[Ischemic heart disease and benign familial leukopenia in Yemenite Jews].
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Biomedical subjects
Publications and source records attributed to Y Shoenfeld.
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Polymyositis is an autoimmune, inflammatory disease affecting human skeletal muscle. In the presence of concomitant vasculitis in the skin, the term dermatomyositis is used. In contrast, systemic lupus erythematosus (SLE) is a multisystem disease in which involvement of the skin, kidneys, joints, brain, and other organs may be found. The clinical manifestations vary according to the organ/system involved. It is clinical and therapeutic importance to define which organ/system is involved during the course of the disease. We approached this problem by studying the specificity of autoantibodies that are generated in patients with SLE and polymyositis/dermatomyositis. Among such antibodies are those directed against nuclear components including a variety of ribonucleoprotein (RNP) complexes. We have utilized mammalian nuclear preparations enriched with RNP particles as the antigenic source for immunoblotting studies to identify specific antigenic polypeptides. In the study reported here, sera from five groups of patients were examined: 10 patients with dermatomyositis/polymyositis; six patients with SLE and myositis; 12 lupus patients with cerebral and/or renal disease; eight patients with SLE but no myositis, renal, or cerebral disease; and 5) 11 patients with muscle weakness or muscle disease not due to myositis. In the first two groups of patients with myositis, antibodies against a nuclear RNP protein of 56 KD was identified in 12 of 16 sera. In contrast, such antibodies were found in the serum of only two of 20 patients with SLE but without muscle involvement (groups 3 and 4), and were not found at all in patients with other muscle diseases. This study has identified a new marker, antibodies against a nuclear RNP protein of 56 KD for detecting muscle involvement among the autoimmune rheumatic diseases.
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Nine human hybridoma cell lines were established from a fusion of axillary lymph node lymphocytes of a patient with breast ductal carcinoma with a human lymphoblastoid cell line. The human hybridoma nature of the fusion products was confirmed by chromosomal analysis and HLA typing. The hybridomas are stable over a year of growth, and can be frozen, thawed and regrown. The carcinoma cells of the patient harbor mouse mammary tumor virus (MuMTV) cross-reacting antigens. The patient's serum and the purified monoclonal antibodies reacted with MuMTV polypeptides. Radioimmunoprecipitation studies using labeled MuMTV confirmed the binding of the patient's serum to the viral proteins. None of the control immunoglobulins reacted with the virus. No binding of the hybridoma immunoglobulins was observed with two other retroviruses (avian myeloblastosis virus and simian sarcoma virus). The ligand binding characteristics of the monoclonal antibodies suggest binding to epitopes on the various structural virus polypeptides. These monoclonal antibodies may serve as a probe to analyze the MuMTV-human breast carcinoma relationship.
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We describe a monoclonal IgM that was purified from the serum of a patient with Waldenström macroglobulinemia and thrombocytopenia. The binding and idiotypic characteristics of the patient's macroglobulin were similar to those of a human monoclonal IgM secreted by a hybridoma established from peripheral blood lymphocytes of a patient with systemic lupus erythematosus and immune thrombocytopenia. In the absence of other causes for thrombocytopenia in this patient, our results suggest an autoimmune mechanism for destruction of platelets by the monoclonal IgM. This is the first report of a Waldenström macroglobulinemia with anti-platelet activity of monoclonal IgM. Although the study involves a single patient, the results suggest that there may be a common origin for autoantibodies in autoimmune diseases and monoclonal immunoglobulins having autoantibody activity in monoclonal gammopathies.
The sera of 57 patients with active, untreated pulmonary tuberculosis were examined for the presence of a common anti-DNA idiotype, 16/6. Thirty-four of the 57 sera (60%) had an increased level of the idiotype, as measured by enzyme-linked immunosorbent assay using a specific rabbit anti-16/6 serum. Of 28 matched control sera, only 1 (4%) was found to be positive for the idiotype. The sera of patients with tuberculosis also showed increased activity against a variety of antigens with which lupus autoantibodies are known to crossreact (e.g., single-stranded DNA, double-stranded DNA, polynucleotides, and cardiolipin). A correlation was observed between serum IgG and IgM levels and the 16/6 idiotype levels.
Sera drawn from 75 patients with systemic lupus erythematosus, 141 healthy relatives (from the families of 51 patients), and 115 healthy control subjects were examined, by enzyme-linked immunosorbent assay, for IgG and IgM antibodies to total histones and their subfractions. Compared with the controls, statistically significant numbers of patients and their relatives had antihistone antibodies of both isotypes. Among the relatives, the sera from females, notably sisters of the patients, contained the highest levels of anti-total histone antibody. Anti-H2A/H2B and H3 antibodies were most prevalent among the lupus patients, but many of the relatives had IgM anti-H4 antibodies. These findings indicate that antihistone antibodies can serve as a genetic marker in patients with systemic lupus erythematosus.
