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J F Meilof

Publications and source records attributed to J F Meilof.

At least 19 recordsLinked to original sources
PubMed1997

Production of anti-Ro/SS-A and anti-La/SS-B autoantibodies is closely coordinated in systemic lupus erythematosus and independent of anti-dsDNA production.

Autoimmune diseases such as Sjögren's Syndrome and systemic lupus erythematosus (SLE) are characterized by serum autoantibodies against protein components of small cytoplasmic ribonucleoproteins (scRNPs). The origin and regulation of these anti-Ro/SS-A and anti-La/SS-B antibodies is not well understood. Regular co-occurrence of these two autoantibodies in humans together with murine studies on antibody responses against scRNPs after immunization suggest a role for scRNPs as common antigen. We sought additional evidence for this hypothesis in a longitudinal serological study of patients with SLE. Quantitative measurement of the antibody responses against Ro/SS-A and La/SS-B proteins and for comparison to dsDNA in 852 serum samples was performed. These samples were collected from nine patients during an average observation period of more than 10 years. A significant and strong correlation between the two anti-scRNP responses emerged during 90% of follow-up. In contrast, correlation of anti-scRNP with anti-dsDNA responses was remarkably absent in the same patients. Our results confirm the unique relationship between anti-Ro/SS-A and anti-La/ SS-B responses and could thus be interpreted as support for a model wherein induction and perpetuation of autoantibody production is dependent on scRNPs containing both proteins as antigen.

Antibodies, Antinuclear↗
PubMed1995

Characterization of murine monoclonal antibodies against 60-kD Ro/SS-A and La/SS-B autoantigens.

Small cytoplasmic ribonucleoproteins (scRNPs) are important autoantigens in patients with systemic lupus erythematosus and Sjögren's syndrome. MoAbs against these proteins were made by immunization of BALB/c mice with purified human recombinant 60-kD Ro/SS-A or 50-kD La/SS-B proteins. Five stable hybridoma cell lines were obtained, of which four secreted anti-Ro/SS-A antibodies (clones 1D8, 1D11, 2G10 and 6G8) and one produced anti-La/SS-B antibodies (clone 7F6). The MoAbs were further characterized using four different immunoassays: immunofluorescence, immunoblotting, RNA precipitation combined with Northern blotting, and recombinant protein precipitation. All four MoAbs against Ro/SS-A recognized the native protein and one of them (2G10) recognized also intact scRNP particles. Interestingly, hY3-RNA was reproducibly not efficiently precipitated by MoAb 2G10. Epitope mapping using deletion mutants of the 60-kD Ro/SS-A antigen showed that MoAb 1D8 recognized the C-terminal part of this protein, while 1D11 and 2G10 recognized distinct epitopes in the region between the RNP motif and the putative zinc finger domain. The epitopes recognized by these MoAbs are highly conserved among species, and the epitope recognized by MoAb 2G10 may be identical to an autoepitope recognized by sera of patients. This is the first report describing the isolation and characterization of MoAbs of the IgG class against the 60-kD Ro/SS-A and La/SS-B autoantigens obtained by immunization with purified human recombinant proteins. These MoAbs can be of great use in studying the cellular processes in which scRNPs are involved, and may help to determine why these scRNPs become autoantigenic in autoimmune diseases.

Animals↗
PubMed1994

Successful outcome of pregnancy after treatment of maternal anti-Ro (SSA) antibodies with immunosuppressive therapy and plasmapheresis.

In this short communication we describe a patient with anti-SSA and anti-SSB antibodies whose first child died of congenital complete heart block (CCHB). During her second pregnancy she was treated with prednisolone, azathioprine, and plasmapheresis, and levels of anti-SSA and anti-SSB antibodies fell significantly. The pregnancy evolved uneventfully and resulted in the birth of an unaffected male infant. This is the fourth reported case of a successful outcome of pregnancy after treatment with immunosuppressive drugs in a woman with a significant risk of recurrence of CCHB.

Adult↗
PubMed1994

Clinical significance of maternal anti-Ro/SS-A antibodies in children with isolated heart block.

OBJECTIVES: We studied 30 consecutive children with isolated heart block to assess the clinical impact of the presence of maternal anti-Ro/SS-A antibodies for isolated heart block. BACKGROUND: Isolated heart block in children, often associated with maternal autoimmune disease leading to anti-Ro/SS-A auto-antibody production, is an infrequent but potentially lethal disorder. METHODS: Thirty children with isolated heart block were studied with respect to medical history and electrocardiographic (ECG) analysis. The presence of anti-Ro/SS-A antibodies was determined in the maternal serum. We also examined the ECGs of all brothers and sisters of the patients for conduction abnormalities. RESULTS: Twenty-one of the 30 children had an anti-Ro/SS-A-positive mother (group A); the other 9 children had an anti-Ro/SS-A-negative mother (group B). Comparison of the clinical data from both mothers and children revealed that these two groups differed significantly with respect to the following: Prenatal diagnosis and obstetric complications occurred more often in group A, whereas progression to complete block, QRS width > 0.08 s, premature ventricular contractions and ventricular standstills > 4.5 s occurred more often in group B. In addition, mothers of children in group A reported more spontaneous abortions. All siblings of children in groups A and B had normal ECGs, excluding a subclinical form of heart block. CONCLUSIONS: Two types of heart block can be recognized: Congenital heart block is associated with maternal anti-Ro/SS-A antibodies and numerous obstetric and neonatal complications. It is diagnosed prenatally or at birth and is usually complete at onset and probably has a substantial recurrence risk. Heart block that is acquired later in life is not associated with maternal autoimmunity and has no risk for recurrence. It often presents as a partial block but progresses to complete block in time.

