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Biomedical subjects

Rhonda R Voskuhl

Publications and source records attributed to Rhonda R Voskuhl.

15 recordsLinked to original sources

A female preponderance for chemically induced lupus in SJL/J mice.

Both spontaneous and chemically induced rodent models of autoimmune nephritis and autoantibody production have been explored to understand mechanisms involved in human systemic lupus erythematosus (SLE). While it has been known for decades that women are more susceptible than men to SLE, mechanisms underlying this female preponderance remain unclear. One chemically induced model involves injection of hydrocarbon oils such as pristane into otherwise normal mouse strains, which results in the development of autoantibodies and inflammation in organs such as kidney and liver. It is unknown whether lupus-like disease induced by chemicals would exhibit a sex bias in disease susceptibility. Here, we show that SJL/J female mice injected with pristane display greater mortality, kidney disease, serum anti-nuclear and anti-dsDNA antibodies than their male siblings. This is the first evidence that a female sex bias exists in a chemically induced lupus model.

Animals↗

Cerebellar cortical atrophy in experimental autoimmune encephalomyelitis.

Brain atrophy measured by MRI is an important correlate with clinical disability and disease duration in multiple sclerosis (MS). Unfortunately, neuropathologic mechanisms which lead to this grey matter atrophy remain unknown. The objective of this study was to determine whether brain atrophy occurs in the mouse model, experimental autoimmune encephalomyelitis (EAE). Postmortem high-resolution T2-weighted magnetic resonance microscopy (MRM) images from 32 mouse brains (21 EAE and 11 control) were collected. A minimum deformation atlas was constructed and a deformable atlas approach was used to quantify volumetric changes in neuroanatomical structures. A significant decrease in the mean cerebellar cortex volume in mice with late EAE (48-56 days after disease induction) as compared to normal strain, gender, and age-matched controls was observed. There was a direct correlation between cerebellar cortical atrophy and disease duration. At an early time point in disease, 15 days after disease induction, cerebellar white matter lesions were detected by both histology and MRM. These data demonstrate that myelin-specific autoimmune responses can lead to grey matter atrophy in an otherwise normal CNS. The model described herein can now be used to investigate neuropathologic mechanisms that lead to the development of gray matter atrophy in this setting.

Animals↗

Treatment with an estrogen receptor alpha ligand is neuroprotective in experimental autoimmune encephalomyelitis.

Multiple sclerosis is an inflammatory, neurodegenerative disease for which experimental autoimmune encephalomyelitis (EAE) is a model. Treatments with estrogens have been shown to decrease the severity of EAE through anti-inflammatory mechanisms. Here we investigated whether treatment with an estrogen receptor alpha (ERalpha) ligand could recapitulate the estrogen-mediated protection in clinical EAE. We then went on to examine both anti-inflammatory and neuroprotective mechanisms. EAE was induced in wild-type, ERalpha-, or ERbeta-deficient mice, and each was treated with the highly selective ERalpha agonist, propyl pyrazole triol, to determine the effect on clinical outcomes, as well as on inflammatory and neurodegenerative changes. ERalpha ligand treatment ameliorated clinical disease in both wild-type and ERbeta knock-out mice, but not in ERalpha knock-out mice, thereby demonstrating that the ERalpha ligand maintained ERalpha selectivity in vivo during disease. ERalpha ligand treatment also induced favorable changes in autoantigen-specific cytokine production in the peripheral immune system [decreased TNFalpha, interferon-gamma, and interleukin-6, with increased interleukin-5] and decreased CNS white matter inflammation and demyelination. Interestingly, decreased neuronal staining [NeuN+ (neuronal-specific nuclear protein)/beta3-tubulin+/Nissl], accompanied by increased immunolabeling of microglial/monocyte (Mac 3+) cells surrounding these abnormal neurons, was observed in gray matter of spinal cords of EAE mice at the earliest stage of clinical disease, 1-2 d after the onset of clinical signs. Treatment with either estradiol or the ERalpha ligand significantly reduced this gray matter pathology. In conclusion, treatment with an ERalpha ligand is highly selective in vivo, mediating both anti-inflammatory and neuroprotective effects in EAE.

Analysis of Variance↗

Testosterone replacement therapy for the treatment of neurological and neuropsychiatric disorders.

There is an accumulating body of evidence in the literature suggesting that testosterone may be neuroprotective and therefore have therapeutic value in the treatment of neurodegenerative diseases. In this article, the potential mechanisms of action of testosterone on the central nervous system are discussed, as well as the current evidence supporting the effect of testosterone on neurological impairment. Lower endogenous testosterone levels appear to be associated with some neurological disabilities. Conversely, a therapeutic benefit of exogenous testosterone supplementation on some cognitive abilities has been shown in pilot trials involving healthy elderly men as well as patients with multiple sclerosis and Alzheimer's disease. Further study of the therapeutic potential of testosterone is warranted in neurological and neuropsychiatric diseases.

Aged↗

A yin-yang effect between sex chromosome complement and sex hormones on the immune response.

