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Biomedical subjects

M Reichlin

Publications and source records attributed to M Reichlin.

At least 127 records · Page 7Linked to original sources

Anti-KJ: a new antibody associated with the syndrome of polymyositis and interstitial lung disease.

Antibodies to aminoacyl-tRNA synthetases (anti-Jo-1, anti-PL-7, anti-PL-12) have been found in the serum of some patients with polymyositis (PM). Patients with these antibodies have an unusually high rate of interstitial lung disease (ILD) in association with their PM. Two patients (K.J. and B.T.) with severe ILD and PM were found to have antibodies to a cytoplasmic antigen, but tests to determine whether the antigen was an aminoacyl-tRNA synthetase were negative, including tests of KJ serum for inhibitory effects on the 20 synthetases. KJ immunoprecipitates did not contain tRNA, in contrast to antisynthetase sera. When IgG samples were added to a reticulocyte in vitro translation system at a concentration of 0.3 mg/ml, KJ IgG inhibited globin mRNA translation by 98%, while anti-Jo-1 IgG inhibited 62% and normal IgG had little effect. Thus, both anti-KJ and the antisynthetases are directed at antigens that are involved in translation and protein synthesis, and both are associated with the syndrome of lung disease and PM. This syndrome may be associated with antibodies to translation-related proteins in general, which may have implications for the link of PM and enteroviruses, which are mRNA viruses.

Adult↗

Autoimmune response to the Ro/SSA particle is directed to the human antigen.

Autoantibodies to defined cellular antigens in systemic lupus erythematosus (SLE) are usually directed to conserved epitopes on ubiquitous macromolecules including histone, Sm + nRNP (URNP particles), DNA, and La(SSB). We report here that the autoimmune response to the Ro(SSA) RNA protein particle is directed to epitopes on the human antigen which are not conserved in evolution. Ro(SSA) from bovine, rat, and mouse Ro(SSA) particles cross-react with human autoantibodies less effectively than does human Ro(SSA), and antigenically active Ro(SSA) is not detectable in chicken thymus extracts with the assays employed. These data suggest a special role for the Ro(SSA) antigen in the initiation and/or perpetuation of the anti-Ro(SSA) response in autoimmune disease.

Absorption↗

A model for disease heterogeneity in systemic lupus erythematosus. Relationships between histocompatibility antigens, autoantibodies, and lymphopenia or renal disease.

We composed a model from autoimmune serologic findings, HLA antigens, and clinical findings that explains, at least partially, the clinical heterogeneity of 40 patients with systemic lupus erythematosus (SLE). In these patients, anti-RO (SS-A) was related to the HLA-DQ1/DQ2 heterozygotes, anti-La (SS-B) was related to HLA-B8 and HLA-DR3, and anti-nuclear RNP (Sm) was related to HLA-DR4. Lymphopenia was associated with anti-Ro (SS-A) and, secondarily, with anti-single-stranded DNA. Renal disease in these SLE patients was inversely associated with anti-La (SS-B) and was positively associated with anti-double-stranded DNA. There were no associations between the HLA antigens and these clinical manifestations. The results support a model of disease expression in which individuals are nonspecifically potentiated for SLE. Their HLA antigen composition influences the production of particular autoantibodies that are related in complex ways to the different particular clinical findings of SLE manifested in individual patients.

Adult↗

Immune response to the RNA protein particles in systemic lupus erythematosus. A distinctive dichotomy.

Antibodies to the small RNA protein particles Ro/Sjögren's syndrome A (Ro/SSA), La Sjögren's syndrome B (La/SSB), Sm, and U1-ribonucleoprotein (U1RNP) occur characteristically in patients with systemic lupus erythematosus. Although not mutually exclusive, those antibodies tend to occur in pairs; anti-Ro/SSA and anti-La/SSB in one group, anti-U1RNP and anti-Sm in another group. The emerging data suggest that these pairs of immune responses differ in fundamental ways, signifying different mechanisms for their initiation and control. Antibodies to Ro/SSA and La/SSB are strongly associated with the class II antigens DR2 and DR3 and the response is directed to epitopes on the particles that change in evolution. These responses are found frequently in normal persons in low titer but not in animal models of systemic lupus erythematosus. Contrariwise, the immune response to Sm and U1RNP is only weakly associated with class II antigens and the response is to epitopes conserved in evolution. These responses are not found in normal persons but are frequently found in animal models. The implications of these differences are explored.

Animals↗

Two Ro (SS-A) autoantibody responses in systemic lupus erythematosus. Correlation of HLA-DR/DQ specificities with quantitative expression of Ro (SS-A) autoantibody.

