Detection of an antigen associated with acute leukemia.

Antiserums to a purified cell membrane component from a Burkitt's lymphoma tissue culture cell line were produced in rabbits. These antiserums were cytotoxic to peripheral white blood cells from 8 of 15 patients with acute leukemia and 5 of 41 relatives, but not to peripheral white blood cells from leukemia patients in clinical remission or from normal individuals. These antiserums appear to be detecting an acute leukemia associated antigen or antigens.

Glucocorticoid-binding proteins in human acute lymphoblastic leukemic blast cells.

The first known step in steroid hormone action is the association of the steroid with specific cytoplasmic steroid-binding proteins (SBP). Using a competitive binding assay, we detected, quantified, and partially characterized such a SBP in cytosol from glucocorticoid-sensitive human lymphoblastic leukemic blasts. The affinity of steroids for the SBP was directly related to their known killing potency. For example, steroids without glucocorticoid effect such as androstenedione, etiocholanolone, and tetrahydrocortisol were unable to displace radiolabeled dexamethasone from the SBP in the binding reaction. The dose-response curve for in vitro inhibition of [(3)H]thymidine uptake in leukemic blasts correlated closely with the binding affinity of glucocorticoids to the SBP, providing additional support for an essential physiologic role for SBP in steroid action. SBP activity was either greatly diminished or absent in glucocorticoid-resistant cells. Six patients who intially had SBP in their blasts and were responsive to combinations of drugs including glucocorticoids no longer had SBP activity detectable at a time when they no longer responded to combinations of drugs including glucocorticoids. In vitro [(3)H]thymidine uptake was not inhibited by steroids in leukemic blast cells lacking SBP activity. Other patients who had received some antileukemic therapy including glucocorticoids and who still had SBP in their leukemic blasts, were still responsive to drug combinations that included glucocorticoids. This appears to be the first study demonstrating glucocorticoid receptors in a human tissue.

Human antisera detecting leukemia-associated antigens on autochthonous tumor cells.

Leukemia patients in remission were immunized with RAJI lymphoid tissue culture cell lines. Four of 7 patients developed antibody to the immunizing cell as well as to allogeneic leukemia cells. Sera from 3 patients were tested against autochthonous tumor cells either frozen or obtained at the time of disease relapse. Patient's sera were cytotoxic to their own leukemia cells; however, this cytotoxicity was lost at the time of relapse.

The relationship of complement-mediated microvasculopathy to the histologic features and clinical duration of disease in dermatomyositis.

Accumulating evidence indicates that a complement-mediated microvasculopathy may play a pathogenic role in dermatomyositis. In a previous study, we demonstrated neoantigens of the C5b-9 complement membrane attack complex in the muscle microvasculature of childhood and adult cases of dermatomyositis. To further characterize the relationship between the vascular complement deposits and histologic changes, quantitative histopathologic analyses were performed on 39 dermatomyositis biopsy specimens (26 adult, 13 children). There was a significant correlation between the percentage of fascicles with fibers having focal myofibrillar loss, a change seen early in the evolution of ischemic muscle fiber damage, and the percentage of fascicles having capillary deposits of membrane attack complex. Conversely, in biopsy specimens with a higher percentage of fascicles with perifascicular atrophy, membrane attack complex deposits were significantly less common. A fascicle-by-fascicle analysis supported these observations. Patients whose biopsy specimens were negative for microvascular membrane attack complex had clinical weakness for a significantly longer time than those patients with vascular complement deposits. These data support the hypothesis that the complement-mediated vasculopathy is a primary immunopathogenic event in the evolution of muscle lesions in dermatomyositis.

Crossreactive antigens on human cells infected with Rauscher leukemia virus and on human acute leukemia cells.

A water-soluble component of membranes of cells from a Burkitt's lymphoma cultured cell line was used to develop an antiserum that detects an antigen(s) on acute leukemia cells. This antiserum did not react with nonlymphoid cultured cell lines except for human embryonic kidney cells infected with the Rauscher murine leukemia virus. Absorption studies demonstrated this antigen to be crossreactive with the antigen detected on the human acute leukemia cells.

Control of separate pathogenic autoantibody responses marks MHC gene contributions to murine lupus.

Previous studies have suggested that MHC and non-MHC genes contribute to the development of autoimmune disease in F1 hybrids of New Zealand black (NZB) and white (NZW) mice. We conducted a genome-wide screen of 148 female (NZB x NZW)F1 x NZB backcross mice to map dominant NZW genetic loci linked with lupus disease traits. In this backcross analysis, inheritance of the NZW MHC (H2(d/z) vs. H2(d/d)) was strongly linked with the development of lupus nephritis (P approximately 1 x 10(-16)), increasing the risk of disease by over 30-fold. H2(d/z) was also linked with elevated serum levels of IgG autoantibodies to single-stranded DNA, double-stranded DNA, histones, and chromatin but not with anti-gp70 autoantibodies, measured as circulating gp70-anti-gp70 immune complexes. Non-MHC contributions from NZW seemed weak in comparison to MHC, although NZW loci on chromosomes 7 and 16 were noted to be suggestively linked with autoantibody production. Strikingly, H2(d/z) (compared with H2(d/d)) enhanced antinuclear antibodies in a coordinate fashion but did not affect anti-gp70 production in the current backcross. However, the opposite influence was noted for H2(d/z) (compared with H2(z/z)) when (NZB x NZW)F1 x NZW backcross mice were analyzed. These results suggest that H2(z) and H2(d) haplotypes differentially regulate two different sets of nephritogenic autoantibody responses. This study confirms a critical role for H2(z) compared with other dominant NZW loci in (NZB x NZW)F1 mice and provides an explanation as to why H2(d/z) heterozygosity is required for full expression of disease in this model.

Acute myelocytic leukaemia and leukaemia-associated antigens in sisters.

In a sibship of 5 brothers and 7 sisters, 3 sisters died from acute myelocytic leukaemia while a 4th probably had the same disease. Laboratory studies on the close relatives revealed that a 5th sister had persistently high erythrocyte sedimentation-rates and serum-IgM levels and serological evidence of acute leukaemia-associated antigens. These findings suggest a possible preleukaemic state in this patient.