Autoantibodies to 90 kD heat-shock protein in sera of breast cancer patients.
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Autoantibodies↗
Biomedical subjects
D Isenberg
Publications and source records attributed to D Isenberg.
Abnormalities in the glycosylation of IgG and its clinical utility.
It is approximately ten years since the first detailed analysis of the variation in oligosaccharide structures attached to human serum IgG was published [1]. This study also showed that the percentage incidence of agalactosyl structures on the bi-antennary oligosaccharide complex linked to the Fc region, was increased in patients with rheumatoid arthritis. An earlier study [2], published in abstract from only, had also suggested that this was the case but was never followed up. In this review the considerable amount of work that has explored the clinical relevance of abnormalities in the glycosylation of IgG is analysed critically.
Arthritis, Rheumatoid↗
Sjögren's syndrome--a house of cards.
Sjögren's syndrome is an autoimmune rheumatic disease that is the result of the interplay between a number of environmental and genetic factors. In this short review an analogy is suggested with a game of cards in which each card is marked with a particular feature. A particular set of cards when dealt together could constitute Sjögren's syndrome if the hand includes cards marked for female sex, HLA DRS, anti Ro antibodies, anti La antibodies, exposure to retroviruses etc.
Animals↗
Increased levels of antibodies to heat shock proteins with increasing age in Mrl/Mp-lpr/lpr mice.
Approximately 30% of human patients with systemic lupus erythematosus (SLE) develop IgG autoantibodies to the highly conserved 90 kDa heat shock protein (hsp90). The development of anti-hsp90 antibodies is shown here to be paralleled in the Mrl/lpr mouse, which is an acknowledged model for SLE, but not in control BALB/c mice (P = 0.005). The generation of these antibodies appears to be closely linked to the onset of disease and titres of these antibodies increase with age, but there is no correlation with well-established clinical parameters of disease. Antibodies to hsp70 and hsp65 are also observed in the Mrl/lpr model; these antibodies appear to be unrelated to the pathogenesis of the disease.
Aging↗
Endorsement and memory bias of self-referential pain stimuli in depressed pain patients.
This study investigates information processing in chronic pain patients by comparing the responses of depressed pain patients, non-depressed pain patients and non-pain control subjects. Each subject contributed two scores: endorsement of adjectives as descriptors of themselves and their best-friends; and free recall of the presented words. The stimuli consisted of depression-related, pain-related and neutral control adjectives, and each content category was split into negative and positive valence. The four-way interaction between group, reference, content and valence was significant both in the recall data and the endorsement data. Further analysis revealed that depressed pain patients exhibited a bias towards self-referential negative pain words, but not towards self-referential negative depression information. These results are interpreted in line with content specificity theory of information processing and have implications for targeting cognitive interventions with pain patients.
Adult↗
Does it take sugar? A clinical role for measuring the glycosylation of IgG?
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Age Factors↗
Factors associated with mood and mood disorders in SLE.
This study examines the relative contribution of factors associated with anxious and depressed mood, and clinical anxiety and depression in SLE. Eighty sequentially consenting patients attending a rheumatology outpatient clinic were assessed on measures of anxiety and depression; disease activity; presence of autoantibodies; neuropsychological performance; and psychological and social factors. Mood and mood disorders were found to be unrelated to measures of disease activity but were found to be associated with psychological and social factors. These findings emphasise the importance of psychosocial factors in attempts to understand mood and psychological distress in SLE.
Adolescent↗
Agalactosyl IgG and antibody specificity in rheumatoid arthritis, tuberculosis, systemic lupus erythematosus and myasthenia gravis.
Agalactosyl IgG (Gal(0) is a glycoform lacking terminal galactose from the oligosaccharides situated on the Fc. The percentage of circulating IgG that is Gal(0) is increased in a a number of autoimmune diseases, and in certain chronic infections associated with autoantibody production. However it is not known whether this represents decreased galactosylation of all IgG, or an increase in the relative concentration of a subset of agalactosyl antibodies of specificity relevant to the disease process. Since there is currently no way to separate agalactosyl from galactosylated IgG, we devised an assay for the relative degree of galactosylation of antibody to tetanus toxoid (TT), an antigen irrelevant to the diseases studied, and compared this value with the %Gal(0) of the whole circulating IgG. In rheumatoid arthritis (RA) and tuberculosis (TB), a raised %Gal(0) in serum IgG was reflected in a parallel rise in the extent to which antibody to TT was agalactosyl. In SLE a rise in %Gal(0) was seen in the presence of very little rise in agalactosyl anti-TT, and in myasthenia gravis (MG), where serum %Gal(0) is normal, an abnormally low percentage of the anti-TT was agalactosyl. These results imply that in RA and TB a systemic influence is downregulating the galactosylation even of irrelevant IgG. However in SLE and MG antibodies of specificities not studied here must be responsible for the %Gal(0) found in serum. It remains to be seen whether these are the autoantibodies involved in the disease process.
Antibody Specificity↗
HLA association of anti-Ro60 and anti-Ro52 antibodies in Sjögren's syndrome.
