Increased lymphocyte beta-adrenergic receptor density in progressive multiple sclerosis is specific for the CD8+, CD28- suppressor cell.

Beta-adrenergic receptor density on T cells from healthy humans is greatest on suppressor cells (CD8+, CD28-) and the effect of catecholamines, secreted by the sympathetic nervous system, predominates on this subset. The sympathetic skin response, a measure of sympathetic nervous system function, is absent in most patients with chronic progressive multiple sclerosis (MS). We measured beta-adrenergic receptor density on suppressor cells, cytotoxic cells, and monocytes from patients with chronic progressive MS and healthy control subjects. Control receptor density on suppressor cells was 2.8 +/- 0.3 fmol/10(6) cells versus a density of 5.1 +/- 0.7 fmol/10(6) cells for patients. Cytotoxic cell (CD8+, CD28+) receptor density was 1.4 +/- 0.4 fmol/10(6) cells in control subjects and 0.9 +/- 0.3 fmol/10(6) cells in the patients. Monocytes displayed beta-adrenergic receptor densities of 2.6 +/- 0.4 fmol/10(6) cells in normal individuals and 2.7 +/- 0.4 fmol/10(6) cells in the patient group. CD8 lymphocyte beta-adrenergic receptor densities in patients with relapsing-remitting and those with stable MS were not different from control values, yet were significantly less than the values for patients with chronic progressive MS. We find that mononuclear cells from healthy control subjects and patients with chronic progressive MS proliferate in response to 200 units/ml of recombinant human interleukin-2 (IL-2) similarly. However, IL-2 treatment increased beta-adrenergic receptor density on normal mononuclear cells, but failed to increase it on mononuclear cells from patients with chronic progressive MS.(ABSTRACT TRUNCATED AT 250 WORDS)     

Increased muscarinic cholinergic receptor density on CD4 lymphocytes in progressive multiple sclerosis

We measured the density and affinity of muscarinic cholinergic receptors (MR) in 29 chronic progressive and ten stable multiple sclerosis (MS) patients and 27 control subjects using [3H]N-methyl-scopolamine. The density of MR on CD4+ lymphocytes was significantly higher in chronic progressive MS (CPMS) than in controls (7.9 +/- 0.7 vs. 4.5 +/- 0.4 fmol/10(6) cells, p less than 0.001). Stable patients did not differ significantly from control subjects. Receptors of the M1 subtype were measured on CD4+ lymphocytes of nine patients and seven controls with the selective antagonist [3H]methylpirenzepine: M1/total receptor ratio was 64.1% in CPMS and 81.2% in controls, suggesting a selective increase of M2-type MR in CPMS. The findings may relate to parasympathetic denervation hypersensitivity of lymphocytes or to lymphocyte activation which is known to be associated with increased MR number.     

Increased T-lymphocyte interleukin-6 binding in patients with multiple sclerosis.

Multiple sclerosis (MS) represents a T-cell-mediated autoimmune demyelinating disease of the central nervous system associated with altered immunoregulation. Interleukin (IL)-6 is a cytokine that has several effects on the neuroimmune system. Specific IL-6 receptors have been found in human lymphocytes and neuroglial cells. The aim of the present study was to assay IL-6 binding on peripheral blood T lymphocytes in MS patients. We found that T cells from MS patients had significantly more IL-6 receptors [Bmax: 279 +/- 7 vs. 246 +/- 8 (mean +/- SEM) receptors/cell, in patients and controls, respectively], whereas Kd values were similar to those of healthy subjects [26.8 +/- 0.7 vs. 25.4 +/- 0.6 (mean +/- SEM) pM, in patients and controls, respectively]. Significant (P < 0.05) differences in IL-6 binding values were observed between stable patients and those relapsing (272 +/- 9 vs. 300 +/- 12 (mean +/- SEM) receptors/cell, respectively). We found significantly (P < 0. 001) higher amounts of IL-6 receptors on CD4+ T cells from MS patients than on CD4+ lymphocytes from controls (434 +/- 11 vs. 363 +/- 9 (mean +/- SEM) receptors/cell, respectively); CD8+ T cells showed very few IL-6 receptors in both patients and controls. These data are discussed in terms of MS immune pathogenesis and pathophysiology, because T-cell activation seems to be linked to increased IL-6 binding. The upregulated IL-6 system might be involved in antibody-mediated demyelinating pathways, because IL-6 is well known to enhance humoral immune response.     

