The protective effect of IFN-gamma in experimental autoimmune diseases: a central role of mycobacterial adjuvant-induced myelopoiesis.
(1/23)
The study of animal models for organ-specific autoimmune disease contributes to our understanding of human diseases such as multiple sclerosis and rheumatoid arthritis. Although experimental autoimmune diseases develop spontaneously in certain strains of mice, others need to be induced by administration of organ-specific autoantigen, often together with complete Freund's adjuvant (CFA), containing heat-killed mycobacteria. In the two types of models, the role of endogenous interferon-gamma (IFN-gamma) has extensively been investigated by using neutralizing anti-IFN-gamma antibodies and by employing mice genetically deficient in IFN-gamma or its receptor. In these studies disease-promoting as well as disease-protective roles of endogenous IFN-gamma have been described. Remarkably, in most models that rely on the use of CFA, there is abundant evidence for a protective role. Here, we review evidence that this role derives from an inhibitory effect of IFN-gamma on myelopoiesis elicited by the killed mycobacteria. These findings explain the bimodal role of IFN-gamma in different models of autoimmune disease and raise questions regarding the clinical relevance of these models. (+info)
Identification of Th2-type suppressor T cells among in vivo expanded ocular T cells in mice with experimental autoimmune uveoretinitis.
(2/23)
Experimental autoimmune uveoretinitis (EAU), which is a T cell mediated organ specific autoimmune disease, is induced by immunization with interphotoreceptor retinoid binding protein (IRBP) in susceptible strains of mice. It has been found that IRBP-derived peptide 518-529 (p518-529) generates Th2-type responses and inhibits IRBP-induced EAU, indicating that the p518-529 might be an epitope for suppressor T cells in IRBP-induced EAU. First, we observed that there were T cells producing the Th2 type cytokines such as IL-4 and IL-10 in late phase of EAU. Furthermore, to examine whether p518-529-reactive T cells expand in the eye during EAU, T cell receptor (TCR) of ocular T cells was compared with that of p518-529 reactive T cells in spleen from mice with EAU by PCR-single strand conformation polymorphism (PCR-SSCP) and nucleotide sequence analysis. SSCP and sequence analyses indicated that p518-529 reactive TCR BV10+ T cells bearing amino acid motif(PWG) and TCR BV13+ T cells bearing amino acid motif(PGLGGY) in their complementary-determining region 3 (CDR3) region were clonally expanding in ocular tissues on day 28 after immunization, although these T cells were not detected on day 14. These findings demonstrate that p518-529 reactive Th2-type T cells expand oligoclonally in the uveitic eyes in the late stage of EAU and may function as Th2-type suppressor T cells for improvement of the disease. (+info)
Intravenous immunoglobulin prevents experimental autoimmune myositis in SJL mice by reducing anti-myosin antibody and by blocking complement deposition.
(3/23)
High-dose intravenous immunoglobulin (IVIG) therapy has been effective in many autoimmune and systemic inflammatory diseases including polymyositis (PM) and dermatomyositis (DM). In the present study we evaluated the efficacy of IVIG using experimental models of PM and DM. An experimental autoimmune myositis (EAM) model was produced in SJL/J mice by an immunization with rabbit myosin B (MB) fraction. In this model, the plasma level of anti-MB antibody was elevated, and mouse IgG and complement C3 were deposited in the muscle fibres. Administration of IVIG dose-dependently reduced the incidences of necrotic and inflammatory changes in the skeletal muscle. IVIG treatment also decreased the elevation of anti-MB antibody level, as well as the deposition of IgG and C3. We next evaluated the effect of IVIG in adoptive EAM mice made by an intravenous injection of lymph node cells previously stimulated with MB. Adoptive EAM mice showed similar lesions in skeletal muscle as EAM mice and IVIG inhibited the lesion development. In vitro experiments demonstrated that IVIG inhibited complement-mediated lysis of human erythrocytes sensitized with anti-human erythrocyte antibodies. The binding of C1q, C4 and C3 to the same cells was also inhibited by IVIG. Taken together these findings suggest that IVIG prevents the development of myositis in EAM and adoptive EAM models by several mechanisms, such as reducing anti-myosin antibody and by blocking complement activation. Our present findings might account for the clinical efficacy of IVIG in PM and DM patients. (+info)
Alpha4-integrin-VCAM-1 binding mediates G protein-independent capture of encephalitogenic T cell blasts to CNS white matter microvessels.
(4/23)
Direct in vivo evidence is still lacking for alpha4-integrin-mediated T cell interaction with VCAM-1 on blood-brain barrier-endothelium in experimental autoimmune encephalomyelitis (EAE). To investigate a possible alpha4-integrin-mediated interaction of encephalitogenic T cell blasts with VCAM-1 on the blood-brain barrier white matter endothelium in vivo, we have developed a novel spinal cord window preparation that enabled us to directly visualize CNS white matter microcirculation by intravital fluorescence videomicroscopy. Our study provides the first in vivo evidence that encephalitogenic T cell blasts interact with the spinal cord white matter microvasculature without rolling and that alpha4-integrin mediates the G protein-independent capture and subsequently the G protein-dependent adhesion strengthening of T cell blasts to microvascular VCAM-1. (+info)
Development of spontaneous autoimmune peripheral polyneuropathy in B7-2-deficient NOD mice.
