Biomedical subjects
Publications and source records attributed to D A Isenberg.
Occular involvement is infrequent and blindness rare in Churg-Strauss syndrome. We describe a patient with Churg-Strauss syndrome who presented with blindness. This was associated with the appearance of circulating autoantibodies to myeloperoxidase.
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An association between systemic lupus erythematosus (SLE) and immunoglobulin A (IgA) deficiency has been reported previously and may have therapeutic consequences for patients who require treatment with intravenous immunoglobulin. We report the prevalence of IgA deficiency in a clinic population of 96 patients with SLE. Five patients were found to be consistently IgA deficient. These patients were more likely to be West Indian, to have anti-Sm and anti-La antibodies and to have a speckled pattern of antinuclear antibody. There were no significant differences in clinical features between IgA deficient and other SLE patients, nor in SLE-related HLA alleles. We thus confirm the increased prevalence of IgA deficiency in patients with SLE. A review of the literature is presented and we speculate on the nature of the link between IgA deficiency and SLE.
The presence of antiphospholipid antibodies, especially of the IgG isotype and in high titre, is associated with additional complications in patients with SLE. The thrombocytopaenia and cerebral events in the patient described are likely to have been linked to her lupus anticoagulant. However, the antibody and anticardiolipin antibodies are not necessarily synonymous and indeed we did not detect anticardiolipin antibodies in the patient, although her sister had them. It is likely that they represent overlapping sets of immunoglobulins. The production and analysis of further such antibodies, as described in this review, is awaited urgently. Much effort is also being expanded on identifying the precise targets for these antibodies. In a very recent report Hörkkö et al have shown that these antibodies may be directed against epitopes of oxidized phospholipids. The management of patients with complex disorders such as described here remain a challenge, although in the short term the patient's major locomotor, neurological, dermatological and haematological problems have been controlled. Long-term problems including impaired fertility and osteoporosis remain to be faced.
Antibodies against the Sm antigen are characteristic of systemic lupus erythematosus (SLE). They are found in 20-30% of SLE patients and it has been shown previously that up to 70% of SLE sera react with synthetic fragments 1-20 and 44-67 of the Sm-D polypeptide. To determine whether injections of these peptides might be pathogenic both were administered intraperitoneally into normal mouse strains BALB/c (H-2d), B10/brown (H-2k) and C57BL/6 (H-2b) and an autoimmune strain MRL/lpr (H-2k). IgG antibodies against peptide 1-20 were detected by ELISA in the sera of BALB/c and MRL/lpr mice but not in the sera of B10/brown and C57BL/6 mice. IgG antibodies against peptide 44-67 were found in the sera of BALB/c, B10/brown and MRL/lpr mice but not in the sera of C57BL/6 mice. Neither fragment induced a response against the whole Sm-D antigen as detected by Western blotting. Reactivity to synthetic fragments from other nuclear antigens was however detected in the sera of MRL/lpr mice, especially in those mice injected with Sm-D peptide 44-67 emulsified in Freund's adjuvant. Following immunization with Sm-D peptides, antibodies to ssDNA or dsDNA were not detected in the sera of BALB/c, B10/brown and C57BL/6 mice and in the MRL/lpr mice the naturally occurring production of these antibodies was not enhanced. No difference in IgG deposition in the renal glomeruli of the mice injected with the peptides compared with the control groups was observed. These results suggest that the humoral response to the Sm-D fragment is, at least partially, controlled by the MHC haplotype of the recipient mice, is related to dose and type of immunogen, and is also influenced by the presence of Freund's adjuvant. It is evident that although the sera of many SLE patients recognize either or both the 1-20 and 44-67 peptides, these peptides when injected into MRL/lpr mice are not directly pathogenic.