Activated suppressor cell function in multiple sclerosis--clinical correlations

Activated suppressor cell function mediated by either freshly isolated peripheral blood mononuclear cells (MNCs), freshly isolated CD8+ lymphocytes or by CD8+ cell lines, has previously been found to be reduced compared to controls in multiple sclerosis (MS) patients with progressive disease (MS-P). In this study, we found that suppressor activity mediated by CD8+ cell lines, derived from MS patients with stable disease (MS-S) patients and maintained in culture for 14 days, was significantly greater (45 +/- 6%) compared to that mediated by MS-P patients' CD8+ cells (11 +/- 4%, P less than 0.005). The MS-S suppressor values were, however, suggestively reduced compared to controls (60 +/- 6%, P less than 0.05). MNC-mediated suppressor values for the MS-S group (61 +/- 5%) did not differ from the control group (67 +/- 6%). Values for the MS-P group (7 +/- 6%) were significantly reduced compared to MS-S and control groups. Cytotoxic activity mediated by CD8+ cell lines showing defective suppressor function did not differ from control values. The cell lines in MS and control did not differ with respect to their rate of proliferation in the presence of IL-2 and OKT3. Suppressor function in this assay was ablated if exogenous IL-2 was removed from the culture media. These data suggest that defective activated suppressor function is characteristic of the progressive form of MS, although a suppressor defect is also partially expressed in stable MS patients when CD8+ cell lines are studied.     

beta-Adrenergic receptor density and function of peripheral blood mononuclear cells are increased in multiple sclerosis: a regulatory role for cortisol and interleukin-1.

An increased density of beta-adrenergic receptors was demonstrated on peripheral blood mononuclear cells (PBMCs) from patients with progressive or relapsing-remitting multiple sclerosis (MS). The same observation was made in patients with chronic active rheumatoid arthritis, but not in those with myasthenia gravis. The affinity of the receptors was within the normal range in all tested groups of patients and there was a positive correlation between density and function as determined by intracellular cyclic AMP production after stimulation with isoproterenol. A putative link between inflammatory process and the functional upregulation of beta-adrenergic receptors on PBMCs was tested by in vitro studies with the soluble mediators interleukin-1 and hydrocortisone. A functional upregulation of beta-adrenergic receptors was observed when PBMCs from normal control subjects were cultured in the presence of either mediator, whereas the already upregulated receptor density on PBMCs from patients with MS remained unchanged. Whether this represents a recovery mechanism to inflammation in MS or a blunting of homeostatic immunoregulatory mechanisms requires further investigation.     

Beta-adrenergic system in myotonic dystrophy.

Myotonic dystrophy (DM) is considered an inherited membrane disorder, but the basic defect is unknown. We studied plasma catecholamines as well as lymphocyte and muscle beta-adrenergic receptor densities and functioning in 19 DM patients and 15 control subjects. Plasma adrenaline and noradrenaline concentrations were not significantly different between DM patients and controls. In isolated lymphocytes basal cAMP production was 157 +/- 26 pmol/mg protein/10 min in DM patients and 91 +/- 12 pmol/mg protein/10 min in controls (n.s.), whereas isoproterenol-stimulated cAMP production was significantly higher in DM patients (285 +/- 42 pmol/mg protein) compared with control subjects (168 +/- 21 pmol/mg protein, P less than 0.05). Lymphocyte beta-adrenoceptor densities were similar among DM patients (50 +/- 3 fmol/mg protein) and controls (47 +/- 5 fmol/mg protein). beta-Adrenoceptor densities were also similar in muscle biopsy specimens (12.9 +/- 1 in DM and 13.1 +/- fmol/mg protein in controls). The correlation between lymphocyte and skeletal muscle receptor densities was r = 0.35 in DM patients and r = 0.22 in controls. The results do not support the hypothesis of adrenergic dysfunction in DM despite its membrane involvement.     

