HLA-E restricted CD8+ T cell subsets are phenotypically altered in multiple sclerosis patients.

BACKGROUND: The importance of Qa-1 restricted CD8(+) T cells in regulating autoreactive T cell responses has been demonstrated in animal models for autoimmune disorders, including multiple sclerosis (MS). OBJECTIVE: We hypothesize that their human variant, HLA-E restricted CD8(+) T cells, fulfills a similar regulatory role in man and that these cells are of importance in MS. METHODS: A large cohort of MS patients and healthy controls was genotyped for the two known HLA-E polymorphisms. Flow cytometry was used to determine HLA-E expression kinetics and to phenotype HLA-E restricted CD8(+) T cells. Immunohistochemistry was performed to investigate HLA-E expression in the central nervous system (CNS) of MS patients. RESULTS: HLA-E is upregulated on immune cells upon in vitro activation and this upregulation is polymorphism-dependent for T and B cells. T and B cells in lesions of MS patients show enhanced HLA-E expression. Furthermore, NKG2C(+)CD8(+) T cells of MS patients have a significantly lower Foxp3 expression, while NKG2A(+)CD8(+) T cells of MS patients produce higher levels of pro-inflammatory cytokines compared to those of healthy individuals. CONCLUSION: Our study indicates that the HLA-E system is altered in MS and could play a regulatory role in disease.

The relationship between upper leg muscle strength and walking capacity in persons with multiple sclerosis.

BACKGROUND: In persons with multiple sclerosis (PwMS) resistance training improves muscle strength but effects on walking capacity are inconsistent. OBJECTIVE: The objective was to determine the relation between different types of upper leg muscle strength measurements and walking capacity in PwMS. METHODS: An observational cross-sectional study design was applied. Upper leg muscle strength of 52 PwMS (Expanded Disability Status Scale, EDSS range 1.5-6.5) was measured using isometric (knee extensors and flexors) and isokinetic (knee extensors) dynamometry. Walking capacity was assessed using the Timed 25-Foot Walk, Timed Up and Go and Two Minute Walk Test. Subgroups with mild (EDSS 1.5-4.0, n=31) and moderate (EDSS 4.5-6.5, n=21) ambulatory dysfunction were distinguished, and results were hypothesized to differ depending on multiple sclerosis (MS)-related disability status. Correlation and regression analyses were performed on the data of the most affected leg. RESULTS: Greatest (r: 0.2-0.7) and significant Pearson correlation coefficients were found in the moderate compared to mild MS subgroup. Within knee extensor measurements, it was found that isokinetic endurance strength related best to walking capacity. When comparing maximal isometric strength measurements, knee flexors (r: 0.5-0.7) related better to walking capacity than knee extensors (r: 0.1-0.4). Regression analyses confirmed endurance knee extensor strength (~25 %) and isometric knee flexor strength (~40%) as main predictors for walking capacity. CONCLUSION: Resistance training protocols may consider inclusion of exercises focusing on endurance knee extensor and isometric knee flexor strength when aiming to enhance walking capacity in persons with moderate ambulatory dysfunction.

CX(3)CR1 drives cytotoxic CD4(+)CD28(-) T cells into the brain of multiple sclerosis patients.

Immunosenescence, or ageing of the immune system, contributes to the increased morbidity and mortality seen in the elderly population. Premature immunosenescence is shown to occur in a subgroup of patients with autoimmune diseases. One of the main characteristics of immunosenescence is the expansion of CD4(+)CD28(-) T cells in the blood. In this study, we investigate the potential contribution of these cells to disease processes in a subgroup of multiple sclerosis (MS) and rheumatoid arthritis (RA) patients. Characterization of CD4(+)CD28(-) T cells in patients and healthy controls reveals that they have an inflammation-seeking effector-memory T cell phenotype with cytotoxic properties, as they expel cytotoxic granules in response to a polyclonal stimulus or MS-related autoantigens. We identify CX(3)CR1, the fractalkine receptor, as a selective marker to discriminate CD4(+)CD28(-) T cells from their CD4(+)CD28(+) counterparts. CX(3)CR1 expression enables CD4(+)CD28(-) T cells to migrate towards a fractalkine gradient in vitro. In addition, we find increased levels of fractalkine in the cerebrospinal fluid and inflammatory lesions of MS patients. We demonstrate for the first time that CD4(+)CD28(-) T cells accumulate in MS lesions of a subgroup of patients. Moreover, we have indications that these cells are cytotoxic in the target tissue. Overall, our findings suggest that CD4(+)CD28(-) T cells migrate in response to a chemotactic gradient of fractalkine to sites of inflammation, where they contribute to the inflammatory processes in a subgroup of patients with MS and RA.

