Expansion of autoreactive T cells in multiple sclerosis is independent of exogenous B7 costimulation

Multiple sclerosis (MS) is an inflammatory disease of the myelinated central nervous system that is postulated to be induced by myelin-reactive CD4 T cells. T cell activation requires an antigen-specific signal through the TCR and a costimulatory signal, which can be mediated by B7-1 or B7-2 engagement of CD28. To directly examine the activation state of myelin-reactive T cells in MS, the costimulation requirements necessary to activate myelin basic protein (MBP) or tetanus toxoid (TT)-reactive CD4 T cells were compared between normal controls and MS patients. Peripheral blood T cells were stimulated with Chinese hamster ovary (CHO) cells transfected either with DRB1*1501/DRA0101 chains (t-DR2) alone, or in combination with, B7-1 or B7-2. In the absence of costimulation, T cells from normal subjects stimulated with the recall antigen TT p830-843 were induced to expand and proliferate, but stimulation with MBP p85-99 did not have this effect. In marked contrast, T cells from patients with MS stimulated with MBP p85-99 in the absence of B7-1 or B7-2 signals expanded and proliferated. Thus, MBP-reactive CD4 T cells in patients with MS are costimulation independent and have been previously activated in vivo. These experiments provide further direct evidence for a role of activated MBP-specific CD4 T cells in the pathogenesis of MS.     

Identification of autoimmune T cells among in vivo expanded CD25+ T cells in multiple sclerosis

Although clonal expansion of autoimmune T cells has been reported in multiple sclerosis (MS), very limited information is available on specificities, clonal size, or activation state of the expanded clones. Here we address the issue of clonal expansion by using a novel technique demonstrating clonotypes defined by single-strand conformation polymorphism of TCR beta-chain cDNAs. Examination of activated T cells (CD3+CD25+) isolated from the peripheral blood of MS revealed limited numbers (20 approximately 82) of expanded clones defined by single-strand conformation polymorphism clonotype. To estimate the Ag specificities of dominant clonotypes in the activated T cells, these samples were examined in parallel with Th1 T cell clones specific for myelin basic protein or proteolipid protein (PLP) derived from the same patients. Analysis of two patients demonstrated that the dominant clonotypes would contain those specific for myelin basic protein or PLP. Although the majority of the clonotypes could be detected only transiently, a PLP95-116-specific clonotype was found to persist for over 1 yr. Thus, single-strand conformation polymorphism clonotype analysis allows us to monitor the kinetics of given T cell clones in vivo and could provide useful information for designing clonotype (Id)-specific manipulation of human diseases such as MS.     

Multiple sclerosis as a cause of partial complex epilepsy

INTRODUCTION: Although the epileptic seizures (ES) have been described on patients with multiple sclerosis (MS), the causal relationship is not clear. Seizure's prevalence in this illness is low and their apparition concerning the MS course is variable, but more common after MS diagnosis. The predominant crises are generalized or partial with secondary generalization; the partial complex seizures have rarely referred. CLINICAL CASES AND CONCLUSIONS: We presented two patients with ES in the MS course. In the first case is arrived to MS diagnosis upon appearing the crisis, having presented two previous cerebral lesions in another level. In both cases demyelinating lesion was located in the temporal lobe, agreeing with EEG anomaly and seizures type.     

Antigen-presenting cells (APC) of mice with chronic graft-versus-host disease (GVHD) cause excessive activation-induced death of T helper cells

