Biomedical subjects
Publications and source records attributed to J R Archer.
Blastomycosis was fatal to a wild wolf in Minnesota, and serologic evidence of blastomycosis was found in a Wisconsin wolf. No unusual movements were detected in the Minnesota animal from October 1983 through October 1985. However, by early December 1985, this wolf was weak and debilitated, and it perished on 14 December after approaching a human residence.
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It has previously been shown that extracts of human articular cartilage, many many of which contain type II collagen, react with heat-aggregated immunoglobulin and artificially prepared immune complexes. Sera from patients with rheumatoid arthritis and psoriatic arthritis, but not from patients with inflammatory bowel disease, react with these extracts. There are two distinct patterns of binding, either as low molecular weight immune complexes or as free antibody directed against collagen. Aggregate-binding activity identified in extracts of human articular cartilage following pepsin digestion was found to be distinct from collagen in its salt solubility. Further purification of this aggregate-binding factor by SDS gel electrophoresis has shown it to be an artefact resulting from the binding of small immune complexes to pepsinogen present in the pepsin preparation used to digest the cartilage.
While screening supernatants of human-human hybridomas for rheumatoid factor and anti-cellular activity we found that a significant number of supernatants which react with the Falcon-polyvinyl chloride immunoassay plate used in an enzyme-linked immunosorbent rheumatoid factor assay also react with intracellular intermediate filaments.
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Hybridization of peripheral blood lymphocytes from patients with rheumatoid arthritis has yielded 14 monoclonal antibodies which react with cultured human epithelial cells. Immunofluorescence staining identifies at last five different types of antibody. Solid phase immunosorbent assays show a variety of cross-reaction patterns with nucleic acids, proteoglycan, cardiolipin and plastic, confirming that the various antibodies react with epitopes which are at least slightly different. These conclusions are confirmed by SDS gel electrophoresis and immunoblotting on epithelial cell extracts. Similar antibodies previously found in association with lupus-like disease have been thought to be representative of the high antinuclear antibody response characteristic of lupus. Our data are more consistent with the hypothesis that all or many of these antibodies are part of the normal inflammatory response.
Rheumatoid lymphocytes tend to transform 'spontaneously' in vitro because of prior infection with Epstein Barr virus (EBV). They are particularly difficult to use in experiments involving cell hybridisation, because in the conventional half-HAT system unfused transformed cells may be confused with hybrids. We describe how the HAT-sensitive, ouabain-resistant human B lymphoblastoid cell line KR4, originally developed to 'rescue' EBV induced B cell clones, can be fused successfully with peripheral blood lymphocytes from patients with rheumatoid arthritis to produce unequivocal hybrids.
Restricted feeding of rodents increases longevity, but its mechanism of action is not understood. We studied the effects of life-long food restriction in genetically obese and normal mice of the same inbred strain in order to distinguish whether the reduction in food intake or the reduction in adiposity (percentage of fatty tissue) was the critical component in retarding the aging process. This was possible because food-restricted obese (ob/ob) mice maintained a high degree of adiposity. In addition to determining longevities, changes with age were measured in collagen, immune responses, and renal function. Genetically obese female mice highly congenic with the C57BL/6J inbred strain had substantially reduced longevities and increased rates of aging in tail tendon collagen and thymus-dependent immune responses, but not in urine-concentrating abilities. When their weight was held in a normal range by feeding restricted amounts, longevities were extended almost 50%, although these food-restricted ob/ob mice still had high levels of adiposity, with fat composing about half of their body weights. Their maximum longevities exceeded those of normal C57BL/6J mice and were similar to longevities of equally food-restricted normal mice that were much leaner. Food restricted ob/ob mice had greatly retarded rates of collagen aging, but the rapid losses with age in splenic immune responses were not mitigated. Thus, the extension of life-span by food restriction was inversely related to food consumption and corresponded to the aging rate of collagen. These results suggest that aging is a combination of independent processes; they show that reduced food consumption, not reduced adiposity, is the important component in extending longevity of genetically obese mice.
Tests of physiological changes with age are illustrated by collagen denaturation times of tail tendon fibers, and urine concentrating abilities; the tests are evaluated using the following four criteria: change with age, repeatability, relationship to other assays, and relationship to longevity. These tests usually showed highly significant changes with age when mice of different ages were compared for nine mouse genotypes, however neither appeared to be related to subsequent longevities of individual mice. When average values for eleven mouse genotypes were compared, the mean longevities of the genotypes were not significantly correlated with their mean collagen denaturation times or mean renal concentrating abilities, testes at two different ages. The relationships between all three factors--collagen denaturation times, urine concentrating abilities, and longevities--were tested in the same individuals for mice of six different genotypes at 600-700 days of age. Only one marginally significant correlation appeared out of 21 tested; this probably occurred by chance. We conclude that tail tendon collagen denaturation times and urine concentrating abilities change with age independently of each other; furthermore, these changes are unrelated to subsequent longevities, at least when linear relationships are tested. These data suggest that aging is timed by more than one mechanism and demonstrate that strong correlations with chronological age do not necessarily indicate that independent tests will be correlated with longevity or with each other.
