Stanley van den Noort

Recommended diagnostic criteria for multiple sclerosis: Guidelines from the International Panel on the Diagnosis of Multiple Sclerosis

The International Panel on MS Diagnosis presents revised diagnostic criteria for multiple sclerosis (MS). The focus remains on the objective demonstration of dissemination of lesions in both time and space. Magnetic resonance imaging is integrated with clinical and other paraclinical diagnostic methods. The revised criteria facilitate the diagnosis of MS in patients with a variety of presentations, including “monosymptomatic” disease suggestive of MS, disease with a typical relapsing‐remitting course, and disease with insidious progression, without clear attacks and remissions. Previously used terms such as “clinically definite” and “probable MS” are no longer recommended. The outcome of a diagnostic evaluation is either MS, “possible MS” (for those at risk for MS, but for whom diagnostic evaluation is equivocal), or “not MS.”

The induction of intercellular adhesion molecule 1 (ICAM-1) expression on human fetal astrocytes by interferon-λ, tumor necrosis factor α, lymphotoxin, and interleukin-1: relevance to intracerebral antigen presentation

Antigen presentation reactions are dependent upon the expression of the class II major histocompatibility antigens (MHC), the T-cell receptor, and the presented antigen. Recent studies demonstrate that such processes also require the presence of adhesion molecules such as lymphocyte functional antigen 1 (LFA-1) and its cell surface ligand, intercellular adhesion molecule 1 (ICAM-1). It has been suggested that the brain astrocyte can function as a facultative antigen presenting cell (APC). This hypothesis is based upon the ability to induce the expression of the class II MHC antigens on astrocytes, and on their ability to present myelin basic protein to encephalitogenic T-cells in vitro. The best in vivo data showing that astrocytes serve as intracerebral APCs is the finding that astrocytes in multiple sclerosis plaques are DR+ (class II MHC in human). However, it still remains to be resolved whether the in vivo expression of the MHC antigens in disease states is instrumental to antigen presentation mechanisms or whether these cell surface glycoproteins are expressed secondary to brain immune responses. If astrocytes function as immunocompetent APCs within the brain, it would seem that they would also be able to express molecules important for intercellular adhesion. Here, we present the first data that indicates that human astrocytes are capable of expressing ICAM-1 in response to cytokines that either induce or upregulate the expression of DR. In essence, cytokines derived from different cell types seem to exert similar pleiotropic effects on the modulation of MHC and ICAM-1 expression on astrocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Intrathecal B-Cell Clonal Expansion, an Early Sign of Humoral Immunity, in the Cerebrospinal Fluid of Patients with Clinically Isolated Syndrome Suggestive of Multiple Sclerosis

The development of somatically mutated memory and plasma B cells is a consequence of T cell-dependent antigen-challenged humoral immunity. To investigate the role of B cell-mediated humoral immunity in the initiation and evolution of multiple sclerosis (MS), we analyzed Ig variable heavy chain genes of intrathecal B cells derived from patients with a first clinical manifestation suggestive of MS. Sequences of Ig variable regions showed that B cells in the cerebrospinal fluid from most of these patients were clonally expanded and carried somatic hypermutated variable heavy chain genes. The mutations showed a high replacement-to-silent ratio and were distributed in a way suggesting that these clonally expanded B cells had been positively selected through their antigen receptor. In comparison, intrathecal B-cell clonal expansion often precedes both oligoclonal IgG bands and multiple magnetic resonance imaging lesions. Clinical follow-up study showed that patients with clonally expanded intrathecal B cells had a high rate of conversion to clinically definite MS. The findings provide direct evidence of recruitment of germinal center differentiated B lymphocytes into the central nervous system during the initiation of MS. These results indicate B cell-mediated immune response in the cerebrospinal fluid is an early event of inflammatory reaction in the central nervous system of MS. This procedure also provides a more sensitive method to evaluate the association of humoral immunity in the evolution of MS.