Both experimental and clinical forms of chronic GVHD have unique immunological features. The affected animals/individuals suffer from autoimmune disorders such as systemic lupus erythematosus (SLE), and yet they are unable to mount a self MHC-restricted T cell response to foreign antigens. Pathogenesis of the latter phenomenon was investigated in an experimental model of chronic GVHD. Chronic GVHD was induced in 8-10-week-old (B6xC3H)F1 mice by tail vein injection of 5 x 10(7) spleen cells of C3H parental strain. The recipients, when tested 3 months later, were unable to mount a T helper (Th) cell response to a randomly selected immunogen, a vaccine of l0(8) killed Mycobacterium vaccae. The animals showed evidence of generalized lymphoid hyperplasia, as indicated by GVH index >1.34, and also revealed autoantibodies against erythrocytes and dsDNA, indicating establishment of chronic GVHD. However, mice with chronic GVHD of only 3 weeks duration were able to mount the Th cell response to M. vaccae. Three consecutive immunizations of these mice at 1-week intervals, with the same immunogen, resulted in the mice becoming non-responsive to the antigen. All the three responses tested, namely the DTH, lymphoproliferation and the antibody responses, were adversely affected. The non-responsiveness induced was antigen-specific. Mice receiving two immunizations with M. vaccae responded normally to Salmonella enteritidis. Pulse treatment with cyclosporin A 0.5 mg/mouse by the i.p. route, on days 0, 1, 2, 3 and 4 at the time of immunization with M. vaccae on day 1, prevented emergence of non-responsiveness. Based on this evidence, it was concluded that repeated activation of T cells of mice with chronic GVHD induces non-responsiveness. Extent of clonal loss due to activation-induced cell death (AICD) caused by i.p. injection with a superantigen Staphylococcal enterotoxin B (SEB) was investigated in F1 mice with chronic GVHD. I.p. injection of 25 microg/mouse of SEB induced loss of SEB responding clones in both normal F1 mice and those having chronic GVHD; however, the extent of loss was much greater in the latter. In vitro antigen-specific proliferation of primed splenic T cells of normal F1 mice was observed to be quite poor when antigen was presented by APC of mice with chronic GVHD of 3 weeks duration. Proliferation profiles of T cells of normal F1 mice, in response to stimulation with concanavalin A (Con A) or SEB, were studied, using as APC irradiated spleen cells of normal F1 mice or of F1 mice with chronic GVHD of 3 weeks duration. With Con A and APC of normal F1 mice, peak proliferation was observed at 48 h, which remained at the same level up to 72 h and declined thereafter, possibly due to AICD. With SEB and the normal APC, proliferation progressively peaked at 72 h and declined thereafter. With APC of mice with chronic GVHD, the 48 h proliferative responses of both Con A and SEB were comparable to those caused by APC of normal F1 mice; however, thereafter the responses declined steeply, suggesting greater AICD. Based on these results, it was concluded that APC of mice with chronic GVHD are functionally altered to induce greater AICD.     

Perivascular T cells express the pro-inflammatory chemokine RANTES mRNA in multiple sclerosis lesions

HIV-1 Tat is a potent transactivator that stimulates expression from the HIV-1 LTR, from certain cellular gene promoters and from several heterologous viral promoters. Previous reports show that HIV-1 Tat transactivates tumor necrosis factor-beta (TNF-beta) promoter-directed gene expression in lymphocytic and monocytic cell lines and further demonstrate that a 'TAR-like structure' downstream of the TNF-beta promoter is essential for Tat activity. The ability of Tat to activate TNF-beta may have profound effects as TNF has been shown to be a potent activator of HIV-1 gene expression and an important immunomodulatory and growth regulatory factor. The studies presented herein demonstrate a novel finding where HIV-1 Tat specifically represses (> 10-fold) TNF-beta promoter-directed gene expression in central nervous system-derived glial cells. Amino acid residues 2 to 36 of HIV-1 Tat are required for TNF-beta repression. Tat repression of TNF-beta, a factor which upregulates HIV-1 gene expression, suggests a novel mechanism whereby HIV-1 is able to establish latent infection of glial cells that present no detectable virions and/or viral antigens.     

Light chain deposition disease as a cause of renal failure

The objective of the paper is to draw attention to a rare cause of rapidly progressing renal failure which developed in the course of four months as a result of light chain deposition disease. The authors submit two case-histories of the disease assessed by renal biopsy after previous clinical and laboratory suspicion of monoclonal gammapathy. In one patient in the sternal punctate plasmacytoma was diagnosed and in the second case it was not possible to detect any type of monoclonal gammapathy or another possible cause of disease. Renal failure was in both cases irreversible and both patients were enlisted in regular haemodialyzation treatment.     

Soluble antigen therapy induces apoptosis of autoreactive T cells preferentially in the target organ rather than in the peripheral lymphoid organs

