Combined influences of Gm and HLA phenotypes upon multiple sclerosis susceptibility and severity.

In some Caucasian populations, multiple sclerosis (MS) susceptibility has been independently related to given alleles of HLA or Gm systems that respectively code for major histocompatibility complex class I and II antigens or immunoglobulin G heavy chains. Whether given combinations of alleles at both series of loci simultaneously influence MS susceptibility and/or severity was investigated by comparing 147 French MS patients and 226 geographically-matched healthy controls. The G2m(-23)/HLA-B35 phenotype and G1m(-1)/HLA-B7(-)/HLA-DR2 phenotype were respectively associated with significant protection against (relative risk = 0.05) and susceptibility to (relative risk = 4.3) MS. When considering MS severity, the presence of HLA-B7 antigen correlated with a more severe disease in Gm1/Gm3 heterozygous patients, but not in Gm3/Gm3 homozygous patients. Conversely, an HLA-B12-associated milder disease was restricted to Gm3/Gm3 homozygotes. These results demonstrate the combined influence on MS of genetic loci that are unlinked but immune response-associated. Combined Gm and HLA typing is very likely able to serve as a prognostic indicator in this disease.

Cerebrospinal myelin basic protein in multiple sclerosis. Identification of two groups of patients with acute exacerbation.

The myelin basic protein concentration in the cerebrospinal fluid (CSF) of 125 patients with multiple sclerosis was measured using a radioimmunoassay technique with a detection level of 200 pg/mL and was correlated with the clinical course of the disease. Myelin basic protein was detected in the CSF of some patients with an active progressive form of the disease and in the CSF obtained during exacerbations with the presence of signs or symptoms not previously experienced by the patient (26 of 29 cases were positive during the period of maximal symptoms). Myelin basic protein was not detected in any patient with an inactive or slowly progressive form of the disease, nor in any patient during exacerbations with only recurrence of old signs or symptoms. These results are consistent with the hypothesis that the two clinical forms of exacerbation defined above may be associated respectively with the absence or presence of an acute demyelination.

Incorporation of fibronectin-impregnated vascular prostheses in the pig. Microscope study.

An interface near the endothelial extracellular matrix is necessary to augment and maintain endothelial cell attachment. The use of plasma lectins constitutes one of the present lines of research designed to improve this interface. We studied the incorporation of 2 series of arterial prostheses with a diameter of 4 mm and a mean length of 9 cm. They were implanted in the carotid arteries of adult Europig minipigs. Prostheses were of two types: polytetrafluoro-ethylene (PTFE) and knitted Dacron. Two series of 12 pigs each were used. One was explanted at 3 months and the other at six. Each pig was grafted with one prosthesis impregnated with the plasma components of diluted Fibrogel and one non-impregnated prosthesis which served as control. The explanted prostheses and adjacent parts of the carotid were prepared for light or scanning electron microscopy. Proximal, median and distal segments were cut and embedded in resin. Collagen distribution was revealed by Milligan's trichrome stain, and fibrin distribution by Picro-Mallory staining. Macroscopic examination showed discrete periprosthetic adhesion for impregnated prostheses and complete adhesion for non-impregnated prostheses. Scanning electron microscopy revealed a median endothelial cell coating on impregnated grafts whereas the only endothelial cells on non-impregnated grafts, were perianastomotic. On impregnated grafts, Milligan's trichrome staining revealed an even collagen distribution. The walls of non-impregnated grafts exhibited capillary cell infiltrations with breaches in the outer structures. In impregnated prostheses, the absence of such breaches enabled us to postulate that their incorporation was better than that of the non-impregnated grafts. The minipig model was hard to handle because of the aggressiveness engendered by restricted feeding designed to limit weight increases. In general, however, we may justifiably conclude that in this model, the use of plasma lectins improved prosthetic incorporation.

[Physiopathology of the clinical manifestation of multiple sclerosis. Electrophysiological hypotheses]. / Physiopathologie de l'expression clinique de la sclérose en plaques. Hypothèses électro-physiologiques.

