Characteristics of improvements in balance control using vibro-tactile biofeedback of trunk sway for multiple sclerosis patients.

BACKGROUND AND AIMS: Previously, we determined that training with vibrotactile feedback (VTfb) of trunk sway improves MS patients' balance impairment. Here, we posed 5 questions: 1) How many weeks of VTfb training are required to obtain the best short-term carry over effect (CoE) with VTfb? 2) How long does the CoE last once VTfb training terminates? 3) Is the benefit similar for stance and gait? 4) Is position or velocity based VTfb more effective in reducing trunk sway? 5) Do patients' subjective assessments of balance control improve? METHODS: Balance control of 16 MS patients was measured with gyroscopes at the lower trunk. The gyroscopes drove directionally active VTfb in a head-band. Patients trained twice per week with VTfb for 4 weeks to determine when balance control with and without VTfb stopped improving. Thereafter, weekly assessments without VTfb over 4 weeks and at 6 months determined when CoEs ended. RESULTS: A 20% improvement in balance to normal levels occurred with VTfb. Short term CoEs improved from 15 to 20% (p ≤ 0.001). Medium term (1-4 weeks) CoEs were constant at 19% (p ≤ 0.001). At 6 months improvement was not significant, 9%. Most improvement was for lateral sway. Equal improvement occurred when angle position or velocity drove VTfb. Subjectively, balance improvements peaked after 3 weeks of training (32%, p ≤ 0.05). CONCLUSIONS: 3-4 weeks VTfb training yields clinically relevant sway reductions and subjective improvements for MS patients during stance and gait. The CoEs lasted at least 1 month. Velocity-based VTfb was equally effective as position-based VTfb.

The ACROSS study: Long-term efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis.

BACKGROUND: In chronic diseases such as multiple sclerosis requiring lifelong treatment, studies on long-term outcomes are important. OBJECTIVE: To assess disability and magnetic resonance imaging-related outcomes in relapsing multiple sclerosis patients from a Phase 2 study of fingolimod 10 or more years after randomization and to compare outcomes in patients who had a higher fingolimod exposure versus those with a lower fingolimod exposure. METHODS: ACROSS was a cross-sectional follow-up study of patients originally enrolled in a Phase 2 fingolimod proof-of-concept study (NCT00333138). Disability and magnetic resonance imaging-related outcomes were assessed in patients grouped according to fingolimod treatment duration, based on an arbitrary cut-off: ≥8 years (high exposure) and <8 years (low exposure). RESULTS: Overall, 175/281 (62%) patients participated in ACROSS; 104 (59%) of these were classified "high exposure." At 10 years, patients in the high-exposure group had smaller increases in Expanded Disability Status Scale (+0.55 vs. +1.21), and lower frequencies of disability progression (34.7% vs. 56.1%), wheelchair use (4.8% vs. 16.9%), or transition to secondary progressive multiple sclerosis (9.6% vs. 22.5%) than those in the low-exposure group. The high-exposure patients also had less progression in most magnetic resonance imaging-related outcomes. CONCLUSION: After 10 years of fingolimod treatment, disability progression was lower in the high-exposure group than in the low-exposure group.

Influence of age at disease onset on future relapses and disability progression in patients with multiple sclerosis on immunomodulatory treatment.

BACKGROUND AND PURPOSE: To investigate the relation of age at disease onset and clinical outcomes across the lifespan from adolescence in patients with multiple sclerosis (MS) on disease-modifying therapy (DMT). METHODS: We analysed data from the Swiss Association for Joint Tasks of Health Insurers database containing data from 14 718 patients with MS. Patients were included in this analysis when they were on DMT for at least 1 year. The influence of age at disease onset on future relapses and disability worsening was explored using multivariable Cox proportional hazard regression models. RESULTS: Data from 9705 patients with MS were analysed. Pediatric-onset MS patients (n = 236) had higher relapse rates and marginally slower disability worsening rates compared with adult-onset MS (n = 9469). The risk of relapses was highest in childhood and decreased continuously to about 35 years of age. It remained stable for about a decade and then again continuously decreased. In contrast, disability worsening hazards remained stable from childhood to about 32 years of age and then increased sharply around the age of 45 years. CONCLUSIONS: Age is an important factor independently affecting clinical outcomes in MS. This should be considered when designing clinical trials or choosing DMT.

Magnetic resonance imaging in immune-mediated myelopathies.

