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Objective: Multiple sclerosis (MS) is a neurological disease with a substantial genetic component and immune-mediated neurodegeneration. Patients with MS show structural brain differences relative to individuals without MS, including smaller regional volumes and alterations in white matter (WM) microstructure. Whether genetic risk for MS is associated with brain structure during early neurodevelopment remains unclear. In this study, we explore the association between MS polygenic risk scores (PRS) and brain imaging outcomes from a large, population-based pediatric sample to gain insight into the underlying neurobiology of MS. Methods: We included 8- to 12-year-old genotyped participants from the Generation R Study in whom T1-weighted volumetric (n = 1,136) and/or diffusion tensor imaging (n = 1,088) had been collected. PRS for MS were calculated based on a large genome-wide association study of MS (n = 41,505) and were regressed on regional volumes, global and tract-specific fractional anisotropy (FA), and global mean diffusivity using linear regression. Results: No associations were observed for the regional volumes. We observed a positive association between the MS PRS and global FA (β = 0.098, standard error [SE] = 0.030, p = 1.08 × 10 −3). Tract-specific analyses showed higher FA and lower radial diffusivity in several tracts. We replicated our findings in an independent sample of children (n = 186) who were scanned in an earlier phase (global FA; β = 0.189, SE = 0.072, p = 9.40 × 10 −3). Interpretation: This is the first study to show that greater genetic predisposition for MS is associated with higher global brain WM FA at an early age in the general population. Our results suggest a preadolescent time window within neurodevelopment in which MS risk variants act upon the brain. ANN NEUROL 2020;87:774–787.

ObjectiveTo investigate the possible human leukocyte antigen (HLA) association of both myelin oligodendrocyte glycoprotein (MOG-IgG)-associated diseases (MOGAD) and aquaporin-4 antibody (AQP4-IgG)-positive neuromyelitis optica spectrum disorders (NMOSDs) in the Dutch population with European ancestry to clarify similarities or differences in the immunogenetic background of both diseases.MethodsBlood samples from patients in the Dutch national MS/NMOSD expert clinic were tested for MOG-IgG and AQP4-IgG using a cell-based assay. HLA Class I and II genotyping was performed in 43 MOG-IgG–seropositive and 42 AQP4-IgG–seropositive Dutch patients with European ancestry and compared with those of 5,604 Dutch healthy blood donors.ResultsNo significant HLA association was found in MOG-IgG–seropositive patients. The AQP4-IgG–seropositive patients had a significant higher frequency of HLA-A*01 (61.9% vs 33.7%, OR 3.16, 95% CI, 1.707–5.863, p after correction [pc] = 0.0045), HLA-B*08 (61.9% vs 25.6%, OR 4.66, 95% CI, 2.513–8.643, pc < 0.0001), and HLA-DRB1*03 (51.2% vs 27.6%, OR 2.75, 95% CI, 1.495–5.042, pc = 0.0199) compared with controls.ConclusionsThe present study demonstrates differences in the immunogenetic background of MOGAD and AQP4-IgG–positive NMOSD. The strong positive association with HLA-A*01, -B*08, and -DRB1*03 is suggestive of a role of this haplotype in the etiology of AQP4-IgG–positive NMOSD in patients with European ancestry, whereas in MOGAD no evidence was found for any HLA association in these disorders.

Background and Objective: Fatigue and physical impairments are a major concern in children with multiple sclerosis (MS) and after acute disseminated encephalomyelitis (post-ADEM). We here aimed to evaluate the interaction between fatigue, exercise capacity, motor performance, neurological status, and quality of life (HRQoL). Methods: In this cross-sectional study, data of 38 children (MS n = 22, post-ADEM n = 16), aged 4–17 years attending our national pediatric MS center, were studied. Fatigue was measured with the Pediatric Quality of Life Multidimensional Fatigue Scale, exercise capacity with the Bruce Protocol, motor performance with the Movement Assessment Battery for Children second edition, HRQoL with the Pediatric Quality of Life Questionnaire, and extent of disability with the Expanded Disability Status Scale (EDSS). Results: Children with MS and post-ADEM experienced more fatigue ( p < 0.001), reduced exercise capacity ( p < 0.001), and impaired motor performance ( p < 0.001), despite low scores on the EDSS. Fatigue, but not the other parameters, was significantly correlated with HRQoL. Fatigue was not correlated with exercise capacity. Conclusion: We confirm the major impact of fatigue on quality of life in children with MS and post-ADEM. Fatigue was not explained by reduced exercise capacity or impaired motor performance. An important finding for clinical practice is that the low EDSS score did not reflect the poor physical functioning.

