Autoantibodies to each protein fraction extracted from cerebral endothelial cell membrane in the sera of patients with multiple sclerosis

doi:10.1016/0165-5728(89)90096-9

Journal of Neuroimmunology

Volume 24, Issues 1–2, September 1989, Pages 41-46

https://doi.org/10.1016/0165-5728(89)90096-9 Get rights and content

Abstract

Damage to the blood-brain barrier (BBB) occurs in multiple sclerosis (MS), probably due to an immunological mechanism. Anti-endothelial cell antibodies may play a pathogenetic role in the BBB damage. Our previous studies led us to search for which protein fraction extracted from cerebral endothelial cell membrane was reactive to antibodies in the sera of patients with MS. The antibodies to each protein fraction extracted from the rat cerebral endothelial cell membrane were studied in patients with MS, other neurological diseases and controls using an enzyme-linked immunosorbent assay (ELISA) method. The patients with active relapsing MS (P < 0.01) displayed significantly higher levels of immunoglobulin G (IgG) binding to the endothelial cell membrane fraction than did the controls. The sera of the same patients (P < 0.001) also showed significantly higher levels of antibodies to fraction I (8.0 kDa) than did the normal controls. The high levels of IgG binding to fraction II (11.0 kDa) and III (12.3 kDa) were significantly increased in the sera of patients with active relapsing MS compared to normal controls (P < 0.01). The immune response to the protein fraction extracted from the cerebral endothelial cell membrane fraction may indicate a result of the BBB damage in the case of MS.

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Cited by (19)

