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Biomedical subjects

R L Wilder

Publications and source records attributed to R L Wilder.

At least 55 records · Page 3Linked to original sources
PubMed1998

Hormones, pregnancy, and autoimmune diseases.

Hormonal factors linked to age, gender, and reproductive status are undoubtedly involved in regulating the onset of numerous autoimmune diseases. For example, systemic lupus erythematosus (SLE), a disease characterized by immune complex-mediated pathology linked to excess Th2 cytokine production (e.g., IL-10) primarily affects women in the reproductive years. Rheumatoid arthritis (RA), a disease characterized primarily by cell-mediated joint immunopathology linked to deficient Th2 cytokine production, is also more common in women, but, in contrast to SLE, the highest incidence is at menopause. Pregnancy-associated changes in these diseases, however, provide the most compelling evidence that hormonal factors play a major role in modulating the expression of these diseases. SLE often flares during pregnancy, whereas RA commonly remits during pregnancy and flares or initially develops in the postpartum period. These observations appear to be explained by the accumulating data indicating that during pregnancy cell-mediated immune function and Th1 cytokine production (e.g., IL-12, interferon-gamma) are suppressed, and humoral immunity and Th2 cytokine production (e.g., IL-4, IL-10) are enhanced. These patterns reverse in the postpartum period. In other words, antithetical Th1/Th2 cytokine profiles appear to characterize pregnancy and the postpartum period. Strong evidence now indicates that changes in the production of cortisol, progesterone, and estrogen play a major role in modulating Th1/Th2 cytokine balance.

Animals↗
PubMed1998

The pathophysiologic roles of interleukin-6 in human disease.

Interleukin-6, an inflammatory cytokine, is characterized by pleiotropy and redundancy of action. Apart from its hematologic, immune, and hepatic effects, it has many endocrine and metabolic actions. Specifically, it is a potent stimulator of the hypothalamic-pituitary-adrenal axis and is under the tonic negative control of glucocorticoids. It acutely stimulates the secretion of growth hormone, inhibits thyroid-stimulating hormone secretion, and decreases serum lipid concentrations. Furthermore, it is secreted during stress and is positively controlled by catecholamines. Administration of interleukin-6 results in fever, anorexia, and fatigue. Elevated levels of circulating interleukin-6 have been seen in the steroid withdrawal syndrome and in the severe inflammatory, infectious, and traumatic states potentially associated with the inappropriate secretion of vasopressin. Levels of circulating interleukin-6 are also elevated in several inflammatory diseases, such as rheumatoid arthritis. Interleukin-6 is negatively controlled by estrogens and androgens, and it plays a central role in the pathogenesis of the osteoporosis seen in conditions characterized by increased bone resorption, such as sex-steroid deficiency and hyperparathyroidism. Overproduction of interleukin-6 may contribute to illness during aging and chronic stress. Finally, administration of recombinant human interleukin-6 may serve as a stimulation test for the integrity of the hypothalamic-pituitary-adrenal axis.

Aging↗
PubMed1998

Familial autoimmunity in pedigrees of idiopathic inflammatory myopathy patients suggests common genetic risk factors for many autoimmune diseases.

OBJECTIVE: To test the hypothesis that many autoimmune diseases share common genetic risk factors and to define the frequency and distribution of autoimmune diseases in relatives of patients with very rare disorders, the idiopathic inflammatory myopathies (IIM). METHODS: We evaluated, in a prospective case-control study, consecutive patients with IIM who were referred to our center and ascertained without regard to family history or known risk factors for autoimmunity, and all available family members. We used a standardized assessment to determine the presence and type of autoimmune disease in each subject. A matched comparison group of control subjects without autoimmune disease who were referred to our center and their families were similarly assessed. RESULTS: Autoimmune diseases were significantly increased in prevalence (21.9%) in the 151 first-degree relatives of the 21 IIM probands compared with the prevalence (4.9%) in the 143 relatives of the 21 control probands (odds ratio [OR] by regression analysis 7.9, 95% confidence interval [95% CI] 2.9-21.9, P < 0.001). Women had more autoimmune disease than men (OR by regression analysis 4.6, 95% CI 2.3-9.0) and the odds ratio for autoimmune disease increased 0.02 per year of age. These disorders tended to follow the frequency distribution of autoimmune diseases in the general population. Genetic modeling studies showed that a non-Mendelian polygenic inheritance pattern for autoimmune disease was most consistent with these data. CONCLUSION: Autoimmune diseases are significantly increased in frequency in first-degree relatives of IIM patients, affect more women than men, increase with age, and are distributed in a pattern similar to that in the general population. Many autoimmune disorders share genes that together act as polygenic risk factors for autoimmunity.