Clinical manifestations of multiple sclerosis cannot always be correlated with the type of lesion present. Plaques in certain regions may be clinically silent whereas, inversely, some neurological disorders appear not to be related to a demyelinization process. The pathophysiology of neurological symptoms and signs in multiple sclerosis may therefore be related to two other factors: 1) membrane phenomena observed in demyelinated fibers and leading to partial or complete conduction block, or 2) conduction blocks due to pathological phenomena that fail to provoke anatomical demyelinization. Demyelinization induces a sudden drop in impedance of the axon membrane which is responsible for the conduction block. Redistribution of sodium ionophores in the demyelinated axon enables transmission of certain messages but in a slower and unreliable manner. Sensitivity of demyelinated fibers to temperature and the extracellular ionic environment provides an explanation for the transient, recurrent stereotyped reactions provoked by fever, physical exercise or digestion. In the absence of demyelinization, a conduction block could be the result of either a minimal lesion at the paranodal myelin with denudation of the specialized parts between axon and glia,or of humoral blocking factors--of debatable specificity--or cellular factors that have been demonstrated recently. The existence of such mechanisms suggests the need for revision of the notion of acute episodes of multiple sclerosis. Finally, knowledge of the mechanisms involved in nerve conduction along demyelinated fibers suggests the possibility of therapy to restore conduction of these fibers by acting on extracellular ionic concentrations or directly on membrane ionic canals.

[Recovery from chronic polyradiculoneuritis after high-dose intravenous corticoid therapy]. / Guérison d'une polyradiculonévrite chronique après corticothérapie intraveineuse à fortes doses.

A chronic relapsing polyneuropathy did not improve with oral prednisone therapy. After 7 years, 3 intravenous infusions of 1,5 g of methylprednisolone led to complete recovery which is present after 4 years.

Polyurethane arterial prosthesis: experimental evaluation.

Two types of microporous polyurethanes have been evaluated both in vitro and in vivo. In vitro polyurethane disks have been seeded by endothelial cells from bovine aortic origin and from fresh human greater omentum. Various pretreatments permit comparison of six different experimental groups. The benefit of poly L lysine, laminin, fibronectin and previous astrocyte cell seeding is shown. The cell proliferation was assessed daily, using trypan blue in Malassez cells. Cell identification was performed by class I MHC antigen characterization and factor VIII staining. In vivo, 4 mm polyurethane arterial prostheses were implanted as carotid interpositions. Evaluation of polyurethane, both in vitro and in vivo, failed to demonstrate a satisfactory hemocompatibility of the material. However, previous treatment of polyurethane with laminin, fibronectin, and astrocyte cell seeding improves the biologic characteristics of the raw material.

Serum and cerebrospinal fluid C2 in multiple sclerosis.

C2 hemolytic activity was quantitated in the serum and cerebrospinal fluid of 46 MS patients studied twice at a 1-year interval. whereas serum C2 levels were found within the normal range, CSF C2 values were decreased (55 and 59% of normal) in patients with severe active disease. In contrast CSF C2 levels were normal in patients with stable or recently improved condition. CSF C2 fluctuations in individuals were found to closely parallel changes in the clinical course.

Solitary plasmacytoma of the skull revealed by a mononeuritis multiplex associated with immune complex vasculitis.

We describe a patient with solitary plasmacytoma of the skull, in whom mononeuritis multiplex was the presenting manifestation. Some features of the POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal [M] protein, skin changes), including thrombocytosis, were found. Muscle and nerve biopsies disclosed a small vessel hypersensitivity-type vasculitis and complement-fixing immune complex deposits in vessel walls. Removal of the plasmacytoma resulted in clinical improvement and clearance of the vasculitis and immune complex deposits.

Shear stress affects expression of major histocompatibility complex antigens on human endothelial cells.