Background: Multiple sclerosis (MS) affects brain structure and cognitive function and has a heritable component. Over a 100 common genetic risk variants have been identified, but most carriers do not develop MS. For other neurodegenerative diseases, risk variants have effects outside patient populations, but this remains uninvestigated for MS. Objectives: To study the effect of MS-associated genetic variants on brain structure and cognitive function in the general population. Methods: We studied middle-aged and elderly individuals (mean age = 65.7 years) from the population-based Rotterdam Study. We determined 107 MS variants and additionally created a risk score combining all variants. Magnetic resonance imaging ( N = 4710) was performed to obtain measures of brain macrostructure, white matter microstructure, and gray matter voxel-based morphometry. A cognitive test battery ( N = 7556) was used to test a variety of cognitive domains. Results: The MS risk score was associated with smaller gray matter volume over the whole brain (βstandardized = −0.016; p = 0.044), but region-specific analyses did not survive multiple testing correction. Similarly, no significant associations with brain structure were observed for individual variants. For cognition, rs2283792 was significantly associated with poorer memory (β = −0.064; p = 3.4 × 10−5). Conclusion: Increased genetic susceptibility to MS may affect brain structure and cognition in persons without disease, pointing to a “hidden burden” of MS.

Multiple sclerosis (MScl) frequently is remitted during the third trimester of pregnancy but exacerbated in the first postpartum period. In this context, we investigated protein identification; its abundance, and its change in urine related to these two periods. Using mass spectrometry (LTQ Orbitrap), we identified 160 tryptic peptides (related to 402 proteins) in urine from 31 MScl and 8 control at these two periods. Pregnancy-related peptides were significantly elevated (p < 0.01) in MScl patients compared with controls (Analysis 1: 531 peptides in MScl and 36 peptides in controls higher abundant in the third trimester compared to postpartum). When comparing the longitudinal differences (Analysis 2), we identified 43 (related to 35 proteins) MScl disease-associated peptides (p < 0.01) with increased or decreased difference ratio in MScl compared with controls. The most discriminating peptides identified were trefoil factor 3 and lysosomal-associated membrane protein 2. Both proteins have a role in the innate immune system. Three proteins with a significant decreased ratio were plasma glutamate carboxypeptidase, Ig mu chain C region, and osteoclast associated immune like receptor. Our results indicate that the protein expression pattern in urine of MScl patients contains information about remote CNS and brain disease processes.

Natalizumab is a very effective, relatively new drug for the treatment of relapsing remitting multiple sclerosis. Inflammatory and neurodegenerative processes in the central nervous system are presumed to cause adverse effects during the course of this disease. To monitor the effects of natalizumab treatment on the cerebrospinal fluid (CSF) proteome of patients, CSF samples were taken from patients before commencing treatment as well as after 1 year of treatment. Profiling proteomics experiments using electrospray Orbitrap mass spectrometry and pair wise comparison of patients before and after 1 year of natalizumab treatment revealed a number of candidate biomarkers that were significantly differentially abundant between the before and after treatment groups. Three proteins were subsequently validated using selected reaction monitoring (SRM) in a new, independent sample set. All three proteins, Ig mu chain C region and haptoglobin, both known inflammation-related proteins, as well as Chitinase-3-like protein 1, were confirmed by SRM to be significantly lower abundant in CSF of multiple sclerosis patients after 1 year of natalizumab treatment. The findings for Chitinase-3-like protein 1, a presumed biomarker for more rapid progression from a first clinically isolated syndrome to clinically definite multiple sclerosis, was further confirmed by ELISA measurements.