Immune-mediated myelopathies are a heterogeneous group of inflammatory spinal cord disorders including autoimmune disorders with known antibodies, e.g. aquaporin-4 IgG channelopathy or anti-myelin oligodendrocyte glycoprotein-associated myelitis, myelopathies in the context of multiple sclerosis and systemic autoimmune disorders with myelopathy, as well as post-infectious and paraneoplastic myelopathies. Although magnetic resonance imaging of the spinal cord is still challenging due to the small dimension of the cord cross-section and frequent movement and susceptibility artifacts, recent methodological advances have led to improved diagnostic evaluation and characterization of immune-mediated myelopathies. Topography, length and width of the lesion, gadolinium enhancement pattern, and changes in morphology over time help in narrowing the broad differential diagnosis. In this review, we give an overview of recent advances in magnetic resonance imaging of immune-mediated myelopathies and its role in the differential diagnosis and monitoring of this heterogeneous group of disorders.

Shortening the washout to 4 weeks when switching from natalizumab to fingolimod and risk of disease reactivation in multiple sclerosis.

BACKGROUND: There is limited evidence about the optimal length of washout when switching from natalizumab to fingolimod. OBJECTIVE: To study if a washout period of 4 weeks is associated with less disease activity compared to 8 weeks. METHODS: 25 patients with Relapsing Remitting Multiple Sclerosis were included in an open label, prospective study with a follow-up of 108 weeks. The primary endpoint (PE) was defined as "time to first relapse or MRI disease activity up to week 56". In addition, a recurrent event analysis (REA) was performed up to week 108. RESULTS: The PE was not met (HR 0.67, 95% CI [0.22,1.97], p = 0.462). Number of relapses before stopping natalizumab was positively associated with the hazard of relapse (HR 3.91, p = 0.0117, 95% CI [1.36, 11.28]). The REA showed a reduction of the hazard to develop a relapse by 77% (HR 0.23, 95% CI [0.08, 0.69], p = 0.00854) in favor of the cohort with 4 weeks washout. CONCLUSIONS: Our study suggests that switching from natalizumab to fingolimod with a shorter washout of 4 weeks might reduce the risk of disease reactivation after switching.

ECTRIMS/EAN guideline on the pharmacological treatment of people with multiple sclerosis.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) is a complex disease of the central nervous system. As new drugs are becoming available, knowledge on diagnosis and treatment must continuously evolve. There is therefore a need for a reference tool compiling current data on benefit and safety, to aid professionals in treatment decisions and use of resources across Europe. The European Committee of Treatment and Research in Multiple Sclerosis (ECTRIMS) and the European Academy of Neurology (EAN) have joined forces to meet this need. The objective was to develop an evidence-based clinical practice guideline for the pharmacological treatment of people with MS to guide healthcare professionals in the decision-making process. METHODS: This guideline has been developed using the GRADE methodology and following the recently updated EAN recommendations for guideline development. Clinical questions were formulated in PICO format (patient, intervention, comparator, outcome) and outcomes were prioritized according to their relevance to clinical practice. An exhaustive literature search up to December 2016 was performed for each question and the evidence is presented narratively and, when possible, combined in a meta-analysis using a random-effects model. The quality of evidence for each outcome was rated into four categories - very high, high, low and very low - according to the risk of bias. GRADE evidence profiles were created using GRADEprofiler (GRADEpro) software (Version 3.6). The recommendations with assigned strength (strong, weak) were formulated based on the quality of evidence and the risk-benefit balance. Consensus between the panellists was reached by use of the modified nominal group technique. RESULTS: A total of 10 questions have been agreed, encompassing treatment efficacy, response criteria, strategies to address suboptimal response and safety concerns and treatment strategies in MS and pregnancy. The guideline takes into account all disease-modifying drugs approved by the European Medicine Agency at the time of publication. A total of 20 recommendations were agreed by the guideline working group members after three rounds of consensus.

[Cell depletion and myoablation for neuroimmunological diseases]. / Zelldepletion und Myeloablation bei neuroimmunologischen Erkrankungen.