Cartilage extracts with affinity for heat aggregated immunoglobulins were prepared from human articular and bovine nasal cartilage. These extracts, containing predominantly collagen, also bound both to immune complexes (IC) prepared in vitro and to immunoglobulins from sera of many patients with rheumatoid arthritis (RA). Cryoprecipitation of rheumatoid sera removed material reacting with the extract and density gradient fractionation of a positive serum showed correlation between binding to the extract and to C1q. These results indicate that the binding materials in rheumatoid sera were likely to be IC. We suggest that some assays which apparently demonstrate anti-collagen autoantibodies in fact measure IC. These findings also have implications for models of the pathogenesis of RA.
Physiological and behavioral measurements were made in a cohort of 29-month-old male C57BL/6J mice to determine whether any correlated significantly with lifespan. Significant linear relationships with lifespan were found among the physiological measures, including hematocrit and hemoglobin levels and collagen denaturation rate; however, body weight failed to be a significant predictor of survival. Among the behavioral variables studied, significant quadratic relationships with lifespan were found for exploratory activity and passive avoidance learning, while performance on a rotorod and a tightwire showed no significant relationships with lifespan. Through the use of multiple regression techniques, about one-third of the variance in lifespan could be explained by a combination of physiological variables, and about two-fifths could be explained by a combination of behavioral variables.
Surgical removal of the pituitary (hypophysectomy) followed by endocrine supplementation in middle-aged rats has been reported to reverse immunologic decline with age. We attempted to confirm and extend these reports by using a well-defined and readily available mouse model system. Hypophysectomy and endocrine supplementation in 8- to 9-mo-old C57BL/6J (B6) male retired breeder mice improved some, but not all, T dependent immune functions tested at 15 mo of age. In hypoxed mice, spleen cell proliferation in response to phytohemagglutinin (PHA) in vitro, and delayed type hypersensitivity (DTH) responses to sheep red blood cells (SRBC) measured by footpad swelling improved to levels shown by young controls. Direct anti-SRBC plaque-forming cell (PFC) responses by spleen cells, and serum agglutination responses against SRBC were not improved. Hypoxed mice had larger thymuses and much higher ratios of cortex-medulla areas than did age-matched controls. Hair regrowth after shaving was much faster in hypoxed mice. Nevertheless, hypophysectomy reduced mean and maximum longevities. These results conflict in several ways with the previously reported studies in rats, in which direct PFC responses and maximum longevities were improved by this treatment. There have been no previous studies of the effect of hypophysectomy and endocrine supplementation on thymic aging in mice, nor has it previously been reported that this treatment causes improvements in PHA and DTH responses and in thymic morphology. These effects show that at least some aging processes are reversible in aging individuals. They also suggest that hypophysectomy of middle-aged mice will be useful for studying neuroendocrine and thymic interactions that occur during the aging process.
Mph-1 is an alloantigen demonstrable on mouse peritoneal macrophages. Two lines, B10M.I and C.I, have been bred for use with strains I/StDa or BALB/c to produce appropriate alloantisera. Optimal immunization procedures for production of anti-Mph-1.2 (the common antigen) are described. Antisera against Mph-1.1 have so far been obtained only erratically. Antisera show complement dependent cytotoxicity against normal peritoneal macrophages and cultured blood monocytes but have no obvious effect on peritoneal lymphocytes or cultured blood neutrophils. Absorption studies show that cell for cell normal peritoneum has about fifteen times more antigen than lymph node, spleen, liver or bone marrow and at least eighty times more than thymus. We were unable to use the antiserum to cause passive enhancement of skin grafts in mice.
HLA B27 is associated with a number of forms of arthritis, including ankylosing spondylitis. It has been suggested that the disease is caused by Klebsiella pneumoniae and that the bacterium evokes an odd immune response because it cross-reacts with HLA B27. This proposed cross-reactivity was investigated in a number of ways. The results consistently failed to confirm evidence from cross reaction, even in antisera with activity against both HLA B27-positive lymphocytes and klebsiella. It is suggested that the anomalous anti-klebsiella response of rabbits immunised with pools of HLA B27-positive leucocytes may be caused by antigenic bacterial fragments on the cells of infected individuals.
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