We have previously shown that patients with SLE have significantly lower percentages and absolute numbers of NK(CD3-/CD16+56) cells in their peripheral blood compared with normals. Patients with active disease had very low levels of NK cells and the reduction was also associated with patients who had renal involvement. We have now performed a serial study immunophenotyping 11 patients with SLE and renal involvement using dual colour immunofluorescence and flow cytometry. Patients were tested every three months on an average of three occasions. As a control, nine SLE patients without renal involvement were immunophenotyped for similar intervals; 11 normal controls were also tested. Major lymphocyte subsets (T, B and NK) remained very stable during serial bleeds. However, the NK cell populations were decreased significantly in patients with renal involvement both as percentages (5 +/- 6 vs 9 +/- 5, P < 0.0001) and absolute counts (75 +/- 108 vs 109 +/- 52, P < 0.001) in comparison to non-renal patients. Analysis of disease activity using BILAG score showed an inverse correlation between renal system activity and percentage and absolute number of NK cells (P < 0.002 and 0.01, respectively). In this study we have also analysed a CD8 T cell subset which we have not studied before. We have found a significantly increased percentage of CD38+CD8+ T cells(activated CD8 subset) in patients with SLE in comparison to normal controls. We did not find any association with the CD38+CD8+ T cells and disease activity as measured by BILAG or renal involvement. NK cells are important factors in immunity against virus infections and tumour cells. CD38+CD8+T cells are increased in viral infections. We speculate that the lack of NK cells in SLE patients might have an association with increased CD38 expression.
Evidence from animal models of lupus suggests that disruption of Fas-mediated apoptotic events may play a role in systemic lupus erythematosus (SLE). The recently described secreted from of Fas (sFas) could interfere with apoptotic events by blockading Fas/Fas ligand interactions. We describe elevated secreted Fas protein in sera from 60 patients with SLE compared with controls but neither sFas protein nor sFas mRNA levels correlated with disease activity. At the mRNA level there is strong evidence that individuals with human leucocyte antigens common in SLE patients have a genetic predisposition for increased secreted Fas production.
OBJECTIVE: To examine the internal consistency and validity of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) with respect to disease activity, health status, and medication score. METHODS: A prospective cross sectional study of patients with systemic lupus erythematosus (SLE) attending a specialist lupus outpatient clinic between July 1994 and February 1995. The internal consistency of the SDI components was examined using Cronbach's coefficient alpha. The associations of the SDI components with disease activity measured by the British Isles Lupus Assessment Group (BILAG) index, health status measured by the Medical Outcomes Study (MOS) Short Form 20, and with a medication score were analyzed using Spearman's rank correlation coefficient (p). RESULTS: 133 women and 8 men ranging in age from 20.1 to 88.7 years (mean 41.1, SD 12.5) were studied. With few exceptions, the components of the SDI that reflect damage in different organ systems were not associated with each other. We found a significant although weak relationship between some related SDI and BILAG components (p 0.25 to 0.28; p < 0.01). While damage to the musculoskeletal system was associated with limitations in physical functioning measured with the MOS Short Form 20 (p-0.30; p < 0.01) and renal damage inversely with fatigue (p-0.23; p < 0.01) there was no significant relationship of other SDI components with the MOS Short Form 20. Renal and neuropsychiatric damage were associated significantly with the medication score (p 0.27 and 0.23; p < 0.01). CONCLUSION: The components of the SDI are valid in that they are associated with disease activity in the respective organ systems and some of them with a medication score. However, damage in different organ systems in SLE does not follow a common pattern. It is thus suggested that the SDI profile be used in addition to the SDI total score as an endpoint in clinical and epidemiological studies.
