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Biomedical subjects

U H Rudofsky

Publications and source records attributed to U H Rudofsky.

At least 19 recordsLinked to original sources
PubMed1995

Defective antigen-receptor-mediated regulation of immunoglobulin production in B cells from autoimmune strains of mice.

B cells are stimulated by antigens or by polyclonal activators such as bacterial lipopolysaccharide (LPS) to produce antibody. In nonautoimmune strains of mice, LPS-stimulated antibody responses are inhibited by crosslinking the B cell antigen-receptor (BCR), while antigen-driven responses are shut down by co-crosslinking the BCR and the receptor for the Fc portion of IgG (Fc gamma R). BCR signals are poor at shutting off LPS-induced antibody production, including anti-ssDNA antibody production, in B cells from NZB, NZB/WF1, and BXSB lupus-prone mice but not MRL/lpr or NZW mice. In the current studies, the defect in NZB B cells was shown to be independent of T cells and macrophages. The inheritance pattern of resistance to BCR ligation of LPS-induced Ig production in BXSB mice could not be assigned to either founding strain. In New Zealand mixed (NZM) recombinant inbred mice, slightly but significantly more resistance was found in a line (NZM2410) that demonstrates a greater degree of clinical autoimmunity than another line (NZM64) with fewer autoimmune problems. The autoimmune defect is specific to BCR signals because inhibition of LPS activation by ligation of MHC class II occurs normally in NZB B cells. Bypassing the BCR by direct stimulation of second messengers with phorbol esters or ionomycin did not overcome the defect, suggesting that defects in downstream signaling events, rather than in the BCR mechanism itself, are responsible for the reduced ability to inhibit the LPS response in NZB B cells. The inability of the BCR signaling pathway to control LPS-induced Ig production in NZB mice was apparent at the level of H mu-chain mRNA for secreted IgM. These results suggest that autoimmunity-associated B cell defects in BCR signaling and subsequent regulation of LPS-driven antibody responses have a number of inheritance patterns and involve downstream events in signaling pathways in B cells. The defect can result in aberrant regulation of H mu-chain mRNA levels for secreted IgM production, and may be a predisposing factor in murine systemic autoimmune disease.

Animals↗
PubMed1994

Polygenic control of susceptibility to murine systemic lupus erythematosus.

Susceptibility to glomerulonephritis (GN) and anti-dsDNA autoantibody production was analyzed in crosses with a newly developed systemic lupus erythematosus-susceptible inbred strain, NZM/Aeg2410. The mode of inheritance and the number and location of systemic lupus erythematosus-associated susceptibility loci were analyzed by interval mapping in a backcross with C57BL/6. Three chromosomal intervals containing strong recessive GN susceptibility alleles were identified on chromosomes 1, 4, and 7, each containing several potentially interesting candidate genes. Heterozygosity at H-2 was also found to correlate strongly with GN susceptibility, consistent with previous findings in the NZB/NZW parental strain model. Logistic regression analysis indicated that each of these susceptibility alleles independently accounted for a component of GN susceptibility, and that susceptibility was inherited as a threshold genetic liability in this model system.

Animals↗
PubMed1989

Modulation of urinary kallikrein and plasma renin activities does not affect established hypertension in the fawn-hooded rat.

Fawn-hooded (FH) rats develop low-renin hypertension which is preceded by a decrease in urinary kallikrein. We examined urinary excretion of active and inactive kallikrein in hypertensive FH male rats and matched animals of the ancestral, normotensive Wistar strain. To determine the effects of modulation of salt intake on the kallikrein profile, rats were given standard rat chow (0.39% NaCl), a low-salt diet (0.02% NaCl), or a high-salt diet (standard chow plus water with 1% NaCl). Control FH rats excreted less active kallikrein (p less than 0.02), had similar amounts of inactive kallikrein, and had a higher inactive/active kallikrein ratio (p less than 0.02) than control Wistar rats. Low salt intake increased active kallikrein 136% (p less than 0.002) and 54% (p less than 0.035) in FH and Wistar rats, respectively, but did not change the level of inactive kallikrein or the inactive/active kallikrein ratio. High salt intake had no effect on kallikrein excretion in either strain. Low salt intake did not change blood pressure in either strain in spite of significant changes in plasma renin activity, angiotensin II and active kallikrein excretion. The low urinary active kallikrein and the high inactive/active kallikrein ratio in FH rats do not appear to play a role in the established hypertension in the FH rat, since modulation of these parameters did not cause a significant change in the elevated blood pressure.

Angiotensin II↗
PubMed1988

Elevation of plasma fibronectin and serum amyloid P in autoimmune NZB, B/W, and MRL/1pr mice.