The possible pathological role of antibody subsets specific for different regions of 60-KD and 52-KD Ro/SSA proteins (Ro60 and Ro52) and La protein is unclear. Previously, we have shown that in patients with Sjögren's syndrome, the fine specificity of Ro60 and Ro52 antibodies, as characterized with synthetic peptides, varied considerably according to the origin of sera. We therefore looked for possible associations of HLA class I and class II alleles with Ro and La IgG antibodies in patients with primary Sjögren's syndrome (n = 24) and secondary Sjögren's syndrome associated with systemic lupus erythematosus (n = 25). Ro60 and Ro52 antibodies were tested by ELISA with the complete parent proteins and with 10 to 24 residue-long peptides of these proteins. Anti-Ro60 antibodies were more frequent in DR3-positive patients and in DQ1-negative patients whereas the presence of Ro52 and La IgG antibodies was significantly increased in patients with A1/B8/DR3 haplotype. Certain HLA associations observed with antibodies reacting with the whole Ro52 protein were not found with antibodies reacting with certain Ro60 and Ro52 peptides and, reciprocally, certain anti-peptide antibodies were linked to particular haplotypes whereas antibodies to the respective parent proteins were not linked to these haplotypes. Thus the production of antibody subsets reacting with different parts or presentations of Ro proteins is, at least in part, influenced immunologically by different HLA haplotypes, and this predisposition may play a role in the pathological development of the disease.
Adult↗
Binding of anti-DNA antibodies to oxidatively damaged DNA in spouses and relatives of patients with systemic lupus erythematosus.
The prevalence of serum anti-DNA antibodies was evaluated by ELISA using oxidatively damaged DNA as antigen in 21 patients with systemic lupus erythematosus (SLE), in 9 spouses and in 15 first-degree relatives. These were compared with 12 healthy controls. There was no significant difference in the levels of serum antibodies detected between the group of spouses and normal controls with all results within the normal range of the assay. Binding of serum antibodies to the oxidatively damaged DNA was detectable in 12 (80%) of the relatives studied, and the range of values obtained overlapped significantly with the SLE patient group. The relevance of these antibodies to the immunopathology of SLE is unclear since they appear to be present in the absence of any clinical symptoms. However, they may be useful predictively as a marker for those individuals who are more likely to develop SLE.
Adolescent↗
Serum metalloproteinases and their inhibitors: markers for malignant potential.
Death from cancer results from the development of metastases or local progression of tumour. Metastasis and local progression may result from the inappropriate activity of metalloproteinases released by tumour cells or of their regulatory peptides. We have developed quantitative assays for interstitial collagenase, stromelysin 1 and tissue inhibitors of metalloproteinase (TIMP) 1 and 2, which have allowed the study of serum levels of these proteins. Sera from 40 patients with prostatic cancer, stored prior to and after 6 and 12 months' treatment with a gonadotrophin-releasing hormone agonist and an anti-androgen were analysed. Levels were compared with two control groups, comprising 21 patients with active rheumatoid arthritis and 56 age-matched hospital attenders without arthritis or cancer. Contrasting levels have been found in patients with prostatic cancer as compared with hospital controls without cancer and patients with rheumatoid arthritis. Patients with prostatic cancer had higher levels of TIMP-1 and collagenase (P = 0.0001) and lower levels of TIMP-2 (P = 0.003) than controls. Patients with metastatic cancer had significantly higher levels of collagenase than those without metastases (P = 0.02). Patients with rheumatoid arthritis had significantly higher levels of stromelysin than either controls (P = 0.002) or patients with cancer (P = 0.008). Serum tissue inhibitor of metalloproteinase 1 in combination with collagenase levels was as sensitive as prostate-specific antigen as a marker of metastatic disease. These findings provide a basis for the investigation of the role of metalloproteinases and their inhibitors in other malignancies.
Arthritis, Rheumatoid↗
Sensitivity to change of 3 Systemic Lupus Erythematosus Disease Activity Indices: international validation.
OBJECTIVE: Three indices, the SLE Disease Activity Index (SLEDAI), the Systemic Lupus Activity Measure (SLAM) and the British Isles Lupus Assessment Group (BILAG), have been found to be reliable and valid measures of disease activity in patients with systemic lupus erythematosus (SLE). Our aim was to investigate their use and comparative ability to assess change in disease activity over time. METHODS: Clinical and laboratory features of 8 patients with SLE on each of 3 consecutive visits were abstracted and sent in 3 separate packages to physicians from 8 centers. The order of the patient visit summaries was randomized, and the 3 indices rated in one of 6 specific sequences. RESULTS: The 3 indices were significantly (p < 0.01) correlated: SLEDAI/SLAM = 0.61, BILAG/SLAM = 0.55, SLEDAI/BILAG = 0.35. The sequence presented, the order of patients and order of index scoring did not contribute significantly (p > 0.05) to the variation of any of the 3 indices. All 3 indices detected differences among patients (p < 0.01). Differences between visits were detectable with SLEDAI (p = 0.04) but not with SLAM or BILAG: CONCLUSION: Our study confirms that the SLEDAI, SLAM and BILAG are comparable disease activity measures. SLEDAI appears to be sensitive to change in disease activity over time.