Adolescent↗
PubMed1998

Identification of a new non-major histocompatibility complex genetic locus on chromosome 2 that controls disease severity in collagen-induced arthritis in rats.

OBJECTIVE: To identify novel non-major histocompatibility complex (non-MHC) genetic loci controlling the severity of homologous rat type II collagen-induced arthritis (CIA). METHODS: We conducted a genome-wide scan to identify CIA regulatory quantitative trait loci (QTL) in an F2 cross between DA (CIA highly susceptible) and ACI (CIA resistant) inbred rats immunized with homologous rat type II collagen (RII). These strains share the MHC/RT1av1 haplotype required for susceptibility to RII-induced CIA. RESULTS: F2 females had higher median arthritis scores than did males. Relative resistance in the males was determined by inheriting either a DA or an ACI Y chromosome and was independent of the source of the X chromosome. In addition, a major QTL was localized on chromosome 2 (Cia7, logarithm of odds score 4.6). Cia7 is in a region that shows linkage conservation with chromosomal regions that regulate autoimmune diabetes and experimental autoimmune encephalomyelitis in mice and multiple sclerosis in humans. CONCLUSION: Sex chromosomes and Cia7 play an important role in regulating CIA in response to RII. This rat model should facilitate positional cloning and functional characterization of regulatory genes that may play a role in several forms of autoimmune disease, including rheumatoid arthritis.

Animals↗
PubMed1998

Familial clustering of rheumatoid arthritis with other autoimmune diseases.

Previous studies have shown that rheumatoid arthritis aggregates within families. However, no formal genetic analysis of rheumatoid arthritis in pedigrees together with other autoimmune diseases has been reported. We hypothesized that there are genetic factors in common in rheumatoid arthritis and other autoimmune diseases. Results of odds-ratio regression and complex segregation analysis in a sample of 43 Caucasian pedigrees ascertained through a rheumatoid arthritis proband or matched control proband, revealed a very strong genetic influence on the occurrence of both rheumatoid arthritis and other autoimmune diseases. In an analysis of rheumatoid arthritis alone, only one inter-class measure, parent-sibling, resulted in positive evidence of aggregation. However, three inter-class measures (parent-sibling, sibling-offspring, and parent-offspring pairs) showed significant evidence of familial aggregation with odds-ratio regression analysis of rheumatoid arthritis together with all other autoimmune diseases. Segregation analysis of rheumatoid arthritis alone revealed that the mixed model, including both polygenic and major gene components, was the most parsimonious. Similarly, segregation analysis of rheumatoid arthritis together with other autoimmune diseases revealed that a mixed model fitted the data significantly better than either major gene or polygenic models. These results were consistent with a previous study which concluded that several genes, including one with a major effect, is responsible for rheumatoid arthritis in families. Our data showed that this conclusion also held when the phenotype was defined as rheumatoid arthritis and/or other autoimmune diseases, suggesting that several major autoimmune diseases result from pleiotropic effects of a single major gene on a polygenic background.

Adult↗
PubMed1998

Cyclical expression of GnRH and GnRH receptor mRNA in lymphoid organs.

Gonadotropin-releasing hormone (GnRH) is known to possess direct immunomodulatory effects. We have previously demonstrated that the administration of GnRH analogues modulates the expression of murine lupus independently of effects on gonadal steroids. We speculate that GnRH exerts direct actions at the level of the immune cells. GnRH receptors have been identified on lymphocytes. Because GnRH and GnRH receptor (GnRH-R) expression varies with the estrous cycle at the levels of the hypothalamus and pituitary, we speculated that similar cyclicity might be demonstrable in lymphoid tissue. In this report, we used competitive reverse transcription PCR to quantitate the expression of GnRH and GnRH-R mRNA in lymphoid organs throughout the estrous cycle in mice. We demonstrate that the pattern of expression of GnRH-R mRNA in spleen agrees closely with the pattern in the pituitaries of the same mice and the pattern previously reported in the rat pituitary, with significantly increased levels of expression seen on the afternoon of proestrus compared to the morning of metestrus. A similar pattern is seen with GnRH-R mRNA expression in the thymus. Furthermore, we show that the expression of GnRH mRNA in both thymus and spleen agrees closely with the pattern of expression of its receptor, with significantly increased levels of expression seen on the afternoon of proestrus compared to the morning of metestrus. Additional in vitro studies demonstrate that both GnRH and estradiol significantly increase the expression of GnRH-R mRNA in immune cells. These findings support an active role for GnRH in the immune system.