BACKGROUND: The treatment of autoimmune disorders of the nervous system is based on interventions for the underlying immune phenomena. OBJECTIVE: To summarize concepts of cell depletion and myeloablation studied in the context of neuroimmunological disorders. METHOD: Evaluation of the available literature on multiple sclerosis as the most widely studied neuroimmunological entity. RESULTS: Three concepts have been introduced: classical immunosuppressants, such as azathioprine, mitoxantrone and cyclophosphamide exert general lymphopenic effects and thereby moderately decrease disease activity. Myeloablative regimens combined with autologous hematopoietic stem cell transplantation have a profound and in most cases long-lasting impact on autoimmunity at the cost of potentially life-threatening side effects. Alemtuzumab (anti-CD52), rituximab and ocrelizumab (both anti-CD20) are depleting antibodies directed against certain lymphocyte subsets and substantially ameliorate disease activity in relapsing-remitting multiple sclerosis. Ocrelizumab also shows efficacy in the primary progressive form of multiple sclerosis. CONCLUSIONS: Most of the presented cell-depleting and myeloablative therapies are highly effective treatment options but are also accompanied by significant risks. In the context of the increasing number of alternative immunomodulatory options the indications for use should be cautiously considered.

Efficacy of fingolimod in patients with highly active relapsing-remitting multiple sclerosis.

OBJECTIVE: There is a need to identify effective switch therapies for patients with relapsing-remitting multiple sclerosis (RRMS) who experience high disease activity despite receiving disease-modifying therapy (DMT). The objective of this study was to assess the efficacy of fingolimod versus placebo in patients with RRMS who had experienced high disease activity despite previously receiving DMT, using post hoc analyses of two phase 3 trials: FREEDOMS (NCT00289978) and FREEDOMS II (NCT00355134). RESEARCH DESIGN AND METHODS: Clinical and magnetic resonance imaging outcomes over 24 months were analyzed in patients from FREEDOMS and FREEDOMS II who had received treatment in the previous year and had: (1) ≥1 relapse in the previous year and either ≥1 gadolinium (Gd) enhancing T1 lesion or ≥9 T2 lesions at baseline and/or (2) as many or more relapses in the year before baseline as in the previous year (as per fingolimod's EU label). MAIN OUTCOME MEASURES: The inclusion criteria were fulfilled by 249 and 257 patients in the fingolimod and placebo groups, respectively. Annualized relapse rates were reduced by 48% for fingolimod versus placebo (p < 0.001). Fingolimod reduced the risk of 3 month and 6 month confirmed disability progression by 34% (p = 0.031) and 45% (p = 0.016), respectively, versus placebo. Brain volume loss was reduced by 46% for fingolimod versus placebo (p < 0.001). The reduction in Gd-enhancing T1 lesion counts for fingolimod versus placebo was 65% (p < 0.001). Furthermore, fingolimod reduced the number of new or newly enlarged T2 lesions by 69% relative to placebo (p < 0.001). LIMITATION: The analyses are post hoc, but the population is specified by the European Medicines Agency in the label for fingolimod. CONCLUSIONS: Fingolimod demonstrated efficacy across all four key RRMS disease measures analyzed in patients with high disease activity despite previous DMT.

Aquaporin-4 antibody negative recurrent isolated optic neuritis: clinical evidence for disease heterogeneity.

Recurrent optic neuritis is frequently observed in multiple sclerosis (MS) and is a typical finding in neuromyelitis optica (NMO). Patients that lack further evidence of demyelinating disease are diagnosed with RION (recurrent isolated optic neuritis) or CRION (chronic relapsing inflammatory neuropathy) if they require immunosuppressive therapy to prevent further relapses. The etiology and disease course of this rare condition are not well defined. We studied a series of 10 patients who presented with recurrent episodes of isolated optic neuritis (ON, n=57) and were followed over a median of 3.5 years. Visual acuity was severely reduced at the nadir of the disease (20/200 to 20/800). All patients had MRI non-diagnostic for MS/NMO and were aquaporin-4 antibody negative. Six patients fulfilled the CRION criteria. In two of these a single ON followed by a long disease-free interval preceded development of CRION for years, suggesting the conversion of an initially "benign" isolated ON into the chronic relapsing course. Cerebrospinal fluid (CSF) analysis revealed mild pleocytosis in 5 patients, identical oligoclonal bands in serum and CSF were observed in 2 patients, while the others remained negative. In conclusion, recurrent ON is a disease entity that requires aggressive glucocorticoid and eventually long-term immunosuppressive therapy to prevent substantial visual impairment.

Neurofilament light and heavy subunits compared as therapeutic biomarkers in multiple sclerosis.