Intracortical multiple sclerosis lesions are not associated with increased lymphocyte infiltration

The present study examined the extent and distribution of lymphocyte infiltration in demyelinated lesions in the cerebral cortex of multiple sclerosis (MS) patients. Tissue sections from the brain of 10 MS patients and five patients without neurological disease were double labeled for myelin basic protein and the lymphocyte markers CD3, CD4, CD8, CD45RO, and CD20. The highest density of CD3-positive T cells was found in MS white matter lesions (40.4/10 high power fields (hpf)). Fewer T cells were detected in cortical lesions that extended through both white and gray matter (12.1/10 hpf; P < 0.001). The lowest number of T cells was detected in intracortical demyelinated lesions (1.1/10 hpf). This was equal to the lymphocyte density in nondemyelinated cerebral cortex within the same tissue block (1.1/10 hpf) or cerebral cortex in control brains (1.8/10 hpf). A similar distribution was found using the CD4, CD8, and CD45RO markers. CD20-positive B cells were scarce in all specimens examined. These data indicate that areas of intracortical demyelination in chronic MS are not associated with an increased number of lymphocytes, or an altered distribution of lymphocyte subsets, when compared with control areas in MS and control patients. This finding indicates that the extent of lymphocyte infiltration in MS lesions is dependent on lesion location.     

T-cell interferon gamma receptor binding in interferon beta-1b-treated patients with multiple sclerosis

OBJECTIVE: To investigate the effects of interferon beta treatment on T-cell interferon gamma binding (which is a possible marker for T-cell-dependent immune function) in patients with multiple sclerosis (MS). DESIGN: Assay interferon gamma binding on T lymphocytes from patients with stable relapsing-remitting MS before, 3 months after, and 6 months after initiating interferon beta-1b treatment. SETTING: The study was performed on ambulatory patients in a tertiary care center, where patients were diagnosed as having definite MS. PATIENTS: Eighteen patients with clinically definite, stable, relapsing-remitting MS (13 women and 5 men; mean age [+/-SD] 32.6+/-7.1 years) were selected consecutively. Clinical status was defined according to the Kurtzke Expanded Disability Status Scale. All patients were treated with 8 x 10(6) IU interferon beta-1b subcutaneously every other day. Eighteen age- and sex-matched healthy subjects with no family history of neuropsychiatric disorders formed the control group. RESULTS: T lymphocytes from untreated patients with MS had significantly smaller amounts of interferon gamma receptors than those from control subjects (638+/-7 [SE] vs 707+/-11 [SE] receptors per cell). After 3 months of interferon beta-1b treatment, they showed a significant increase in interferon gamma binding (681+/-9 [SE] receptors per cell). After 6 months, T-cell interferon gamma maximal receptor values were even higher (700+/-7 [SE] receptors per cell), only slightly lower than those of control subjects. CONCLUSION: Given that reduced interferon gamma binding might be related to lymphocyte activation, our data seem to demonstrate that the major effect of interferon beta-lb treatment is a decrease in T-cell activation.     

Increased serotonin2 and beta-adrenergic receptor binding in the frontal cortices of suicide victims

A statistically significant 28% increase in the mean (+/- SD) number of serotonin2 receptors (127.8 +/- 13.4 vs 99.6 +/- 11.1 fmol/mg of protein) and a 73% increase in beta-adrenergic receptor binding (14.5 +/- 1.5 vs 8.4 +/- 1.5 fmol/mg) was found in the frontal cortices of violent suicide victims compared with matched controls. No significant differences were found in the number of serotonin1 binding sites (109.5 +/- 13.4 vs 99.9 +/- 8.8 fmol/mg). We have previously reported a reduced density of presynaptic tritiated imipramine binding sites on serotonergic nerve terminals in the frontal cortices of suicide victims. These data support the hypothesis that suicide completed by violent methods is associated with reduced presynaptic serotonergic activity that has generated compensatory upregulation of the postsynaptic serotonin2 receptor sites. The increase observed in beta-adrenergic binding suggests that there may also be a concomitant reduction in presynaptic noradrenergic activity associated with suicide. If antidepressant pharmacotherapies specifically downregulate cortical beta-adrenergic and/or serotonin2 receptors in depressed subjects, as has been demonstrated in animal studies, and since these effects would be in the opposite direction of the receptor changes found in suicide victims, they may account for the therapeutic action of antidepressants on suicidal behavior and depressive disorders.     

