuclear↗
Biomedical subjects
D A Isenberg
Publications and source records attributed to D A Isenberg.
Characterization of a cross-reactive idiotype on two human autoantibodies associated with systemic autoimmune disease.
A human-human hybridoma was derived from a patient with primary Sjogren's Syndrome. The monoclonal antibody from this hybridoma, P36, was found to be polyreactive. P36 shared idiotypic cross-reactivity with a lupus-associated monoclonal antibody called 4B4. There was a strong correlation between P36 and 4B4 idiotype levels in systemic lupus erythematosus sera. Western blot studies showed that this shared idiotype was found on the heavy chain of both antibodies. This study shows that the heavy chain is important in the expression of this idiotype and provides another immunologic link between these two rheumatic diseases.
Antibodies, Monoclonal↗
Elevated levels of the 90 kD heat shock protein in patients with systemic lupus erythematosus are dependent upon enhanced transcription of the hsp90 beta gene.
The level of the 90 kD heat shock protein (hsp90) has been shown to be elevated in the peripheral blood mononuclear cells of a subset of SLE patients. We show that this increased level of hsp90 is primarily dependent upon the enhanced transcription of the hsp90 beta gene which is observed in these patients but not in normal controls or SLE patients without elevated protein levels. Elevated transcription of the hsp90 beta gene in SLE patients is not in general paralleled by enhanced transcription of the hsp70 or ubiquitin genes indicating that the hsp90 beta gene is specifically activated in some SLE patients.
Adult↗
Haematological manifestations of systemic lupus erythematosus.
Haematological involvement is common in systemic lupus erythematosus (SLE). Whilst anaemia is most often due to chronic disease, other causes such as autoimmune haemolytic anaemia and hypoplastic anaemia need to be considered. The increased risk of infection in patients with SLE is due in part to changes in the white blood cells though treatments do not yet aim to modify these. Thrombocytopenia occurs frequently and is almost invariably autoimmune. It is often of little consequence, but may occasionally be severe and serious, requiring aggressive treatment. Patients with SLE have an increased risk of thrombosis, increased further in the presence of antiphospholipid antibodies (aPL). Changes in the haemostatic system and new insights into the nature of aPL are described.
Anemia↗
Autoantibodies in central nervous system lupus.
Central nervous system (CNS) involvement in patients with lupus remains both a diagnostic and a therapeutic challenge. The role of autoantibodies in the pathogenesis of CNS lupus and/or as markers for disease activity is reviewed. Doubt is cast on the value of measuring anti-neuronal antibodies. Those antibodies binding ribosomal-P protein antigens or certain phospholipids appear to have greater utility, although even in these cases there is no uniform agreement as to their precise role in CNS disease induction, or how well antibody levels reflect disease activity.
Antibodies, Antiphospholipid↗
Anti-DNA antibodies in the primary antiphospholipid syndrome (PAPS)
Primary antiphospholipid syndrome (PAPS) is considered a distinct entity from SLE and patients with PAPS are generally regarded as being dsDNA antibody negative. Levels of IgG and IgM ss and ds DNA antibodies were measured by ELISA in 30 patients who fulfilled the criteria for the diagnosis of PAPS. We compared these patients with 20 normal controls and seven patients with idiopathic SLE. We also examined all the sera for anti-nuclear antibodies by Hep-2 cells and for dsDNA antibodies by Crithidia. We found that 16 patients with PAPS had antibodies to ss and/or dsDNA. Only three of the 16 positive patients had both IgG and IgM anti-DNA antibodies. Twelve patients had anti-nuclear antibodies, but only two were weakly positive for dsDNA antibodies by Crithidia immunofluorescence. Eleven out of 30 patients with PAPS had IgM anti-dsDNA antibodies compared to two out of the seven SLE patients. The PAPS patients with anti-DNA antibodies were clinically indistinguishable from the PAPS patients without antibodies against DNA. Our results show that 53% of patients with PAPS had antibodies to DNA which supports the view that PAPS and SLE are probably overlapping disorders.
Antibodies, Antinuclear↗
Antiribosomal P protein antibodies in different populations of patients with systemic lupus erythematosus.