The administration of soluble myelin proteins is an effective way of down-regulating the inflammation in the central nervous system (CNS) in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. To shed more light on the mechanism of this antigen-specific therapy, we determined the effect of the intraperitoneal (i.p.) injection of soluble myelin basic protein (MBP) on Tcell apoptosis in the CNS and peripheral lymphoid organs of Lewis rats with EAE induced by inoculation with MBP and complete Freund's adjuvant. In particular we assessed the level of apoptosis of Vbeta8.2+ Tcells, which constitute the predominant encephalitogenic MBP-reactive T cell population in the Lewis rat. The daily i.p. injection of MBP for 3 days from the onset of neurological signs inhibited the further development of neurological signs of EAE. Using two-color flow cytometry we found that a single i.p. injection of MBP increased the level of apoptosis of the Vbeta8.2+ T cell population in the CNS to 26.2% compared to 7.4% in saline-treated rats and 7.6% in ovalbumin-treated rats. In contrast, treatment with MBP did not increase the level of apoptosis of the Vbeta8.2+ population in the popliteal lymph node draining the inoculation site (1.4%) or in the spleen (1.6%) above that occurring in saline-treated rats (1.6% and 1.1%, respectively). Limiting dilution analysis revealed that the frequency of T cells reactive to the major encephalitogenic epitope, MBP72-89, was decreased in the CNS but not in the popliteal lymph node by this treatment. Three-color flow cytometry in MBP-treated rats demonstrated that CNS Vbeta8.2+ T cells expressing Fas (CD95) and Fas ligand were highly vulnerable to apoptosis compared to Vbeta8.2+ Tcells not expressing these proteins. We conclude that the i.p. injection of MBP increases the spontaneously occurring Fas-mediated activation-induced apoptosis of autoreactive T cells in the CNS in EAE and that this contributes to the therapeutic effect of the injection.     

Patient attitude as a function of disease state in multiple sclerosis

The present study investigated the attitude of 243 patients with Multiple Sclerosis (MS) as a function of their perceived disease state. Data was collected via a closed-format questionnaire developed through the Fishbein and Ajzen [1-3] Theory of Reasoned Action. Results indicated clearly that patients with MS are not an homogenous group and vary in characteristics across disease states and that disease state differentially affects the psycho-social attitudes of patients. Results also indicated that persons in remission were more positive in their attitude associated with their disease state than persons with a chronic progressive form of the disease.     

CD4+CD25+ T cells inhibit both the induction and effector function of autoreactive T cells and represent a unique lineage of immunoregulatory cells

Thymectomy of susceptible strains of mice on day 3 of life results in a spectrum of organ-specific autoimmunity that can be prevented by reconstitution of the thymectomized animals early in life with normal adult lymphocytes. The effectors and suppressors of autoimmunity in this model have been convincingly shown to be CD4+ T cells. It has been demonstrated recently that the regulatory CD4+ T cells that prevent disease coexpress CD25. We have further characterized the population of CD4+CD25+ immunoregulatory cells and demonstrated that they can suppress not only the induction of disease post-thymectomy, but can also efficiently suppress disease induced by cloned autoantigen-specific effector cells. Furthermore, the CD4+CD25+ T cells appear to be members of a unique lineage of regulatory T cells, as the induction of CD25 expression on a monospecific population of T cells derived from TCR transgenic SCID mice did not result in suppression of post-thymectomy autoimmunity. In addition, the TCR transgenic SCID mice were highly susceptible to autoimmune disease induced by the cloned line of autoantigen-specific effectors, while normal mice were relatively resistant. The capacity of the cloned line to transfer disease to nu/nu recipients could be inhibited by normal spleen cell populations containing CD4+CD25+ cells and by purified CD4+CD25+ cells. Although the target Ag(s) and mechanism of action of the CD4+CD25+ T cells remain to be determined, it is likely that they also play an important role in modulating other autoimmune diseases that are mediated by activation of "ignorant" self-reactive T cells present in the normal peripheral lymphocyte pool.     

Promoting remyelination as a future therapeutic principle in multiple sclerosis?

Certain factors have been studied that might influence whether interferon-gamma (IFN-gamma) or interleukin-4 (IL-4) will predominate in cultures of peripheral blood mononuclear cells (PBMC). ELISA was used to measure cytokine protein, and PCR was used to quantitate mRNA. It was found that induction with plant lectins produced greater yields of IFN-gamma than induction with ionophores, but ionophores alone produced at least equal yields of IL-4 as did lectins. Phorbol myristate acetate (PMA) greatly enhanced IFN yields in the presence of ionophores but had no significant influence on IL-4 production. Calcium-independent cytokine induction using anti-CD28 and PMA resulted in production of both cytokines, whereas depletion of extracellular calcium and magnesium adversely influenced the yield of both IL-4 and IFN-gamma. Finally, calmidazolium, an inhibitor of calmodulin, had an enhancing effect on IFN-gamma yields when phytohemagglutinin (PHA) was the inducer and an adverse effect when A23187 was the inducer. In contrast, calmidazolium reduced IL-4 yields with both PHA and A23187 induction.     