Interleukin-1 and interleukin-2 production by peripheral blood mononuclear cells in multiple sclerosis patients

The production of interleukin-1 (IL-1) and interleukin-2 (IL-2) by peripheral blood mononuclear cells (PBM) was assessed in multiple sclerosis (MS) patients in relapse, chronic progressive MS patients, patients with other neurological diseases (OND) and healthy subjects. Production was defined as the level of IL-1 and IL-2 in PBM supernatants. Neither spontaneous nor LPS-induced IL-1 production differed significantly in MS, OND patients or healthy individuals. On the other hand PHA-induced PBM IL-2 production was significantly less in MS patients in relapse (130 +/- 10.0 U/ml) than in chronic progressive MS patients (172 +/- 9.8 U/ml), OND patients (192 +/- 11.5 U/ml) and healthy subjects (215 +/- 13.8 U/ml) (P less than 0.02). Spontaneous IL-2 production was also diminished in MS patients in relapse (31 +/- 7.2 U/ml) as compared to chronic progressive MS patients (46 +/- 8.8 U/ml) and healthy subjects (49 +/- 11.1 U/ml) (P less than 0.01). Anti-Tac monoclonal antibody was used to study IL-2 receptor expression on the same sample of PBM that was used for IL-2 study. MS patients in relapse had significantly higher levels of IL-2 receptor-positive unstimulated PBM (6.0 +/- 2.2%) as compared to chronic progressive MS (2.0 +/- 0.9%), OND (2.5 +/- 1.1%) and healthy subjects (1.5 +/- 0.7%) (P less than 0.002). We postulate that reduced apparent IL-2 production by PBM of MS patients in relapse may result from immediate IL-2 binding to receptor expressed on activated T lymphocytes and internalization of IL-2-receptor complex.     

Beta-adrenergic receptors and cAMP levels of rat parotid and submandibular glands during chronic isoproterenol treatment

The number of cell surface beta-adrenergic receptors and the level of cyclic AMP of the parotid and the submandibular gland were examined in rats treated for up to 10 days with twice daily injections of the beta-adrenergic agonist, isoproterenol. Receptor densities of 125 +/- 8.7 fmol/mg membrane protein for the parotid and 60.1 +/- 5.6 fmol/mg for the submandibular glands were found with [3H]dihydroalprenolol (beta-adrenergic receptor antagonist) binding of glands from control rats. No change from levels of controls was found in the number of beta-receptors of the submandibular gland with chronic isoproterenol stimulation; the parotid glands, on the other hand, showed a 22% decrease in dihydroalprenolol binding from the 4th until the 8th day of treatment. By day 10 of isoproterenol treatment the parotid gland demonstrated a shift from a population consisting of primarily beta-adrenergic receptors to one consisting of equal numbers of beta 1- and beta 2-adrenoceptors. The basal level of cAMP present in cell lysates remained unchanged in the isoproterenol-treated submandibular gland while the parotid gland showed a 30-40% decrease. Control and isoproterenol-treated animals demonstrated the same time course of cAMP accumulation after a single challenge with isoproterenol.     

CD80 (B7-1) and CD86 (B7-2) expression in multiple sclerosis patients: clinical subtype specific variation in peripheral monocytes and B cells and lack of modulation by high dose methylprednisolone.