Systemic lupus erythematosis (SLE) is a multifactorial disease with both genetic and environmental etiology. The complexity of factors contributing to SLE are considered in an analogy with a card game. The hears suit represents sex hormones. SLE is a disease of marked female prevalence and abnormal estrogen metabolism has been described in women with SLE. The clubs suit considers complement and other genetic factors. Increased risk of SLE has been described in association with some HLA markers and the complement C4A0 null allele. Although convincing evidence has not yet emerged, other candidate genes of importance are T cell receptor genes and genes encoding B cell immunoglobulin receptors and antibodies. Recently, abnormalities of apoptosis and of expression of the protooncogene Bcl-2 have been investigated. Overall different genes have been shown to increase the risk of SLE, and/or to influence the development of particular antibodies, and particular subsets of disease. The diamonds suit considers antigens and antibodies in the etiopathogenesis of SLE. Numerous autoantibodies have been described that bind a variety of targets on the cell surface, within the cytoplasm, or in the nucleus. It is generally agreed that autoantibodies develop as a consequence of both generalized polyclonal activation and antigen drive. The final suit of spades considers infectious, environmental, and other agents such as drugs, as triggers in the development of SLE.
OBJECTIVE: To investigate the metric properties and validity of the assessment of quality of life by the MOS Short Form 36 (SF-36) in patients with systemic lupus erythematosus (SLE) and to examine the effect of disease on quality of life. METHODS: Cross sectional study of 150 patients with SLE (age: mean 39.7 yrs, SD 11.4 yrs; 95% female) attending 2 specialist lupus clinics between November 1994 and April 1995. Shortly before or after the consultation patients completed the SF-36 and the MOS SF-20 with an additional question about fatigue (SF-20+) in random order. Disease activity was measured by the British Isles Lupus Activity Group System (BILAG), disease damage by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) damage index (SLICC). RESULTS: SF-36 domains were shown to be internally consistent (Cronbach's coefficient alpha > or = 0.71). Significant associations of the SF-36 domains with the corresponding domains of the SF-20+ and with global disease activity measured by BILAG were observed. SF-36 scores in patients with SLE were significantly lower than in controls. Different disease activity levels were significantly associated with different quality of life scores, with excellent ability to record the continuum from good health to serious illness by the SF-36. Disease activity had greater effect on quality of life than age, cumulative damage, or disease duration. CONCLUSION: This study shows the SF-36 is internally consistent and proves construct, discriminatory, and criterion validity for the SF-36 and construct validity for the SF-20+ in patients with SLE. The SF-36 is preferred because of its broader scope of questions, its widespread use, and previous international validation for a wide variety of diseases.
beta 2-Glycoprotein I (beta 2-GPI), a plasma protein with in vitro anticoagulant properties, has been recognized to have an important role in the antiphospholipid syndrome (APS) as a cofactor and an (co)antigen in ELISA assays. Although beta 2-GPI levels were found to be increased in some patients with APS, the clinical value of measuring beta 2-GPI levels in APS is not known. Several reports have suggested that anti-beta 2-GPI antibodies may be a marker for the APS and might be more specific for the vascular complications of the APS than anticardiolipin antibodies. There have been major discoveries about phospholipid (PL) and antibody binding sites on beta 2-GPI, although more studies are needed. Reports of changes in cell membrane PL composition or exposure of other anionic molecules by apoptosis, cell activation and oxidative injury suggest mechanisms to explain beta 2-GPI binding and the generation of cryptic epitopes for aPL/anti-beta 2-GPI antibodies.
The V4-34 gene encodes the majority of autoanti-red cell Abs of I/i specificity. It also encodes a proportion of autoanti-DNA Abs found in patients with systemic lupus erythematosus. Nucleotide sequence analysis of mAbs that use this gene has indicated a role for CDR3 in discrimination between these autoantigens. Specifically, anti-DNA activity may require basic amino acids, such as arginine, found in this region. To investigate this requirement, we have expressed VH and VL sequences from a patient's IgG anti-DNA mAb, as Fab molecules at the surface of phage. Expressed Fab bound strongly to DNA, whereas control VH and VL pairs from an anti-red cell mAb did not. Replacement of the homologous mutated V4-34 sequence by germ-line sequence did not affect binding, indicating that somatic mutations in VH did not contribute significantly. In contrast, replacement of the basic CDR3 by an anti-red cell CDR3 abrogated anti-DNA activity, confirming its major role. However, an influence of VL was revealed by replacing homologous mutated V kappa IIIb by an unmutated V kappa IIIb sequence, reducing binding by approximately 50%. This influence was apparent only with homologous VH since the mutated V kappa was unable to generate anti-DNA activity when combined with anti-red cell VH. The 9G4 idiotope, which arises from FWR1, was expressed by all constructs. Substitution of Trp by Ser at position 7 in FWR11 caused complete loss of idiotope expression, with no effect on recognition of DNA, indicating no influence of idiotope expression on anti-DNA activity. Phage surface expression provides a powerful and rapid technique for assessing sequences relevant for Ab specificity or idiotope expression.