Diastolic dysfunction as a cause of heart failure in the hypertensive patient

A study was undertaken to investigate physical work load, physical capacity, physical strain and perceived health among elderly aides in home-care service. A secondary aim was to compare the work load and strain between the two main types of home-care service available in Sweden today. Work tasks and their distribution among 20 elderly aides (aged 45-65 years), working in open home-care service (clients living in their original flats or houses) and at service apartment houses (clients living in private flats constructed for the elderly and handicapped with service functions) were observed during whole work days. Heart rate and number of steps taken were also measured continuously during the whole work day. Oxygen consumption and work postures for upper arm and back were measured during parts of the work day. The results showed that home-care work is characterised by long periods of standing and walking and that postures potentially harmful for the low back and shoulders occurred frequently. Average physiological strain measured as relative oxygen consumption and heart rate during the work day did not exceed present recommendations. Average physical work load and strain in open home-care service slightly exceeded those in service apartment houses because of more frequent cleaning and walking outdoors. Many aides in this study showed slightly reduced physical capacity, and musculoskeletal problems were common. Many elderly aides in home-care service are probably exposed at work to high risks of overexertion and impaired health as a result of high postural loads in combination with other known important factors, such as time stress and lack of equipment.     

Why diets fail--expert diet advice as a cause of diet failure.

Comments on an article titled Medicare's Search for Effective Obesity Treatments: Diets Are Not the Answer, by Mann et al (see record 2007-04834-008). The current author states that this article offers the following broad, sweeping conclusion: "The benefits of dieting are simply too small and the potential harms of dieting are too large for it to be recommended as a safe and effective treatment for obesity" (p. 230). This statement is provocative and unproven in the text. According to the laws of thermodynamics, which appear to apply everywhere in the known universe, anytime one consumes fewer Calories than one burns, there will be weight loss (Brooks, Fahey, & Baldwin, 2005, p. 22), despite the claims of some diet gurus and MDs (Cruise, 2005, p. 55; Katz, 2005). Any and every diet must work so long as a person voluntarily sustains a condition of fewer Calories in than out for a sufficient duration. Yet the article's conclusion denies this simple universal truth. This is a failing. Since the laws of thermodynamics are likely to remain operational on this planet for the foreseeable future and all episodes of fewer Calories in than out will always result in weight loss, the better approach to analyzing why diets fail is to look to expert diet advice as the primary cause. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

MR identification of white matter abnormalities in multiple sclerosis: a comparison between 1.5 T and 4 T

BACKGROUND AND PURPOSE: Although MR spectroscopy and functional MR imaging of the brain have been successful at 4 T, conventional fast spin-echo imaging of the brain at 4 T has not been adequately evaluated. The purpose of this study was to compare the detection of white matter abnormalities in multiple sclerosis (MS) at 1.5 T and 4 T. METHODS: Fifteen patients with clinically definite MS were imaged at both 1.5 T and 4 T within a 1-week period. Comparison was made between fast spin-echo long-TR images at both field strengths. Pulse sequences were tailored to maximize resolution and signal-to-noise ratio in clinically relevant imaging times (< 7 min). Four interpreters independently reviewed the images obtained at both field strengths in separate sessions and evaluated them for lesion identification, size, characterization, and subjective resolution. Differences in interpretations at 1.5 T and 4 T were subsequently recorded. RESULTS: Images obtained at 4 T showed a mean of 88 more lesions as compared with images obtained at 1.5 T. All the lesions measured less than 5 mm and were typically aligned along perivascular spaces. Twenty-five consensually identified lesions on 4-T images were not seen at all on 1.5-T images. Moreover, 4-T images showed 56 additional consensually identified lesions, which were indistinct and seen only in retrospect on 1.5-T images. These lesions were frequently (n = 48) identified in large confluent areas of white matter signal intensity abnormality at 1.5 T. All observers also agreed that 4-T images subjectively enhanced the perception of normal perivascular spaces and small perivascular lesions. CONCLUSION: MR imaging at 4 T can depict white matter abnormalities in MS patients not detectable at 1.5 T through higher resolution with comparable signal-to-noise ratio and imaging times.     

Do microbes with peptides mimicking myelin cause multiple sclerosis if the T cell response to their unique peptides is limited?