B lymphocytes play a pivotal role in multiple sclerosis pathology, possibly via both antibody-dependent and -independent pathways. Intrathecal immunoglobulin G in multiple sclerosis is produced by clonally expanded B-cell populations. Recent studies indicate that the complementarity determining regions of immunoglobulins specific for certain antigens are frequently shared between different individuals. In this study, our main objective was to identify specific proteomic profiles of mutated complementarity determining regions of immunoglobulin G present in multiple sclerosis patients but absent in healthy controls. To achieve this objective, we purified immunoglobulin G from the cerebrospinal fluid of 29 multiple sclerosis patients and 30 healthy controls and separated the corresponding heavy and light chains via SDS-PAGE. Subsequently, bands were excised, trypsinized, and measured with high-resolution mass spectrometry. We sequenced 841 heavy and 771 light chain variable region peptides. We observed 24 heavy and 26 light chain complementarity determining regions that were solely present in a number of multiple sclerosis patients. Using stringent criteria for the identification of common peptides, we found five complementarity determining regions shared in three or more patients and not in controls. Interestingly, one complementarity determining region with a single mutation was found in six patients. Additionally, one other patient carrying a similar complementarity determining region with another mutation was observed. In addition, we found a skew in the κ-to-λ ratio and in the usage of certain variable heavy regions that was previously observed at the transcriptome level. At the protein level, cerebrospinal fluid immunoglobulin G shares common characteristics in the antigen binding region among different multiple sclerosis patients. The indication of a shared fingerprint may indicate common antigens for B-cell activation.

Background: Current MRI criteria can help predict a second attack after a clinically isolated syndrome (CIS). Given the known association between corpus callosum lesions (CC) and multiple sclerosis (MS), such lesions on MRI could provide additional predictive information. This study assessed whether the presence of CC lesion on MRI could, next to the modified Barkhof criteria, further enhance prediction of conversion from CIS to MS. Methods: Follow-up study of 158 patients with CIS who underwent MRI after CIS was performed. MRI were scored for the Barkhof criteria and CC lesion. Patients were classified as having MS according to Poser criteria. Cox regression models were used for the time to conversion from CIS to MS. Results: The Barkhof criteria and CC lesion were strongly associated with conversion to MS with hazard ratios (HR), respectively, of 2.6 (95% confidence interval [CI] 1.5-4.3) and 2.7 (95% CI 1.6-4.5). The HRs of CC lesion adjusted for the Barkhof criteria and the Barkhof criteria adjusted for CC lesion were similar (HRs 1.8, not significant). The combined prediction of the Barkhof criteria and CC lesion was 3.3 (95% CI 1.9-5.7). Patients not fulfilling the Barkhof criteria had a fourfold increased risk of MS (HR 3.8, 95% CI 1.5-9.3) when they had a lesion in the CC. Conclusions: Corpus callosum (CC) lesion and the Barkhof criteria both predicted conversion to multiple sclerosis (MS). When both variables were combined, the association was stronger. The assessment of CC lesion may be a useful additional tool for predicting conversion to MS in patients with clinically isolated syndrome. Neurology (R) 2009; 73: 1837-1841

HLA-DRB1 is the major locus associated with risk for multiple sclerosis (MS). A recent genome-wide study showed three additional single-nucleotide polymorphisms (SNPs), within the IL2RA and IL7RA genes respectively, also to be associated with MS. Consistent association but lower significance was found for 13 other SNPs. In this study, we aimed to verify association of these SNPs with MS in 46 MS patients and 194 controls from a Dutch genetically isolated population. Apart from the human leukocyte antigen locus, the EVI5 gene on chromosome 1 was confirmed as a novel risk gene, with odds ratios (ORs) even higher than those from the MS Consortium (ORs 2.01 and 1.9; P = 0.01). The risk effect of EVI5 was further validated for the general MS population in an independent set of 1318 MS patients from the Canadian Collaborative Project on the Genetic Susceptibility to MS. On the basis of the transmission disequilibrium testing, a weak but significant risk effect was observed (OR 1.15; P = 0.03 and OR 1.15; P = 0.04). This study confirms EVI5 as another risk locus for MS; however, much of the genetic basis of MS remains unidentified.

