Chemokine receptors as biomarkers in multiple sclerosis

Leukocyte infiltrates characterize tissue inflammation and are thought to be integral in the pathogenesis of multiple sclerosis (MS). This attribute underlines the importance of understanding mechanisms of leukocyte migration. Chemokines are secreted proteins which govern leukocyte trafficking into targeted organs. Chemokine receptors (CKR) are differentially expressed on leukocytes and their modulation is a potential target for MS disease modifying therapies. Chemokines and their receptors are also potential biomarkers of both disease activity and response to treatment. We describe the fluctuations in CKR expression on peripheral leukocytes in a group of MS patients followed longitudinally for up to 36 months. We observed little fluctuation in CKR expression within each patient over time, despite considerable variability in CKR expression between patients. These observations suggest that individual patients have a CKR set point, and this set point varies from one patient to another. Evaluation of chemokines or chemokine receptors as biomarkers in MS will need to account for this individual variability in CKR expression.     

Fungal infection in cerebrospinal fluid from some patients with multiple sclerosis

Multiple sclerosis (MS) is the prototypical inflammatory disease of the central nervous system and spinal cord, leading to axonal demyelination of neurons. Recently, we have found a correlation between fungal infection and MS in peripheral blood of patients. The present work provides evidence of fungal infection in the cerebrospinal fluid (CSF) of some MS patients. Thus, fungal antigens can be demonstrated in CSF, as well as antibodies reacting against several Candida species. Comparison was made between CSF and blood serum for the presence of fungal antigens (proteins) and antibodies against different Candida spp. Analyses of both CSF and serum are complementary and serve to better evaluate for the presence of disseminated fungal infection. In addition, PCR analyses indicate the presence of DNA from different fungal species in CSF, depending on the patient analyzed. Overall, these findings support the notion that fungal infection can be demonstrated in CSF from some MS patients. This may constitute a risk factor in this disease and could also help in understanding the pathogenesis of MS.     

Monounsaturated fatty acids in blood cell membranes from patients with multiple sclerosis

The aim of this study was to investigate whether blood cell membrane monounsaturated fatty acids were associated with inflammation and disease outcome in patients with multiple sclerosis. The fatty acid composition in peripheral blood mononuclear cell and red blood cell membranes from 26 patients and 25 controls were determined by gas chromatography. Results showed positive associations between C-reactive protein and C16:1n-7, C18:1n-7, and C24:1n-9 in membranes from controls only. In general, C18:1n-9 and C20:1n-9 showed inverse correlations, while C16:1n-7 and C18:1n-7 showed positive correlations with disease outcome. Multiple sclerosis has a known inflammatory component. There is scarcity of literature on the role of monounsaturated fatty acids in inflammation, but results from this study suggested an association in healthy subjects between monounsaturated fatty acids and C-reactive protein, even at physiologically low levels. This association was not found in the plasma from patients. Furthermore, the n-9 and n-7 fatty acids played different roles in disease outcome, and therefore warrant inclusion, together with polyunsaturated fatty acids when investigating the inflammatory aspects of the disease.     

Serum alkaline phosphatase in patients with multiple sclerosis

Sera from multiple sclerosis patients show a deficit of intestinal alkaline phosphatase (serum type Pp2) by comparison with normal sera. This is not due to variation in ABO frequency, since the specimens from patients and normals are matched for ABO frequency, and it is not due to differences in secretor frequency, but represents a real dificit for Pp2 in patients with multiple sclerosis, particularly noticeable in group 0 individuals.     

Total knee replacement in patients with multiple sclerosis

Total knee replacement was performed on two patients with Multiple sclerosis. Severe hamstring spasticity was encountered in both patients in the immediate post-operative period requiring further surgery. Both patients remain ambulatory at follow-up. The disease, and its implications in patients warranting total joint replacement are discussed.     

T cells from multiple sclerosis patients recognize multiple epitopes on Self-IgG

The highly diversified variable regions of immunoglobulin (Ig) molecules contain immunogenic determinants denoted idiotopes. We have previously reported that T cells from multiple sclerosis (MS) patients recognize IgG from autologous cerebrospinal fluid (CSF), and mapped a T-cell epitope to an IgG idiotope. To test the ability of CSF IgG molecules to elicit a broad polyclonal T-cell response in MS, we have analysed T-cell responses in the blood and CSF against idiotope peptides spanning complementarity determining region (CDR) 3 and somatic mutations within the variable regions of monoclonal CSF IgG. Consistent with a diversified idiotope-specific T-cell repertoire, CD4(+) T cells from both patients recognized several idiotope peptides presented by HLA-DR molecules. Mutations were critical for T-cell recognition, as T cells specific for a mutated CDR1 peptide did not recognize corresponding germline-encoded peptides. One T-cell clone recognized both an idiotope peptide and the B-cell clone expressing this idiotope, compatible with endogenous processing and presentation of this idiotope by B cells. These results suggest that mutated CSF IgG from MS patients carry several T-cell epitopes, which could mediate intrathecal IgG production and inflammation in MS through idiotope-driven T-B-cell collaboration.     

