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Biomedical subjects

A Møller-Larsen

Publications and source records attributed to A Møller-Larsen.

At least 19 recordsLinked to original sources
PubMed2003

Antibodies against a human endogenous retrovirus and the preponderance of env splice variants in multiple sclerosis patients.

The human endogenous retrovirus HERV-H is associated with multiple sclerosis (MS). Previously performed reverse transcriptase-polymerase chain reactions (RT-PCR) on virion-RNA demonstrated sequence variants of the HERV-H family located in the particulate fraction of MS patient plasma samples and not in controls. In this study a significantly elevated level of antibodies towards peptides derived from HERV-H/RGH-2 DNA sequences in serum and cerebrospinal fluid (CSF) from MS patients is demonstrated. Further, Wistar rats immunized with purified virions develop a specific serologic response, indicating that some virion proteins are encoded by HERV-H-related sequences. Also shown is that in RNA from blood cells, a HERV-H protease-env splice variant can be found together with an env splice variant in about 40% of MS patients but only in 10% of controls. The results substantiate the association between activated HERV-H and MS, but a causal relationship is yet to be demonstrated. HERV-H could represent a causal factor either by eliciting an autoimmune response or through the pathogenic potential of the retrovirus itself.

Adult↗
PubMed2001

[Endogenous retroviruses in multiple sclerosis].

INTRODUCTION: In recent years, it has been suggested that human endogenous retroviruses (HERVs) may play a role in autoimmune diseases. HERVs represent both putative susceptibility genes and putative pathogenic viruses in multiple sclerosis (MS). Initially, our objective was to characterize a retrovirus produced by MS derived cell lines and to investigate this association in vivo. METHODS: The retrovirus was identified by RT-PCR on virion RNA purified from RT-positive retroviral particles from the MS cell lines, and from blood samples from MS patients. Wistar rats were immunized with purified virions and serological responses analyzed by ELISA. RESULTS: Sequence variants highly homologous to the HERV-H family were found. The same sequences were specifically found in the particulate fraction of a series of MS patient plasma samples and were absent in controls. A database search demonstrated HERV-H copies in several chromosome regions implied in MS susceptibility. Virion-immunized rats developed a specific serological response towards HERV-H peptides indicating that immunogenic virion proteins are encoded by HERV-H. DISCUSSION: Activation of normally replicatively quiescent HERVs may be causally involved in MS.

Animals↗
PubMed2000

Molecular characterization of HERV-H variants associated with multiple sclerosis.

Our objective was to characterize retroviral sequences by RT-PCR with gag and env primers on RNA from RT-positive retroviral particles produced by multiple sclerosis (MS) derived B-lymphoblastoid cell lines. Sequence variants with high homology to the potentially functional subgroup RGH of the human endogenous retrovirus RTVL-H/HERV-H family were found. The same sequences were also specifically found in the particulate fraction of a series of MS patient plasma samples and were absent in controls. South-Western blots demonstrate the presence of a nucleic acid binding protein, corresponding in size and function to the nucleocapsid protein, Gag NC, of other retroviruses. We also present indications for transmission of the retrovirus to PHA-stimulated lymphocytes from healthy individuals.

B-Lymphocytes↗
PubMed1999

Reverse transcriptase activity and particle production in B lymphoblastoid cell lines established from lymphocytes of patients with multiple sclerosis.

We have established spontaneously formed B lymphoblastoid cell lines from long-term cultured peripheral blood mononuclear cells (PBMNCs) from multiple sclerosis (MS) patients. The MS cell lines actively produce retrovirus-like particles as well as Epstein-Barr virus (EBV). Using three different variations of the highly sensitive polymerase chain reaction (PCR)-based assays for the detection of reverse transcriptase (RT) activity, we have verified the retroviral origin of the retrovirus-like particles that are produced in very low amounts by the MS cell lines.

B-Lymphocytes↗
PubMed1998

Isolation of a retrovirus from multiple sclerosis patients in self-generated Iodixanol gradients.