Cell-Derived Microparticles and Exosomes in Neuroinflammatory Disorders
2007, International Review of Neurobiology
Citation Excerpt :
The neurological manifestations of APS are well‐known and have often been confused with MS (Cuadrado et al., 2000; Hughes, 1999; Ijdo et al., 1999; Karussis et al., 1998). Antiphospholipid antibodies (APLA) are frequently detected in MS (Cordoliani et al., 1998; Fukazawa et al., 1993; Marchiori et al., 1990; Scott et al., 1994; Sugiyama and Yamamoto, 1996; Tanaka et al., 1987; Tintore et al., 1996; Tsukada et al., 1989). Reported frequencies of APLA in active MS vary widely, as they do for other conditions, due to different assay methodologies, but range from approximately 30% to 60% in the studies mentioned above, and in our own studies (cited below), similar to systemic lupus erythematosus (SLE) and ITP.
All blood cells and the vascular endothelium shed microparticles (MP) from their plasma membranes when suitably stimulated, and assay of MP in patient blood has found increasing application to the monitoring of disease states. In addition, mounting evidence suggests that MP are not mere epiphenomena but play significant roles in the pathophysiology of thromboses, inflammation, and cancers.
This chapter endeavors to summarize the limited number of studies thus far done on MP in neurological disorders such as multiple sclerosis (MS), transient ischemic attacks, and the neurological manifestations of antiphospholipid syndrome (APS). In addition, the chapter offers some plausible hypotheses on possible roles of MP in the pathophsyiology of these disorders, chiefly, the hypothesis that MP are indeed important participants in some neuropathologies, especially those which are ischemic in nature, but probably also inflammatory ones.
The chapter also goes over the history and general principles of MP studies (e.g., assay methods and pitfalls), comparison with alternative methods (e.g., soluble markers of disease states), subclasses of MP (such as exosomes), and other topics aimed at helping readers to consider MP studies in their own clinical fields. Tables include a listing of bioactive agents known to be carried on MP, many of which were heretofore considered strictly soluble, and some of which can be transferred from cell to cell via MP vectors, for example certain cytokine receptors.
Wegener's granulomatosis is associated with organ-specific antiendothelial cell antibodies
2004, Kidney International
Wegener's granulomatosis is associated with organ-specific antiendothelial cell antibodies.
Antiendothelial cell antibodies (AECA), usually detected using human umbilical vein endothelial cells (HUVEC), are frequently observed in systemic vasculitis, but their pathogenic role is unclear. Heterogeneity of endothelial cells necessitates use of clinically relevant endothelial cells for elucidation of the role of AECA in systemic vasculitis involving small blood vessels of specific organs.
Human endothelial cells were isolated from normal tissue specimens from the nose, kidney, lung, liver, and umbilical vein. Using flow cytometry, AECA were detected against both unstimulated and cytokine-stimulated [tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ)] endothelial cells. Functional capacity of AECA was determined by complement fixation assay. Sera from patients with Wegener's granulomatosis (16), limited Wegener's granulomatosis (8), renal limited disease (4), microscopic polyangiitis (MPA) (5), rheumatoid arthritis (10), and systemic lupus erythematosus (SLE) (9), and from healthy controls (20) were analyzed.
Compared with controls (1) Wegener's granulomatosis is significantly associated with noncytotoxic AECA that selectively bind surface antigens on unstimulated nasal, kidney, and lung endothelial cells; (2) binding of Wegener's granulomatosis AECA to kidney and nasal endothelial cells in particular was lost upon treatment with IFN-γ and TNF-α; (3) the two cytokines per se were cytotoxic (30%) to nasal and lung endothelial cells and lysis was further increased (60%) by addition of systemic vasculitis serum; and (4) Wegener's granulomatosis serum caused agglutination of cytokine-stimulated nasal endothelial cells.
Based on these findings we suggest that AECA may be one factor involved in the initiation of Wegener's granulomatosis. Antigen identification and elucidation of the pathogenic roles of AECA and inflammatory cytokines in systemic vasculitis using these cells will be particularly important.
Thrombomodulin in the sera of patients with multiple sclerosis and human lymphotropic virus type-1-associated myelopathy
1995, Journal of Neuroimmunology
Damage to the blood-brain barrier, which mainly consists of cerebral endothelial cells, has been demonstrated in multiple sclerosis (MS) clinically and histochemically. To investigate the endothelial cell damage, we evaluated the presence of soluble thrombomodulin in the sera of patients with MS and human T lymphotropic virus type-1-associated myelopathy (HAM) using an enzyme-linked immunosorbent assay. Serum thrombomodulin levels were significantly increased in patients with acute relapsing MS during an exacerbation and chronic progressive MS as compared with those of controls (P < 0.001, respectively). Patients with HAM also had higher serum levels of thrombomodulin than did controls (P < 0.001). There was significant difference between patients with HAM and seropositive non-HAM carriers (P < 0.01). These results suggest that the detection of serum thrombomodulin could be used as a marker of endothelial cell damage in inflammatory diseases such as MS and HAM.
Increased levels of soluble tumor necrosis factor receptor in patients with multiple sclerosis and HTLV-1-associated myelopathy
1994, Journal of Neuroimmunology
Tumor necrosis factor-α (TNF-α) is a potent mediator produced by activated T lymphocytes and macrophages, which may play a role in the pathogenesis and development of multiple sclerosis (MS) and HTLV-1-associated myelopathy (HAM). The first step in the induction of many biological effects elicited by TNF-α is its binding to specific cell surface receptors. A soluble form of TNF receptors (sTNF-R) can be detected in the body fluid. We measured sTNF-R levels in the sera and cerebrospinal fluid (CSF) of patients with either MS or HAM, and evaluated the correlation between this mediator and diseaseaactivity. The levels of sTNF-R in the sera and CSF of patients with MS were significantly increased compared with controls, particularly patients with acute relapsing MS during an exacerbation (P < 0.001). CSF levels of sTNF-R showed a strong correlation with those of TNF (r = 0.716, P < 0.001). Higher levels of sTNF-R in the sera of HAM patients were detected as compared with those of either controls (P < 0.001) or non-HAM carriers (P < 0.001). Patients with HAM exhibited significantly higher CSF levels of sTNF-R than those with other neurological diseases (P < 0.0001). These results suggest that the detection of sTNF-R in the sera and CSF may predict disease progression. Availability of such a marker wou ld be useful in monitoring disease activity.
Cytotoxicity of T cells for cerebral endothelium in multiple sclerosis
1993, Journal of the Neurological Sciences
We investigated the cytotoxic effect of peripheral blood T cells on cerebral endothelium in patients with MS. We examined in vitro the damage to ⁵¹Cr-labelled dissociated human brain endothelial cells produced by mitogen-stimulated T cell lines from patients with MS and controls. Endothelial targets were lysed by T-lymphocytes from patients with acute relapsing MS during an exacerbation at every target-effector cell ratio tested compared with controls (P < 0.001). The percentage of endothelial targets lysed was not significantly increased by incubation with T cells from patients with acute relapsing MS in remission and chronic progressive MS, compared with that of normal subjects. Relapsing MS patients during an exacerbation had significantly higher interleukin-1 (IL-1)-α concentrations in cultures of targets with effector cells than normal subjects (P < 0.02). Experiments of major histocompatibility complex (MHC)-restricted cytotoxicity in MS demonstrated incomplete blocking of specific lysis by either anti-MHC class I or class II monoclonal antibody (mAb). These results indicate that cytotoxicity of T cells for cerebral endothelial cells may play a role in the initiation of immune response in acute relapsing MS during an exacerbation which appears to cause an increase in blood-brain barrier (BBB) permeability.
Anti-lymphocyte natibodies and circulating immune complexes in the sera of patients with myelopathy associated with human T lymphotropic virus type_I
1993, Journal of Neuroimmunology
We measured levels of circulating immune complexes in the human T-lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM) by Raji cell assay and C1q binding assay using an enzyme-linked immunosorbent assay (ELISA). The levels of anti-lymphocyte antibody were also measured using normal donor peripheral blood T-lymphocytes. The levels of anti-lymphocyte antibodies were significantly higher in the sera of patients with HAM compared to controls (P < 0.01). The concentrations of immune complexes measured by Raji cell assay were also significantly higher in the HAM patient's sera than in controls. However, when levels of immune complexes were measured by C1q binding assay, there was no significant difference between HAM patients and controls. There was no significant difference in the levels of anti-lymphocyte antibodies and immune complexes between HTLV-I carriers and controls. Circulating immune complexes detected by the Raji cell assay did not include HTLV-I p-19 as detedted by the indirect immunofluorescent method. Levels of anti-lymphocyte antibody were correlated with levels of circulating immune complexes as detected by the Raji cell assay in the sera of patients with HAM. These findings indicate that anti-lymphocyte antibodies and circulating immune complexes are presented in the sera of HAM patients, and that the levels of complexes detected by Raji cell assay may reflect anti-lymphocyte antibody levels.

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^☆: This study was supported by grants No. 61570385 and 63570363 from the Japanese Ministry of Education and the Intractable Disease Division, Japanese Public Health and Welfare.

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Autoantibodies to each protein fraction extracted from cerebral endothelial cell membrane in the sera of patients with multiple sclerosis☆

Abstract

Immunol. Today

Brain Res.

Brain Res.

J. Neuroimmunol.

J. Neuroimmunol.

J. Neuroimmunol.

Blood-brain damage in multiple sclerosis. Supravital test observation

Acta Neurol. Scand.

The capillaries in acute and subacute multiple sclerosis plaques: a morphometric analysis

Neurology

Primary demyelination in Theiler's virus infection: an ultrastructured study

Lab. Invest.

Activated T-lymphocytes in patients with multiple sclerosis

Neurology

In vivo activated T-lymphocytes in the peripheral blood and cerebrospinal fluid of patients with multiple sclerosis

New Engl. J. Med.