Prevalence of eight human herpesviruses (HHV1-8) was determined by real-time PCR in cell-rich cerebrospinal fluid (CSF) samples, obtained early after disease symptoms, of Dutch patients with multiple sclerosis (MS) and other noninfectious central nervous system diseases (NIND). Whereas HHV1-8 DNA was undetectable in CSF samples of MS patients, HHV6 DNA was detected in a plexus neuritis case and HHV7 DNA in an ependymoma and a Behccts' disease patient. However, intrathecal HHV infection was not detected. Data indicate that HHV1-8 are rarely detected in CSF of Dutch NIND patients and do not support the role of intrathecal HHV infection early after onset of disease symptoms in MS.

Systemic lupus erythematosus (SLE) patients are characterized by a low lymphocyte count, which is considered a specific disease marker and is related to disease activity. The membrane bound molecules CD25 and CD27 are expressed and released in a soluble CD25 (sCD25) and soluble CD27 (sCD27) form by activation of predominantly T cells. In previous studies it was claimed that sCD25 as well sCD27 might be used as parameters for activation of the immune system; a correlation between the sCD25 profile with the disease course in SLE patients was also shown. To assess the relationship between lymphocyte count and these T cell activation markers, we performed a cross-sectional and a longitudinal study. In the longitudinal study three SLE patients who were known for a long time at our outpatient clinic were studied. Both T cell markers strongly correlated with each other and formed a reflection of the disease course. In all 7 periods of exacerbation, which we observed in the 3 investigated patients, both levels increased preceding this period; however, no correlation was found with the lymphocyte count. In the cross sectional study of 69 patients with SLE, sCD25 and sCD27 levels were correlated with defined disease manifestations; sCD25 was elevated in all periods of increased disease activity. The same holds true for sCD27, with the exception of patients with nephritis in which the highest levels were observed. Both profiles of sCD25 and sCD27 were strongly correlated during the whole disease course. Our data prove that in the pathogenesis of SLE an active recruitement of unprimed and primed T cells takes place.

The expression of the T cell membrane molecule CD27 — a molecule that has recently been shown to belong to the nerve growth factor receptor superfamily — is strongly increased after activation of T lymphocytes via the T cell receptor/CD3 complex. In addition, activated cells release a 28–32 kDa soluble form of CD27 in their supernatant which can also be detected in serum and urine of healthy individuals. In this study we show that levels of soluble (s) CD27 are significantly elevated in cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients and of patients suffering from other inflammatory neurological diseases (OIND), whereas increased levels of sCD25 (soluble interleukin-2 receptor) were only found in CSF of patients with OIND. In MS patients, a significant correlation was found between CSF sCD27 titer and IgG index.

Background: Acute retinal necrosis (ARN) has been observed in several cases after herpetic encephalitis (HE). ARN is a devastating ocular disease with a very disappointing visual outcome. Therefore, early recognition and diagnosis are crucial. Objective: To study the association between ARN and preceding neurologic illness, especially the co-occurrence of HE in patients with ARN; to compare the causal agent in ARN and HE; and to determine the visual outcome of ARN with HE vs ARN without HE. Methods: A retrospective study including ophthalmologic and neurologic follow-up together with virologic data of patients with ARN. Participants: Seven patients with ARN diagnosed with a history of HE (13.5%) out of a source population of 52 patients with ARN admitted to a major academic ophthalmologic referral center between 1983 and 2008. Results: In five out of seven patients unilateral ARN occurred after HE under immunocompetent conditions, and both ARN and HE were caused by the herpes simplex virus (HSV), whereas the other two patients were immunocompromised, had bilateral ARN, and both ARN and HE were caused by the varicella zoster virus (VZV). The latency period between the HE and the ARN was shorter when VZV was involved than with HSV (5 weeks vs 20.6 months). The visual outcome in patients with ARN with HE, as defined by legally blind eyes after a follow-up of 1 year, did not differ significantly from patients with ARN without HE. Conclusion: Herpetic encephalitis seems to be a risk factor for acute retinal necrosis syndrome. Since treatment may improve the outcome at least for the second eye, it is relevant for clinicians to be aware of this association.