BACKGROUND: Neurofilaments are promising biomarkers in multiple sclerosis (MS) and increased levels in cerebrospinal fluid (CSF) indicate axonal damage or degeneration. In a previous study, neurofilament light chain (NfL) levels in CSF of relapsing remitting (RR) patients with MS were normalized by natalizumab treatment. AIMS OF THE STUDY: We compared the coherence between NfL and neurofilament heavy chain (NfH(SMI) (35) ) levels in longitudinal CSF samples in a subset of these patients. METHODS: In 30 patients with RRMS, CSF was obtained prior to and following 12 months of natalizumab treatment. NfH(SMI) (35) was measured by an electrochemiluminescence-based immunoassay. NfL levels were determined previously by the UmanDiagnostics NF-light(®) assay. RESULTS: NfH(SMI) (35) decreased in 73.3% and NfL in 90% of the patients following natalizumab treatment (32.4 vs 27.4 pg/ml, P = 0.002 and 820 vs 375 pg/ml, P < 0.0001). Patients experiencing a relapse showed higher NfH(SMI) (35) levels compared with patients in remission (47.7 vs 27.6 pg/ml, n = 8, P = 0.001). This difference was less obvious for NfL (1055 vs 725 pg/ml, P = 0.256). In patients in remission, NfL levels were lower following natalizumab treatment (830 vs 365 pg/ml, n = 20, P = 0.0002), whereas the same comparison failed significance for NfH(SMI) (35) (28.3 vs 26.9 pg/ml, P = 0.086). CONCLUSIONS: We confirm previous findings, indicating reduced axonal damage under natalizumab treatment by measuring NfH(SMI) (35) , using an assay with independent methodology. In comparison with NfH(SMI) (35) , NfL changes were more pronounced and the treatment effect also included patients in remission. Our results suggest that NfL is superior over NfH(SMI) (35) as therapeutic biomarker and is a promising candidate to measure neuroaxonal damage in MS treatment trials.

Management and outcome of CSF-JC virus PCR-negative PML in a natalizumab-treated patient with MS.

OBJECTIVE: To describe the diagnosis and management of a 49-year-old woman with multiple sclerosis (MS) developing a progressive hemiparesis and expanding MRI lesion suspicious of progressive multifocal leukoencephalopathy (PML) 19 months after starting natalizumab. RESULTS: Polyomavirus JC (JCV)-specific qPCR in CSF was repeatedly negative, but JCV-specific antibodies indicated intrathecal production. Brain biopsy tissue taken 17 weeks after natalizumab discontinuation and plasmapheresis was positive for JCV DNA with characteristic rearrangements of the noncoding control region, but histology and immunohistochemistry were not informative except for pathologic features compatible with immune reconstitution inflammatory syndrome. A total of 22 months later, the clinical status had returned close to baseline level paralleled by marked improvement of neuroradiologic abnormalities. CONCLUSIONS: This case illustrates diagnostic challenges in the context of incomplete suppression of immune surveillance and the potential of recovery of PML associated with efficient immune function restitution.

Antibodies to MOG are transient in childhood acute disseminated encephalomyelitis.

OBJECTIVE: To study the longitudinal dynamics of anti-myelin oligodendrocyte glycoprotein (MOG) autoantibodies in childhood demyelinating diseases. METHODS: We addressed the kinetics of anti-MOG immunoglobulins in a prospective study comprising 77 pediatric patients. This was supplemented by a cross-sectional study analyzing 126 pediatric patients with acute demyelination and 62 adult patients with multiple sclerosis (MS). MOG-transfected cells were used for detection of antibodies by flow cytometry. RESULTS: Twenty-five children who were anti-MOG immunoglobulin (Ig) positive at disease onset were followed for up to 5 years. Anti-MOG antibodies rapidly and continuously declined in all 16 monophasic patients with acute disseminated encephalomyelitis and in one patient with clinically isolated syndrome. In contrast, in 6 of 8 patients (75%) eventually diagnosed with childhood MS, the antibodies to MOG persisted with fluctuations showing a second increase during an observation period of up to 5 years. Antibodies to MOG were mainly IgG 1 and their binding was largely blocked by pathogenic anti-MOG antibodies derived from a spontaneous animal model of autoimmune encephalitis. The cross-sectional part of our study elaborated that anti-MOG Ig was present in about 25% of children with acute demyelination, but in none of the pediatric or adult controls. Sera from 4/62 (6%) adult patients with MS had anti-MOG IgG at low levels. CONCLUSIONS: The persistence or disappearance of antibodies to MOG may have prognostic relevance for acute childhood demyelination.

Mitochondrial cytochrome redox states and respiration in acute pulmonary oxygen sensing.