Autoantibodies to Ro (SS-A), La (SS-B), and Sm/nuclear RNP were quantitated by enzyme-linked immunosorbent assay in 106 white patients with systemic lupus erythematosus. Two Ro autoantibody subgroups were identified that differed quantitatively, genetically, and clinically. The subgroup having anti-Ro only demonstrated significantly lower mean anti-Ro levels than did the subgroup with concomitant anti-La and showed a strong association with the linked HLA alleles DR2 and DQw1. The anti-Ro with anti-La subgroup was associated with the linked HLA alleles B8, DR3, DRw52, and DQw2 (DR3 was primary), and this subgroup consisted of patients with older ages at disease onset, sicca complex, and less renal involvement. Overall, the relative risk (RR) for having anti-Ro was highest in HLA-DR2/DR3 heterozygotes compared with non-DR2/DR3 heterozygotes (RR 15) and all other DR combinations (RR 7), suggesting a compound effect of 2 immune responses. Heterozygotes for HLA-DQw1/DQw2 demonstrated significantly higher mean levels of anti-Ro, which may be indicative of trans gene interaction at HLA-DQ. These data suggest the hypothesis that HLA genes exert their major effects on Ro/La autoantibody subsets of systemic lupus erythematosus.

Autoantibodies↗

Antibody to threonyl-transfer RNA synthetase in myositis sera.

The prevalence and clinical correlations of anti-threonyl-transfer RNA synthetase (anti-PL-7), as well as the relationship of anti-PL-7 to anti-histidyl-transfer RNA synthetase (anti-Jo-1) were studied in 109 sera from patients with myositis. Inhibition of threonine aminoacylation was used to screen for anti-PL-7. Sera from 3 patients, 2 with polymyositis and 1 with polymyositis-overlap syndrome, and a fourth serum from a patient with dermatomyositis, which was previously found to contain anti-PL-7, inhibited greater than 90% of activity (3.7% of 109 sera). All 4 sera reacted strongly in an enzyme-linked immunosorbent assay with enzyme that was either affinity purified with anti-PL-7 or was biochemically purified. There was no indication of cross-reactivity by aminoacylation inhibition or, for most sera, by enzyme-linked immunosorbent assay. Anti-PL-7 is an uncommon myositis-associated antibody that is independent of anti-Jo-1, but is directed at a functionally related enzyme.

Acylation↗

Immunopathologic studies of cutaneous lupus erythematosus.

The studies, as outlined above, strongly suggest that there may be several pathophysiologic mechanisms resulting in the development of cutaneous lupus lesions. It appears that all lupus lesions are associated predominantly with a T-cell infiltrate. Based upon the studies of the neonatal lupus infants, it has been hypothesized that the U1RNP and Ro(SS-A) autoantibodies of maternal origin play a direct pathologic role in the genesis of the annular polycyclic SCLE lesions and this may be mediated by antibody-dependent cellular cytotoxicity mechanisms in which the antibody binds to the respective antigen present on the keratinocyte plasma membrane and the effector cells are T cells derived from the infants. Other studies, using direct immunofluorescence techniques, have demonstrated an association of cutaneous lupus lesions occurring in the presence of immunoglobulin and complement at the dermal/epidermal junction (positive lupus band test) in which the neoantigen of the complement membrane attack complex (C5b-C9) is detected. These data have been interpreted as indicating that immunoglobulin and complement, perhaps in the form of immune complexes, may play a role in the pathogenesis of some cutaneous lupus lesions. Additional studies have determined that there is a substantial number of lupus patients with cutaneous disease, without antinuclear antibodies, who fail to demonstrate the deposition of immunoglobulin and complement at the dermal/epidermal junction. Furthermore, other studies have indicated that ultraviolet light is capable of inducing lesions in lupus patients that histologically are identical to those of cutaneous lupus erythematosus but that failed to demonstrate the deposition of the immunoglobulin and complement components. Since discoid lupus lesions demonstrate a preponderance of T cells, it has been proposed that some of these lesions are the direct result of a T-cell cytotoxic event. However, the nature of the autoantigens responsible for this putative T cell-mediated cytotoxic response is unknown at the present time. The role of ultraviolet light in the genesis of the cutaneous lupus lesions appears to involve, within the epidermis, the generation of autoantigen macromolecules which then react with autoantibodies or specific T cells of the lupus host.

Humans↗

Complete congenital heart block followed by anti-Ro/SSA in adult life. Studies of an informative family.

A family is described in which an asymptomatic woman gave birth to a male child with complete congenital heart block. Precipitating antibodies to the Ro/SSA antigen have developed in this child, now aged 33, who is clinically well. In the mother, features of both systemic lupus erythematosus and Sjögren's syndrome developed 26 years after the birth of her son. Her serum currently has precipitating antibodies to both the Ro/SSA and La/SSB antigens. The presence of anti-Ro/SSA in the child with complete congenital heart block and the extremely long delay of 26 years between the delivery of the child and the development of clinical disease in the mother are discussed in light of investigators' developing knowledge of both neonatal and adult systemic lupus erythematosus.

