Immunogenetics of multiple sclerosis and optic neuritis: DNA polymorphism of HLA class II genes.
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Alleles↗
Biomedical subjects
M Sandberg-Wollheim
Publications and source records attributed to M Sandberg-Wollheim.
Primary Sjögren's syndrome in patients with multiple sclerosis.
The relationship between multiple sclerosis (MS) and primary Sjögren's syndrome (PSS) is ambiguous; it was suggested that some patients diagnosed with MS may instead have PSS. In a recent epidemiologic study, the prevalence of PSS was 2.7% in southern Sweden. We randomly selected 30 patients with definite MS from our patient population and investigated them for evidence of PSS according to the Copenhagen criteria. One patient had clinical symptoms compatible with PSS and also fulfilled the Copenhagen criteria. In addition, five patients had keratoconjunctivitis sicca, one had xerostomia, and three had histopathologic evidence of sialadenitis in the lower lip salivary glands. However, one of these findings alone is not sufficient to support the diagnosis of PSS. We conclude that MS and PSS may coexist in the same individual, but PSS is not more common among MS patients than expected in the general population.
Antibodies, Antinuclear↗
A randomized study of chemotherapy with procarbazine, vincristine, and lomustine with and without radiation therapy for astrocytoma grades 3 and/or 4.
The authors undertook a controlled, prospective, randomized study of 171 patients with supratentorial astrocytoma grades 3 and/or 4 (classified according to Kernohan). All patients were given chemotherapy consisting of procarbazine, vincristine, and lomustine (CCNU) (PVC). Half of the patients received whole-brain irradiation (RT) to a dose of 5800 cGy in the tumor-bearing hemisphere and 5000 cGy in the contralateral hemisphere. After diagnosis of progressive tumor growth, patients received individual treatment. The endpoint of the study was time to progression, but cases were followed until the patients died. Median time to progression (MTP) for the whole randomized population was 21 weeks. Median survival time (MST) was 53 weeks; 18% of patients survived for 2 years or longer. Survival analysis showed that patients less than 50 years of age treated with PVC plus RT had significantly longer MTP (81 weeks) and MST (124 weeks) than all other patients. For patients less than 50 years of age treated with PVC alone, MTP was 21 weeks and MST was 66 weeks. For patients more than 50 years of age treated with PVC plus RT, MTP was 23 weeks and MST was 51 weeks; in the PVC group, MTP was 17 weeks and MST was 39 weeks. Age, Karnofsky index, areas of Grade 2, and absence of extensive necrosis in the tumor were significant prognostic factors in the univariate analyses. Patients less than 50 years of age treated with PVC plus RT had significantly longer survival (P = 0.037) when correcting for these factors in a multi-variate analysis.
Adult↗
Increased frequency of chromosome aberrations in long-term cultured cerebrospinal fluid lymphocytes of patients with multiple sclerosis.
A method employing long-term lymphocyte culturing was developed to study chromosome aberrations in samples with very few cells. It was used to examine lymphocytes from the cerebrospinal fluid (CSF) and peripheral blood (PB) in 23 patients with clinically definite multiple sclerosis (MS), nine patients with other neurological diseases (OND), and eight healthy individuals. MS patients had significantly more aberrations in CSF lymphocytes than in PB lymphocytes (6.4 vs 4.1; P = 0.003). In contrast, no such difference was noted among patients with OND (3.8 vs. 3.7; P = 0.89) or healthy controls (3.6 vs 3.5; P = 0.90). CSF lymphocytes from MS patients had more aberrations than CSF lymphocytes from healthy controls (P = 0.012), but there was no difference between PB lymphocytes from MS patients and controls (P = 0.58). The patients with OND were similar to healthy controls both in CSF (3.8 vs 3.6; P = 0.91) and PB lymphocytes (3.7 vs 3.5; P = 0.90).
Adult↗
Analysis of peripheral blood lymphocyte phenotype and function during dexamethazone treatment of progressive multiple sclerosis.