Computers↗
Utilization of the VH4-21 gene segment by anti-DNA antibodies from patients with systemic lupus erythematosus.
A monoclonal antibody (9G4) which detects an idiotope (Id) rising from heavy chains encoded by the VH4-21 gene segment has been utilized to investigate the role of this gene in encoding anti-DNA antibodies in SLE. Two hybridomas secreting Id-positive anti-DNA antibodies were established from two patients with SLE, with one (RT-79) an IgM kappa and the other (D-5) IgG kappa. Nucleotide sequence analysis of the heavy chain variable regions revealed involvement of the VH4-21 gene; the IgM antibody used the gene in germ line configuration, whereas the IgG antibody had 18 nucleotide changes. The CDR3 sequences for both the antibodies had a predominance of basic amino acids, with RT-79 having five and D-5 two arginine residues respectively. The VH4-21 gene segment, often in germ line configuration, is also used by IgM autoantibodies against red cell Ii antigens. However, IgM from a panel of six hybridomas secreting antibodies of Ii specificity, had no detectable activity against DNA. Conversely, RT-79 had only a weak ability to agglutinate red cells. Comparisons of Ig variable regions indicate that the amino acids in the CDR3 region of the mu chain influence the ability of IgM encoded by the VH4-21 gene segment to discriminate between a carbohydrate Ii antigen and DNA, and strongly support the suggested role of arginine in interaction with DNA. Sera from patients with SLE were found to have significantly raised levels of Id which was expressed by anti-DNA antibodies against both ss and dsDNA.
Amino Acid Sequence↗
Autoimmune diseases--at the molecular level.
Autoimmunity and autoimmune diseases are the focus of intensive research using the concepts and tools of immunology, molecular genetics and cell biology. A group of scientists recently gathered to discuss recent developments in organ-specific and systemic autoimmune diseases in both human and animal models. In this article, we hope to convey some of the excitement and enthusiasm evident at the meeting which placed emphasis on work at the molecular level.
Animals↗
Identification of the 9G4 idiotope in systemic lupus erythematosus.
An idiotope designated 9G4 (9G4Id) is known to be a marker for immunoglobulins which utilize a particular VH gene, VH4-21. The idiotope has been found to be present on anti-DNA antibodies, and have been identified in 45% of sera from patients with SLE. This idiotope is strongly associated with lupus being very uncommon amongst the other autoimmune rheumatic diseases tested. This distinction is unlike virtually any of the other DNA antibody idiotypes described which are much more widely distributed. 9G4Id levels were found to fluctuate with disease activity in some lupus patients and this idiotope was detected in 3/11 SLE renal biopsies tested. Its presence is associated with the HLA markers A1 and B8 and raised 9G4Id levels are not simply a reflection of hypergammaglobulinaemia. Thus a new DNA antibody associated idiotope has been identified. Expression of the idiotope indicates that a notable proportion of anti-DNA antibodies have VH segments encoded by the same, or closely related genes, and that these restricted immunoglobulins are involved in the renal pathology found in SLE.
Humans↗
The differential expression of heat shock proteins in rheumatic disease.
The concept of overexpression of endogenous heat shock proteins (hsps) is central to hypotheses in which hsps are implicated in the pathogenesis of autoimmune rheumatic disease. Hsps were quantitated in protein samples prepared from peripheral blood mononuclear cells (PBMC) of patients and controls by Western blotting and scanning densitometry. Evidence is presented for a specific pattern of overexpression of the 90 kDa hsp (hsp 90) and the highly inducible member of the 70 kDa hsp family (hsp 72) occurring overall in SLE relative to other diseases. Evidence is also presented for the differential expression of individual hsps in other autoimmune rheumatic diseases such as RA, primary SS and systemic sclerosis, and in other relevant conditions such as infectious diseases and multiple sclerosis. It is concluded that, while hsp 90 overexpression may have a specific role in, for example, SLE, overexpression of hsp 72 and underexpression of the constitutive member of the hsp 70 family (hsp 73) may be a more general reflection of ongoing disease states.
Adolescent↗
Communication channels of the Arthritis and Rheumatism Council--the role of the Honorary Medical Secretaries.
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Arthritis↗
Rheumatoid factor: primary or secondary event in the pathogenesis of RA?
Rheumatoid factors have been recognised and studied for over fifty years. They are anti-IgG immunoglobulins which occur in most patients with rheumatoid arthritis. Their precise contribution to the pathology of this disease however remains an enigma, since they are also demonstrable in other autoimmune and infectious diseases, as well as in normal healthy controls. Thus the importance of RF in RA may not pertain merely to their presence, but to the nature of the autoantibodies themselves. RF in RA are found to differ from those in control subjects and in other diseases such Waldenstrom's macroglobulinaemia in terms of their binding affinities for IgG, subclass specificity and V gene usage. The role of RF as either the initiating factor or its occurrence as a secondary event in RA is discussed.
Arthritis, Rheumatoid↗