The acute-phase proteins, fibronectin (Fn) and serum amyloid P (SAP), are opsonins which by virtue of their adhesive properties may be involved in the glomerular nephritis associated with splenic lupus erythematosus (SLE). Because of their possible involvement in the pathophysiology of lupus, plasma Fn and SAP levels from three strains of autoimmune mice were measured over time to determine if Fn and SAP rose as the mice sickened and renal function degenerated. Baseline levels of Fn and SAP were measured when the mice were between 1.5 and 3 months of age. The characteristic rapid onset of autoimmune disease in MRL/1pr mice was accompanied by a two- to threefold increase in plasma Fn and SAP by Day 100. The B/W mice, which develop autoimmune disease more slowly, did not have a significant increase in plasma Fn and SAP until Day 240. The NZB mice, with the most delayed onset of disease, exhibited a modest but significant elevation of plasma Fn and SAP by Day 360. Histologic examination of the kidneys of B/W and NZB mice indicated that pathological abnormality of the glomeruli and tubules coincided with the elevation of plasma Fn and SAP levels. In contrast, blood samples taken over time from normal BALB/c mice did not possess abnormal levels of Fn or SAP. It appears that elevation of plasma Fn and SAP in the MRL/1 pr, B/W, and NZB mice is related to the onset and severity of autoimmune disease and the subsequent loss of renal function.

Age Factors↗
PubMed1988

Characterisation of IgE-mediated histamine release from equine basophils in vitro.

In vitro IgE-mediated histamine release by equine blood basophils was characterised as the basis for a screening test for immediate hypersensitivity responses in horses. The responses are initiated by inducing agents that are capable of crosslinking or bridging the membrane-bound IgE molecules. The release process is complete within 40 mins. In vitro histamine release is dose-dependent, with a submaximal response at less or greater than the optimal dose of inducing agent. Exogenous calcium is required but not magnesium; the optimal release calcium concentration is 1.0 to 1.5 mM. If an IgE-mediated inducing agent is added in the absence of exogenous calcium, the basophils become desensitised. The pH and temperature optima for release are physiological (pH 7.4, 37 degrees C). Histamine release is potentiated by deuterium oxide.

Animals↗
PubMed1988

Lack of passive transfer of renal tubulointerstitial disease by serum or monoclonal antibody specific for renal tubular antigens in the mouse.

Mice immunized with rabbit renal basement membranes form autoantibodies to their kidney glomerular and tubular basement membranes (GBM/TBM). Development of renal tubular disease (RTD) consists of deposition of autoantibodies along the GBM/TBM with the inter- and intratubular accumulation of lymphocytes and macrophages and destruction of the TBM. Transfer of this disease in mice with either serum or monoclonal antibodies, however, has been difficult to demonstrate and, therefore, attempts were made to confirm a report that RTD is passively transferred by anti-TBM autoantibodies. Using the revised protocol in this later report, we found that 12 weeks after transfer autoantibodies were deposited along the GBM and/or TBM of the recipients, yet RTD was not observed. Although qualitative and quantitative characteristics of the antibody may play a role in the pathogenesis in the murine model of RTD, we could not obtain evidence to support and confirm this study.

Animals↗
PubMed1987

Contrasting effects of early and late orchiectomy on hypertension and renal disease in fawn-hooded rats.

Fawn-hooded (FH) rats, primarily males, develop spontaneous low-renin hypertension associated with reduced urinary excretion of kallikrein as early as 2 months of age, followed by progressive glomerular sclerosis and proteinuria as early as 3 months of age. In the present study we determined the effects of early (5-7 weeks) or late (5 months) orchiectomy on the blood pressure and nephropathy of FH rats, compared to sham-operated (control) FH males. Early orchiectomy reduced significantly the progression of glomerular sclerosis and of proteinuria and ameliorated the hypertension but had no significant effect on excretion of urinary kallikrein. Late orchiectomy, in contrast, had no significant effect on the progression of glomerular sclerosis or proteinuria but did significantly reduce the blood pressure and marginally increase the excretion of urine kallikrein. These results suggest that (a) male sex hormones may play a role in the pathogenesis of hypertension and nephropathy in the FH rats and (b) renal disease in this strain progresses in spite of improvement in blood pressure.

Aging↗
PubMed1987

HLA and survival in lung cancer.