Five patients with chronic progressive multiple sclerosis (MS) and three control patients with lumbar disc herniation were treated with dexamethazone during 14 days. The effect on peripheral blood T-cell subsets and on the proliferative response of peripheral blood mononuclear cells (PBMC) to pokeweed mitogen (PWM) and anti-mu antibody was analyzed. Before treatment, the proportion of CD3+ and CD4+ PBMC was similar in MS and control patients, but the proportion of CD8+ and DR+ PBMC was lower and the PBMC were less responsive to anti-mu stimulation in MS patients compared to controls. Steroid treatment induced reversible granulocytosis and lymphocytosis. CD3+ and CD4+ cells increased and DR+ cells decreased in MS patients but not in controls. Proliferation of anti-mu stimulated PBMC increased in MS-patients during the two weeks of treatment, but decreased in controls. The enhancement in the MS patients of pre-existing immune abnormalities suggests that a cautious attitude is warranted in the use of steroid treatment in chronic progressive MS.
Adult↗
A long-term prospective study of optic neuritis: evaluation of risk factors.
Eighty-six patients with monosymptomatic optic neuritis of unknown cause were followed prospectively for a median period of 12.9 years. At onset, cerebrospinal fluid (CSF) pleocytosis was present in 46 patients (53%) but oligoclonal immunoglobulin in only 40 (47%) of the patients. The human leukocyte antigen (HLA)-DR2 was present in 45 (52%). Clinically definite multiple sclerosis (MS) was established in 33 patients. Actuarial analysis showed that the cumulative probability of developing MS within 15 years was 45%. Three risk factors were identified: low age and abnormal CSF at onset, and early recurrence of optic neuritis. Female gender, onset in the winter season, and the presence of HLA-DR2 antigen increased the risk for MS, but not significantly. Magnetic resonance imaging detected bilateral discrete white matter lesions, similar to those in MS, in 11 of 25 patients, 7 to 18 years after the isolated attack of optic neuritis. Nine were among the 13 with abnormal CSF and only 2 belonged to the group of 12 with normal CSF (p = 0.01). Normal CSF at the onset of optic neuritis conferred better prognosis but did not preclude the development of MS.
Adolescent↗
The germline repertoire of T-cell receptor beta chain genes in patients with relapsing/remitting multiple sclerosis or optic neuritis.
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Gene Frequency↗
DNA typing for HLA-DPB1*02 and -DPB1*04 in multiple sclerosis and juvenile rheumatoid arthritis.
DP gene typing using in vitro DNA amplification combined with sequence-specific oligonucleotide probes (SSOP) has recently been reported. The amplification step may be specific for the HLA-DPB locus, or it may be specific for one or a group of HLA-DPB alleles, thus increasing the discriminatory power of the system. We report the combined use of group-specific DNA in vitro amplification followed by SSOP in typing for DPB1*02 and DPB1*04 variants. The method was used to type for these variants in 96 randomly selected, healthy Danes, in 37 patients with pauciarticular juvenile rheumatoid arthritis (PJRA), and in 38 patients with multiple sclerosis (MS). Increased frequencies of the cellularly defined HLA-DPw2 in PJRA and of HLA-DPw4 in MS have previously been reported. In the patient groups, the frequencies of the DPB1*02 and DPB1*04 variants did not differ significantly from those expected based on the cellularly defined HLA-DP types of the patients and the frequencies of the DPB1*02 and DPB1*04 variants among healthy Danes.
Amino Acid Sequence↗
Tumor necrosis factor alpha gene polymorphism in multiple sclerosis and optic neuritis.
The NcoI tumor necrosis factor (TNF alpha) polymorphism was studied in relapsing/remitting multiple sclerosis and monosymptomatic optic neuritis. The frequency of the NcoI marker phenotypes did not differ between healthy controls and the two disease groups. No extra or missing DNA fragments were observed in the disease groups when compared with controls.
Adolescent↗
Failure to demonstrate human T cell lymphotropic virus type I in multiple sclerosis patients.
