The major histocompatibility complex and rheumatic diseases.
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Biomedical subjects
Publications and source records attributed to R Bluestone.
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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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The effect of continuous versus interrupted high-dose aspirin (ASA) for 14 days was evaluated in a randomized double-blind study in 8 rheumatoid arthritis patients. Acute gastric mucosal injury was measured by serial gastroscopy and gastric biopsy. Significant gross mucosal damage was seen in all patients following 3 days of ASA (P less than 0.01) and persisted without significant change in severity to the end of the study. Histologic gastritis in areas free of hemorrhages and erosions was not increased significantly by ASA. In spite of gross mucosal injury, symptoms occurred infrequently. Serum pepsinogen I, but not serum gastrin, increased significantly following 3 days of ASA, and the elevation persisted to the end of the study. The extent of mucosal injury at 14 days was not significantly different in those receiving ASA continuously from those on an interrupted schedule. Thus, gastric mucosal adaptation to ASA in man was not demonstrated.
Many autoimmune diseases show a significant association with one or two second segregant series histocompatibility antigens. These associations are of great scientific interest, since they support the concept of HL-A-linked immune-response genes governing specific disease susceptibility. However, with one major exception, the association of HL-A antigens with diseases is not striking enough to provide a worthwhile diagnostic test. The exception is the extraordinarily high incidence of HLA B27 in patients with seronegative spondyloarthropathy best typified by ankylosing spondylitis (AS) and Reiter's disease (RD). In patients with these rheumatic syndromes, the antigen is present in more than 90% of cases compared to an incidence of approximately 6% in normal Caucasians and 4% in black Afro-Americans. The vast majority of rheumatic diseases are readily diagnosable on the basis of a history, physical examination and careful radiographic survey. This applies to most patients with a seronegative spondyloarthropathy, especially when the disease presents as a typical and fully formed clinical syndrome characterized as AS or RD. Sometimes the initial clinical nature may be atypical and only long-term follow-up of the patient will reveal an evolution toward the typical syndrome. In these situations, the correct diagnosis is reinforced by detecting the presence of HLA B27 on the patient's cells. Examination of the patient's family often reveals a high incidence of similar clinical syndromes, nearly always associated with the presence of the antigen. Since tissue typing at the moment is an expensive and relatively unavailable laboratory technic, its widespread and indiscriminatory use as a diagnostic test cannot be encouraged. However, in the clinical settings outlined above, tissue typing provides an invaluable diagnostic test. Presently, the combination of a negative test for rheumatoid factor and a positive test for HLA B27 is one of the strongest diagnostic laboratory profiles available to the physician when faced with a patient with early or atypical rheumatic disease. Aside from the purely clinical setting, the most exciting aspect of the association between these diseases and a specific cell surface antigen lies in the hope that we have a clue to the pathogenesis of a group of common rheumatic disorders. If the cause or causes of spondyloarthropathy can one day be found, the detection of HLA B27 may provide a useful public health measure facilitating preventive medicine. Even now, the detection of susceptible subjects within a family or a population will open the way for early diagnosis and treatment.
A simple method for the collection of peritoneal cells from small laboratory animals is described. Peritoneal exudates were induced by either caseinate or glycogen, and the cells were retrieved through a closed system. The technique permitted repeated studies on individual animals and yielded consistently sterile cell suspensions.
In the use of anti-inflammatory compounds, sustained serum levels are thought to be related to drug efficacy. This study shows that frequent clinical administration of indomethacin can result in sustained serum levels of the drug and that food and antacid may have important modifying effects on serum indomethacin concentrations. After oral ingestion by fasting subjects, indomethacin rapidly appeared in the serum, usually reaching peak concentrations in 30 to 90 minutes. Food delayed and decreased the mean peak level; antacid delayed the peak and slightly enhanced subsequent concentrations. With multiple dose schedules plateau levels were reached after 24 hours. When a total daily dose of 150 mg was given as 25 mg every 4 hours peak concentrations were the same but fluctuations were smaller and average concentrations were higher than with a dosage of 50 mg every 8 hours.
Twenty-five grossly obese males were investigated for evidence of osteoarthrosis. A roentgenological survey of multiple joints obtained from 22 of these patients showed few significant degenerative changes. 6 patients (20%) had previously incurred traumatic rents in their menisci necessitating meniscectomy. Our results refute previous claims that obesity is a factor in the genesis of osteoarthrosis but do indicate that obese individuals are more predisposed to traumatic injury of the knee.