Autoimmune activation of T cells by central nervous system (CNS)-derived antigens is hypothesised to underlie neural damage in multiple sclerosis (MS) patients. The role of coreceptor mediated signalling is currently under investigation in order to further elucidate the immunopathogenic mechanisms implicated and to determine possible targets for immune modulation. We have investigated whether differential coreceptor (B7-1/CD80; B7-2/CD86; CD28) expression on circulating lymphocytes and monocytes is (i) a feature of distinctive clinical subtypes of MS (relapsing-remitting in remission/stable-RRMS; relapsing-remitting in relapse/relapsing-RRMS; primary progressive/PPMS), (ii) related to disease activity, and (iii) altered by high dose corticocosteroid treatment. CD80(+) B cells were significantly reduced (P<0.05) in PPMS (4.0+/-0.8%) compared with normal subjects (CON) (9.1+/-1.1%), stable-RRMS (6.7+/-0.7%) and relapsing-RRMS (7.8+/-0.9%) patients. Comparatively fewer monocytes from relapsing-RRMS patients expressed CD86 (relapsing-RRMS 50+/-4.9% vs. stable-RRMS 75.1+/-3.4%, PPMS 77. 7+/-3.2%, CON 72.1+/-3.6%/P<0.05). Otherwise expression of coreceptors did not vary significantly between the groups. A 3-day course of methylprednisolone therapy did not alter coreceptor expression, but did suppress monocyte and B cell HLA-DR expression. There is evidence for differential coreceptor expression on circulating B cells and monocytes in MS disease subtypes. The biological significance of these findings is discussed in relation to alternative theories regarding coreceptor functioning.     

Circulating natural killer cells but not cytotoxic T lymphocytes are reduced in patients with active relapsing multiple sclerosis and little clinical disability as compared to controls

Triple antibody flow cytometry was used to compare the populations of CD56⁺ effector cells in the peripheral circulation of 29 patients with relapsing multiple sclerosis (MS) and little disability who were exacerbation-free for over 2 months and 29 healthy control subjects. Populations were characterized by two panels of antibodies (CD8, CD16, CD56 and CD3, CD8, CD56), as well as by size or granularity. In the MS patients, mature natural killer (NK) cells (CD3⁻CD8⁻CD56⁺) of small size and low granularity were significantly reduced compared to normals (P 〈 0.0003). The quantities of other effector cells (cytotoxic T lymphocytes, large granular lymphocytes and monocytes) were not different in MS patients compared to the control subjects. Also, we identified a previously unrecognized population of CD56⁺ monocytes (CD3⁻CD14⁺CD56⁺) in both the normal control subjects and the MS patients which would have been misclassified as NK cells using one or two antibody cytometry employed in previous studies.     

T-cells expressing natural killer (NK) receptors are altered in multiple sclerosis and responses to alpha-galactosylceramide are impaired

Multiple sclerosis (MS) is an autoimmune disorder characterised by clinical relapse and remission and pathological demyelination with varying inflammation. Because it is suggested that T-cells expressing natural killer cell receptors (NKR) play important roles in regulating human autoimmune diseases, we have quantified populations of T-cells expressing the NKR CD56, CD161 and CD94 in the peripheral blood of MS patients, in healthy control subjects (HS) and in patients with other neurological diseases (OND). CD161(+) T-cells and CD94(+) T-cells were significantly decreased in MS patients with primary progressive disease and secondary progressive disease respectively whereas CD56(+) T-cell numbers were unchanged. In contrast NKT-cells that express the invariant Valpha24-Jalpha18(+) T-cell receptor identified here by specific receptor antibody and CD1d-tetrameric PBS57-loaded complexes, were increased in MS patients compared with HS. Reductions in CD161(+) T-cells and CD94(+) T-cells relative to HS were also observed in the OND group and this was particularly prominent in Parkinsonian patients. A striking functional finding was that while NKT-cells in unfractionated peripheral blood from healthy subjects expanded in number and produced IFN-gamma upon stimulation with alpha-galactosylceramide, NKT-cells from MS patients did not. Thus we have identified alterations in a number of potentially important lymphocyte sub-populations warranting further investigation in the immune response in MS.     