The use of Iodixanol, a relatively new iodinated gradient medium, is described for isolation of a retrovirus, which was harvested from the supernatant of lymphoid cell lines originating from patients with multiple sclerosis (MS). The virus is produced in low amounts and has been shown to be fragile, as manifested in a loss of surface glycoproteins when purified in other gradient media. The gradient fractions were analysed after centrifugation in Iodixanol by incorporation of 3H-UTP, reverse transcriptase (RT) assays and electron microscopy (EM) and it was found that Iodixanol does not cause the degree of damage to the particles observed previously. These more favourable conditions are probably due to low viscosity and almost iso-osmotic conditions even in high concentrations. Furthermore, these advantages go together with higher reproducibility in self-forming gradients, easier handling and shorter centrifugation time. Iodixanol can also be used for preparation of HTLV-1.

Cell Line↗
PubMed1998

The significance of Epstein-Barr virus seropositivity in multiple sclerosis patients?

The objective of this study was to evaluate and investigate the significance of the previously found 100% seropositivity toward Epstein-Barr virus (EBV) found in multiple sclerosis (MS) patients in contrast to healthy controls. Using a commercially available ELISA-test (Biotest), which differentiates infections with EBV into previous infections, primary infections, reactivated infections and no previous infection, we found 137 of 138 MS patients and 124 of 138 healthy controls seropositive. A primary infection in 4 of the 124 EBV seropositive healthy controls in contrast to no primary infections in the MS EBV seropositive group was significant (P=0.049652, Fishers exact test). This may be suggestive of a lack of primary infections in MS patients, and thus strengthens the idea that MS patients are infected with EBV before development of MS. Further studies are in progress to analyse whether EBV infection is a prerequisite for the development of this disease.

Adult↗
PubMed1998

A single subtype of Epstein-Barr virus in members of multiple sclerosis clusters.

OBJECTIVES: Epidemiological studies strongly indicate an infectious involvement in multiple sclerosis (MS). Epstein-Barr virus (EBV), to which all multiple sclerosis patients are seropositive, is also interesting from an epidemiological point of view. We have reported a cluster of MS patients with 8 members from a small Danish community called Fjelsø. To further evaluate the role of EBV in MS we have investigated the distribution of EBV subtypes in cluster members and in control cohorts. MATERIALS AND METHODS: Blood mononuclear cells were isolated from cluster members, unrelated MS patients, healthy controls, including healthy schoolmates to the Fjelsø cluster patients and finally from persons with autoimmune diseases in order to investigate the number of 39 bp repeats in the EBNA 6-coding region in the EBV seropositive individuals. RESULTS: We observed a preponderance of the subtype with 3 39 bp repeats in the EBNA 6-coding region both in the MS patients and the healthy controls. In the Fjels cluster all 8 cluster members were harbouring this subtype, which is significantly different from the finding in healthy controls (n = 16), which include 8 schoolmates to the cluster members and 8 randomly selected healthy persons (Fischer's exact test P = 0.0047), and also compared to all non-clustered individuals studied (P = 0.017). CONCLUSION: Infection with the same subtype of EBV links together the 8 persons from the Fjelsø cluster who later developed MS. This finding adds to the possibility that development of MS is linked to infection with EBV.

Adult↗
PubMed1997

Characterization of retroviruses from patients with multiple sclerosis.

These studies were performed to characterize retroviruses found in cell lines spontaneously developed from peripheral blood mononuclear cells (PBMNC) from 6 multiple sclerosis patients, a patient with progressive myelopathy and a healthy control. The cell lines are B-lymphoblastoid and produce Epstein-Barr virus (EBV) particles or express EBV proteins. The B-lymphoblastoid cell lines are also characterized by production of low, fluctuating amounts of retrovirus. The low productivity complicates purification and characterization, but implementation of product-enhanced reverse transcriptase (PERT) assays has provided a highly useful tool for monitoring retrovirus production. By electron microscopy, the retroviral particles appear type-C-like. Functional assays indicate the presence of Pol, Gag and Env. Indirect ELISA demonstrates a significant relation between disease activity and reactivity towards retroviral peptides. Molecular characterization is primarily based on RT-PCR, cloning, sequencing and Northern- or Southern analyses. Molecular characterization is continuing.