Lymphocyte responsiveness to IgG was measured by an agarose method in nine patients with ankylosing spondylitis (AS), one patient with Reiter's Syndrome (RS), and thirty-six of their family members. Similar studies were also performed in five patients with rheumatoid arthritis (RA) and twenty-nine of their first degree relatives as well as in seven control families (twenty-seven subjects). Lymphocytes from the ten spondylitic patients and twenty-four of thirty-six family members responded in vitro to autologous IgG. Although most of these subjects had the histocompatibility antigen, B27, there was no association between B27 and response to IgG. Four of the five patients with RA and twenty of their twenty-nine first degree relatives responded in vitro to IgG, whereas only six of twenty-seven control family members gave a positive reaction. There was no difference in the incidence of antiglobulins (detected by agglutination tests) in the family members of patients with AS and RA or in control family members. These data indicate that lymphocyte responsiveness to IgG is the only aberrant immune response thus far described which is shared by patients with AS and RA and their family members.
Male Wistar rats fed 2 per cent oxonic acid plus 3 per cent uric acid for 3 weeks developed hyperuricemia and an extraordinary uricosuria. The kidneys had gross abnormalities similar to those seen in humans with gouty nephropathy. The cortical surfaces were granular and the kidneys had uric acid and urate deposits in the intratubular and intestitial spaces of the medullary region. Both histologic and ultrastructural studies of the glomeruli failed to disclose any unusual morphologic changes. Glomerular cells were normal and glomerular basement membranes maintained the granular structure of the lamina densa with a clear demarcation between the lamina rara externa and lamina rara interna. These morphologic findings suggest that in acutely hyperuricemic rats with a lesion comparable to hyperuricemic tubular blockade, there is no associated glomerular alteration.
Relapsing polychondritis (RP) is not a totally rare rheumatic disease. We have seen 23 patients from 1960-1975, and there are now a total of 159 reported cases, which form the basis of this study. RP occurs equally in both sexes, and has a maximum frequency in the fourth decade. 2) Empirically defined diagnostic criteria are proposed, to include the most common clinical features: a) Bilateral auricular chondritis b) Nonerosive sero-negative inflammatory polyarthritis c) nasal chondritis d) Ocular inflammation e) Respiratory tract chondritis f) Audiovestibular damage The diagnosis is based primarly upon the unique clinical features, and is quite certain if three or more criteria are present together with histologic confirmation. 3) Fifty percent of patients present with either auricular chondritis or the arthropathy of RP; but with prolonged follow-up, a majority of patients develop four or more of the above mentioned criteria. 4) Approximately 30 percent of patients have a preceding or coexistent rheumatic or autoimmune disease, which can lead to initial diagnostic confusion. 5) Laboratory and radiographic investigations help mainly to rule out other diagnostic possibilities, with no characteristic abnormalities being present in a majority of patients. 6) On follow-up, three-fourths of our patients required chronic corticosteroid therapy with an average dose of 25 mg per day of prednisone. Corticosteroids decrease the frequency, duration, and severity of flares, but do not stop disease progression in severe cases. 7) The mortality rate has been 30 percent in our series and 22 percent in the other 136 reported cases. Of the 29 cases where the cause of death was known, 17 were from respiratory tract involvement and 9 from cardiac valvular or vasculitic involvement, emphasizing the need to search for critical involvement of either of these organ systems in each patient. 8) Detailed reports of selected cases are presented to illustrate the clinical diagnosis and differential diagnosis, and to demonstrate the need for careful prolonged follow-up. 9) Although the etiology remains unknown, there is a frequent association with, and clinical similarity to, other rheumatic diseases. 10) Careful clinicopathological study of our 23 patients leads us to postulate an underying systemic vascultis as an important pathologic mechanism in RP.
Lymphocyte typing for HL-A B27 is useful under conditions in which data based on history and examination are suggestive but not diagnostic of a seronegative spondyloarthropathy. The presence of HL-A B27 would increase the probability of a patient's having one of these entities, but its absence does not rule out such a diagnosis. Furthermore, tissue-typing allows one to predict the probability that a patient with inflammatory bowel disease will develop AS and the likelihood that the family member of a patient with AS will develop a related disease.
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The sera and polymorphonuclear leukocytes (PMNs) of healthy human subjects were tested against several isolates of Bacteroides fragilis. All sera killed most of the fecal isolates, but were active aganist only one of the clinical isolates. The degree of killing was directly related to the serum concentration but was independent of the bacterial inoculum within the range of bacterial concentrations studied. The serum bactericidal activity was heat-labile. Engulfment and killing of B. fragilis by PMNs were demonstrated consistently. The opsonim involved in phagocytosis was also heat liable. Calculations involving log-transformed data permitted the quantitative study of the separate and combined effects of serum and PMNs on bacteria which were killed by serum alone. Whereas serum alone usually killed 0.5 log of serum-sensitive bacteria, the addition of PMNs was usually associated with one log further killing. The studies reported here demonstrate the presence of heat-labile serum factors in normal human sera which killed B. fragilis directly and which promote its phagocytosis and killing by PMNs. These observations provide a foundation for investigations into host defense mechanisms against anaerobes.