Endothelialization of the inner face of a prosthesis appears to improve patency of small caliber arterial substitutes. The importance of understanding the factors that affect human endothelial cell behavior is highlighted by failure of vascular prosthetic grafts to endothelialize when implanted in man. In the present study, endothelial cells isolated from microvasculature are used for their ability to be easily selected from human adult fat, their proliferative capacity, and for their immunologic properties relevant to human pathology: allograft implantation, vessel injury or atherosclerosis. The system described provides a tool for assessing the individual roles of shear stress in modulating endothelial cell morphology and major histocompatibility complex (MHC) antigen expression. Using indirect immunofluorescent staining, initial results showed a homogenous increase of class I and appearance of class II expression after an exposure for 30 hr to physiologic arterial values. Significantly increased staining intensity was observed following exposure to supraphysiologic values. Moreover, precoating of substrate with fibronectin instead of poly-L-Lysine enhanced MHC straining intensity. Scanning electron microscopy (SEM) confirmed the activated morphology of stained cells. This provides a model to study involvement of MHC expression in endothelial cell activation under physical constraints. It may contribute to the development of biomaterial for implantation.

A case-control epidemiological study of MS in the Paris area with particular reference to past disease history and profession.

A retrospective case-control study was carried out on 230 patients with multiple sclerosis (MS) and 230 controls matched for year of birth and sex. The geographical distribution of residence of MS patients and controls was similar. Two peak ages of onset of MS were observed among woman patients (20-24, 30-34 years). There was no difference in histories of infectious diseases and autoimmune diseases between the two groups. A greater number of hairdressers was noticed among the patient group (p less than 0.05) and three patients (no control) had had professional contact with pathology specimens.

HLA and multiple sclerosis: population and families study.

Association between HLA and multiple sclerosis (MS) was investigated at the population level on 100 MS patients genotyped for HLA-A, B, C, DR and Bf, Glo, and on 155 patients phenotyped for the same HLA antigens. Association between MS and DR2 was clearly confirmed, although its strength is rather weak. No other genetic marker could be related to the disease, no haplotype nor any allelic combination could be recognized as MS specific, and antigen genotype frequencies among the diseased could not ascertain the mode of inheritance, although dominance is very likely. Computer analysis between HLA, Bf, Glo and age of the patient, sex, age of onset and evolution of MS, impairment indexes, titres of anti-DNA and anti-measles antibodies in CSF did not show any interaction. Twenty sib pairs and two trios of MS were also studied; they showed no significant distortion with the random distribution of haplotypes. DR2 gene frequency, however, was significantly higher in sib pairs showing one or two haplotypes than in HLA different affected siblings. Three crossing-overs were identified which suggest where the HLA-linked MS susceptibility (MSS) gene could be located within the HLA segment, while other epistatic MSS genes or environmental factors are likely to be important.

HLA-DR-dependent variation of intrathecal IgG1 (Gm) allotype synthesis in multiple sclerosis.

Genetic susceptibility to multiple sclerosis (MS) in Caucasians was previously shown to be correlated to the presence of given alleles at the HLA-DR and Gm loci. We now demonstrate that the humoral immune response in MS central nervous system (CNS) is modulated by both loci: the levels of IgG1 subclass and IgG1 allotypes in cerebrospinal fluid of MS patients depend on both their Gm genotype and their HLA-DR2 or HLA-DR7 phenotype. That HLA-DR molecules may either participate in a preferential recruitment of IgG1 allotype-producing B cells in MS CNS or act after such a selective homing is discussed. These results demonstrate that both HLA and Gm loci are synergistically involved in the modulation of the humoral immune response.

IgG (Gm) allotypes and multiple sclerosis in a French population: phenotype distribution and quantitative abnormalities in CSF with respect to sex, disease severity, and presence of intrathecal antibodies.

The association of a given Gm allotype or phenotype with MS susceptibility, as previously described in some Caucasian populations, was not observed in a large French MS group, whether or not considering the possible influence of sex or disease severity. This result could be related to variations in geographical distribution of Gm alleles and MS susceptibility gene(s) or suggests the simultaneous involvement of Gm and other genetic system(s). In contrast, the corresponding CSFs exhibited already known MS-associated abnormalities of IgG1 (G1m) allotype contents, which therefore did not merely result from a Gm-associated MS susceptibility. These quantitative abnormalities were not sex dependent, but may fluctuate with MS severity. The G1m allotype levels in each CSF were not correlated with titers of various intrathecal antibodies but with the number of antibody specificities detected, a picture arguing for a polyclonal, non-antigen-specific activation of G1m allotype-producing B cells present in MS brain.