Animals↗
PubMed1998

Plasma levels of corticotropin-releasing hormone in the inferior petrosal sinuses of healthy volunteers, patients with Cushing's syndrome, and patients with pseudo-Cushing states.

The objective of this study was to determine whether measurements of human CRH in the inferior petrosal sinuses could distinguish patients with Cushing's syndrome from those with pseudo-Cushing states or normal physiology. Twenty-five patients with Cushing's disease, 17 patients with the syndrome of ectopic ACTH, 7 patients with Cushing's syndrome of adrenal origin, 6 patients with pseudo-Cushing states, and 11 volunteers believed to have normal hypothalamic-pituitary-adrenal axes were studied. Basal plasma human CRH and ACTH were measured at two time points in the petrosal sinuses and in a peripheral vein. Most subjects were studied after the administration of intravenous diazepam or midazolam and fentanyl, but because of the known inhibitory effects of such sedation on CRH secretion, 2 normal volunteers and 3 patients with pseudo-Cushing states were studied without sedation. Human CRH levels were near or below the detection limit of the assay in all subjects. Although the normal volunteers and patients with pseudo-Cushing states who were studied without sedation had significantly greater inferior petrosal sinus ACTH levels than those who received sedation, there were no differences in measured human CRH levels for any of the groups. We conclude that inferior petrosal sinus human CRH levels are not easily measured in the inferior petrosal sinuses and cannot be used to determine whether individual patients may have hypersecretion of CRH causing their ACTH secretion.

Adrenocorticotropic Hormone↗
PubMed1998

Distinct patterns of cytokine secretion characterize new onset synovitis versus chronic rheumatoid arthritis.

OBJECTIVE: To compare patterns of cytokine secretion in patients with new onset synovitis (< 1 yr duration, n = 14), chronic rheumatoid arthritis (RA) (n = 16), and healthy controls (n = 17). METHODS: ELIspot assays were used to detect mononuclear cells in the peripheral blood (PMBC) and synovial fluid (SFMC) secretion the type 1 cytokines interleukin 2 (IL-2) and interferon-gamma (IFN-gamma), the type 2 cytokines IL-4, IL-6 and IL-10, and the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). Results were correlated with measures of disease activity. RESULTS: Patients with new onset synovitis had increased (p < 0.05) numbers of PBMC secreting IL-2. The number of PBMC secreting IFN-gamma correlated with the joint score in the new onset synovitis population (p = 0.006). By comparison, patients with chronic RA had significantly increased numbers of PBMC secreting IL-6, IL-10, and TNF-alpha (p < 0.05). The production of these cytokines correlated with joint score in chronic RA (p = 0.008, 0.06, 0.001, respectively). CONCLUSION: Patients with new onset synovitis have increased numbers of PBMC secreting IL-2 and IFN-gamma, while patients with chronic RA have increased numbers of PBMC secreting IL-6, IL-10, and TNF-alpha. Correlations between joint score and number of PBMC secreting cytokines suggest the number of PBMC secreting IFN-gamma is most relevant in new onset synovitis, while the number of PBMC secreting IL-6, IL-10, and TNF-alpha is of greater relevance in chronic RA.

Adult↗
PubMed1997

Genetic susceptibility to experimental autoimmune uveitis involves more than a predisposition to generate a T helper-1-like or a T helper-2-like response.