Adult↗

T-lymphocyte specificity differences to horse cytochrome c in different lymphoid cell compartments.

T-lymphocyte proliferative responses were determined with peripheral blood lymphocytes (PBL), peritoneal exudate lymphocytes (PEL) and lymph node lymphocytes (LNL) of guinea pigs immunized with horse cytochrome c (HCytc). The proliferative response of PBL activated by peptide 81-104 from animals immunized with HCytc was equal to or better than HCytc while the proliferative response activated by peptide 1-65 was small and no reactivity was seen when peptide 66-80 was tested. In contrast, the proliferative responses of PEL and LNL stimulated by peptide 1-65 approached those activated by HCytc, while peptide 81-104 was far less effective. The differences in the proliferative responses of PBL and PEL activated by peptide 81-104 and peptide 1-65 suggest that different lymphoid compartments may have T-cells directed to different T-cell epitopes displayed on the same antigen. The possible roles of different T-cell clones, antigen processing, and differential induction of suppressor cells are discussed in relation to these findings.

Animals↗

Ro(SS-A) positive Sjogren's/lupus erythematosus (SC/LE) overlap patients are associated with the HLA-DR3 and/or DRw6 phenotypes.

Ro(SS-A) positive female Sjögren's syndrome (SS) lupus erythematosus (LE) overlap patients are a clinically and serologically homogeneous group generally demonstrating prominent subacute cutaneous lupus erythematosus (SCLE) lesions, cutaneous vasculitis, peripheral and central nervous system disease, pulmonary disease, and a low frequency of glomerulonephritis. They commonly demonstrate rheumatoid factor, hypergammaglobulinemia, antinuclear and Ro(SS-A) La(SS-B) antibody activity. This study indicates that these patients are also immunogenetically similar, sharing a statistically significant increased frequency of HLA-B8, DR3, DRW6, DQ2, and DRw52. Sixty-three percent of these SS/LE patients possess the extended haplotype (P-value 6.0 X 10(-3); RR 9.5) HLA-B8, DR3, DQ2, DRw52. One hundred percent of this SS/LE cohort was DR3 or DRw6 (P-value less than or equal to 5.0 X 10(-3); relative risk 19.1). Fifty percent of these patients were HLA DR3/DRw6 heterozygotes (P-value 1.5 X 10(-6); relative risk 31.2). Thus, HLA-DR3 and DRw6 Ro(SS-A) positive SS/LE patients may possess a similar, if not unique, DR region DNA nucleotide sequence involved in disease susceptibility or immune regulation.

Autoantigens↗

Increased frequencies of Sm and nRNP autoantibodies in American blacks compared to whites with systemic lupus erythematosus.

Frequencies of autoantibodies to Sm, nRNP, Ro (SSA) and La (SSB) were determined by countercurrent immunoelectrophoresis (CIE) and/or enzyme linked immunosorbent assays (ELISA) in 106 whites and 60 blacks with systemic lupus erythematosus. Anti-Sm occurred significantly more frequently in blacks (25%) than whites (10%) (p = 0.02), as did anti-nRNP (40% versus 23%; p = 0.03). By CIE, anti-Sm and/or nRNP occurred in 47% of blacks and 24% of whites (p = 0.004), and by ELISA the Sm/nRNP complex was detected in 52% of blacks versus 26% of whites (p = 0.003). Antibodies to Ro and La occurred with equal frequencies between the races.

Autoantibodies↗

The relationship between anti-Ro (SS-A) antibody-positive Sjögren's syndrome and anti-Ro (SS-A) antibody-positive lupus erythematosus.

Ten Ro(SS-A) antibody-positive patients with Sjögren's syndrome and lupus erythematosus are described. These patients have a disease process characterized by the frequent appearance of annular polycyclic lupus lesions of subacute cutaneous lupus erythematosus (SCLE), as well as neurologic and pulmonary disease. The Ro(SS-A) antibody-positive patients may have Sjögren's syndrome for many years and then suddenly develop lupus erythematosus, and vice versa. These studies demonstrate that the patient with Ro(SS-A) antibody may exhibit a dynamic clinical disease expression over time and that there is a closer pathologic relationship between Sjögren's syndrome and SCLE in these patients with Ro(SS-A)-antibody than has previously been appreciated. Furthermore, Ro(SS-A)-positive patients with Sjögren's syndrome and lupus erythematosus appear to have a much more guarded prognosis than those Ro(SS-A)-positive lupus patients described under the classifications of antinuclear antibody-negative lupus erythematosus and SCLE.

Adult↗

Autoantibodies against RNA polymerase I in scleroderma and Sjögren's syndrome sera.