Sex chromosome complement, by determining whether an ovary or testis develops, exerts indirect hormone-mediated effects on the development of sex-specific traits. However, this does not preclude more direct effects that are independent of gonadal hormones. To look for gonadal hormone-independent effects in sexually dimorphic immune responses, we used mice in which the testis determinant Sry has been moved from the Y chromosome to an autosome, thus allowing the production of mice that differ in sex chromosome complement while having the same gonadal type. This model permits comparison of XX and XY mice with ovaries or testes. These mice were immunized with an autoantigen, and draining lymph node cells were assessed for autoantigen-specific proliferative responses and cytokine production. Surprisingly, we found that the male complement of sex chromosomes (XY) was relatively stimulatory, whereas male sex hormones were inhibitory, for this immune response. This is the first experimental evidence of a compensatory yin-yang effect of sex chromosome complement and sex hormones on a biologic process.

Animals↗

Method to detect functional estrogen receptor expression using estrogen receptor probing compound.

A novel method to detect functional estrogen receptor expression with estrogen receptor probing compound (ERPC) has been established. ERPC is composed of estradiol-BSA-biotin. ERPC can be used to detect functional estrogen receptor expression in both Western blot and immunohistochemistry. ERPC based techniques are non-radioactive, sensitive, relatively inexpensive, and can be used with all species. The use of both ERPC and ERalpha- or ERbeta-specific antibodies provides complementary information in characterizing estrogen receptors' expression and functional binding to ligand.

Blotting, Western↗

Dysregulation of IL-10 and IL-12p40 in secondary progressive multiple sclerosis.

Multiple sclerosis (MS) is a putative T helper 1 (Th-1) mediated inflammatory disorder of the central nervous system, and levels of pro-inflammatory and anti-inflammatory cytokines have been found to correlate with changes in MS relapses. However, it is unclear if cytokine profiles differ between relapsing-remitting (RRMS) versus secondary progressive (SPMS) disease stages. Cytokine production (IL-2, IL-4, IL-5, IL-10, IL-12p40, TNF-alpha, and IFN-gamma) was assessed by cytometric bead array (CBA) and intracellular cytokine staining from alphaCD3 antibody and mitogen stimulated peripheral blood mononuclear cells (PBMCs) from female RRMS and SPMS patients, and healthy controls. Significantly increased production of IL-12p40 and decreased production of IL-10 were observed in SPMS patients. Differences in immune responsiveness in RRMS and SPMS are important in the understanding of the evolution of the immunopathogenesis of the disease and for the development of disease type specific treatments.

Adult↗

Androgens are protective in experimental autoimmune encephalomyelitis: implications for multiple sclerosis.

A gender difference prevails in some murine strains of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). Our results showed that castration of SJL males, a strain characterized by decreased susceptibility of males as compared to females, displayed increased disease severity. In contrast, castration had no effect on disease in C57BL/6 males, a strain in which no gender difference in EAE is observed. Regardless of whether endogenous androgens were protective in a given genetic background, supplemental androgen treatment was protective in gonadally intact males of both strains. These data provide a basis for the novel therapeutic use of supplemental testosterone for men with MS.

Androgens↗

Estriol treatment ameliorates disease in males with experimental autoimmune encephalomyelitis: implications for multiple sclerosis.

Estrogen treatment has been found to be protective in experimental autoimmune encephalomyelitis (EAE) and possibly multiple sclerosis (MS). We investigated whether the effect of estrogen treatment is gender-specific. Estrogen receptor (ER) expressions, ERalpha and ERbeta, were found to be equivalent in both genders. EAE disease severity in both females and males was decreased with estriol treatment as compared to placebo. Finally, proinflammatory cytokine production during autoantigen-specific immune responses was decreased with estriol treatment in both females and males. These data support a potential role for estriol treatment for men in addition to women with MS.

Analysis of Variance↗

Estrogen receptor alpha mediates estrogen's immune protection in autoimmune disease.

Estrogens are known to influence a variety of autoimmune diseases, but it is not known whether their actions are mediated through classic estrogen receptor alpha (ERalpha). The presence of a functional ER was demonstrated in secondary lymphoid tissues, then ERalpha expression was shown at both the RNA and protein levels in these tissues. Use of ERalpha knockout mice revealed that both the estrogen-induced disease protection and the estrogen-induced reduction in proinflammatory cytokines were dependent upon ERalpha in the prototypic Th1-mediated autoimmune disease experimental autoimmune encephalomyelitis. These findings are central to the design of selective ER modifiers which aim to target biologic responses in specific organ systems.

Adjuvants, Immunologic↗

Immune modulation in multiple sclerosis patients treated with the pregnancy hormone estriol.