Expression of intercellular adhesion molecule 1 (ICAM-1) in Alzheimer's disease

In this study, 13 clinically and pathologically diagnosed cases of Alzheimers disease were analyzed for the presence of intercellular adhesion molecule 1 (ICAM-1), ICAM-2, lymphocyte function associated antigen-1 (LFA-1), HLA-DR, LN-1, and LN-2. ICAM-1 was observed primarily on neuritic plaques and cerebrovascular endothelium. ICAM-1 was also shown to be present in brain tissue derived from 14 normal cases; however, the degree of immunoreactivity was quantitatively less compared to Alzheimer cases and was largely restricted to cerebrovascular endothelium. LFA-1 was shown to be present on microglial cells and leukocytes. Consistent with the findings of previous reports, HLA-DR was found to be expressed on microglial cells. In this study we failed to demonstrate dual immunolocalization for ICAM-1 and LFA-1, ICAM-1 and HLA-DR, or ICAM-1 and LN-2. As microglial cells express both HLA-DR and LFA-1, they may serve to mediate antigen presentation functions by interacting with lymphocyte ICAM-1. Alternately, the expression of these immune-associated glycoproteins on glial cells may be epiphenomenal occurring secondary to some aspect of the disease process. Finally, the presence of ICAM-1 within neuritic plaques raises the question as to whether adhesion may play some role in the process of neurite outgrowth and neurodegeneration.

Astrocytes and intracerebral immune responses

The astrocyte is the most abundant cell within the central nervous system (CNS). This cell subserves a multiplicity of important functions that contribute to the process of neural development as well as to the integrity of normal brain function. Adding to the already exhaustive list of capabilities, the astrocyte has now been demonstrated to function as an intracerebral antigen presenting cell. These findings are serving to revise our view of the brain as an immunoprivileged site and perhaps will shed some light on the pathogenetic mechanisms involved in a number of CNS disorders of immune dysregulation. In this review we provide some perspective on the regulatory mechanisms that influence astrocyte immune functions. Specifically, we address the role played by the major histocompatibility complex (MHC) antigens as well as adhesion molecules in the initiation of brain immune responses.

Norepinephrine inhibits gamma-interferon-induced MHC class II (Ia) antigen expression on cultured brain astrocytes

Recent evidence that astrocytes can be induced to express the class II major histocompatability (MHC) antigens suggests that these cells may be involved in the development of intracerebral immune responses. The principal inducer of MHC class II antigen (Ia) expression is a soluble lymphokine, gamma-interferon (gamma-IFN). Normally astrocytes do not express significant levels of Ia antigens despite the fact that agents such as gamma-IFN may be present in the central nervous system (CNS). Here we report that a major neurotransmitter, norepinephrine (NE), inhibits, in a dose-response fashion, the ability of gamma-IFN to induce Ia antigen expression on cultured astrocytes derived from newborn BALB/c mice. This finding may indicate that the brain contains inhibitory modulators that serve to prevent the up-regulation of intracerebral immune responsiveness.

Triosephosphate Isomerase- and Glyceraldehyde-3-Phosphate Dehydrogenase-Reactive Autoantibodies in the Cerebrospinal Fluid of Patients with Multiple Sclerosis

Our previous results revealed that Igs in lesions and single chain variable fragment Abs (scFv-Abs) generated from clonal B cells in the cerebrospinal fluid (CSF) from patients with multiple sclerosis (MS) bind to axons in MS brains. To study the axonal Ags involved in MS, we identified the glycolytic enzymes, triosephosphate isomerase (TPI) and GAPDH, using Igs from the CSF and scFv-Abs generated from clonal B cells in the CSF and in lesions from MS patients. Elevated levels of CSF-Abs to TPI were observed in patients with MS (46%), clinically isolated syndrome (CIS) suggestive of MS (40%), other inflammatory neurological diseases (OIND; 29%), and other noninflammatory neurological diseases (ONIND; 31%). Levels of GAPDH-reactive Abs were elevated in MS patients (60%), in patients with CIS (10%), OIND (14%), and ONIND (8%). The coexistence of both autoantibodies was detected in 10 MS patients (29%), and 1 CIS patient (3%), but not in patients with OIND/ONIND. Two scFv-Abs generated from the CSF and from lesions of a MS brain showed immunoreactivity to TPI and GAPDH, respectively. The findings suggest that TPI and GAPDH may be candidate Ags for an autoimmune response to neurons and axons in MS.