(5/23)
An increasing number of studies have documented the central role of T cell costimulation in autoimmunity. Here we show that the autoimmune diabetes-prone nonobese diabetic (NOD) mouse strain, deficient in B7-2 costimulation, is protected from diabetes but develops a spontaneous autoimmune peripheral polyneuropathy. All the female and one third of the male mice exhibited limb paralysis with histologic and electrophysiologic evidence of severe demyelination in the peripheral nerves beginning at 20 wk of age. No central nervous system lesions were apparent. The peripheral nerve tissue was infiltrated with dendritic cells, CD4(+), and CD8(+) T cells. Finally, CD4(+) T cells isolated from affected animals induced the disease in NOD.SCID mice. Thus, the B7-2-deficient NOD mouse constitutes the first model of a spontaneous autoimmune disease of the peripheral nervous system, which has many similarities to the human disease, chronic inflammatory demyelinating polyneuropathy (CIDP). This model demonstrates that NOD mice have "cryptic" autoimmune defects that can polarize toward the nervous tissue after the selective disruption of CD28/B7-2 costimulatory pathway. (+info)
Experimental allergic encephalomyelitis (EAE) and multiple sclerosis (MS) are characterized by strong sexual dimorphisms, many of which may be due to genetically controlled sex hormone effects on the immune system, the central nervous system (CNS), or both. In the present study we used 487 gonadectomized and 376 intact age-matched F(2) mice generated through crosses of B10.S/SgMcdJ and SJL/J mice to assess the role of adult gonadal hormones in regulating clinical and histopathological quantitative traits (QT) associated with EAE in the context of genetic heterogeneity. We found that gonadectomy resulted in different effects, depending on the QT and the sex of the mouse. Ovariectomized mice on average had lower cumulative clinical disease scores, shorter duration of clinical signs, and increased peak disease scores. This trend was accompanied by a significant increase in the incidence of acute, progressive EAE which is more frequently seen in intact and orchiectomized males. Although spinal cord (SC) inflammation was the better predictor of clinical signs of EAE in both sexes, ovariectomized females had considerable reductions in nearly all histopathological QT in both the brain and SC. Orchiectomy resulted in modestly significant increases in disease severity and peak score and earlier onset of clinical signs. With the exception of SC demyelination and lesion scores, orchiectomy had no effect on histopathological QT. Importantly, gonadectomy reduced but did not completely abolish any of the sexually dimorphic clinical QT seen in intact mice. It did however, lead to a significant sexual dimorphism in incidence and severity not seen in intact mice. For histopathological QT, no sexual dimorphism was detected for brain lesions in either intact or gonadectomized mice. In contrast, SC histopathological QT exhibited significant sexual dimorphisms, which were impacted by gonadectomy. The results from this study indicate that within the context of genetic heterogeneity, circulating gonadal hormones influence both clinical and histopathological QT in this model of MS, but they do not solely account for the sexual dimorphisms seen in these traits. Thus, additional mechanisms must play a role in regulating gender differences in autoimmune disease of the CNS. (+info)
Anti-disialoside antibodies kill perisynaptic Schwann cells and damage motor nerve terminals via membrane attack complex in a murine model of neuropathy.
(7/23)
Anti-disialoside antibodies (Abs) that bind NeuAc(alpha2-8) NeuAc epitopes on GQ1b and related gangliosides are found in human autoimmune neuropathy sera and are considered to be pathogenic. In a model system in mice, one mechanism by which anti-disialoside Abs have been demonstrated to induce paralysis is through a complement dependent blocking effect on transmitter release at the neuromuscular junction, similar to the effects of alpha-latrotoxin. Although direct targeting of presynaptic neuronal membranes occurs in this model, concomitant injury to perisynaptic Schwann cells (pSC) could indirectly contribute to this paralytic effect by influencing nerve terminal function and survival. To examine this possibility and the specific complement components that might mediate these effects, we exposed neuromuscular junctions in vivo and in vitro to an anti-disialoside Ab in conjunction with intact and selectively deficient complement sources. Using immuno-electron microscopy, we observed Ab deposits equally distributed on both neuronal and pSC membranes, and ultrastructural evidence of injury at both sites. Presynaptic neuronal injury was demonstrated functionally with microelectrode recordings and histologically as neurofilament loss. As hypothesized, concomitant pSC injury occurred, as indicated by abnormal uptake of ethidium dimer into pSC nuclei. The pSC and nerve terminal damage indicators correlated well with deposition of the pore-forming terminal complement component, membrane attack complex (MAC) in pSC and nerve terminal membranes. Furthermore, both neuronal and pSC injury were exacerbated in tissues from mice lacking the inhibitory complement regulator, CD59, where MAC formation is increased. These data demonstrate that both presynaptic neuronal membranes and pSCs are targets for anti-disialoside Abs, and that the injury to both sites is mediated by MAC and further regulated by CD59. This is the first demonstration that complement mediated pSC injury occurs in a model of autoimmune neuropathy and provides a rationale for investigating the possibility of pSC injury in equivalent conditions in man. (+info)
Blockade of the C5a receptor fails to protect against experimental autoimmune encephalomyelitis in rats.
(8/23)
Complement activation contributes to inflammation and tissue damage in human demyelinating diseases and in rodent models of demyelination. Inhibitors of complement activation ameliorate disease in the rat model antibody-dependent experimental autoimmune encephalomyelitis and rats unable to generate the membrane attack complex of complement develop inflammation without demyelination. The role of the highly active chemotactic and anaphylactic complement-derived peptide C5a in driving inflammation and pathology in rodent models of demyelination has been little explored. Here we have used a small molecule C5a receptor antagonist, AcF-[OPdChaWR], to examine the effects of C5a receptor blockade in rat models of brain inflammation and demyelination. C5a receptor antagonist therapy completely blocked neutrophil response to C5a in vivo but had no effect on clinical disease or resultant pathology in either inflammatory or demyelinating rat models. We conclude that C5a is not required for disease induction or perpetuation in these strongly complement-dependent disease models. (+info)