This study examines whether genetic susceptibility vs resistance to experimental autoimmune uveoretinitis (EAU) in mice is associated with dominant type 1 vs type 2 cytokine response profiles. Mice from six strains were immunized with the uveitogenic retinal Ag IRBP. EAU was evaluated by histopathology. As judged by disease scores, three of the strains were susceptible, one was minimally susceptible, and two were resistant. Ag-specific type 1 vs type 2 cytokine responses (protein and/or mRNA) in draining lymph node cells, and IgG2a vs IgG1 Ab isotypes to IRBP, were measured as indicators of Th1-like vs Th2-like responses, respectively. The three susceptible strains (B10.A, C57BL/10, and BALB/k) showed a dominant Th1-like response profile characterized by high IFN-gamma and IL-12p40 (but not IL-4) responses, and a predominance of IgG2a Abs. The minimally susceptible strain (A/J) had an IFN-gamma response detectable only at the mRNA level, but produced predominantly IgG2a Abs. One of the two resistant strains (BALB/c) showed a characteristic Th2-like response with dominant Ag-specific IL-4 and IL-10 responses but no IFN-gamma, and predominantly IgG1 Abs. However, the other resistant strain (AKR) did not show a Th2-dominated response pattern, in that it had low, or no, IL-4 and IL-10 responses, and made predominantly IgG2a Abs to IRBP. These results suggest that whereas a Th1 response is required for susceptibility, resistance is not dependent on a Th2 response pattern. We suggest that regulatory influences other than skewing the response toward the Th2 pathway may be equally effective at conferring genetic resistance to EAU.

Animals↗
PubMed1997

Does differential neuroendocrine control of cytokine production govern the expression of autoimmune diseases in pregnancy and the postpartum period?

Pregnancy and the postpartum period are associated with significant changes in levels of several hormones, such as estrogen, progesterone, cortisol and possibly catecholamines. Moreover, several autoimmune diseases such as rheumatoid arthritis tend to remit, develop or exacerbate during pregnancy or the postpartum period. Thus, the question arises: are the changes in the hormones and the expression of autoimmune diseases during these periods causally linked, or are these associations an epiphenomenon? Here we suggest that a causal link might be provided through differential neuroendocrine regulation of Th1-type and Th2-type cytokine production.

Autoimmune Diseases↗
PubMed1997

T cell mechanisms in experimental autoimmune uveoretinitis: susceptibility is a function of the cytokine response profile.

This study addresses the question whether susceptibility versus resistance to experimental autoimmune uveoretinitis (EAU) is connected to a Th1-type (interferon-gamma high, interleukin-4 low), versus a Th2-type (IFN-gamma low, IL-4 high) response. Primed lymph node cells of susceptible Lewis rats produced IFN-gamma in response to antigen in culture and transferred EAU to syngeneic recipients, whereas lymph node cells of resistant F344 rats made no IFN-gamma and did not transfer disease. Reversal of the disease pattern, by treatment of F344 rats with B. pertussis toxin and immunisation of Lewis rats with antigen in incomplete Freund's adjuvant, resulted in a parallel reversal of these response patterns. Neither strain produced significant IL-4 responses. A study of the response patterns in mice confirmed that high Th1 responders were susceptible, whereas low Th1 responders and Th2 responders were resistant. We conclude that susceptibility to EAU is connected with a Th1-dominant response, but resistance can involve either a 'null', F344-like response (Th1-low/Th2-low) or a Th2-dominant response.

Adoptive Transfer↗
PubMed1997

Circadian relationships between interleukin (IL)-6 and hypothalamic-pituitary-adrenal axis hormones: failure of IL-6 to cause sustained hypercortisolism in patients with early untreated rheumatoid arthritis.