Axon Reactive B Cells Clonally Expanded in the Cerebrospinal Fluid of Patients with Multiple Sclerosis

Demyelination and axonal loss have been described as the histological hallmarks of inflammatory lesions of multiple sclerosis (MS) and are the pathological correlates of persistent disability. However, the immune mechanisms underlying axonal damage in MS remain unknown. Here, we report the use of single chain-variable domain fragments (scFv) from clonally expanded cerebrospinal fluid (CSF) B cells to show the role of an anti-axon immune response in the central nervous system (CNS) in MS. The cellular and subcellular distribution of the antigen(s) recognized by these CSF-derived clonal scFv antibodies (CSFC-scFv Abs) was studied by immunochemical staining of brain tissues obtained at autopsy from patients with MS. Immunochemistry showed specific binding of CSFC-scFv Abs to axons in acute MS lesions. The stained axons showed three major types of axonal pathological changes: 1) linear axons, axonal ovoid formation, and axonal transection were seen in the myelinated white matter adjacent to the lesion; 2) accumulation of axonal ovoid formations and Wallerian degeneration were seen at the border between demyelinated lesions and the adjacent white matter; and 3) Wallerian degeneration occurred at the center and edge of acute demyelinated lesions. These findings suggest a B cell axonal specific immune response in the CNS in MS.

Clonal expansion of IgA-positive plasma cells and axon-reactive antibodies in MS lesions.

Immunoglobulin A (IgA), the predominant immunoglobulin class in mucosal secretions, has been found in the cerebrospinal fluid of patients with multiple sclerosis (MS). In this study we examined the infiltration of clonally expanded IgA plasma cells in lesions of MS brains. Sequences of complementarity-determining region 3 of IgA variable heavy chain (V(H)) genes demonstrated the clonal expansion of IgA-bearing plasma cells in MS lesions. Somatic mutations and ongoing intra-clonal mutations occurred in their V(H) genes. Immunohistochemical study demonstrated infiltration of dimer and polymer IgA1- and A2-positive plasma cells in perivascular spaces, in the parenchyma of MS lesions, and in the adjacent white matter. Double immunofluorescence staining showed binding of IgA antibody on axons and walls of microvessels in the areas of chronic active and inactive demyelination. Bielshowskys silver impregnation revealed axonal damage in these areas. These findings suggest that IgA in the CNS are localized on axons in lesions and may contribute to axonal damage in MS.

Vasoactive intestinal polypeptide inhibits the expression of the MHC class II antigens on astrocytes

The brain has been traditionally viewed as an immunologically privileged site. However, recent findings suggest that the brain is in fact equipped with its own immune circuitry. Astrocytes and microglia have been considered the most likely candidates to assume the role of intracerebral antigen presenting cells (APC). Using the techniques of immunofluorescence cytochemistry and flow cytometric analysis, we observed that vasoactive intestinal polypeptide (VIP) can significantly inhibit gamma-interferon (IFN-gamma)-induced Ia expression on astrocytes derived from newborn Lewis rats. Further, we analyzed a number of neuropeptides and transmitters for their ability to exert a similar inhibitory modulation on IFN-gamma induced Ia expression or for the ability to induce or augment Ia expression on rat astrocytes. Our results showed that only norepinephrine (NE), a major brain neurotransmitter, and VIP, a ubiquitous brain peptide, have the ability to inhibit Ia expression on Lewis rat astrocyte cultures. Alternately, we report that cholecystokinin (CCK), a brain/gut peptide, has the ability to induce Ia on about 5-10% of the cells analyzed. These findings suggest that endogenous brain substances have the ability to modulate intracerebral immune responses by regulating the expression of Ia on astrocytes.