The polymerase chain reaction (PCR) technique was employed in searching for human T cell lymphotropic virus type I (HTLV-I) gag, env and pol sequences in samples of DNA prepared from two HTLV-I seropositive patients with tropical spastic paraparesis (TSP), the Swedish multiple sclerosis (MS) patients who recently have been reported to be PCR-positive for HTLV-I gag and env sequences, and eight healthy individuals. Precautions were taken in order to reduce the risk of cross-contamination in the PCR. In the two TSP patients strong signals were obtained with gag, env and pol amplification primers and detection probes. In MS patients and healthy individuals, no signals were obtained with gag and env. In occasional experiments, weak signals were seen for the pol segment for a single MS patient and/or healthy individuals, but these signals were not reproducible in subsequent experiments. Thus, the present data do not confirm the presence of HTLV-I sequences in MS patients.
Base Sequence↗
Amplification and molecular cloning of HTLV-I sequences from DNA of multiple sclerosis patients.
Techniques of gene amplification, molecular cloning, and sequence analysis were used to test for the presence of sequences related to human T-lymphotropic virus type I (HTLV-I) in peripheral blood mononuclear cells of six patients with multiple sclerosis (MS) and 20 normal individuals. HTLV-I sequences were detected in all six MS patients and in one individual from the control group by DNA blot analysis and molecular cloning of amplified DNAs. The viral sequence in MS patients were associated with adherent cell populations consisting predominantly of monocytes and macrophages. Molecular cloning and nucleotide sequence analysis indicated that these amplified viral sequences were related to the HTLV-I proviral genome.
Adolescent↗
Increased proportion of CD4+CDw29+CD45R-UCHL-1+ lymphocytes in the cerebrospinal fluid of both multiple sclerosis patients and healthy individuals.
In this study we confirm earlier reports of an increase of the proportion of T and CD4+ lymphocytes and a decrease of B and CD8+ lymphocytes in cerebrospinal fluid (CSF) as compared to peripheral blood (PB) in MS patients. In addition we now demonstrate that this difference between CSF and PB lymphocyte populations is of the same magnitude in healthy individuals suggesting that it is physiological and not associated with disease. Functionally distinct subsets of the T human helper cell (CD4+) population have previously been defined by the monoclonal antibodies 4B4 (CDw29), Leu-18 (CD45R), and UCHL-1. In the present investigation we demonstrate a selective increase in the proportion of CD4+CDw29+CD45R-UCHL-1+ lymphocytes in CSF as compared to PB of both MS patients and healthy individuals, which strongly indicates that also this enrichment is physiological rather than associated with disease. A possible relationship between this subset of CD4+ lymphocytes and T memory cells is discussed.
Antigens, Differentiation↗
Bone marrow derived cells express human T-cell lymphotropic virus type I (HTLV-I)-related antigens in patients with multiple sclerosis.
Mononuclear cells in peripheral blood (PB) and cerebrospinal fluid (CSF) of seven patients and lymph nodes of three patients with clinically definite multiple sclerosis (MS) expressed antigens that reacted with monoclonal antibodies (MoAb) specific for HTLV-I p19 and p24 gag proteins. The labelled cells were visualized with immunoperoxidase staining and indirect immunofluorescence and identified at the ultrastructural level with immunogold technique. The frequency of these cells was low, ranging from 0.1% to less than 0.01% in blood. In CSF it was approximately 10 times lower. Cells reacting with anti-p19 Ab were found in all MS samples, whereas cells reacting with anti-p24 Ab were found in 3 out of 6 blood samples and in 3 out of 7 CSF samples. All lymph nodes (3/3) obtained from MS patients contained cells that reacted with anti-HTLV-I. p19 and p24 Ab. Cells reacting with the same AB were detected in blood of one out of 12 healthy controls. Stained cells were irregular, distinctly larger than lymphocytes, and had abundant cytoplasm, suggesting that they may be monocytes/macrophages. Immunogold particles were located in vacuole-like structures in the cytoplasm. The presence in MS patients of cells that react with HTLV-I Ab indicates that a human retroviral genome is being expressed, and suggests that a virus may be present. Our data support a role for a human retrovirus in multiple sclerosis.