HLA A and B antigens were determined in a study of 125 patients with lung cancer. Differences between antigen frequencies in cancer and control populations were determined by chi 2 analysis or Fisher's exact test. Survival data were analyzed using the Cox model for censored data. Cancer patients had an increased frequency of the antigen Aw33 (relative risk = 10.5, P less than 0.016). The Cox model (D. R. Cox, J. R. Stat. Soc. B, 34, 187, 1972) indicated that four covariates had a significant effect on mean survival time independently: the presence of A3 (P less than 0.005) and of Aw33 (P less than 0.05) increased mean survival time of the cancer population; patients with anaplastic carcinoma and stage three of any histological type of cancer had a decreased mean survival time. The determination of HLA phenotypes, cancer type, and the stage of the disease can provide the expected mean survival time of any particular patient. This could be of importance for evaluating prognosis. The effect of Aw33 and A3 on survival time may be related to HLA closely linked genes, possibly coding for resistance to the disease.

HLA Antigens↗
PubMed1986

Analysis of lead effects on in vivo antibody-mediated immunity in several mouse strains.

The effect of administration of lead acetate (10 mM in the drinking water) for 8 weeks on the in vivo sheep red blood cell (SRBC) specific plaque-forming cell (PFC) responses of inbred A, BALB/c, C57Bl/6, DBA/1, SJL, and NZW/NZB F1 mice and outbred CFW mice was examined to determine if lead was immunomodulatory in a genetically related manner. Lead did not suppress the SRBC-specific PFC/10(6) splenocytes or PFC/spleen response in any mouse strain when compared to the responses of strain-matched control mice. In addition, 10 mM lead-treated BALB/c mice manifested augmented PFC/10(6) splenocytes (17%; p less than .05) but unchanged PFC/spleen responses. Correspondingly, serum concentrations of SRBC-specific antibody (measured by radioimmunoassay) and serum immunoglobulin G, M, or A isotypes were also unchanged by lead acetate treatment in all tested mouse strains. There were no observable lead-related histopathological changes or deposition of immune complexes or antibasement membrane antibody in the kidneys of treated mice. Further, splenocytes from lead-treated, SRBC-immunized mice cultured with T-independent antigens (TNP-LPS, TNP-Ficoll) or with a T-dependent antigen (SRBC) exhibited direct and indirect specific PFC responses that were unchanged from those of control mice. The H-2K/D haplotypes of the outbred CFW mice were determined by microcytotoxicity to include r, q, u, and s. These results suggest that lead acetate (10 mM) administered po for 8 weeks does not suppress the primary direct humoral immune response to SRBC in inbred and outbred mice of several H-2 haplotypes (k/d; d; b; q; d,z; s; r; and u).

Administration, Oral↗
PubMed1986

Increased catecholamine output in the hypertensive fawn-hooded rat.

The total 24 hour urinary outputs of the catecholamines norepinephrine (NE), epinephrine (E), dopamine (DA) and the DA metabolite homovanillic acid (HVA) were measured in hypertensive fawn-hooded rats and compared to the ancestral strain of normotensive Wistar rats. The hypertensive fawn-hooded rats demonstrated significantly higher urinary outputs of the catecholamines NE and DA, and of the DA metabolite HVA. Following treatment with the antihypertensive, debrisoquin sulfate, the blood pressure of the fawn-hooded rats decreased until it approached the levels observed in normotensive Wistar rats. By inhibiting sympathetic nervous activity and monoamine oxidase, the debrisoquin treatment significantly decreased the output of DA, NE and HVA but not E. The data suggest the fawn-hooded rat is a model of neurogenic hypertension which is characterized by an increased sympathetic output.

Animals↗
PubMed1984

Differences in the occurrence of hypertension among (NZB X NZW)F1, MRL-lpr, and BXSB mice with lupus nephritis.

Lupus-prone (NZB X NZW)F1 (B X W) mice and MRL-lpr and BXSB mice were examined for the prevalence of hypertension and levels of plasma renin activity (PRA). Hypertension (greater than 145 mmHg) was observed only in female and male B X W mice with severe nephritis; in female MRL-lpr and male BXSB mice severe nephritis developed without blood pressure elevation (80-135 mmHg). The B X W parental strains, NZB and NZW, and the MRL-lpr congenic partners, MRL- +, did not become hypertensive as they aged. Other strains of mice, aged 3-32 months (A/HeN, BALB/cJ, BALB/cByJ, B10.S/Sg, B10.D2/ oSn , CBA/J, C3H/HeJ, SJL/J and [SJL X NZW]F1), also had normal blood pressure (98-122 mmHg). All mice with lupus nephritis had low PRA, even those with hypertension; furthermore, the MRL-lpr strain had low or undetectable PRA (2 +/- 1 ng/ml/hr), even when kidneys were normal. NZB, NZW, and MRL- + mice had normal PRA (10-16 ng/ml/hr). Thus, B X W mice frequently developed low renin hypertension during the last phase of their renal disease; whereas MRL-lpr and BXSB mice died from renal disease without observable increases in blood pressure.