We report a significantly increased prevalence of antiribosomal P protein antibodies in Malaysian Chinese patients (38%) with SLE compared to white Caucasian (13%) and Afro-Caribbean (20%) patients. The increased prevalence was not due to a generalized increase in autoantibody production because anti-dsDNA and anti-SSA antibodies were present in comparable frequencies in the three ethnic groups while anti-Sm and anti-SSB antibodies were rarely found in the Malaysian Chinese patients.
Antibodies, Anti-Idiotypic↗
Production and analysis of IgG monoclonal anti-DNA antibodies from systemic lupus erythematosus (SLE) patients.
This study compares recently devised methods for producing IgG anti-DNA MoAbs from patients with SLE and analyses the antibodies generated from one patient at different phases of disease. Lymphocytes from SLE patients were transformed with Epstein-Barr virus(EBV) and/or fused with a heteromyeloma cell line, CB-F7. Direct fusion with CB-F7 resulted in the highest proportion of IgG-secreting lines, whereas EBV transformation resulted in a high percentage of IgM-secreting lines. Using direct fusion, five IgM anti-DNA antibody-secreting hybridomas were generated using lymphocytes from a patient with relatively inactive SLE. Six months later when the disease was active, only IgG anti-DNA antibodies were produced. The antigen-binding patterns of the MoAbs were analysed. Only one of the IgM anti-DNA antibodies reacted with dsDNA by ELISA and none by Crithidia immunofluorescence, whereas two of the IgG antibodies reacted with dsDNA by ELISA and Crithidia but did not bind to ssDNA. Only the two IgG high affinity anti-dsDNA antibodies bound to histones, and this was enhanced by added DNA, whereas three IgM antibodies bound to cardiolipin. This study supports the notion that MoAbs derived from a patient with SLE represent those found in the serum of SLE patients at different stages of disease activity. The binding to histones by the two IgG anti-dsDNA antibodies supports the recently expressed view that antibodies binding DNA/histone may be important in the pathogenesis of SLE.
Animals↗
Elevation of heat shock protein synthesis and hsp gene transcription during monocyte to macrophage differentiation of U937 cells.
During the phorbol myristate acetate (PMA)-induced differentiation of U937 cells to a macrophage-like phenotype, the levels of the heat shock proteins hsp90, hsp72 and hsp65 increased dramatically to a peak level following 24 h of treatment, and then declined. In contrast, no significant increase was observed in the level of the constitutive hsp73 protein in this process. The observed increases in hsp levels were preceded by an increase in the transcription of each of the genes encoding these hsps, including both of the two genes which encode hsp90. The mechanism of this effect and the possible role of the hsps in the function of differentiated macrophages and in the differentiation process are discussed.
Cell Differentiation↗
Vascular cell adhesion molecule 1 and alpha 4 and beta 1 integrins in lymphocyte aggregates in Sjögren's syndrome and rheumatoid arthritis.
OBJECTIVES: Interactions between vascular cell adhesion molecule 1 (VCAM-1) and its ligand, the alpha 4/beta 1 integrin, have been shown to be important in a number of cellular events in vitro. To assess the importance of such interactions in the development of lymphocytic infiltration in diseased tissue the distribution of the two ligands has been studied immunohistochemically. METHODS: Cryostat sections of labial tissue from patients with Sjögren's syndrome, normal labial tissues, rheumatoid synovia, and normal tonsils were stained using antibodies to VCAM-1, alpha 4 and beta 1 integrin chains, and markers for T cells, B cells, macrophages, and follicular dendritic reticulum cells (FDRCs), visualised using alkaline phosphatase and fast red. RESULTS: Staining patterns for VCAM-1 and integrin chains in lymphocyte aggregates in synovial and labial tissues were similar. VCAM-1 staining was found on both vascular and ramifying dendritic cells at the centre of large T cell aggregates and in all aggregates where there was a central clustering of B cells. VCAM-1 colocalised with, but also extended beyond, staining for the FDRC marker R4/23. Staining for the alpha 4 and beta 1 integrin chains was more widespread than staining for VCAM-1, with no significant increase in staining at sites of maximum VCAM-1 staining. In tonsils VCAM-1 and R4/23 codistributed in germinal centres, but staining for the alpha 4 and beta 1 integrin chains was chiefly seen in T lymphocyte areas. CONCLUSIONS: VCAM-1 may be more important in determining the distribution of B than T lymphocytes in lymphocytic infiltration of non-lymphoid tissue. Unlike the follicles of lymphoid tissue, ectopic follicle-like structures in non-lymphoid tissues may form by immigration of B cells via VCAM-1+ vessels at the centre of T cell aggregates.