Anti-RNA polymerase I antibodies were detected by radioimmunoassay in the sera of 8 out of 9 Sjögren's syndrome patients, 11 out of 19 individuals with scleroderma, and 19 out of 19 systemic lupus erythematosus patients. The results of the radioimmunoassay were confirmed by demonstrating the ability of the patients' IgG to inhibit RNA polymerase I activity in vitro. Sera from four patients in each category were also tested for reaction with individual subunits of RNA polymerase I. All 4 SLE sera, 3 out of 4 scleroderma sera and 1 out of 4 Sjögren's syndrome sera contained antibodies against the 65 kDa (S3) subunit of RNA polymerase I in addition to antibodies against one other subunit. Sera from the remaining scleroderma and Sjögren's syndrome patients tested in this assay contained only anti-S3 antibodies. These results demonstrate that anti-RNA polymerase I antibodies are characteristic of a variety of rheumatic autoimmune sera.

Autoantibodies↗

Measurement of antibody to Jo-1 by ELISA and comparison to enzyme inhibitory activity.

Antibody to the Jo-1 antigen (histidyl-tRNA synthetase) is found almost exclusively in myositis patients, usually those with adult PM, but has been found in only 30% of that group by immunodiffusion or other techniques thus far reported. We have reexamined the prevalence of antibody to Jo-1 in sera from 130 patients and 82 controls by using the sensitive ELISA technique. The ELISA used affinity-purified, enzymatically active bovine Jo-1 antigen. A wide range of antibody level by ELISA was found among 24 immunodiffusion positive sera. Six myositis and two control sera had apparent specific antibody detectable only by ELISA. Overall, however, the antibody continued to show high myositis specificity with predominance in adult PM (35.8% in that group). Because the antibody inhibits enzymatic activity of the synthetase antigen, we also studied the quantitative inhibitory activity of these sera to compare with the antibody activity as determined by ELISA. Twenty-four immunodiffusion-positive sera, 29 immunodiffusion-negative sera, and 15 normal sera were tested at 1/50 dilution in the reaction mixture. There was background inhibition by all normal sera tested that averaged 30.5%. All but one immunodiffusion negative myositis sera (a high binder by ELISA) inhibited less than 50% of the average with normal serum. Twenty-three of 24 immunodiffusion positive sera inhibited greater than 80% of this normal average; the other inhibited 66%. The serum dilution giving 50% inhibition was highly correlated (R = 0.83) with the ELISA activity. Thus, inhibition of histidyl-tRNA synthetase activity is a relatively accurate measure of Jo-1 antibody. This method should be applicable to measuring antibody to other aminoacyl-tRNA synthetases.

Amino Acyl-tRNA Synthetases↗

Antibodies against nuclear poly(A) polymerases in rheumatic autoimmune diseases.

Sera from 53 patients, 26 with systemic lupus erythematosus (SLE), 8 with rheumatoid arthritis (RA), 9 with Sjogren's syndrome (SS), and 10 with scleroderma (Scl), were screened for the presence of antibodies against liver-type poly(A) polymerase and tumor-type poly(A) polymerase. Sixty percent of the patients with the above four autoimmune diseases have antibodies directed against liver poly(A) polymerase, whereas sera from 74% of the patients contained anti-hepatoma poly(A) polymerase antibodies. About 25% of the patients produced antibodies exclusively against the tumor poly(A) polymerase. IgG containing anti-liver or anti-tumor poly(A) polymerase antibodies inhibited the activity of the respective enzyme. IgG containing antibodies against liver and tumor enzymes inhibited the activity of both enzymes, whereas IgG from sera that did not react with poly(A) polymerase had no effect on either enzyme. These data demonstrated the specificity of these autoantibodies and confirmed the results of the radioimmunoassay.

Antibody Specificity↗

HLA-DR antigens in systemic lupus erythematosus: association with specificity of autoantibody responses to nuclear antigens.

HLA-DR antigens and autoantibodies to the nuclear or cytoplasmic antigens Ro/SSA, La/SSB, Sm, and RNP were determined in North American and Austrian patients with systemic lupus erythematosus (SLE). Analysis of the association of antibodies to these ribonucleic acid (RNA)-protein antigens with HLA-DR antigens showed that HLA-DR3 was related to the presence of anti-Ro/SSA or anti-La/SSB, or both. In contrast, anti-Sm or anti-RNP, or both were associated with HLA-DR4. HLA-DR5 was associated with absence of these autoantibodies. The data extend evidence for the complexity and heterogeneity of SLE. Moreover, they indicate that, in SLE, genes linked to those coding for HLA-DR antigens, are related to the specificity of autoantibody responses rather than to the primary immunological abnormalities of this disorder.

Adolescent↗