In 2 children, both aged 7 years, multiple sclerosis (MS) was diagnosed. In children, the initial clinical features of MS may vary greatly. The first patient presented with an acute disseminated encephalomyelitis (ADEM), and the other with a hemiparesis on the left side. In both patients, the disease was controlled by prolonged pharmacotherapy, starting with methylprednisolone and followed in the first patient by intravenous infusions of immunoglobulins and in the second patient by beta-interferon.

Objective To report the relationship between disease activity and health-related quality of life (HRQoL) in relapsing multiple sclerosis, and the impact of natalizumab. Methods HRQoL data were available from 2,113 multiple sclerosis patients in natalizumab clinical studies. In the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM) study, patients received natalizumab 300mg (n = 627) or placebo (n = 315); in the Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis (SENTINEL) study, patients received interferon beta-1a (IFN-β-1a) plus natalizumab 300mg (n = 589), or IFN-β-1a plus placebo (n = 582). The Short Form-36 (SF-36) and a subject global assessment visual analog scale were administered at baseline and weeks 24, 52, and 104. Prespecified analyses included changes from baseline to week 104 in SF-36 and visual analog scale scores. Odds ratios for clinically meaningful improvement or worsening on the SF-36 Physical Component Summary (PCS) and Mental Component Summary were calculated. Results Mean baseline SF-36 scores were significantly less than the general US population and correlated with Expanded Disability Status Scale scores, sustained disability progression, relapse number, and increased volume of brain magnetic resonance imaging lesions. Natalizumab significantly improved SF-36 PCS and Mental Component Summary scores at week 104 in AFFIRM. PCS changes were significantly improved by week 24 and at all subsequent time points. Natalizumab-treated patients in both studies were more likely to experience clinically important improvement and less likely to experience clinically important deterioration on the SF-36 PCS. The visual analog scale also showed significantly improved HRQoL with natalizumab. Interpretation HRQoL was impaired in relapsing multiple sclerosis patients, correlated with severity of disease as measured by neurological ratings or magnetic resonance imaging, and improved significantly with natalizumab. Ann Neurol 2007

In three women aged 20, 34 and 21, with a combination of optic neuritis and transverse myelitis, the diagnosis of neuromyelitis optica (Devic's disease) was made. All three were treated with methylprednisolone. The first patient died from respiratory failure associated with tetraparesis, over two years after experiencing initial symptoms. The other two women recovered to varying extents. By employing a combination of clinical investigations and MRI supplemented by laboratory investigations, it is possible to differentiate neuromyelitis optica from multiple sclerosis. Neuromyelitis optica is treated by a stronger form of immunosuppression. Despite recorded differences it remains possible that these conditions form part of the same spectrum in which the genetic background is important. In neuromyelitis optica the underlying condition seems to be in the field of the human immune response.

Studies demonstrating reduced quality of life and psychological well-being in multiple sclerosis (MS) have typically investigated patients within more advanced stages of disease. The aim of the present paper was to evaluate the emotional burden and quality of life of recently diagnosed MS patients and their partners.Data on health-related quality of life (SF-36), anxiety and depression (Hospital Anxiety and Depression Scale) and disease-related distress (Impact of Event Scale) were obtained in 101 patients and their partners (n=78).On average 8 months after diagnosis (range 0-24 months), 34% of the patients and 40% of the partners had clinically high levels of anxiety, and 36% of the patients and 24% of the partners had levels of severe distress. Scores of anxiety, depression and distress were higher in patients with more functional limitations (Expanded Disability Status Scale=3.0). Quality of life was significantly poorer in patients compared with controls, particularly among those with higher disability.Both patients and their partners demonstrated high levels of anxiety and distress in the early period after the diagnosis. These findings indicate careful attention by health care professionals to identify those who may benefit from further psychological support.