Sixty-seven patients on treatment with procainamide were examined for the presence of two common idiotypes of anti-DNA antibodies (16/6 Id and 32/15 Id). These idiotypes have been shown previously to have clinical relevance in patients with systemic lupus erythematosus (SLE). An enzyme-linked immunosorbent assay (ELISA) with rabbit anti-Id antibodies revealed increased concentrations of the 16/6 Id and 32/15 Id in 25 (37%) and 16 (24%) patients, respectively. Five of eight patients with drug-induced lupus had elevated titers of both idiotypes. A high correlation (R = 0.56, P less than 0.001 for 16/6 Id) was found between Id levels and anti-single-stranded DNA (ssDNA) antibody titers and between 16/6 Id titers and antihistone antibodies (IgG, R = 0.43; IgM, R = 0.25). It seems that procainamide, a component known to be associated with drug-induced lupus, may induce an increased production of common anti-DNA idiotypes in apparently normal subjects.
The initial studies of anti-DNA antibody idiotypes we performed, along with those of our colleagues and other groups, focused on the narrow question of their relevance to lupus autoantibodies. The subsequent studies in this report have forced us to examine a much broader range of issues. It is evident that despite the great advances in understanding the structure and function of antibodies, lymphocytes, and receptors, our knowledge of many fundamental elements in autoimmune disease is woefully incomplete. We are still unsure whether the germ line gene sequences controlling antibody production have evolved solely in response to exposure to new foreign antigens. Alternatively, these antibodies (and the idiotypes they bear) may have developed largely in response to changes in the internal environment. Superficially, it can be argued that "self reactivity" associated with the clinical expression of a disease results from a combination of immunologic, genetic, hormonal, and environmental elements. For example, the expression of the 16/6 Id in an appropriate setting may have pathogenetic consequences for some individuals. However, our knowledge of the precise sequence of events that result in devastating disease for some but minimal disease for others is just one of the remaining mysteries.
Sera from 249 patients with monoclonal gammopathies (85 multiple myeloma, 92 benign monoclonal gammopathies, 53 cryoglobulinemia, 19 Waldenström's macroglobulinemia) were examined for the presence of anti-histone activity. Thirty-four sera were found positive. In 12 of these cases the serum monoclonal immunoglobulins were purified and in all, the anti-histone activity appeared to reside in the monoclonal component. None of the patients had symptomatology of lupus despite high titers of anti-histone activity. This study demonstrates an anti-histone activity of monoclonal components of patients with monoclonal gammopathies.
Chronic liver diseases may be associated with the appearance of antinuclear antibodies. To further analyze the relationship between connective tissue and liver diseases the sera of 88 patients with chronic liver disorders were examined for the presence of common lupus anti-DNA idiotypes (16/6-id, 134-id, and 32/15-id), using an enzyme-linked immunosorbent assay. The 16/6-id was found in 58 (65.9%), the 134-id in 43 (48.9%), and the 32/15-id in 13 (14.8%) of the patients' sera. Distinct diagnostic groups displayed different lupus anti-DNA idiotype profiles. Patients with primary biliary cirrhosis (PBC) and chronic active hepatitis (CAH) had mainly the 16/6 idiotype, while in alcoholic (AC) and in cryptogenic cirrhosis (CC) the 16/6-id and 134-id were the main idiotypes recorded. There was considerable correlation among the different anti-DNA idiotypes but not between any of these idiotypes and an unrelated common anti-HBsAg idiotype. The occurrence of the various idiotypes was not found to be correlated with increased serum immunoglobulin levels. It can be concluded that the similarities between chronic liver diseases and connective tissue diseases are extended also to the presence of specific common anti-DNA antibody idiotypes.
Serum immunoglobulins levels were determined in 42 patients with active pulmonary tuberculosis as a prototype of chronic infection and 41 patients with Klebsiella infection representing acute infection, using a radial immunodiffusion technique. The mean serum concentration of IgG, IgA and IgM of the patients with pulmonary tuberculosis (1980 +/- 688, 314 +/- 152 and 222 +/- 123 mg/dl, respectively) were found to be significantly higher than normal control levels (P less than 0.005). The mean serum IgG, IgA and IgM concentration of the patients with Klebsiella infection (1102 +/- 340, 287 +/- 133 and 168 +/- 105 mg/dl, respectively), were also higher than normal levels but only IgM level differed significantly from the normal control levels (P less than 0.05). The difference in serum IgG and IgM between the patients with pulmonary tuberculosis and Klebsiella infection was statistically significant (P less than 0.05 and P less than 0.05, respectively). These findings reflect the polyclonal hypergammaglobulinemia found in chronic infections, on the one hand, and the rise of IgM of the primary immune response in acute infection, on the other.
Recent studies have indicated that both ankylosing spondylitis and the anti-DNA antibodies found in systemic lupus erythematosus may be related to Klebsiella surface antigens. In order to explore these possible relationships further, the sera of 24 patients with ankylosing spondylitis (AS), and 20 controls, have been examined for binding to a wide range of antipolynucleotide antibodies, antibodies binding to the Klebsiella pneumoniae polysaccharide K30 and two DNA antibody idiotypes designated 16/6 and 134. We report that although 21% of the AS patients had IgG ssDNA antibodies it is evident that the aetiopathogenesis of this disease is not through the mechanism of autoantibodies or the common DNA antibody idiotypes tested.
In four of five patients with gastric cancer who also had a chronic duodenal ulcer, the histologic type was "early gastric cancer," which offers a better prognosis than the more common type. Patients with duodenal ulcer who develop gastric cancer may have a better prognosis than patients with gastric cancer without duodenal ulcer because their duodenal ulcer places them under more frequent surveillance, including clinical and endoscopic follow-up.