Jef Raus

Quadriceps and Grip Strength Are Related to Vitamin D Receptor Genotype in Elderly Nonobese Women

Osteoporotic fragility fractures are related to bone density and injury, which are both related to muscle strength. The influence of genetic factors, such as the vitamin D receptor (VDR) polymorphism on bone mineral density (BMD), is documented but still controversial, and is not known for muscle strength. In the present study, we investigated the association between the VDR BsmI polymorphism and BMD (femoral neck [FN], lumbar spine [LS], and proximal forearm [FA]) and muscle strength (quadriceps and grip strength) in 501 healthy women older than 70 years. No association was found between the VDR genotypes and BMD in elderly women. However, in nonobese women (body mass index <30 kg/cm2), the BMD in the FN was 5% higher in women with the bb BsmI genotype than in women with the BB genotype (p < 0.05). After correction for muscle strength, no association was found. A significant association between the VDR genotypes and quadriceps and grip strength was observed. In nonobese women, a 23% difference in quadriceps strength (p < 0.01) and 7% in grip strength (NS) was observed between the bb and BB genotype of the VDR. After correction for confounding factors and BMD, this association was significant for quadriceps and grip strength. These results indicate a major association of an allelic variant at the VDR locus with muscle strength in elderly nonobese women, which could explain a small association between VDR polymorphism with BMD in the femoral neck in nonobese women. No such associations were found in obese women, suggesting that factors related to obesity obscure such an association.

Secondary progressive in contrast to relapsing-remitting multiple sclerosis patients show a normal CD4+CD25+ regulatory T-cell function and FOXP3 expression

Accumulating evidence indicates an immunosuppressive role for CD4+CD25+ regulatory T cells (Tregs) in autoimmune diseases. Although an impaired Treg function in patients with relapsing‐remitting multiple sclerosis (RR‐MS) has been reported recently, no information is available so far about Treg function in the progressive stage of the disease. In the present study, the phenotypic and functional characteristics of CD4+CD25+ T cells isolated from the peripheral blood of patients with RR‐MS and secondary progressive multiple sclerosis (SP‐MS) were investigated. No significant quantitative or phenotypic abnormalities in CD4+CD25+ T cells from RR‐ and SP‐MS patients were detected. However, whereas a reduced suppressor function of CD4+CD25+ T cells toward proliferation and interferon‐γ production of CD4+CD25– responder T cells was found in RR‐MS patients, SP‐MS patients showed a normal Treg function. The suppressive capacity of MS‐derived CD4+CD25+ T cells was correlated with disease duration but not with age, indicating that Treg function is more affected in the early phase of the disease process. Consistently with the suppressive capacity, CD4+CD25+ T cells from SP‐MS patients showed normal levels of FOXP3 mRNA in contrast to RR‐MS patients that had a reduced FOXP3 expression. These data are the first to demonstrate differences in function and FOXP3 expression of CD4+CD25+ T cells from patients with RR‐ and SP‐MS.

T-cell reactivity to multiple myelin antigens in multiple sclerosis patients and healthy controls

Myelin proteins, including myelin basic protein (MBP), proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein (MOG) are candidate autoantigens in MS. It is not clear whether MS patients show a predominant reactivity to one or several myelin antigens. We evaluated the IFN‐γ production induced by MBP and MOG and selected MBP‐, MOG‐ and PLP‐peptides in MS patients and healthy controls using the IFN‐γ ELISPOT assay. Most MS patients and healthy controls showed a heterogeneous anti‐myelin T‐cell reactivity. Interestingly in MS patients a positive correlation was found between the anti‐MOG and anti‐MBP T‐cell responses. No myelin peptide was preferentially recognized among the peptides tested (MBP 84–102, 143–168, MOG 1–22, 34–56, 64–86, 74–96, PLP 41–58, 184–199, 190–209). In addition the frequency of IL2R+ MBP reactive T‐cells was significantly increased in blood of MS patients as compared with healthy subjects, indicating that MBP reactive T‐cells exist in an in vivo activated state in MS patients. Most of the anti‐MBP T‐cells were of the Th1‐type because reactivity was observed in IFN‐γ but not in IL‐4 ELISPOT‐assays. Using Th1 (IL‐12) and Th2 (IL‐4) promoting conditions we observed that the cytokine secretion pattern of anti‐MBP T‐cells still is susceptible to alteration. Our data further indicate that precursor frequency analysis of myelin reactive T‐cells by proliferation‐based assays may underestimate the true frequency of myelin specific T‐cells significantly. J. Neurosci. Res. 63:290–302, 2001.