The aim of the present paper was to quantify expectations of wheelchair-dependency in patients recently diagnosed with MS (n = 101) and their partners (n = 78). Expectations focused on the risk and seriousness of becoming wheelchair-dependent in 2 years, 10 years or lifetime. Expectations were compared with natural history data, compared between patients and their partners, and related to clinical characteristics. Our results show that patients overestimated their 2-year and 10-year risks of wheelchair-dependency, but underestimated their lifetime risks. A large number of patients were uncertain about their 2-year risk, even those with no or only minimal disability [Expanded Disability Status Scale (EDSS)3.0]. One-third of the patients perceived the 10-year and lifetime risk to be 50%, which, as they explained in the interviews, reflected their uncertainty: they did not know what to expect - it might happen or not. Patients with more functional limitations had higher perceptions of risk, but lower perceptions of seriousness. Concordance in perceived risk and seriousness between patients and partners was moderate. The overestimation of the short-term risks and the substantial differences in expectations within couples warrant further research on the impact of expectations on their treatment decisions and psychological well-being.

A middle-aged woman was admitted to the hospital after being found unconscious at home. A brain CT scan excluded an intracranial bleed or other focal abnormality. Laboratory analysis showed hyponatraemia (sodium: 121 mmol L(-1)) and a low plasma osmolality, with normal sodium excretion and urine osmolality. A diagnosis of hyponatraemic coma was made. The patient was treated with water restriction; 24 h later the sodium was 135 mmol L(-1) and the patient was neurologically fully recovered. The patient, who suffered from von Willebrand's disease, had received desmopressin and ibuprofen for analgesia 2 days before after a dental intervention. She had received desmopressin several times in the past without any complications. A few patients treated with desmopressin for coagulation abnormalities have been reported to develop water intoxication and severe hyponatraemia resulting in seizures and coma. By inhibiting prostaglandin synthesis, non-steroid anti-inflammatory agents (NSAIDs) potentiate the effect of water reabsorption in the renal tubules of vasopressin, therefore enhancing water retention. Desmopressin and NSAIDs should not be used in combination in patients with bleeding disorders, but it is often followed in clinical practice. In addition, this is probably not an unusual situation in patients treated with desmopressin for other 'non-haemorrhagic' indications. This report emphasizes the need for practitioners to be aware of this rare but severe complication.

BACKGROUND: Measuring proliferative responses of T lymphocytes is a simple, reproducible and widely used assay of immune competence. Evidence suggests a role of T cell reactivity in autoimmune diseases. Interferon (IFN)-beta blocks in vitro proliferation of human T cells. OBJECTIVES: To assess (i) the relation between T cell proliferation and disease characteristics of MS patients, (ii) differences in T cell proliferation between subgroups and HC, and (iii) the predictive value of T cell proliferation for efficacy of IFN-beta. METHODS: Proliferative responses were measured in phytohaemagglutinin (PHA), anti-CD2/CD28 and anti-CD3 stimulated whole blood of 189 MS patients and 249 healthy controls (HC). Forty-eight patients started treatment with IFN-beta. Based on EDSS progression, number of relapses and steroid interventions, patients were classified as either clinical responder or nonresponder to IFN-beta. RESULTS: Significant differences between MS subgroups and HC were found in T cell responses upon both PHA stimulation (RR>HC: p=0.001 and SP>HC: p=0.001) and CD2/CD28 stimulation (RR>HC, SP>HC and PP>HC: all p values

Recently, effector T-cell subpopulations have been identified that can be distinguished by expression of members of the TNF-R family: CD4+OX-40+ cells are CD4 helper-effector cells CD8+CD45RA+CD27 cells are CD8-killer-effector cells. We investigated whether these lymphocyte subsets were increased in the active phase of multiple sclerosis (MS).Multiple colour immunofluorescence staining was performed on peripheral blood lymphocytes of 28 patients with active MS and of 29 healthy controls, followed by FACS analysis.Frequencies of CD8-killer-effector cells showed a wide interindividual range in both groups and percentages of CD4 helper-effector cells were low. No significant difference between the groups was observed for these subsets, but CD8+CD45RA-CD27 were increased in MS. In healthy individuals, CD4 helper-effector cells correlated with the total percentages of memory cells. Moreover, CD4+ and CD8 memory cells were strongly correlated.The here described recently identified effector CD4 and CD8 lymphocyte subpopulations were not increased in clinically active MS. It is however still possible that in MS, myelin-specific encephalitogenic cells reside within these subsets.