Autoantigens↗
PubMed1997

The implications of Epstein-Barr virus in multiple sclerosis--a review.

The objective of this article is to bring together knowledge about Epstein-Barr virus (EBV) in relation to multiple sclerosis (MS) in order to evaluate its implications in this disease. All MS patients are EBV seropositive, but EBV is not normally detected in the brain. EBV can explain many of the epidemiological dogmas known in MS. In addition, other studies point towards the involvement of EBV in MS. Despite this, other co-actors seem also to be involved. We still need to know whether EBV may be an initiating factor in MS or whether it is a factor in the pathogenesis. Possible ways of EBV involvement are discussed: direct involvement, an autoimmune inducing factor or a transactivating factor. A current treatment study of MS patients with a specific herpes antiviral drug may add further information to the etiology and pathogenesis of MS.

Autoimmune Diseases↗
PubMed1995

Increased risk of multiple sclerosis after late Epstein-Barr virus infection: a historical prospective study.

An association between infectious mononucleosis (IM) and MS has been proposed. In a historical prospective study we used records from the Danish State Serum Institute on heterophile antibody (HA) tests for IM performed in all Danish patients over a number of years. Included in the analysis were 6853 HA-positive persons analyzed from 1968 to 1978 (except 1975) and 12,886 HA-negative per sons analyzed in the years 1968, 1969, 1970 and 1978. A search for these persons in the central nationwide Danish Multiple Sclerosis Registry (DMSR) was performed. Among the HA-positive persons 16 cases of MS which met the diagnostic criteria were found with onset of MS after the year of the HA test and before follow-up on 1 January 1991. The expected number for a Danish population, matched by sex, age and year at start of observation, was 5.70 (P < 0.05), the risk ratio being 2.81. No patient had developed MS before contracting IM. Among the HA-negative persons 12 were registered with onset of MS after the year of the HA test and before follow-up, the expected number being 10.47 (P > > 0.05). Although Epstein-Barr virus is not suggested in itself to be the cause of MS, we propose that it is a co-factor in the pathogenesis of this disease.

Adolescent↗
PubMed1995

B-lymphoblastoid cell lines from multiple sclerosis patients and a healthy control producing a putative new human retrovirus and Epstein-Barr virus.

On several occasions we have observed retrovirus-like particles (RVLPs) by transmission electron microscopy (EM) of cultured T cells from a patient with MS. Later we established spontaneously formed B-lymphoblastoid cell lines (LCLs) from a patient with an MS-like disease and from another patient with MS who had a reactivated Epstein-Barr virus (EBV) infection. Both LCLs were found by EM to produce RVLP and EBV particles. Reverse transcriptase (RT) assays were positive in purified viral material from both LCLs. To substantiate these findings we initiated an intensified culturing procedure and were able to establish LCLs from 5 out of 21 consecutive MS patients and 1 out of 13 consecutive healthy controls. All LCLs were found to produce both RVLP and EBV particles by EM. Whether the putative new retrovirus(es) and EBV have any causal relationship to MS is still not known, but the findings support this possibility.

Adult↗
PubMed1994

A putative new retrovirus associated with multiple sclerosis and the possible involvement of Epstein-Barr virus in this disease.