Adolescent↗
PubMed1993

Autoimmunity and filariasis. Autoantibodies against cytoplasmic cellular proteins in sera of patients with onchocerciasis.

Onchocerciasis or "river blindness" is a vector-borne tropical disease resulting from infection with the filarial nematode Onchocerca volvulus. Disease manifestations include dermatitis, rheumatic complaints, and blindness. Recent findings have suggested an autoimmune etiology for the occurrence of chorioretinopathy, a disease of the eye which together with sclerosing keratoconjunctivitis is responsible for approximately 400,000 onchocerciasis-related cases of blindness. The identification of onchocerciasis as an important cause of tropical rheumatism prompted us to evaluate serologically the presence of systemic autoimmune disease in onchocerciasis patients and local controls from a hyperendemic area in Sierra Leone. In both groups there was a marked autoimmune response against cytoplasmic non-RNA-associated proteins consisting of autoantibodies against five major Ag with respective m.w. of 35, 51, 64, 83, and 110 kDa. These five proteins are novel autoantigens that could be distinguished from calreticulin, the human homologue of the onchocercal Ag RAL-1, and known autoantigens such as the 50-kDa La/SS-B or 52- and 60-kDa Ro/SS-A proteins by immunoblotting and ELISA assays. Furthermore, autoantibody reactivity against calreticulin was significantly higher in O. volvulus-infected individuals than in endemic controls. Autoantibody reactivity against the five major autoantigens, anti-calreticulin reactivity, and antibody reactivity against the 65-kDa arthritis-associated mycobacterial heat shock protein were intercorrelated as parts of an onchocerciasis-associated autoimmune response. The implication of autoimmunity in the disease pathogenesis of onchocerciasis could have important consequences for future research on therapeutical regimens, pathogenetic mechanisms, and serological diagnosis of onchocerciasis.

Antibodies, Antinuclear↗
PubMed1993

Maternal autoantibodies and congenital heart block: no evidence for the existence of a unique heart block-associated anti-Ro/SS-A autoantibody profile.

One of the rare examples of the transfer of autoimmune disease from mother to (unborn) child is the neonatal lupus syndrome. This syndrome comprises the development of fetal heart disease (congenital heart block) or neonatal skin rash and is specifically associated with maternal anti-Ro/SS-A autoantibodies. Previous studies have suggested that especially maternal autoantibody reactivity against the 52 kDa protein of the Ro/SS-A antigen and/or against the La/SS-B antigen is responsible for the development of congenital heart block (CHB). To determine the CHB-associated antibody response in more detail, we analysed the presence of autoantibodies in sera from mothers of children with isolated heart block. All 14 mothers of children with congenital heart block were positive for anti-Ro/SS-A antibodies. Remarkably, their antibody profile, including recognition of different Ro/SS-A proteins and autoantibody levels against these proteins, did not differ from anti-Ro/SS-A positive mothers of healthy children. In contrast, all 8 anti-Ro/SS-A negative mothers had children with acquired heart block. We conclude from our data that maternal anti-Ro/SS-A antibodies are essential for CHB but that fine analysis of this autoantibody response does not predict the occurrence of CHB.

Adult↗
PubMed1992

The development of a quantitative assay for the detection of anti-Ro/SS-A and anti-LA/SS-B autoantibodies using purified recombinant proteins.

A characteristic of patients with autoimmune diseases such as Sjögren's syndrome and systemic lupus erythematosus is the presence of anti-Ro/SS-A and anti-La/SS-B autoantibodies in their circulation. In order to investigate specific autoantibody levels in the sera of these patients quantitative assays for the detection of both anti-Ro/SS-A and anti-La/SS-B reactivity were developed. Ro/SS-A (60 kDa) and La-SS-B (50 kDa) cDNAs were cloned and expressed in E. coli as non-fusion proteins. These were purified to homogeneity using two different purification protocols. With these recombinant antigens, specific enzyme-linked immunosorbent assays (ELISAs) were developed. 40 sera positive for anti-Ro/SS-A autoantibodies in counterimmunoelectrophoresis (CIE) were tested in both the Ro/SS-A and La/SS-B ELISA. Activity values reproducibly ranged from 1536 to 120,000 U in the Ro/SS-A ELISA and from 763 to 2,500,000 U in the La/SS-B ELISA. The suitability of these ELISAs as screening assays was further investigated by testing 200 sera sent to our laboratory for routine detection of autoantibodies to extractable nuclear antigen (ENA: anti-Sm, anti-RNP, anti-Ro/SS-A and anti-La/SS-B). Both ELISAs showed a high sensitivity and specificity (Ro/SS-A ELISA 85% and 94%, La/SS-B ELISA 100% and 98% respectively), when compared to the standard assays, the RNA-precipitation assay and the HeLa immunoblotting test. From these data we conclude that a quantitative analysis of both anti-Ro/SS-A and anti-La/SS-B autoantibodies is now possible using purified recombinant non-fusion proteins. For screening purposes the La/SS-B ELISA showed a great improvement in sensitivity for the detection of anti-La/SS-B activity in comparison to the La/SS-B CIE, while the Ro/SS-A ELISA almost equalled the performance of the Ro/SS-A CIE.