Arthritis, Rheumatoid↗
Expression of public idiotypes in patients with Lyme arthritis.
OBJECTIVE: Joints are often affected in Lyme disease and in some instances this may be due to immune autoreactivity. To characterise further the immune response in this disease investigations were carried out to determine the expression of three public idiotypes on serum immunoglobulins in patients with Lyme disease during the development of varying degrees of arthritis. METHODS: The expression of idiotypes (Ids) 16/6, BEG2, and PR4, first identified on monoclonal antibodies to DNA, was determined by an enzyme linked immunosorbent assay (ELISA) in serial blood samples from 12 patients with Lyme disease over a mean period of six years during the development of a variety of arthritic symptoms, and in serum samples from healthy control subjects and control subjects with systemic lupus erythematosus. RESULTS: Expression of serum IgM or IgG public Ids 16/6 and BEG2 was significantly increased in patients with Lyme disease. IgA Id 16/6 expression, in contrast, was significantly increased only during episodes of arthritis and was also related to its severity. IgM and IgG Id 16/6 expression was related to their respective total immunoglobulin concentration and, in the case of IgM, to the level of IgM antibodies to Borrelia burgdorferi, whereas similar findings were not apparent with IgA antibodies. This may indicate that the IgA response is related to the pathogenesis of arthritis, especially as total IgA and IgA Id 16/6 levels were found to increase over the duration of disease. Sequential analysis of antibodies also showed restriction in the expression of Id 16/6 as it was never found on all immunoglobulin isotypes at the same time, and Id PR4 was never expressed. Ids 16/6 and BEG2 expression, however, may be associated as seven patients expressed these idiotypes simultaneously. CONCLUSIONS: These data indicate the use of public idiotypes in the immune response against B burgdorferi, which may be restricted in terms of idiotype class and isotype expression, and a possible association between IgA antibodies bearing Id 16/6 with arthritis.
Adult↗
Differential heat shock protein overexpression and its clinical relevance in systemic lupus erythematosus.
OBJECTIVES: To determine which heat shock proteins (hsps) are overexpressed in systemic lupus erythematosus (SLE), and to examine the relevance of these findings to clinical disease activity. METHODS: Hsp levels in peripheral blood mononuclear cells (PBMC) of patients with SLE and normal controls were measured. Levels were analysed with respect to detailed clinical activity scores. Other hsps were also quantified in 30-50% of these samples. RESULTS: There was significant increase of the 90 kilodalton heat shock protein (hsp90) in patients with SLE and active neuropsychiatric (p < 0.005) and cardiorespiratory (p < 0.01) disease. There was also significant increase of the inducible 72 kilodalton member (hsp72), but not the constitutive 73 kilodalton member (hsp73) of the hsp70 family, and no increase of the 60 kilodalton hsp (hsp60) was seen in patients compared with controls. There was no association of hsp72 with disease activity, and no correlation between hsp90 and hsp72 levels was seen in individual patients. CONCLUSION: There may a specific role for hsp90 in distinct, clinically active subsets of patients with SLE.
Adolescent↗
Health screening: the temporomandibular joint.
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Dentistry↗
Role of beta 2-glycoprotein I and anti-phospholipid antibodies in activation of protein C in vitro.
AIMS: To investigate the effect of beta 2-glycoprotein I (beta 2 GPI) on the thrombin/thrombomodulin dependent activation of protein C; and to determine whether beta 2 GPI dependent anticardiolipin antibodies have any effect. METHODS: Protein C was activated by thrombin in the presence of thrombomodulin and phospholipid vesicles in an in vitro system. The effect of adding purified beta 2 GPI to this system was observed. Affinity purified anticardiolipin antibodies and total IgG from patients with anticardiolipin antibodies and the lupus anticoagulant were studied for their effects on protein C activation in the presence and absence of beta 2 GPI. RESULTS: beta 2-Glycoprotein I had no effect on the activity of preformed activated protein C. When the phospholipid vesicles were incubated with beta 2 GPI before the addition of protein C, the activation of protein C was inhibited in a dose dependent manner. With phosphatidylserine:phosphatidylcholine vesicles at a concentration of 1 microM:2 microM, beta 2 GPI began to inhibit the reaction at a concentration of 15 nM, and at 4 microM (the normal plasma concentration) the activation of protein C was reduced to 40%. Anticardiolipin antibodies had no demonstrable effect. CONCLUSIONS: beta 2-Glycoprotein I inhibits protein C activation in an in vitro system. Its physiological role is unknown but it has potential procoagulant as well as anticoagulant properties. An effect of antiphospholipid antibodies on protein C activation, which might explain their association with thrombosis, could not be shown.