Since tropical spastic paraparesis in 1985 was found to be associated with HTLV-I infection, it has been suggested that a retrovirus might be involved in multiple sclerosis (MS). Our group has studied long-term cultures of cerebrospinal fluid cells and peripheral blood mononuclear cells from MS patients and controls with the purpose of elucidating the possible involvement of a retrovirus in MS. For an extended period electron microscopical analysis (EM) of T-cell lines, derived from MS patients and controls and cultured for 4 weeks was performed. In two cultures obtained 8 months apart from a patient with progressive MS, retrovirus-like particles were observed in 1-2% of the cells examined. Recently a B-lymphoblastoid cell line (LCL) producing retrovirus-like particles and EBV was established from a 30-year-old male patient with a chronic progressive myelopathy, clinically resembling multiple sclerosis. Similar cell lines have now been established from two MS patients. The retrovirus-like particles produced by the LCL have been purified by gradient ultracentrifugation. In the purified material reverse transcriptase assays are clearly positive in the gradients where EM shows retrovirus-like particles. Antigen characterization, nucleic acid sequence analysis and antibody studies are now being performed. The retrovirus found is definitively different from other known human retroviruses. It has previously been found that 100% of patients with MS have antibodies against EBV, in contrast to controls where only 86-95% have antibodies against this virus. Previous epidemiological studies have pointed toward a post-pubertal primary EBV infection as an important event in the induction of MS disease. These studies have now been substantiated by our group. Though it is still unknown whether EBV infection is a prerequisite for development of MS or whether the 100% EBV seropositivity is a consequence of the MS disease, we have put forward the hypothesis that the etiological agent for development of MS and MS-like diseases is a new hitherto uncharacterized retrovirus, whereas development of neurologic disease is related to or even dependent on a delayed infection with a virus from the herpes group, most likely EBV. This dual infection hypothesis has been analyzed and was found to be in accordance with the most consistent epidemiological characteristics of MS. We have previously, also from epidemiological data, negated retroviruses, behaving as the known human retroviruses, as an independent cause of MS.

Adult↗
PubMed1994

A retroviral implication in multiple sclerosis?

The etiology of multiple sclerosis (MS) is still unexplained. Epidemiological studies indicate that environmental agents are involved, and MS shares both clinical and histopathological features with retrovirus-mediated neurological diseases in animals and humans. Thus, combining the fields of microbiology and epidemiology may throw new light on the many unanswered questions posed by MS.

HTLV-I Infections↗
PubMed1993

Retrovirus-like particles in an Epstein-Barr virus-producing cell line derived from a patient with chronic progressive myelopathy.

A B-lymphoblastoid cell line (LCL) of polyclonal origin was isolated from a 30-year-old male patient with a chronic progressive myelopathy clinically resembling multiple sclerosis (MS). The LCL expresses Epstein-Barr virus (EBV) encoded proteins and on transmission electron microscopy (EM) the LCL was shown to produce both EBV particles and retrovirus-like particles spontaneously. The LCL was negative for human retrovirus (HIV-I and HTLV-I) sequences by polymerase chain reaction (PCR). Furthermore the patient was seronegative to these retroviruses including HTLV-II and HIV-II. We, therefore, suggest that the LCL is double-infected with EBV and a hitherto uncharacterized human retrovirus. The possible implications of these two viruses on development of diseases are discussed.

Adult↗
PubMed1992

[Disseminated sclerosis and retrovirus].

Multiple sclerosis is a disease characterized by neurologic dysfunction due to focal CNS lesions with demyelination. The cause of the disease is unknown; but it may be due to a virus and/or autoimmune reactions. The latter cause is suspected on account of family- and ethnical studies, the first on account of locally produced antibodies in the cerebrospinal fluid, and also epidemiologic investigations. The newly discovered human retroviruses, especially HTLV-I which is the cause of tropical spastic paraparesis, has been suspected as a possible cause; but this has been disproved by multiple antibody- and PCR-studies. An uncharacterized exogenous or an endogenous retrovirus is still considered to be a possible cause or possibly partial cause of the disease which could be multifactorial.

Autoimmune Diseases↗
PubMed1992

Is multiple sclerosis caused by a dual infection with retrovirus and Epstein-Barr virus?

Although the etiology of multiple sclerosis is as yet unknown, epidemiological observations strongly point toward one or more infectious agent(s) being involved in the disease. In recent years some studies have indicated involvement of retrovirus in multiple sclerosis (MS). However, an intrafamilial epidemiological study revealed that MS and the known human retroviruses had a divergent epidemiology. Some studies have shown the association of Epstein-Barr virus (EBV) with MS and one recent study revealed dual infection by retrovirus and EBV in a cell line established from a patient with an MS-like disease. Our hypothesis for the development of MS and MS-like diseases is that a hitherto uncharacterized retrovirus is the etiological agent, but development of neurologic disease is related to or even dependent on a delayed EBV infection. The dual infection hypothesis is analyzed and found to be consistent with the epidemiological characteristics of MS.

Cluster Analysis↗