Rat C6 glioma cells contain type I as well as type II corticosteroid receptors

Rat brain cytosol contains Type I corticosteroid receptors. Unlike Type II (glucocorticoid) receptors, Type I receptors have high affinity for the endogenous corticosteroids - aldosterone, deoxycorticosterone, and corticosterone - and much lower affinities for synthetic glucocorticoids. In the present study, we report that Type I corticosteroid receptors are present in C6 glioma cells. Type I receptors were identified in C6 cell cytosol and whole cells by the binding of [3H]aldosterone. The specific glucocorticoid RU 26988 was used to block Type II receptors. Measured in whole C6 cells, Type I receptors had a density of 2.1 +/- 1.1 fmol/10(6) cells and a dissociation constant (Kd) for [3H]aldosterone of 0.41 +/- 0.06 nM. The density of Type I receptors was only 2% of the density of Type II corticosteroid receptors (96 +/- 7 fmol/10(6) cells), measured in whole C6 cells by [3H]triamcinolone binding. The steroid specificity of glial cytosolic Type I receptors (deoxycorticosterone greater than corticosterone greater than aldosterone greater than dexamethasone greater than triamcinolone much greater than RU 26988) was identical to the steroid specificity of Type I receptors in rat brain cytosol. The potency of deoxycorticosterone was somewhat reduced when measured in whole cells. The steroid specificity of the Type I receptor differed markedly from that of the Type II (glucocorticoid) receptor (triamcinolone greater than dexamethasone greater than RU 26988 corticosterone greater than deoxycorticosterone greater than aldosterone). Since Type I receptors in the kidney mediate effects of aldosterone upon renal transport of sodium and potassium, it is proposed that glial Type I corticosteroid receptors may be involved in the regulation of glial ion transport.(ABSTRACT TRUNCATED AT 250 WORDS)     

T-cell interleukin-6 receptor binding in interferon-β-1b-treated multiple sclerosis patients

Multiple sclerosis (MS) is a T-cell-mediated autoimmune demyelinating disease of the central nervous system, associated with an altered cytokine network. We previously assayed peripheral blood T-lymphocyte binding for two prototypic cytokines, tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), and found that T cells from MS patients had significantly more TNF-alpha and IL-6 receptors than those from healthy controls. In the present work, paralleling a previous one on T-cell TNF-alpha binding, we studied the effect of interferon (IFN)-beta-1b treatment on T-lymphocyte IL-6 binding in patients with relapsing-remitting MS. T cells from MS patients had significantly (P < 0.001) higher amounts of IL-6 receptors than those from controls [292 +/- 6 vs. 228 +/- 8 (mean +/- SEM) receptors per cell, respectively], whereas the ligand-receptor affinity values were similar in the two groups [26.2 +/- 0.7 and 25.7 +/- 0.4 (mean +/- SEM) pmoles/l, respectively]. After a 3-month IFN-beta-1b treatment, they showed a significant decrease in IL-6 binding [266 +/- 7 (mean +/- SEM) receptors per cell]. After 6 and 9 months, T-cell IL-6 B(max) values were even lower [258 +/- 8 and 251 +/- 8 (mean +/- SEM) receptors per cell]. Since an increased IL-6 binding might be linked to a lymphocyte activation, our data give further support for an enhanced immune response in patients with MS. Our data seem to demonstrate that the major effects of IFN-beta-1b treatment result in a decrease of T-cell activation.     

Bradykinin B1 receptor expression and function on T lymphocytes in active multiple sclerosis

BACKGROUND: Lesion development in MS is initiated by migration of inflammatory cells into the central nervous system, a process dependent on endothelial cell-lymphocyte interaction. Bradykinin B1 receptor is a membrane-bound G protein-coupled receptor shown to be upregulated on the surface of various cells types during inflammation. OBJECTIVE: To assess the expression and function of the bradykinin B1 receptor on T lymphocytes from MS patients. METHODS: The authors used multiplex polymerase chain reaction amplification and Western blot techniques to demonstrate B1 receptor expression by T cells. A modified Boyden chamber assay also was used to assess the effect of B1 agonist and antagonist on T cell migration. RESULTS: The authors demonstrated that the expression of B1 receptor was upregulated on T cells derived from peripheral blood of MS patients. Expression of this receptor was upregulated on T cells from patients with secondary progressive MS and relapsing-remitting patients in active relapse. Expression was lower in relapsing remitting patients in remission and least in control subjects, including patients with epilepsy, chronic inflammatory demyelinating polyneuritis, and systemic lupus erythematosus. In vitro treatment of cells from healthy control subjects with tumor necrosis factor-alpha and interferon-gamma also induced the expression of B1 receptors. The authors also found that the significantly higher rate of migration of MS T lymphocytes, compared with control subjects in the Boyden chamber assay, could be prevented by the addition of the selective and stable B1 agonist Sar (D-Phe8) desArg9-BK. CONCLUSION: The authors demonstrate that B1 receptors are upregulated by T lymphocytes during the course of MS and that signaling through this receptor with a B1 agonist can negatively regulate T-cell migration in vitro.     