Antibodies, Antiphospholipid↗
Lupus anticoagulant activity of some antiphospholipid antibodies against phospholipid bound beta 2 glycoprotein I.
AIMS: To determine whether beta 2 glycoprotein I (beta 2GPI) dependent anticardiolipin (aCL) antibodies detected in solid phase enzyme linked immunosorbent assays can also have lupus anticoagulant activity. METHODS: Six anticardiolipin antibodies were affinity purified from patients with these antibodies and lupus anticoagulant activity in their plasma. RESULTS: The anticardiolipin antibodies bound only to anionic phospholipids in the presence of beta 2GPI and bound to beta 2GPI in the absence of phospholipids. Four out of six had lupus anticoagulant activity in the dilute Russell viper venom time test. CONCLUSIONS: The results show that some beta 2GPI dependent aCL are lupus anticoagulants. It is unclear why only some should have lupus anticoagulant activity while others do not.
Anions↗
The association of malignancy with SLE: an analysis of 150 patients under long-term review.
We describe seven patients who developed malignancy before, after or at the onset of systemic lupus erythematosus (SLE). They comprise three cases of breast adenocarcinoma, two cases of Hodgkin's lymphoma, and one each of cholangiocarcinoma and thymoma. Only one of this group had been treated with cytotoxic agents, and five have subsequently died. They belonged to a group of 150 SLE patients, many of whom had been treated with steroids and cytotoxic agents, under long-term follow-up at a specialized lupus clinic. We discuss the reported association of malignancy in patients with SLE.
Adenocarcinoma↗
Elevated levels of the 70 kD heat shock protein in patients with systemic lupus erythematosus are not dependent on enhanced transcription of the hsp70 gene.
The level of the heat inducible hsp70 protein (hsp72) has been shown to be elevated in the peripheral blood mononuclear cells of a subset of SLE patients. We show that this increased level of hsp70 is not dependent on enhanced transcription of the hsp70 gene or elevated levels of the hsp70 mRNA, neither of which are observed in SLE patients with enhanced protein levels. This indicates that posttranscriptional processes involving either improved translatability of the hsp70 mRNA or increased protein stability are responsible for the observed increase in protein levels in these patients.
Adult↗
Primary sequence and location of the idiotopes of V-88, a DNA-binding monoclonal autoantibody, determined by idiotope scanning with synthetic peptides on pins.
In this study, the primary sequence and location of the idiotopes of monoclonal antibody (mAb) V-88 have been examined. V-88 was derived from an adult (NZB x NZW)F1 mouse, has been partially defined previously with polyclonal anti-idiotype antisera, and is a member of the 16/6 idiotype (Id) family. From the inferred primary amino acid sequence of the antibody, sets of hexapeptides, overlapping by five residues, were synthesized on pins and used to scan the expression of epitopes (idiotopes) in the V regions of the light and heavy chains. A heterologous rabbit antiserum raised against the native antibody V-88, and absorbed to make it idiotype specific, was found to react with eight major epitopes distributed between the VH and VL regions. Half of these determinants mapped to the complementarity determining regions, with the others in framework sequences. Thus, the idiotype of antibody V-88 comprises, at least in part, continuous linear idiotopes in both hypervariable and framework areas. The process of absorbing the anti-idiotype antiserum on normal mouse immunoglobulin removed much of the background antibody activity against V region peptides, but left the activity against the dominant idiotopes. The sequence of a major idiotope, VATISG, in the FW2/CDR2 VH region is homologous to sequences of human antibodies that express the 16/6 idiotype, suggesting that Id.16/6 is at least in part defined by this region of the antibody. The same VH area is also homologous to sequences in bacterial and mammalian heat-shock proteins (hsp60-65). Thus there may be a functional link through idiotype connections, especially those involving Id.16/6, between anti-bacterial responses and production of autoantibodies, and some bacterial antigens may function indirectly as superantigens for B cells.
Amino Acid Sequence↗