Really practical rheumatology.
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Biomedical subjects
Publications and source records attributed to R Bluestone.
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The motility of human polymorphonuclear neutrophils was studied in vitro under aerobic and anaerobic conditions. Chemotactic factors were generated from plasma with immune complexes or with whole bacteria (Staphylococcus aureus, Escherichia coli, and Bacteroides fragilis). Chemotaxis induced by chemotactic factors generated from immune complexes was identical under both conditions. However, chemotaxis utilizing chemotactic factors generated from bacteria was markedly depressed under anaerobic conditions. Mean random tubemoltility was not significantly different under aerobic and anaerobic conditions. These data indicate that different metabolic pathways may be involved in polymorphonuclear neutrophil movement. Some of these pathways require oxygen (chemotaxis in response to factors generated by bacteria in plasma), whereas others do not (random tube migration and chemotaxis in response to factors generated by immune complexes in plasma). These observations may be important in the induction of inflammatory responses within hypoxic tissues.
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In spite of the increasing use of single and multiple pharmacologic intravenous pulses of MPS for immunosuppression in various diseases, their immunosuppressive effects have not been documented. We treated two groups of six patients with classic RA unresponsive to conventional therapy with either one or three daily 1 gm intravenous doses of MPS and measured the immune response and clinical activity over 16 weeks. Lymphocytopenia with selective T lymphocyte suppression was noted 2 hr following each infusion, which was maximal at 6 hr with complete recovery 24 hr after each dose beyond which no lymphocytopenia or T lymphocyte depletion was seen. Preservation of skin test positivity to recall antigens such as PPD and histoplasmin, rise in antibody titers to the secondary antigens tetanus and typhoid, and primary antibody response to KLH were found in both groups after treatment. Serum gamma globulin concentrations were unchanged. Five of six patients receiving 3 doses and three of six receiving 1 dose had satisfactory improvement in clinical parameters, with maximal benefit seen within the first 4 days. Six patients still felt better at 4 weeks, and one patient in each group entered a clinical remission greater than 16 weeks. We conclude that higher and repeated doses of MPS caused neither greater lymphocytopenia nor more prolonged suppression of recirculating lymphocytes than the conventional oral doses. The clinical benefits stem from reduction of inflammation, and it is doubtful that pulse therapy by itself induced significant generalized immunosuppression.
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Histocompatibility typing has assumed an increasingly important role as a clinical and research tool in rheumatic diseases. The HLA antigens which are serologically defined (A and B series) are being used most extensively for clinical work, but the role of other immunologic determinants in the HLA complex is being evaluated. These include D-locus (MLC) determinants, several complement components, and immune response genes which have been well characterized in the mouse, but not in man. The products of the major histocompatibility complex are inherited in a simple Mendelian fashion as a series of co-dominant alleles. Large population studies have characterized the frequencies of various alleles, and family studies have allowed tentative mapping of the various loci within the complex on the sixth chromosome in man. A number of diseases which are considered to be autoimmune in nature are now known to be associated with specific HLA antigens. Of these disease associations, the strongest and best studied are the seronegative spondyloarthropathies which are highly associated with the B27 antigen. Included in this group are ankylosing spondylitis, Reiter's syndrome, psoriatic arthropathy, colitic arthropathy, Yersinia arthritis and a small group of juvenile rheumatoid arthritis patients with features of ankylosing spondylitis. The clinical application of tissue typing or B27 testing is most helpful in regard to difficult diagnostic problems in patients with early or atypical seronegative spondyloarthropathy. Its value as an indicator of prognosis, and its value in counselling family members is not well established. There are many interesting hypotheses regarding pathogenetic mechanisms of these rheumatic diseases based on susceptibility factors related to the major histocompatibility complex. An abnormal immune response gene within the complex is probably a key feature of the mechanism, but the exact details are little more than speculative at this point.
"Colitic arthropathy" is commonly used to describe the arthritis associated with ulcerative colitis or regional enteritis. The term also describes the acute sterile arthritis which infrequently follows infection of the intestinal tract with Salmonella, Shigella, or Yersinia. Sterile arthritis is the most common extraintestinal manifestation of Whipple's disease, in which an unidentified bacteria is present in greatest concentration in the small bowel. Although arthritis and intestinal symptoms are common in Behcet's syndrome, the arthritis is not usually thought of as a colitic arthropathy because of the prominence of other signs, such as oral and genital ulceration and eye involvement. Joint and intestinal manifestations may, however, appear first or overshadow for a time involvement of other systems. Arthritis and arthralgia also occur frequently after jejunocolic and jejunoileal bypass.
Peripheral blood T (SRBC rosette) and B (AgG- and C-receptor) lymphocyte subpopulations and responsiveness to phytohaemagglutinin (PHA) were assayed in 40 patients with ankylosing spondylitis and in 55 normal subjects. There was no significant difference in the lymphocyte concentrations or responsiveness to PHA between the two groups. However, the percentages of T lymphocytes were significantly lower in the patients irrespective of their HLA typing. This was probably due to an increase in the 'null' population since the percentages of both the AgG- and C-receptor cells were normal.
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A rosette-type assay of the physical interaction between lymphocytes and monocytes after treatment with neuraminidase-galactose oxidase (NGAO) is reported. Monocyte-lymphocyte (ML) rosette formation and subsequent lymphocyte proliferation occurred when either lymphocytes or homologous monocytes were treated with NGAO and cultured together. Maximal ML rosette formation took place at 37 degrees C 4 hr after culture in media containing 10% serum at lymphocyte to monocyte ratios of 10:1 to 20:1. The percentage of rosette formation correlated with the extent of thymidine incorporation when increasing concentrations of NGAO were used. When NGAO-treated monocytes were added to untreated T and non-T lymphocytes, they bound preferentially to T lymphocytes and induced proliferation only in the T subpopulation. These results indicate that the ML rosette assay measures a highly specific monocyte-lymphocyte physical interaction after a mitogenic stimulus which is an early event in lymphocyte activation since it reflects the degree of subsequent lymphocyte proliferation.
Guinea pig polymorphonuclear neutrophils (PMN's; harvested from the blood and from peritoneal exudates) and monocytes (harvested from the peritoneal cavity with and without stimulation of an exudate) were compared in their capacities to kill three pyogenic bacteria. All combinations of phagocytes and bacteria required heat-labile opsonic factors. No significant differences in killing of the three organisms were observed between blood and peritoneal PMN's or between stimulated and unstimulated monocytes. PMN's killed Staphylococcus aureus more effectively than monocytes after both 1 and 2 hr of incubation (p less than 0.05). Although PMN's appeared to have greater bactericidal activity against Escherichia coli than did monocytes, this differences was significant only after 2 hr of incubation (p less than 0.05). The killing of Bacteroides fragilis by PMN's and monocytes was identical. These data demonstrate that guinea pig exudates provide suitable models for the study of phagocytosis and killing of bacteria and suggest that the relative bactericidal capacities of phagocytes depend not only on the phagocyte but also on the species of pyogenic bacteria being studied. These observations may have important implications in host defense against serious infections.
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