Differentiation of CD4 + T-cells is reflected by the change from the CD45RA + CD27 + phenotype via CD45RO + CD27 + to the CD45RO + CD27 − phenotype. To provide insight into the migration and activation of T-cells at the site of inflammation in rheumatoid arthritis (RA), CD27 expression by T-cells in peripheral blood (PB), synovial fluid (SF), and synovial tissue (ST) as well as the levels of the soluble form of CD27 (sCD27) in plasma and SF were studied in patients with RA. Since CD4 + CD27 + T-cells are involved in providing helper activity for B-cells, we also investigated the levels of rheumatoid factors in serum and SF in relation to CD27 expression. The mean level of sCD27, which is produced by CD27 + cells, and the mean percentage of CD27 − T-cells within the CD4 + CD45RA − subset were higher in SF than in PB. SF sCD27 levels were higher in the patients with RA than in the patients with osteoarthritis, who served as controls. In ST infiltration by CD4 + CD45RO + CD27 + T-cells could be demonstrated in the rheumatoid perivascular lymphocytic aggregates with a relative increase in the percentage of CD27 − T-cells in the diffuse lymphocytic infiltrate. The sCD27 levels and the percentages of CD4 + CD27 + cells in SF correlated positively with the levels of rheumatoid factors in serum and SF. The findings presented in this study suggest a continuous influx of preactivated CD4 + CD45RO + CD27 + cells from the PB into the rheumatoid ST and further activation and differentiation to CD4 + CD45RO + CD27 − cells in situ, followed by migration to the SF. These activated T-cells are likely to play a role in synovial inflammation.

Function and phenotype of peripheral blood (PB) T cells in multiple sclerosis (MS) patients were analyzed. In whole blood cultures, T cell proliferation of multiple sclerosis (MS) patients, using soluble CD3 mAb and CD2 mAb as stimulants, was reduced in comparison to healthy controls. A similar difference was seen when isolated PBMC were tested after stimulation with soluble CD3 mAb. However, in accessory cell-independent activation systems, i.e. after stimulation of PBMC with immobilized CD3 mAb or after co-stimulation with CD28 mAb, both patients and controls responded equally well. Phenotypical analysis of the circulating T cell population showed that there were no differences in the percentage of CD26+, 'memory' (CD45R0+) or 'effector' (CD4+CD45R0+CD27-) cells between MS patients and healthy controls. Finally, although MS patients did show an enhanced proportion of 'naive' (CD4+CD45RA+) T cells, this did not correlate with the observed functional defects.

We have characterized the activation state of T cells in the bronchoalveolar lavage fluid (BALF) and peripheral blood (PB) from patients with sarcoidosis, to obtain more information about their mechanisms of activation. We analyzed the expression of activation markers (CD25, HLA-DR, Leu-8, and two recently defined markers, CD69 and CD27) on T cells by two-color flow cytometry. We also measured the levels of soluble CD27 and soluble CD25 in nonconcentrated BALF and in serum by ELISA. We found that most T cells in BALF from patients, but not in the peripheral blood, expressed CD69, whereas they did not express CD27. The phenotype (CD69+CD27-) of most BALF T cells and the coexpression of CD69 with HLA-DR and/or VLA-1 indicates that they are in a state of recent and persistent activation. We confirmed previous findings of expression of CD25, HLA-DR, and Leu-8 by T lymphocytes in BALF from patients. We also confirmed increased levels of soluble CD25 in the serum from these patients. The levels of sCD27 and sCD25 in the epithelial lining fluid (ELF) were calculated on the basis of urea in BALF and serum. They were increased in the patients compared with control subjects. In both patients and control subjects, levels in ELF were higher than in the peripheral blood. This indicates shedding of sCD27 (and sCD25) in the lung compartment, which likely contributes to levels in the serum. It is known that in vitro CD27+ cells become CD27- after repeated stimulation and that CD27- cells, after restimulation, do not shed sCD27.(ABSTRACT TRUNCATED AT 250 WORDS)