Hypoxic pulmonary vasoconstriction (HPV) is an essential mechanism to optimise lung gas exchange. We aimed to decipher the proposed oxygen sensing mechanism of mitochondria in HPV. Cytochrome redox state was assessed by remission spectrophotometry in intact lungs and isolated pulmonary artery smooth muscle cells (PASMC). Mitochondrial respiration was quantified by high-resolution respirometry. Alterations were compared with HPV and hypoxia-induced functional and molecular readouts on the cellular level. Aortic and renal arterial smooth muscle cells (ASMC and RASMC, respectively) served as controls. The hypoxia-induced decrease of mitochondrial respiration paralleled HPV in isolated lungs. In PASMC, reduction of respiration and mitochondrial cytochrome c and aa3 (complex IV), but not of cytochrome b (complex III) matched an increase in matrix superoxide levels as well as mitochondrial membrane hyperpolarisation with subsequent cytosolic calcium increase. In contrast to PASMC, RASMC displayed a lower decrease in respiration and no rise in superoxide, membrane potential or intracellular calcium. Pharmacological inhibition of mitochondria revealed analogous kinetics of cytochrome redox state and strength of HPV. Our data suggest inhibition of complex IV as an essential step in mitochondrial oxygen sensing of HPV. Concomitantly, increased superoxide release from complex III and mitochondrial membrane hyperpolarisation may initiate the cytosolic calcium increase underlying HPV.

Interferon-beta increases BAFF levels in multiple sclerosis: implications for B cell autoimmunity.

B cells are increasingly recognized as major players in multiple sclerosis pathogenesis. The BAFF/APRIL system is crucial for B cell homoeostasis and may drive B cell-dependent autoimmunity. We asked whether this system is affected by Interferon (IFN)-beta therapy. We analysed transcription of the ligands (BAFF, APRIL, TWE-PRIL) and the corresponding receptors (BAFF-R, TACI and BCMA) by TaqMan-PCR ex vivo in whole blood and in immune cell subsets purified from IFN-beta-treated multiple sclerosis patients. Serum BAFF concentrations were determined by ELISA. This cross-sectional study involved 107 donors. IFN-beta therapy strongly induced BAFF transcription proportionally to the IFN-beta biomarker MxA in monocytes and granulocytes in vivo. BAFF serum concentrations were elevated in IFN-beta-treated multiple sclerosis patients to a similar level as observed in SLE patients. In cultured PBMC, neutrophils, fibroblasts and astrocytes, BAFF was induced by IFN-beta concentrations similar to those reached in vivo in treated multiple sclerosis patients. BAFF turned out to be the main regulated element of the BAFF/APRIL system. In untreated multiple sclerosis patients, there was no BAFF increase as compared to healthy controls. Our study reveals a complex situation. We show that IFN-beta therapy induces a potent B cell survival factor, BAFF. However, B cell depletion would be desirable at least in some multiple sclerosis patients. The systemic induction of BAFF by IFN-beta therapy may facilitate the production of various autoantibodies and of IFN-neutralizing antibodies. Individual MS/NMO patients who have major B cell involvement may benefit less than others from IFN-beta therapy, thus explaining interindividual differences of the therapeutic response.

CCL19 is constitutively expressed in the CNS, up-regulated in neuroinflammation, active and also inactive multiple sclerosis lesions.

CCL19 and CCL21 bind to CCR7, which is crucial for both inducing an immune response and establishing immunological tolerance. We report that in the normal human brain CCL19, but not CCL21, is transcribed, and detectable as a protein in tissue lysates and in cerebrospinal fluid. In both active and inactive multiple sclerosis (MS) lesions CCL19 transcripts were elevated. In cerebrospinal fluid from MS and OIND patients CCL19 protein was increased. In relapsing-remitting and secondary progressive MS patients CCL19 correlated with intrathecal IgG production. This study suggests that CCL19 plays a role in both the physiological immunosurveillance of the healthy CNS and the pathological maintenance of immune cells in the CNS of MS patients.

Immunoadsorption patients with multiple sclerosis: an open-label pilot study.