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Blood cells spontaneously secreting IgG and IgM and the level of plasma immunoglobulins and antibodies to dsDNA, ssDNA and influenza virus haemagglutinin have been determined in families of patients with SLE, in 'normal' families and groups of 'normal' individuals. IgM values were consistently higher in females than in males. About one in three of healthy blood relatives gave values in excess of the sex-matched control range in one or more of these test, particularly notable being raised values of IgG anti-dsDNA and total IgG shown by female relatives. High-scoring relatives were more likely to be offspring or parents than siblings of patients, suggesting, together with evidence from a spouse group, the involvement of environmental as well as genetic factors in these families. Correlation analysis between the various assays in the different groups showed a clear distinction between the female control group, where there were no associations, and the female relative group where there were strong associations, including a significant correlation between IgM and IgG antibodies to dsDNA. The male groups produced a more variable picture but the patients gave a remarkably consistent pattern of moderate positive associations. Pokeweed mitogen induced a higher level of IgG production in blood cells of relatives than in controls. These findings are suggestive of a breakdown in relatives of normal antibody regulation. Investigation of immunological abnormalities in family members provides a powerful tool for the analysis of a complex disease.
Our aim was to investigate links between systemic lupus erythematosus (SLE)-associated autoantibodies, idiotypes (Id) and genetic predisposition to their development. We studied four public Ids (16/6, WRI 176 beta, RT72 and RT84), identified the Km and Gm phenotypes and sought six selected autoantibodies in 32 SLE patients, 174 of their relatives and 15 spouses. Though anti-double-stranded DNA antibody was uncommon in the relatives (9%), the range of antinuclear reactivities was as broad in the relatives as in the probands. Antibodies to the synthetic peptide U1-RNP-A 35-38 were found in 56% of the patients, 28% of their relatives and 20% of the spouses, whereas antibodies to the Golgi apparatus was present in 7% of the patients, 26% of their relatives and 33% of the spouses. However, most of these family members were unaffected. RT84 Id was positively associated with antibodies to Sm-D peptide 1-20 and to Ro/SSA 60 kD peptide 304-324, but negatively associated with anti-dsDNA activity. The median of age was significantly lower in the RT84 Id-positive than in the RT84 Id-negative individuals. These data suggest that genetic as well as environmental factors are involved in the aetiology of SLE. In addition, RT84-carrying immunoglobulins (Ab2) might be directed to one of many cross-reactive Ids of dsDNA-binding antibodies (Ab1), perhaps down-regulating their production.
Neither the incidence nor the severity of neonatal autoimmune disease correlates with maternal or neonatal autoantibody titres. However, there is now evidence that the agalactosyl [Gal(0)] fractions of autoantibodies are the most pathogenic. We found that systemic lupus erythematosus (SLE) mothers whose infants developed congenital heart block (CHB) had higher %Gal(0) at the end of pregnancy than did mothers of unaffected infants (P < 0.05) or control mothers (P < 0.01). Similarly, affected infants had higher %Gal(0) than control infants (P < 0.01). Then we studied the Gal(0) content of the anti-Ro and we found that it was higher in affected neonates than in unaffected neonates (P < 0.05), though there was no difference between the corresponding groups of mothers by this criterion. We propose that agalactosyl IgG may have a regulatory or effector role and that the risk of neonates developing maternal autoantibody-mediated disorders may be related to the quantity of agalacotsyl autoantibody present at birth, rather than to its absolute titre.