Quality of life in Polish patients with multiple sclerosis

PurposeThis study is a pilot evaluation of the quality of life (QoL) in Polish patients with multiple sclerosis (MS).Material/methodsData from 21 centers in Poland were collected from May 2008 to January 2009. QoL was assessed using the questionnaire Euro Quality of Life (EQ-5D), with Polish population norms. Demographic profile of patients, duration/form/relapsing activity of the disease, disability and comorbidity were also analyzed.ResultsData from 3521 patients (F/M ratio 2.4:1) were collected. The average EQ-5D index was 0.8 ± 0.27 and the mean score in a visual analog scale (EQ-VAS) was 65.6 ± 21.5. There was a highly significant positive correlation between both indices (r = 0.7334, p < 0.0001). The mean patient age was 40.7 years (11.2–92.3 years) and disease duration was 10.3 ± 8.8 years (0.04–53 years). 74.2% of subjects had relapsing-remitting form of MS, while 17.2% were classified as secondary progressive and 8.6% as primary progressive. In the group of relapsing-remitting MS subjects there were 2.5% patients with “benign MS”. The average degree of disability on EDSS scale was 3.6 ± 2.2, while disability ≥6 was observed in 20.3% of patients. Most patients did not have other diseases besides MS.ConclusionsThis is the first large study of QoL in patients with MS in Poland (approximately 18% of all patients). Our results confirm a reduction in QoL compared with the general population. Further studies are indicated to identify the modifiable risk factors (e.g. type of treatment) that may affect QoL.     

Proteasome antibodies in patients with cancer or multiple sclerosis

Proteasome antibodies were detected by enzyme-linked immunosorbent assay in two of the 45 (4.4%) patients with lung cancer, 0 of the 39 patients with breast cancer and six of the 51 (11.8%) patients with ovarian cancer. Six of the 47 (12.8%) patients with relapsing remitting multiple sclerosis had proteasome antibodies, as well as two of the 100 (2%) blood donors. Significant higher odds ratios compared to the blood donors were found for the patients with ovarian cancer (OR: 6.4; 95% CI: 1.1–68) and multiple sclerosis (OR: 7.1; 95% CI: 1.2–74). There was no association between proteasome antibodies and metastases or onconeural antibodies. The antibodies showed reactivity to 23, 25 and 27 kD proteins of the 20S proteasome using Western blot. The increased prevalence of proteasome antibodies in patients with ovarian cancer or multiple sclerosis may reflect cellular damage and release of intracellular antigens. Whether the antibodies take part in the clearance of released proteasomes and thus participate in the pathogenesis of cancer or autoimmune disease is not known.     

Management of urinary incontinence in patients with multiple sclerosis

We investigated the management of urinary incontinence in 50 patients with multiple sclerosis (MS) in two London boroughs. Only seven appeared to be satisfied with the management of their bladder problems. A total of 51 suggestions was made for improving management in 33 of the patients. Most of these suggestions involved services which were available though not being used. The management of urinary incontinence in patients with MS should be tailored to the requirements of the individual. Alternative forms of management may often not be reaching patients who might benefit from them.     

Extensive cortical remyelination in patients with chronic multiple sclerosis

Recent studies revealed prominent cortical demyelination in patients with chronic multiple sclerosis (MS). Demyelination in white matter lesions is frequently accompanied by remyelination. This repair process, however, often remains incomplete and restricted to the lesion border. In the present study, we examined the frequency and extent of remyelination in cortical and white matter lesions in autopsy brain tissue of 33 patients with chronic MS. The majority of patients (29 of 33) harbored cortical demyelination. Remyelination of cortical lesions was identified light microscopically by the presence of thin and irregularly arranged myelin sheaths, and confirmed by electron microscopy. Extensive remyelination was found in 18%, remyelination restricted to the lesion border in 54%, and no remyelination in 28% of cortical lesions. A direct comparison of the extent of remyelination in white matter and cortical lesions of the same patients revealed that remyelination of cortical lesions was consistently more extensive. In addition, g-ratios of fibers in areas of "normal appearing cortex" yielded values consistent with remyelination. Our data confirm the high prevalence of cortical demyelination in chronic MS and imply that the propensity to remyelinate is high in cortical MS lesions.     