BACKGROUND: Immunoadsorption (IA) is occasionally applied in patients with acute relapses of multiple sclerosis (MS). This pilot study was undertaken to determine whether IA might help in secondary progressive and relapsing-remitting multiple sclerosis. DESIGN: IA was performed at 1-week intervals in 12 patients with secondary progressive or relapsing-remitting MS. These patients had an extended disability status scale (EDSS) score of 4.5-7 and an EDSS increase of 0.5 within 6 months before inclusion in the study despite conventional drug therapy. The change in the EDSS and that in the MS functional composite (MSFC) score, which consisted of quantitative tests of arm function, ambulation, visual acuity and cognition, served as the primary outcome variables, which were measured at baseline and at 3, 6 and 12 months. Changes in quality of life and cerebral lesions by magnetic resonance imaging (MRI) were also assessed at baseline and after the last immunoadsorption (month 3). RESULTS: A significant reduction of the median EDSS change was observed after the treatment period, which reversed 3 months after the immunoadsorptions had been stopped. Ten of 12 patients remained stable during the first year of follow-up with no significant changes of the MSFC scores. No significant changes in magnetic resonance imaging T2-hyperintense brain lesions or in the number of gadolinium-positive lesions and in the patients' quality of life were observed. Western blot analyses demonstrated a reduction of serum myelin-specific antibodies, which were collected in the adsorber eluates. CONCLUSIONS: Removal of immunoglobulins, including myelin-specific antibodies by immunoadsorption, seems to delay disease progression as defined by EDSS, MSFC and MRI, while the patients' quality of life did not deteriorate.

Herpesviral proteins regulating apoptosis.

The induction of apoptosis of virus-infected cells is an important defense mechanism of the host. Apoptosis of an infected cell can be induced cell autonomously as a consequence of viral replication or can be mediated by CTLs attacking the infected cells. Herpesviruses have developed different strategies to interfere with cell-autonomous apoptosis and to block CTL-induced apoptosis mediated by death receptors such as Fas and TRAIL. Herpesviruses, which establish a lifelong persistence in the infected host, can be found principally in two different conditions, episomal persistence with a limited number of genes expressed and lytic replication with expression of almost all genes. To meet the need of the virus to enhance survival of the infected cell, herpesviruses have evolved different strategies that function during both episomal persistence and lytic replication. Herpesviruses, which encode 70 to more than 200 genes have incorporated cell homologous antiapoptotic genes, they code for multifunctional genes that can also regulate apoptosis, and, finally, they modulate the expression of cellular apoptosis-regulating genes to favor survival of the infected cells. Viral interference with host cell apoptosis enhances viral replication, facilitates virus spread and persistence, and may promote the development of virus-induced cancer.

[Multiple sclerosis. Chlamydia hypothesis in debate]. / Multiple Sklerose. Chlamydien-Hypothese in der Diskussion.

Recently, an association between multiple sclerosis and Chlamydia pneumoniae infection has been suggested. Because standardized PCR protocols are lacking, a series of studies could not clarify whether C. pneumoniae is present in brain tissue and CSF of MS patients. Therefore, other studies focused on the humoral immune response against C. pneumoniae: 24% of MS patients, but only 5% of the control patients showed intrathecally produced antibodies against C. pneumoniae. If an infection with C. pneumoniae was involved in the pathogenesis of MS, one would expect that, in analogy to other infections of the CNS, the oligoclonal bands in the CSF of MS patients would recognize the responsible agent. However, the results we obtained by affinity-mediated immunoblots showed that the oligoclonal bands in the CSF of MS patients are not directed against Chlamydia antigen. In contrast to this, we found that the immunoglobulins in the CSF of neuroborreliosis patients reacted strongly against Borrelia antigen in the affinity-mediated immunoblots. In light of these results we assume that the intrathecal immunoglobulin production against C. pneumoniae is part of a polyspecific immune response. Thus, it is not likely that C. pneumoniae is causally linked to the pathogenesis of multiple sclerosis.

Signaling lymphocytic activation molecule (SLAM) regulates T cellular cytotoxicity.

Signaling lymphocytic activation molecule (SLAM) is a CD2-related surface receptor expressed by activated T cells and B cells. SLAM is a self ligand and enhances T cellular proliferation and IFN-gamma production. A defective SLAM associated protein (SAP) causes X-linked lymphoproliferative syndrome (XLP), a frequently lethal mononucleosis based on the inability to control EBV. We report that SLAM augments TCR-mediated cytotoxicity. In normal CD4(+) and CD8(+) T cells, SLAM enhanced TCR-mediated cytotoxicity. In CD4(+) and CD8(+) Herpesvirus saimiri (H.saimiri) infected T cells, SLAM engagement alone triggered cytotoxicity. Using H.saimiri-transformed T cells as a model system we found that SLAM-engagement promotes the release of lytic granules and a CD95-independent killing that requires extracellular Ca(2+), cytoskeletal rearrangements, and signaling mediated by mitogen-activated protein kinase kinases MEK1/2. SLAM-enhanced cytotoxicity implies an immunoregulatory function by facilitating the elimination of APC and a role in overcoming infections with pathogens requiring a cytotoxic immune response.