Disturbances in acute phase plasma proteins during melancholia: Additional evidence for the presence of an inflammatory process during that illness

1. Leukocyte enumeration through flow cytometry has revealed that severe depression may be accompanied by a systemic immune activation, indicative of an inflammatory response. The latter condition allegedly involves an important modification of acute phase plasma protein (APP) equilibrium. 2. In order to elucidate whether the state of severe depression is represented by alterations in APPs, the authors measured: alpha 1 antitrypsin (alpha 1 AT), alpha 2 macroglobulin (alpha 2 M), haptoglobin (Hp), alpha 1 acid glycoprotein (alpha 1 S), transferrin (Tf), complement component 4 (C4) and C-reactive protein (CRP). Interleukin-1-beta (II-1 beta) and interleukin-6 (II-6) circulating levels were determined. 3. Hyperhaptoglobinemia and hypotransferrinemia are hallmarks for major depression and depression per se, respectively. The disorders in Hp and Tf circulating levels are highly sensitive to (83%) and specific for (100%) melancholia as opposed to the healthy state. 4. Disorders in both APPs are significantly related to the absolute number of blood monocytes. 5. The authors observed a trend towards lower alpha 2M and higher alpha 1S values in severely depressed subjects. Severity of depression was significantly related to Hp and alpha 1S (both positively) and to alpha 2M and Tf (both negatively) values. 6. No significant intercategory differences in C4 could be established, whilst only a few subjects exhibited measurable CRP, II-1 beta and II-6 circulating levels. 7. Our findings may support the hypothesis that depression is accompanied by an inflammatory response.

Influence of the Vitamin D Receptor Gene Alleles on Bone Mineral Density in Postmenopausal and Osteoporotic Women

It is well established that genetic factors contribute to bone turnover and bone density. Evidence exists suggesting that a major part of this genetic influence may be due to polymorphisms in the vitamin D receptor (VDR) gene. However, it is not clear whether the VDR genotype effect persists in elderly women. In the present study, the relationship between the BsmI, ApaI, and TaqI polymorphisms in the VDR gene, and the bone mineral density (BMD) at the lumbar spine, the femoral neck (FN), and the proximal radius was investigated in a large group of elderly women (75.5 ± 5.0 years) of Caucasian origin and in 84 Type I osteoporotic women (66.6 ± 8.4 years). We did not find a correlation between the VDR genotypes and BMD in elderly women. However, a significantly higher FN‐BMD was observed in obese (body mass index [BMI] > 30 kg/m2) versus nonobese (BMI < 30 kg/m2) women (p < 0.01). This relationship was observed for all BsmI genotypes. Furthermore, the FN‐BMD of nonobese women with bb BsmI genotype was 5% higher than that of women with the BB genotype (p = 0.04). We conclude that the VDR gene polymorphisms influence the FN‐BMD in nonobese postmenopausal women. In a second part of the study, possible correlations between the VDR gene polymorphisms and osteoporosis Type I were analyzed. Our data could not reveal any association between these parameters.

Cytokine-induced cell death in human oligodendroglial cell lines: I. Synergistic effects of IFN-γ and TNF-α on apoptosis

Multiple sclerosis is a chronic inflammatory disease of the central nervous system. Myelin and oligodendrocytes are considered the major targets of injury caused by a cell‐mediated immune response. There is circumstantial evidence that proinflammatory cytokines like tumor necrosis factor α (TNF‐α) and interferon γ (IFN‐γ) could have disease‐promoting roles in multiple sclerosis (MS). In the present study, the cytotoxic effects of IFN‐γ and TNF‐α on the human oligodendroglial cell lines human oligodendroglioma (HOG) and MO3.13 were analyzed. When the oligodendroglial cell lines were cultured in the presence of IFN‐γ or TNF‐α, apoptotic cell death was observed in both cell lines after >24 hr incubation. Apoptosis was evidenced by a decrease in cell viability, apoptotic changes in cell and nucleus morphology, and disruption of the membrane asymmetry. Our data show that TNF‐α and IFN‐γ induce apoptosis in a dose‐dependent fashion in both oligodendroglial cell lines and that their synergistic effect results in enhanced cell death. Understanding the regulation of cell death pathways in oligodendrocytes is critical for protecting myelin‐producing cells and their associated axons during injury in patients with MS.