Systemic symptoms in rheumatoid arthritis (RA) are mediated, at least in part, by elevated levels of circulating interleukin (IL)-6, and this cytokine is also a potent stimulus of the hypothalamic-pituitary-adrenal axis. To evaluate the 24-h circadian secretory dynamics of ACTH, cortisol, and IL-6 and their interactions in patients with early untreated RA, we recruited and studied five newly diagnosed, untreated RA patients early in the course of their disease and five age-, gender-, and race-matched control subjects. We collected serial blood samples over 24 h and measured plasma ACTH and cortisol every 30 min and IL-6 every hour. The 24-h collection was followed by administration of ovine CRH (oCRH) and post-oCRH serial blood samples over 2 h. We analyzed the 24-h overall levels of these hormones and their circadian variations and performed time-lagged cross-correlation analyses among them. The untreated RA patients had 24 h time-integrated plasma ACTH, plasma cortisol levels, and urinary free cortisol excretion that were not significantly different from control subjects, in spite of their disease activity. However, an earlier morning surge of plasma ACTH and cortisol in the patients was suggested. Plasma ACTH and cortisol responses to oCRH were similar in RA patients and controls. IL-6 levels were significantly increased in the RA patients compared with control subjects during the early morning hours (P < 0.05). There was pronounced circadian variation of plasma Il-6 levels. In the RA patients, we detected a positive temporal correlation between plasma levels of IL-6 and ACTH/cortisol, with elevated levels of IL-6 before the elevations of ACTH and cortisol by 1 and 2 h, respectively. In the same patients, we detected a negative effect of cortisol upon IL-6 exerted with a delay of 5 h. The data presented here suggest that although endogenous IL-6 may stimulate secretion of ACTH and cortisol, overall activity of the hypothalamic-pituitary-adrenal axis remains normal and apparently is insufficient to inhibit ongoing inflammation in early untreated RA patients.

Adrenocorticotropic Hormone↗
PubMed1997

In vivo gene expression of type 1 and type 2 cytokines in synovial tissues from patients in early stages of rheumatoid, reactive, and undifferentiated arthritis.

It has been reported that the mRNA of the type 1 cytokine, interferon-gamma (IFN-gamma)--but not the type 2 cytokine interleukin-4 (IL-4)--is detected in synovial tissues of rheumatoid arthritis (RA) patients, whereas both IFN-gamma and IL-4 mRNA are detected in reactive arthritis (ReA). To evaluate such data more extensively, we obtained 208 synovial specimens in a prospective study of 52 early synovitis patients (13 RA, 11 ReA, 28 undifferentiated oligoarthropathy) and analyzed type 1 and type 2 cytokine mRNA expression in specimens containing sufficient mRNA. Using a nested reverse transcriptase polymerase chain reaction technique, we measured the relative mRNA levels of 10 cytokines and CD3 delta chain. We detected IL-10, IL-15, and CD3 delta chain mRNA in all RA and ReA patients and frequently detected tumor necrosis factor-alpha, IL-1 beta, and IFN-gamma mRNA. IL-6 and IL-12 p40 mRNA were detected in approximately one-half of the patients. We also detected greater amounts of IL-2 and IFN-gamma mRNA in ReA than were detected in RA. However, we rarely detected IL-4 or IL-13 mRNA. Similar cytokine profiles were observed in undifferentiated oligoarthropathy. The amounts of cytokine mRNAs, except for IL-10, in specimens from the patients taking prednisone or second-line antirheumatic drugs tended to be less than in specimens from the patients taking neither prednisone nor second-line antirheumatic drugs. These results suggest that cytokine mRNA profiles in patients with RA, ReA, and undifferentiated arthritis in their early stages are skewed toward proinflammatory macrophage-derived and type 1 cytokines. IL-10--not IL-4 or IL-13--mRNA appears to be the major antiinflammatory cytokine mRNA. Drug therapy is associated with depressed proinflammatory and type 1 cytokine mRNA production. The differences in the expression of IL-2 and IFN-gamma mRNA between RA and ReA may reflect unique etiological or host factors associated with the early stages of these diseases.

Adult↗
PubMed1996

A simple nested RT-PCR method for quantitation of the relative amounts of multiple cytokine mRNAs in small tissue samples.

It is difficult to quantitate cytokine mRNA profiles in small human tissue specimens obtained by a needle biopsy, even using standard RT-PCR methods, because the amount of mRNA in the specimens is very small. To address this problem, we developed highly sensitive, quantitative, nested RT-PCR techniques to evaluate the expression of multiple cytokine mRNAs in synovial specimens obtained by needle biopsy. To reduce effects of variation of initial RNA concentrations, cDNA from each target RNA sample was normalized, using a simplified competitive PCR method, to the levels of beta-actin cDNA. The first and the second (nested) PCR were performed in the same tube to prevent contamination. The number of PCR-product bands, evident on polyacrylamide gel electrophoresis, was used to quantitate the relative amounts of target cDNA. Using our methods, it was possible to evaluate, in a single synovial tissue specimen obtained by needle biopsy, the relative amounts of mRNAs for 10 cytokines (TNF-alpha, IL-1 beta, IL-2, IL-4, IL-6, IL-10, IL-12 p40, IL-13, IL-15, IFN-gamma) and CD3 delta chain. Our methods are particularly valuable if there are multiple target mRNAs, numerous samples, or if the amounts of mRNAs are limited. The methods are applicable to a wide variety of tissues and target mRNAs.