The protective effect of pregnancy on putative Th1-mediated autoimmune diseases, such as multiple sclerosis and rheumatoid arthritis, is associated with a Th1 to Th2 immune shift during pregnancy. The hormone estriol increases during pregnancy and has been shown to ameliorate experimental autoimmune encephalomyelitis and collagen-induced arthritis. In addition, estrogens induce cytokine changes consistent with a Th1 to Th2 shift when administered in vitro to human immune cells and in vivo to mice. In a pilot trial, oral estriol treatment of relapsing remitting multiple sclerosis patients caused significant decreases in enhancing lesions on brain magnetic resonance imaging. Here, the immunomodulatory effects of oral estriol therapy were assessed. PBMCs collected longitudinally during the trial were stimulated with mitogens, recall Ags, and glatiramer acetate. Cytokine profiles of stimulated PBMCs were determined by intracellular cytokine staining (IL-5, IL-10, IL-12 p40, TNF-alpha, and IFN-gamma) and cytometric bead array (IL-2, IL-4, IL-5, IL-10, TNF-alpha, and IFN-gamma). Significantly increased levels of IL-5 and IL-10 and decreased TNF-alpha were observed in stimulated PBMC isolated during estriol treatment. These changes in cytokines correlated with reductions of enhancing lesions on magnetic resonance imaging in relapsing remitting multiple sclerosis. The increase in IL-5 was primarily due to an increase in CD4(+) and CD8(+) T cells, the increase in IL-10 was primarily due to an increase in CD64(+) monocytes/macrophages with some effect in T cells, while the decrease in TNF-alpha was primarily due to a decrease in CD8(+) T cells. Further study of oral estriol therapy is warranted in Th1-mediated autoimmune diseases with known improvement during pregnancy.

Adjuvants, Immunologic↗

Experimental autoimmune encephalomyelitis relapses are reduced in heterozygous golli MBP knockout mice.

Increased golli MBP (golli) expression has been observed in the peripheral immune system of mice in the relapsing phase of EAE, raising the possibility that golli MBP expression in the periphery may contribute to relapses. Here we describe the generation of golli MBP-deficient mice and a comparison of the clinical course of EAE between heterozygous (golli(+/-)) and wild-type (golli(+/+)) mice. There was no difference between the two groups in incidence of disease, severity of the first episode of disease, or remission after the first episode. However, there was a significant reduction in relapses in golli(+/-) mice vs. controls, suggesting a role for golli proteins in the relapses in EAE.

Animals↗

Comparison of multiple sclerosis lesions at 1.5 and 3.0 Tesla.

OBJECTIVE: To evaluate the relative sensitivity of MR scanning for multiple sclerosis (MS) at 1.5 Tesla (T) and 3.0 T using identical acquisition conditions, as is typical of multicenter clinical trials. METHODS: Twenty-five subjects with MS were scanned at 1.5 T and 3.0 T using fast spin echo, and T(1)-weighted SPGR with and without gadolinium contrast injections. Image data, blinded to field strength, were analyzed using automated segmentation and lesion counting. RESULTS: Relative to scanning at 1.5 T, the 3.0 T scans showed a 21% increase in the number of detected contrast enhancing lesions, a 30% increase in enhancing lesion volume and a 10% increase in total lesion volume. DISCUSSION: The improved detection ability using high-field MR imaging is prominent even when sequence parameters are optimized around the midfield units. Multicenter trials using both 1.5 T and 3.0 T instruments may be affected by these sensitivity differences.

Adolescent↗

Treatment of multiple sclerosis with the pregnancy hormone estriol.

Multiple sclerosis patients who become pregnant experience a significant decrease in relapses that may be mediated by a shift in immune responses from T helper 1 to T helper 2. Animal models of multiple sclerosis have shown that the pregnancy hormone, estriol, can ameliorate disease and can cause an immune shift. We treated nonpregnant female multiple sclerosis patients with the pregnancy hormone estriol in an attempt to recapitulate the beneficial effect of pregnancy. As compared with pretreatment baseline, relapsing remitting patients treated with oral estriol (8 mg/day) demonstrated significant decreases in delayed type hypersensitivity responses to tetanus, interferon-gamma levels in peripheral blood mononuclear cells, and gadolinium enhancing lesion numbers and volumes on monthly cerebral magnetic resonance images. When estriol treatment was stopped, enhancing lesions increased to pretreatment levels. When estriol treatment was reinstituted, enhancing lesions again were significantly decreased. Based on these results, a larger, placebo-controlled trial of estriol is warranted in women with relapsing remitting multiple sclerosis. This novel treatment strategy of using pregnancy doses of estriol in multiple sclerosis has relevance to other autoimmune diseases that also improve during pregnancy.

Adolescent↗

Gender issues and multiple sclerosis.

Gender-related issues in multiple sclerosis include the important and widely accepted clinical observations that men are less susceptible to the disease than women and also that disease activity in multiple sclerosis is decreased during late pregnancy. This article reviews mechanisms underlying each of these clinical observations and discusses the role of sex hormones in each. Specifically, the protective role of testosterone in young men and the protective role of the pregnancy hormone estriol in pregnant women are discussed. Rationale for novel therapies in multiple sclerosis based on the protective roles of these sex hormones is presented.

Animals↗