Antibodies, Monoclonal↗
HLA-DP antigens are involved in the susceptibility to multiple sclerosis.
Forty-five unrelated patients with multiple sclerosis (MS) from Sweden and 166 Danish controls were typed for HLA-DP using Primed Lymphocyte Typing. Thirty-nine MS-patients and 63 controls were also DNA-typed with the Restriction Fragment Length Polymorphism (RFLP) technique for HLA-DP and -DR genes. The frequencies of DPw4 were 93.3% in MS patients and 72.3% in controls (relative risk, RR = 5.4, p = 0.0014). The DR2 antigen was present in 75.5% of the patients and in 33.7% of the controls (RR = 6.1, p less than 10(-6)). DPw4 was not associated (i.e., was not in linkage disequilibrium) with DR2 in patients or controls. Thus, in MS the associations with DP and DR are independent of each other. However, the combined presence of DPw4 and DR2 gave a significantly higher risk than each antigen alone, indicating that synergism between DP and DR gene products may play a role in the genetic susceptibility to MS.
HLA-D Antigens↗
The intrathecal immune response in the early stage of multiple sclerosis.
Sequential pairs of cerebrospinal fluid (CSF) and serum samples from 10 patients followed for 2.5-12 years after onset of unilateral optic neuritis (ON) were studied. Eight patients developed definite multiple sclerosis (MS) during the observation period. All patients had normal CSF protein patterns on agar or agarose gel electrophoresis at onset. Six patients developed oligoclonal immunoglobulin (Ig) bands in the CSF during the observation period. Imprint immunofixation of electrofocused specimens disclosed intrathecal synthesis of oligoclonal IgG antibodies to 1 or more of 6 viruses (measles, herpes simplex type 1, varicella-zoster, cytomegalo, mumps, rota) during the observation period in 8 patients. Changes in patterns of intrathecally synthesized viral antibodies, characterized by the appearance of "new" antibody populations and the waxing or waning of others were observed in 6 patients. The results suggest that the early stage of MS in some patients is associated with transient as well as permanent recruitment of B cell clones producing viral antibodies of different specificities.
Antibodies, Viral↗
Multiple sclerosis: facts or artifacts?
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Humans↗
Humoral immune responses within the human central nervous system following systemic immunization.
We investigated sequential humoral immune responses in the CSF and blood of 6 stable multiple sclerosis (MS) patients without decreases in the blood-brain barrier. Anti-tetanus toxoid antibodies (anti-TT Ab) increased to a similar relative degree within the CSF and blood starting within 2 weeks after subcutaneous booster injection of TT. In 3 of 4 subjects, CSF lymphocytes obtained at 2 weeks secreted anti-TT Ab to the same degree as autologous blood lymphocytes when cultured with pokeweed mitogen. These findings suggest a prompt antibody response within the CSF to systemically administered antigen, not due to diffusion from the serum, with active trafficking of TT-sensitized lymphocytes into the central nervous system.
Adult↗
Regulation of interleukin 2 receptors on T cells from multiple sclerosis patients.
Receptors for interleukin 2 (IL-2) are absent on resting T lymphocytes and are induced by antigenic and mitogenic stimulation. After a limited time (8-12 days), these receptors on normal T cells are down-regulated despite the presence of receptor-saturating concentrations of IL-2. We report here that both antigen- and mitogen-induced T-cell lines and clones obtained from peripheral blood and cerebrospinal fluid of multiple sclerosis patients show prolonged expression of IL-2 receptors. This expression is coincident with a prolonged responsiveness to the proliferative effects of IL-2. In addition, Leu 3+, IL-2 receptor-positive T-cell clone from the cerebrospinal fluid of a multiple sclerosis patient has been established and maintained for more than 1 year without IL-2. This clone has some morphologic and histochemical properties of T cells transformed or infected by human T-lymphotropic virus type I.
Antibodies, Monoclonal↗