Anti-DNA antibodies and the problem of autoimmunity

Several different classes of autoreactive antibodies are known to exist: those that are stimulated by bacterial infection (e.g., streptococci/rheumatic fever), those that react with tissue-specific antigens (e.g., thyrotropin receptor/Graves' disease), and those that bind to ubiquitous autoantigens (e.g., DNA/systematic lupus). The origin of the last kind of autoantibody is unknown, but it now seems that their production is an inherent property of the normal immune system. Indeed, it would appear that autoantibodies of the lupus variety actually have a physiological role in normal immunity. The development of the autoimmune disease may occur when there is an "escape" from the normal function of lupus autoantibodies.     

Rapid transient analysis of myosin cross-bridge kinetics in hypertrophied hearts

Essential hypertension, with pressure overload leading to left ventricular hypertrophy, often results in coronary artery disease and congestive heart failure. The spontaneously hypertensive rat (SHR) is an attractive model for studying the effects of long-term antihypertensive therapy on the contractile properties of the myocardium. In this study we investigated differences in mechanical and biochemical characteristics of papillary muscles from SHR and normal (Wistar-Kyoto [WKY]) rats as a function of age and treatment. We found that the rate of delayed force redevelopment after rapid stretch was less in SHR than in WKY in every age group studied, even at 2 wk of age, before hypertension was evident in the SHR. In the treated SHR, blood pressure was lower, hypertrophy was reduced and the rate of delayed force redevelopment was increased compared with the untreated SHR. Finally, the pattern of myosin isoenzymes was different in treated than in untreated SHR, being shifted to more of the fast V1 and less of the slow V3 isomyosin. We conclude that long-term antihypertensive therapy not only prevents the development of left ventricular hypertrophy, but may do so by preventing the shift in myosin isoenzyme pattern normally found in hearts subjected to a long-term pressure overload.     

Inherited X-chromosome inverted tandem duplication in a male traced to a grandparental mitotic error.

A male infant was referred for cytogenetic evaluation because of dysmorphic features and developmental delay. In both lymphocytes and skin fibroblasts, a modal number of 46 chromosomes was obtained with an obvious elongation of the long arm of the X chromosome (Xq+). Studies of seven members in 3 generations of this family showed that the proband's mother, sister, and maternal grandmother were phenotypically normal carriers of this abnormal X chromosome. High resolution GTG- and RBG-banding defined the extra chromatin material as an inverted duplication of Xq21----Xq24. This was supported by an approximate twofold increase in alpha-galactosidase A activity, localized to Xq21----q24, observed in the proband's lymphocytes and fibroblasts. BrdU-incorporation studies of the mother's lymphocytes showed the abnormal X to be late replicating in all 100 cells studied and normal alpha-galactosidase A levels. Cytogenetic analysis of the maternal grandmother revealed cytogenetic mosaicism with one cell line containing the abnormal X (37%), and the other, a normal female karyotype (63%). This family is instructive since: (1) it represents only the second case of a dysmorphic male demonstrating a confirmed interstitial partial Xq duplication, and (2) the origin of this familial structural rearrangement has been traced to a grandparental mitotic error.     

Relationships between the human pepsinogen DNA and protein polymorphisms.

Pepsinogens (PGA) are the inactive precursors of pepsin, the major acid protease found in the stomach. The PGA gene family exhibits polymorphic variation in human populations that can either be demonstrated by electrophoretic analysis of the proteins or by analysis of the respective genes with cDNA probes. Here, we describe the interrelationships between the most common pepsinogen protein phenotypes and the corresponding pepsinogen haplotypes (A, B, and C) containing different combinations of the PGA3, PGA4, and PGA5 genes. We propose that this unusual genetic variation involving haplotypes that contain three, two, and one genes, respectively, is the result of molecular evolution by gene duplication.     

Inhibitory Effect of Autoclaving Whey-Based Medium on Propionic Acid Production by Propionibacterium shermanii

Propionic acid production by Propionibacterium shermanii was compared in pasteurized and autoclaved whey-based media. Propionic acid production decreased with increasing whey concentration in autoclaved media but not in pasteurized media. Increasing the yeast extract concentration from 5 to 10 g/liter greatly reduced the inhibitory effect of autoclaving.     