Autoantibodies↗
PubMed1992

Anti-Ro/SS-A and anti-La/SS-B autoantibody levels in relation to systemic lupus erythematosus disease activity and congenital heart block. A longitudinal study comprising two consecutive pregnancies in a patient with systemic lupus erythematosus.

OBJECTIVE: To analyze the anti-Ro/SS-A and anti-La/SS-B autoantibody responses, both quantitatively and qualitatively, in relation to the occurrence of congenital heart block (CHB) and disease activity in a patient with systemic lupus erythematosus. METHODS: The patient's course was carefully documented for a period of 80 months. Specific enzyme-linked immunosorbent assays, a HeLa cell immunoblotting test, and an RNA precipitation assay were used to determine autoantibody levels and fine specificities. RESULTS: Anti-Ro/SS-A and anti-La/SS-B antibody did not disappear. Levels of anti-Ro/SS-A appeared to fluctuate more frequently than levels of anti-La/SS-B. Fluctuations were unrelated to disease activity or immunosuppressive treatment. There was no characteristic relationship between levels of these antibodies and the occurrence of CHB. CONCLUSION: The occurrence of CHB cannot be predicted by frequent measurement of anti-Ro/SS-A and anti-La/SS-B levels. The immunoregulatory control of anti-Ro/SS-A and anti-La/SS-B antibodies differs from that of anti-DNA and anti-tetanus toxoid antibodies.

Adult↗
PubMed1992

Analysis of heavy and light chain use of lupus-associated anti-La/SS-B and anti-Sm autoantibodies reveals two distinct underlying immunoregulatory mechanisms.

The immunoregulatory mechanisms involved in autoimmune diseases are still unclear. One approach to elucidating these mechanisms involves evaluation of the clonality of the lymphocytes involved in autoimmunity. Molecular analysis of the rearrangement patterns of antigen receptor genes in T cells and B cells has produced ambiguous results. The present study focuses on the analysis of the autoantibodies themselves, being the end products of autoimmune reactivity. Heavy and light chain use of autoantibodies and of total IgG was determined in sera containing anti-La/SS-B and/or anti-Sm antibodies, two autoantibody specificities associated with rheumatic diseases such as systemic lupus erythematosus and Sjögren's syndrome. From our experiments, the anti-La/SS-B response emerges as an oligoclonal, IgG1-restricted B-cell response associated with sharply elevated levels of total serum IgG1-kappa. These characteristics are in sharp contrast to the polyclonal, IgG-subclass-unrestricted anti-Sm response which is accompanied by normal or slightly elevated total serum IgG levels. These findings suggest that anti-La/SS-B autoantibodies, in contrast to anti-Sm autoantibodies, are the product of a restricted oligoclonal B-cell response and thus may be the consequence of a (virally triggered) benign B-cell lymphoma.

Autoantibodies↗
PubMed1992

Autoantibodies and their target antigens in Sjögren's syndrome.

The subject of this review is the humoral autoimmune response in Sjögren's syndrome. Autoantibodies in this disease are primarily directed against the Ro/SS-A and La/SS-B autoantigens and against IgG (rheumatoid factor). The Ro/SS-A and La/SS-B autoantigens consist of a number of antigenic proteins coupled to small RNA molecules. These RNA-protein particles are present in all human cells and are strongly conserved throughout various species. Anti-Ro/SS-A and anti-La/SS-B autoantibodies can be detected using counter-immunoelectrophoresis, immunoblotting technique, ELISA or RNA precipitation assays. The preferred method of screening for anti-Ro/SS-A antibodies in human sera is counter-immunoelectrophoresis; anti-La/SS-B antibodies are best detected with the immunoblotting technique. Anti-Ro/SS-A antibodies are found in 60% of patients with Sjögren's syndrome, but are not specific markers for this disease. Anti-La/SS-B antibodies are present in approximately 40% of patients with Sjögren's syndrome; the only other disease where the antibody has been detected is systemic lupus erythematosus (15% positive). The origin and possible pathogenetic role of autoantibodies in Sjögren's syndrome is still unclear. Our view is that the current evidence supports a mechanism whereby autoantibodies are the product of an oligoclonal B-cell proliferation. The only instance where autoantibodies probably play a direct pathogenetic role is the occurrence of congenital heart block in the offspring of anti-Ro/SS-A and anti-La/SS-B positive mothers.

Autoantibodies↗