Analysis of multiple sclerosis cerebrospinal fluid reveals a continuum of clonally related antibody-secreting cells that are predominantly plasma blasts

Fluorescence-activated cell sorting (FACS) analysis of B cell subtypes in 17 CSF samples from 15 patients with clinically-definite MS revealed that CD19+ B cells accounted for 2 to 11% (mean 5%) and CD138+ cells constituted 0 to 5% (mean 2%) of total CSF lymphocytes. Further stratification of CD138+ cells based on expression levels of CD19 showed that CD138+19+ plasma blasts constituted 89+/-2% (mean+/-SE) of the CD138+ cell population (P<0.00001), with more mature plasma cells (CD138+19-) constituting the remaining 11+/-2%. Sequence analysis of immunoglobulin variable regions in single CD138+19+ and CD138+19- cells sorted from MS CSF identified many of the same clonal populations in both populations, indicating a continuum of clonally related plasma cell subtypes of which CD138+19+ plasma blasts are most abundant.     

Association of Th1/Th2-related chemokine receptors in peripheral T cells with disease activity in patients with multiple sclerosis and neuromyelitis optica

We evaluated 30 patients with clinically definite multiple sclerosis (MS) and 8 patients with neuromyelitis optica (NMO) to investigate correlations between Th1/Th2 balance, disease activity, effects of interferon (IFN)-β treatment, and expressions of chemokine receptors CXCR3 and CCR4 on CD4+ and CD8+ T cells in peripheral blood. MS and NMO patients in the relapsing phase showed a significantly increased CD4+CXCR3+/CD4+CCR4+ ratio and CD8+CXCR3+/CD8+CCR4+ ratio compared with respective patients in the remission phase. After IFN-β treatment, the CD4+CXCR3+/CD4+CCR4+ ratio and CD8+CXCR3+/CD8+CCR4+ ratio were significantly decreased compared with the relapsing phase and slightly lower than in the remission phase. The CD8+CXCR3+/CD8+CCR4+ ratio showed a more marked change associated with disease activity than CD4+ T cells in MS and NMO patients. Moreover, in patients in the relapsing phase of NMO, the CD4+CXCR3+/CD4+CCR4+ ratio and CD8+CXCR3+/CD8+CCR4+ ratio were significantly higher than in MS patients in the relapsing phase. We confirmed marked changes in the CD8+CXCR3+/CD8+CCR4+ ratio according to disease activity and treatment of MS and NMO. Furthermore, this ratio was more strongly linked to immune and inflammatory activity in NMO patients than in MS patients, and may represent an important factor in differentiating the pathogenesis of MS and NMO.     

Lymphocyte beta-adrenoreceptor density in patients with unipolar depression and normal controls

Values of binding maximum (Bmax) and dissociation constant (Kd) of (-)3-[125I]iodocyanopindolol (ICYP) were determined in beta-adrenergic receptors of membranes of peripheral lymphocytes in 32 patients with unipolar depression (DSM-III-R) and 31 normal controls. Results were analyzed by a two-way Analysis of Covariance method. A significant difference was noted for group assignment (patient versus control, p less than 0.05). Mean Bmax (fmol ICYP bound/mg lymphocyte membrane fraction total protein) of patients was 31.9 +/- 3.84 (SE) and controls 46.3 +/- 3.92 (SE). A significant interaction was found between group membership and gender (p less than 0.05). In the female patient group (n = 14), mean Bmax was 30.5 +/- 5.79 (SE); in female controls, mean Bmax was 56.0 +/- 5.15 (SE). Differences between male patients and male controls were not significant. Mean values of Kd (pmol/liter) showed a trend for patient values to be lower than control values [69.0 +/- 13.66 (SE) versus 108.5 +/- 14.42 (SE), respectively]. A significant inverse relationship was noted between lymphocyte beta-receptor Bmax and frequency of panic attacks during the depressive episode in 18 patients (p = 0.05). No relationship was found between values of Kd and frequency of panic attacks in these patients. Thus, preliminary evidence is provided for relationships among altered beta-adrenergic receptor binding, gender, and indices of panic-anxiety in unipolar depressed patients.