Production of High-Viscosity Whey-Glucose Broths by a Xanthomonas campestris Strain

Acclimation of a sandy soil to an air-natural gas mixture stimulated the biological oxidation of chloroform to carbon dioxide. Acetylene and methane inhibited chloroform oxidation. Chloroform oxidation continued up to 31 days in the absence of methane. Chloroform oxidation rates increased at chloroform concentrations up to 5 μg g of soil^-1.     

Effect of gamma radiation on resting B lymphocytes. I. Oxygen-dependent damage to the plasma membrane results in increased permeability and cell enlargement

Although the susceptibility of resting B lymphocytes to radiation-induced interphase death is well known, the mechanism by which this occurs is not understood. In this report, we use three measures of plasma membrane integrity (increase in cell volume, uptake of trypan blue, and release of 51Cr) to assess the effect of radiation on the resting B cell plasma membrane. The delivery of 500 to 1000 rad caused the majority of resting B cells to enlarge slightly, whereas 3000 rad caused virtually all of the cells to approximately double in size within 3 to 4 hr. Measurement of the release of 51Cr from resting B cells revealed a similar relationship between the dose of radiation and the loss of radioactive label. Trypan blue exclusion was also found to diminish as a function of radiation dose. An analysis of a variety of lymphoid cells suggested that sensitivity to the membrane damaging effects of gamma radiation was in the order of resting B cells greater than resting T cells greater than a long-term L3T4+ T cell clone greater than a B cell lymphoma. LPS-induced B cell blasts treated with 3000 rad were equivalent to 1000 rad-treated resting B cells. The effects of the gamma radiation could be ameliorated by excluding oxygen (a diradical molecule that can potentially enhance the generation and propagation of highly reactive free radicals) at the time of irradiation, or by adding the free radical scavenging agent cysteamine. These data are compatible with the hypothesis that gamma radiation results in damage to the plasma membrane of resting lymphocytes via the generation of highly reactive free radical species. This damage is reflected in a rapid increase in plasma membrane permeability and swelling of the cells, and may play a major role in causing interphase death.     

Lupus serum and normal human serum contain anti-DNA antibodies with the same idiotypic marker

We have previously shown that serum from patients with active SLE contain high levels of Id-16/6 and anti-DNA antibodies. In this study we investigated whether serum Id 16/6 is related to anti-DNA antibodies. Sera from 12 patients with active SLE were absorbed individually with poly(dT) cellulose (to purify anti-DNA antibodies) and rabbit (R) anti-Id-16/6 Sepharose (to purify Id 16/6 Ig). Removal of all anti-DNA activity removed most of the Id-16/6. Conversely, removal of all Id 16/6 removed most of the anti-DNA activity. Although there was no measurable anti-DNA antibody activity in normal serum, such antibodies were isolated by absorption with poly(dT) cellulose. The eluted immunoglobulins also had Id 16/6 activity. Similarly, Id 16/6 with anti-DNA activity were isolated from normal serum by absorption with R anti-Id 16/6 Sepharose. We conclude that a large fraction of anti-DNA antibodies in SLE serum are Id-16/6+, and that most Id 16/6 immunoglobulins in lupus serum have anti-DNA activity. Our observations suggest that lupus anti-DNA antibodies result from an overproduction of autoantibodies that are present in normal people.     

Specificity of human natural killer cells in limiting dilution culture for determinants of herpes simplex virus type 1 glycoproteins.

The frequency and specificity of human cells with natural killer (NK) cytotoxic activity for herpes simplex virus type 1 (HSV-1)-infected targets was measured by limiting dilution culture. The frequency of NK cell precursors (NK-p) reactive with HSV-1-infected cells was 2- to 11-fold higher than that of NK-p reactive with mock-infected cells. The frequency of NK-p reactive with infected target cells lacking viral glycoprotein C or presenting an antigenically altered glycoprotein B was approximately twofold lower than that with wild-type virus-infected cells. Specificity analysis demonstrated that NK cells with a high statistical probability of being monoclonal were reactive with either glycoprotein B or C. These results provide the first evidence that cells with human NK activity possess clonal specificity for HSV-1-infected target cells.