Arthritis, Rheumatoid↗
PubMed1996

The epimorphin gene is highly conserved among humans, mice, and rats and maps to human chromosome 7, mouse chromosome 5, and rat chromosome 12.

A genomic DNA fragment containing the rat epimorphin gene sequence was cloned from a rat DNA cosmid library using a mouse epimorphin cDNA probe. Within the cosmid insert, nine epimorphin exons were identified and sequenced. The predicted amino acid sequence of the rat epimorphin protein exhibited 96 and 86% identity with the mouse and human epimorphin proteins, respectively. Consistent with the developmentally related expression pattern of the mouse epimorphin gene, transcripts of the rat epimorphin gene were detected in 17-day postfertilization rat embryos. The gene, designated Epim, was assigned to rat chromosome 12 by somatic cell hybrid analysis and localized to 12q16 by fluorescence in situ hybridization. The mouse and human homologs of this gene were localized on mouse chromosome 5 and human chromosome 7 by linkage analysis and chromosomal in situ hybridization, respectively.

Amino Acid Sequence↗
PubMed1996

Genetic susceptibility to experimental autoimmune uveoretinitis in the rat is associated with an elevated Th1 response.

This study examines whether genetic susceptibility vs genetic resistance to experimental autoimmune uveoretinitis (EAU) are connected to a predisposition to mount a Th1-dominated (IFN-gamma high, IL-4 low) vs a Th2-dominated (IL-4 high, lFN-gamma low) response. Lewis rats developed disease with high incidence after immunization with the uveitogenic peptide R16, whereas F344 rats were resistant. Primed lymph node cells from both strains proliferated in culture in response to R16. However, while the Lewis cultures transferred EAU to syngeneic recipients, those of F344 did not. The Lewis cultures produced substantially more IFN-gamma mRNA and protein in response to R16, than did those of F344. Both strains made low levels of IL-10 mRNA and IL-4 mRNA. Unlike the primary cultures, long-term (R16-specific) T cell lines derived from each of the strains transferred EAU equally well to their respective recipients, and produced similar, high levels of IFN-gamma mRNA and protein. Treatment of F344 with Bordetella pertussis toxin concurrently with immunization abrogated its resistance, enhanced Ag-specific IFN-gamma production in culture, and yielded a primed cell population capable of transferring EAU. Conversely, immunization of Lewis rats with R16 in IFA induced little or no disease; the primed cells produced minimal amounts of IFN-gamma and did not transfer EAU. However, addition of IL-12 into the culture resulted in a highly pathogenic, IFN-gamma-producing cell population. We conclude that genetic susceptibility to ocular autoimmunity in this model is connected to an elevated Th1 response. Genetic resistance, however, does not seem to involve an elevated Th2 response, but rather an inhibited development of Th1-like effector cells.

Amino Acid Sequence↗
PubMed1996

A simplified, competitive RT-PCR method for measuring rat IFN-gamma mRNA expression.

We describe an adaptation of competitive RT-PCR to quantitate rat IFN-gamma mRNA expression. An IFN-gamma DNA mimic that shared the same primers and had an identical sequence to the target mRNA except for deletion of 66 nucleotides was created by a simple PCR amplification from target cDNA. To reduce variations of initial RNA concentrations, beta-actin cDNAs from each target RNA sample were normalized using the densitometric data. A known amount of pretitrated DNA competitor was then used to analyze the relative levels of target cDNA in different samples by PCR co-amplification. The amplification efficiency for both target and competitor remained constant throughout the PCR reaction, and the ratio of target to competitor PCR product remained proportional to the initial ratio of target to competitor. Relative mRNA levels among samples determined by this method were comparable to levels determined by northern blot analysis. They were also comparable to levels of IFN-gamma protein estimated by ELISA. We conclude that this method can be used to estimate the relative abundance of the target mRNA. This method is adaptable to quantitation of other cytokines and is particularly valuable if there are numerous samples or if the amount of initial mRNA is limited.

Animals↗