Variants of personality maladaptation in patients with multiple sclerosis

A total of 34 patients with multiple sclerosis (MS) aged 14–52 years, with disease onset at age 24.3 ± 7.5 years, were studied. Disease severity on the Kurtzke scale (EDSS) was 3.6 ± 1.7 points. Seven patients were in exacerbation of MS and 27 were in remission. Personality characteristics in terms of MS-associated maladaptation were studied using a modified MMPI (the SMPT method). Neurotic, psychotic, and mixed types of maladaptation were identified. Measures of brain metabolic activity were simultaneously determined (in terms of the rate of glucose utilization) by positron emission tomography (PET). Data were obtained on the relationship between the activity of metabolic processes in the frontal, temporal-parietal, and limbic areas of the cerebral cortex and different variants of personality maladaptation and, respectively, with different personality profiles in the SMPT. __________ Translated from Zhurnal Nevrologii i Psikhiatrii imeni S. S. Korsakova, Vol. 106, No. 8, pp. 13–20, August, 2006.     

Antibodies to oligodendroglia in patients with multiple sclerosis.

We demonstrated antibodies to isolated oligodendrocytes and to oligodendroglia in brain sections by indirect immunofluorescence technic in serums of 19 of 21 patients with multiple sclerosis. We also found such antibodies in three of five patients with subacute sclerosing panencephalitis and one of four patients with acute disseminated encephalomyelitis, but not in patients with other neurologic diseases or normal persons. The antibodies were absorbed by preincubation of serum with isolated oligodendrocytes or whole white matter, but not with purified myelin or liver tissue. Immunofluorescent staining was blocked by either rabbit anti-oligodendrocyte serum or non-fluoresceinated goat anti-human immunoglobulin. These findings suggest that antibodies to oligodendroglia are distinct from antibodies to myelin and that demyelination in multiple sclerosis could be a consequence of an immunopathologic reaction directed against oligodendroglial cells.     

Virological and immunological indices in patients with multiple sclerosis

The level of specific antibodies to viruses of measles, parotitis, type-6 herpes, Epstein-Barr, tick-borne encephalitis and Borrelia burgdorferi as well as presence of genetic samples and antigens of the above infectious antigens were studied in patients with multiple sclerosis (MS). The cytokines Th1 and Th2 parameters were investigated in blood serum of patients at different MS stages. The titer of antibodies to measles virus was noted to be increasing in MS patients with age and disease aggravation. The level of antibodies to any of the studied infectious agents, except for the type-6 herpes virus, was not dynamically changing for as long as 9 months. The viral genetic samples (measles RNA) were detected just once in 2 patients; the detection time coincided in both cases with MS aggravation. The cytokines dynamics failed to correlate with MS aggravation or exacerbation while the total index of all studied cytokines was decreased. A high MMPw 9 content in blood serum correlated with MS exacerbation in 1 patient.     

Amylolytic activity of IgM and IgG antibodies from patients with multiple sclerosis

IgG and IgM antibodies from the sera of patients with multiple sclerosis (MS) were found to possess amylolytic activity hydrolyzing alpha-(1-->4)-glucosyl linkages of maltooligosaccharides, glycogen, and several artificial substrates. Individual IgM fractions isolated from 54 analyzed patients with the clinically definite diagnoses of MS had approximately three orders of magnitude higher specific amylolytic activity than that for healthy donors, whereas IgG from only a few patients had high amylolytic activity. Strict criteria were used to prove that the amylolytic activity of IgMs and IgGs is their intrinsic property and is not due to any enzyme contamination. Fab fragments produced from IgM and IgG fractions of the MS patients displayed the same amylolytic activity. IgMs from various patients demonstrated different modes of action in hydrolyzing maltooligosaccharides.     

Degradation of human myelin in vitro by leucocytes from patients with multiple sclerosis.

In order to study the possible autoimmune basis of multiple sclerosis (MS) a quantitative method has been used to investigate breakdown of human myelin in vitro. We found that serum from MS patients and controls was generally devoid of any myelin degradative activity. However, isolated peripheral blood mononuclear cells from 43% of MS patients showed significant myelin degradative activity as did those from 61.5% of patients with rheumatoid arthritis (RA). Myelin degradation by cells was found in only 13% of patients with other neurological diseases and in no healthy controls. It is proposed that this non-specific peripheral cellular immune degradative activity originates from cells activated within the central nervous system of MS patients or the joints of individuals with RA. As a result, activity in the blood only indirectly reflects the ongoing inflammatory response at the primary site, accounting for the lack of correlation between changes in the blood and the clinical status of the MS patient. We further propose that the lack of in vitro myelin degradative activity in cells recovered from the cerebrospinal fluid is due to autoaggressive cells being sequestered to the brain.