Insights into the immunopathogenesis of multiple sclerosis

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). Significant progress has been made in our understanding of the etiology of MS. MS is widely believed to be an autoimmune disease that results from aberrant immune responses to CNS antigens. T cells are considered to be crucial in orchestrating an immunopathological cascade that results in damage to the myelin sheath. This review summarizes the currently available data supporting the idea that myelin reactive T cells are actively involved in the immunopathogenesis of MS. Some of the therapeutic strategies for MS are discussed with a focus on immunotherapies that aim to specifically target the myelin reactive T cells.

Characterization of three human oligodendroglial cell lines as a model to study oligodendrocyte injury: morphology and oligodendrocyte-specific gene expression.

Oligodendrocytes, the myelin-forming cells of the central nervous system, are the target of pathogenic immune responses in multiple sclerosis. Primary cultures of human oligodendrocytes have been used to unravel the cellular and molecular mechanisms of immune-mediated injury of oligodendrocytes. However, these studies are hampered by the limited availability of viable human brain tissue. The present study was aimed at comparing the morphological and biochemical characteristics of the human oligodendroglial cell lines HOG, MO3.13 and KG-1C. We have determined oligodendrocyte-associated features of these lines and analyzed the degree to which they can be used as a model of human oligodendrocytes arrested at specific developmental stages. The oligodendroglial cell lines all exhibited markers of immature oligodendrocytes, such as CNPase and GalC, but not the astrocytic marker GFAP. Differentiation could be induced in HOG and MO3.13 cells, as was seen through a decrease in proliferation, an increase in process extension without formation of myelin sheets and up-regulation of genes associated with mature oligodendrocytes such as MBP and MOG. Microarray analysis revealed the expression of MAG, MOBP and OMG genes in HOG cells. The KG-1C cells displayed poor growth characteristics in the recommended conditions. In conclusion, our data show that the oligodendroglial cell lines HOG and MO3.13 can be used as a model of human oligodendrocytes ‘arrested’ in an immature developmental stage. Culturing in appropriate medium can induce further differentiation of these cells. These cell lines can therefore be applied as a model to study immune-mediated injury of oligodendrocytes in relation to disease.

Premature immunosenescence in rheumatoid arthritis and multiple sclerosis patients.

Abstract: Patients with T‐cell‐mediated autoimmune diseases show immune system abnormalities that resemble the typical characteristics of autoimmune dysfunction described in the elderly. In addition, the incidence of autoimmune disease increases with advancing age. To evaluate whether patients with rheumatoid arthritis (RA) and multiple sclerosis (MS) have premature immuno‐senescence, we measured two indicators of aging: the number of T‐cell‐receptor excision circles (TRECs) and the percentage of CD4+CD28null T cells. We studied them in the peripheral blood mononuclear cells (PBMCs) of 60 RA patients, 32 MS patients, and 40 healthy controls (HCs). We found that TREC numbers were lower in RA and MS patients than in age‐matched HCs, indicating premature thymic involution. Moreover, a subset of these patients contained age‐inappropriate high frequencies of CD4+CD28null T cells. This study provides evidence of premature immune system senescence in both RA and MS patients. Premature aging could be a risk factor for developing autoimmune disorders in genetically predisposed individuals in a susceptible environment.

A further exploration of the relationships between immune parameters and the hpa-axis activity in depressed-patients

In order to investigate the relationship between the immune apparatus and the hypothalamic-pituitary-adrenal (HPA)-axis activity in depressed patients, we measured in vitro lymphocyte responses to the mitogens Phytohaemagglutinin (PHA), Pokeweed (PWM) and Concanavalin A (Con A) and 8 a.m. baseline cortisol values in plasma, free cortisol excretion in 24 h urine (UFC), basal and post-dexamethasone beta-endorphin values. Major depressed patients with melancholia/psychotic features exhibited a significantly lower mitogen-induced blast transformation as compared to minor and simple major depressed patients. The lymphocyte responses to the three mitogens were significantly inversely related to baseline cortisol values and postdexamethasone beta-endorphin values. The proliferative capacity of lymphocytes to stimulation with PHA and PWM was significantly and positively related to UFC excretion. Up to 45% of the variance in the immune-responses to the mitogens was explained by the baseline cortisol, post-dexamethasone beta-endorphin and UFC values.