This hypothesis for the pathogenesis of multiple sclerosis is based upon assumptions about the response of the T cell repertoire to pathogens. Immunologic and epidemiologic observations of several conditions suggest that activation of T cells formed in early life mediate injury to the central nervous system. Early in life, selection of lymphocytes by the thymus produces a weakly autoreactive T cell repertoire which, with the help of transient maternally-derived defenses, recognizes pathogens. These responses later are supplemented by pathogen-specific responses, acquired as microbes are encountered. As the thymus involutes, the diversity of pathogen-specific responses to microbial epitopes is progressively fixed. Reduced and delayed pathogen exposure, common in developed societies, limits the repertoire of memory T cells, which can efficiently eliminate pathogens. Due to their small number, pathogen-specific lymphocytes which mature extrathymically may not be able to rapidly eliminate most pathogens, and without the editing of the thymus, they may be autoreactive. In this setting, novel pathogens with epitopes mimicking myelin may elicit a T cell response which is autoreactive. Peptides of common microbes are known to activate T cells recognizing dominant antigens of myelin. It is postulated that at the equator, intense, non-seasonal encounters with microbes elicit an immune repertoire that produces resistance to autoimmunity, while, in temperate climates, moderate, seasonal exposures increase susceptibility to it. The differences in responses to microbes between populations with a low or high prevalence of multiple sclerosis suggests that T cell repertoires are divergent in these groups. An exuberant innate response, postulated to diminish as the load of enteric microbes falls and sanitation improves in relation to the distance from the equator, may increase resistance to multiple sclerosis by eliminating the need for T cell activation. Human herpesvirus-6 and respiratory syncytial virus are possible prototypes of microbes which activate myelin-directed T cells.     

Apoptosis as a cause of death in measles virus-infected cells

To determine the mechanism of measles virus-induced cell death, we studied the infection of Vero cells and monocytic cell lines with wild-type (Chicago-1) and vaccine (Edmonston) strains of measles virus. DNA fragmentation indicative of apoptosis was apparent by flow cytometry, agarose gel electrophoresis, and electron microscopy. Within syncytia, DNA strand breaks were demonstrated by end labeling with terminal transferase and then by visualization.     

Mycobacterium tuberculosis exploits the CD95/CD95 ligand system of gammadelta T cells to cause apoptosis

Vgamma9/Vdelta2+ T cells specifically recognize Mycobacterium tuberculosis in vitro and are precociously recruited in early mycobacterial lesions. Even if gammadelta T cells are only fortuitously detected in granulomas or bronchoalveolar lavages of patients with active pulmonary tuberculosis, a role in shaping the mature alphabeta T cell response against M. tuberculosis is substantiated. Here we provide a molecular explanation for this paradox: the engagement of the gammadelta TCR by mycobacterial antigens induced the expression of CD95 ligand (CD95L) by chronically activated CD95+/CD95L- gammadelta T lymphocytes. The receptor was functional, as CD95/CD95L interaction triggered the bystander death of CD95+ cells by apoptosis. Cell death was abolished by CD95-blocking antibodies. The transient accumulation at the site of infection of CD95L+ gammadelta lymphocytes, capable of interacting with CD95+ leukocytes attracted by the response towards the pathogen, may determine the characteristics of the ensuing granulomatous disease.     

Dystonia as an isolated symptom of multiple sclerosis?

Sustained dystonia has seldom been reported during the course of multiple sclerosis (MS) [5-8, 10], and has been described as the first manifestation of the disease in only three cases [1,3]. We describe a patient with a diagnosis of laboratory-supported, defined MS in which sustained dystonia was the only neurological symptom.     

Insulin-like growth factor-1 acts as a chemoattractant factor for 5T2 multiple myeloma cells

The chemotactic and growth-stimulatory effect of insulin-like growth factor 1 (IGF-1) was investigated in the experimental mouse 5T2 multiple myeloma (MM) model. Chemotaxis was analyzed by classical checkerboard analysis. Bone marrow fibroblasts-conditioned medium exhibited a chemotactic effect on 5T2 MM cells that could be neutralized by adding a blocking antibody to IGF-1. On the other hand, exogenously added IGF-1 also had a chemotactic effect on the 5T2 MM cells. Moreover, in vitro analysis demonstrated that transmigrated 5T2 MM cells have a higher expression of IGF-1 receptor, both in bone marrow-conditioned medium and in IGF-1-induced chemotaxis, in comparison to cells before migration. When analyzed in vivo, 18 hours after injection of the heterogeneous 5T2 MM population, 5T2 MM cells present in the bone marrow show a higher expression of the IGF-1 receptor than their counterparts before injection. When the proliferative effect of IGF-1 was analyzed, no stimulation was observed, which is in contrast to the influence of bone marrow-conditioned medium and interleukin-6. Our results suggest a causal relationship between the presence of IGF-1 in the bone marrow and the chemotaxis of MM cells to and their subsequent presence in the bone marrow.