Animals↗
PubMed1983

Experimental autoimmune antiglomerular basement membrane antibody-induced glomerulonephritis. I. The effects of injecting sheep with human, homologous or autologous lung basement membranes and complete Freund's adjuvant.

We compared the effects of injecting human, homologous or autologous lung basement membrane (LBM) and complete Freund's adjuvant into 6-month-old sheep and injecting the same antigens into guinea pigs. All sheep receiving human LBM died of antiglomerular basement membrane (GBM) nephritis by Day 126. They had autoantibodies to antigenic determinants shared by fetal or adult sheep and human LBM and GBM and certain nonvascular basement membranes, but these autoantibodies did not localize in the lung in vivo or cause lung hemorrhages. No sheep injected with homologous or autologous LBM had any evidence of anti-GBM autoantibodies or nephritis or specific lung lesions. Their kidneys are indistinguishable by histologic, immunohistologic, and functional studies from kidneys of age-matched controls. Thus, sheep are very tolerant to their own LBM. Although all guinea pigs developed anti-GBM autoantibodies, they did not get anti-GBM nephritis or specific lung lesions. A hypothesis for the pathogenesis of Goodpasture's syndrome is presented.

Animals↗
PubMed1983

Effect of sulfhydryl-reactive ATPase inhibitors upon mast cell and basophil activation.

Ethacrynic acid is an inhibitor of Ca2+-Mg2+-activated ATPases which also inhibits histamine release. By testing analogs of ethacrynic acid, the molecular structural requirements for ATPase inhibition and for inhibition of histamine release were compared. The results indicated that effective inhibition involves several structural features of the molecule. Analogs void of chlorine atoms were ineffective as inhibitors of histamine release and ATPase activity. Inhibition of both ATPase and histamine release requires a sulfhydryl-reactive olefinic bond, but sulfhydryl reactivity alone is not sufficient, as certain analogs which have a high capacity to react with sulfhydryl moieties were not active. Replacement of carboxy by highly ionized moieties like sulfo, rendered the molecules ineffective as an inhibitor of histamine release. Compounds which did not inhibit ATPase activity did not inhibit histamine release. The data indicate that mast cells and basophils require an intact ATPase system for histamine release, and raises the question of whether both ecto and endo ATPases are essential.

Adenosine Triphosphatases↗
PubMed1983

Experimental autoimmune glomerulonephritis induced by anti-glomerular basement membrane antibody. II. Effects of injecting heterologous, homologous, or autologous glomerular basement membranes and complete Freund's adjuvant into sheep.

The effects of injecting human, rabbit, rat, or single-kidney homologous glomerular basement membrane (GBM) or autologous GBM, each in complete Freund's adjuvant (CFA), into 15- to 18-month-old sheep are compared. All sheep receiving heterologous GBM and 3 of 6 sheep receiving homologous GBM had anti-GBM nephritis, but such sheep did not bind autoantibodies or have Goodpasturelike lesions in their lungs. Sheep given injections of human GBM had autoantibodies to antigenic determinants shared by fetal or adult sheep and human GBM, by lung basement membranes, and by certain nonvascular basement membranes. Sheep given homologous GBM had two populations of autoantibodies: one was neither species- nor organ-specific; the other was sheep-specific. No sheep given autologous GBM had any evidence of anti-GBM autoantibodies or nephritis. Their kidneys were indistinguishable by histologic, immunohistologic, and functional studies from CFA-treated controls. Thus, sheep seem very tolerant to autologous GBM. These findings suggest that human anti-GBM nephritis may occur if the GBM is altered so that it becomes cross-reacting and induces autoantibodies, as does homologous GBM.

Animals↗
PubMed1982

Plasma renin activity decrease precedes spontaneous focal glomerular sclerosis in aging rats.

An association between the activity of the renin-angiotensin system and the development of spontaneous focal glomerular sclerosis (FGS) in rats has been observed: the onset is preceded by a decrease in plasma renin activity (PRA). This observation was facilitated by the use of Fawn-hooded rats, which develop spontaneous FGS at an early age. Male Fawn-hooded rats develop severe FGS as early as 3 months of age. Male Wistar rats do not develop similar lesions until after 1 year of age. Correspondingly the PRA drops much sooner in Fawn-hooded than in Wistar rats. The low PRA appears to be due to low plasma renin rather than a limitation of the renin substrate, angiotensinogen, which appears to be present in the Fawn-hooded plasma in nonlimiting quantities. In the FH male rats renin content of the kidney drops only after severe glomerular pathology is evident, implying that the low PRA may be due to a decrease in renin secretion by the chromaffin cells of the juxtaglomerular apparatus.

Aging↗