Physical fitness affects the quality of single operator cardiocerebral resuscitation in healthcare professionals.

OBJECTIVE: Sustained external chest compressions during cardiocerebral resuscitation (CCR) are physically demanding. It might be hypothesized that a high cardiopulmonary exercise capacity and/or muscle strength delays the development of physical fatigue and, consequently, preserves CCR quality. We intended to assess the impact of cardiopulmonary exercise capacity and muscle strength on CCR quality. METHODS: Fifteen healthcare professionals (10 men and five women, mean age 34±9 years) performed a 15-min hands-on CCR session on an adult training manikin. CCR compression depth (from which CCR quality was calculated) and frequency were monitored. During CCR we assessed serial blood lactate concentrations, and provided continuous heart rate monitoring. Relationships were examined between participant characteristics, peak cardiopulmonary exercise capacity, ventilatory threshold, maximal muscle strength, muscle strength endurance and CCR quality. RESULTS: Significant univariate correlations were found between 15-min CCR quality and body height (r=0.53), ventilatory threshold (r=0.67), peak oxygen uptake capacity (r=0.54), peak cycling power output (r=0.54), and maximal isometric elbow extension strength (r=0.55) (P<0.05). CCR quality was significantly lower in females, when compared with males (P<0.05). Within different timeframes, CCR quality was mainly related to the ventilatory threshold up to the first 5 min (P<0.05), whereas CCR quality was mainly related to maximal isometric elbow extension strength after 5 min (P<0.05). CONCLUSION: In healthcare professionals, the ventilatory threshold is significantly related to CCR quality during the first few min. Healthcare professionals who are regularly involved in CCR should therefore aim to achieve/sustain a high aerobic exercise capacity. CLINICAL TRIAL REGISTRATION INFORMATION: Study registration number: ISRCTN70447230, www.controlled-trials.com/ISRCTN70447230.

Clinical benefits of the addition of lower extremity low-intensity resistance muscle training to early aerobic endurance training intervention in patients with coronary artery disease: a randomized controlled trial.

OBJECTIVE: Muscle resistance training is often combined with aerobic endurance training during rehabilitation of patients with coronary artery disease. However, the clinical effects of additional lower-extremity low-intensity muscle resistance training during early rehabilitation (within the first month after coronary revascularization) in patients with coronary artery disease remain unclear. DESIGN: Prospective randomized controlled trial. SUBJECTS: Sixty patients with coronary artery disease. METHODS: Subjects were randomly assigned to early aerobic endurance training (n = 30) or combined aerobic endurance and resistance muscle training (n = 30). Subjects performed 18 (standard deviation 2) exercise sessions (at 65% VO(2peak), for 40 mins/session). In resistance muscle training, additional low-intensity (12-20 repetition maximum) resistance muscle exercises were performed. The following parameters were evaluated: exercise capacity, body composition, blood lipid profile, glycaemic control, blood endothelial progenitor cell and cytokine content, and muscle performance. RESULTS: A total of 47 patients with coronary artery disease completed the intervention. Total body lean tissue mass tended to increase with greater magnitude (p = 0.07), and blood high-density lipid cholesterol content increased with significantly greater magnitude in resistance muscle training (p < 0.05), compared with aerobic endurance training. Maximal exercise capacity, ventilatory threshold, and muscle performance increased, and steady-state exercise respiratory exchange ratio, and adipose tissue mass reduced significantly (p < 0.05), without differences between groups (p < 0.05). CONCLUSION: In early aerobic endurance training intervention in patients with coronary artery disease, additional low-intensity resistance muscle training contributes to a greater increase in blood high-density lipid cholesterol content, and tends to affect lean tissue mass.

Effects of long-term resistance training and simultaneous electro-stimulation on muscle strength and functional mobility in multiple sclerosis.

BACKGROUND: Resistance training studies in multiple sclerosis (MS) often use short intervention periods. Furthermore, training efficiency could be optimized by unilateral training and/or electrical stimulation. OBJECTIVE: To examine the effect(s) of unilateral long-term (20 weeks) standardized resistance training with and without simultaneous electro-stimulation on leg muscle strength and overall functional mobility. METHODS: A randomized controlled trial involving 36 persons with MS. At baseline (PRE) and after 10 (MID) and 20 (POST) weeks of standardized (ACSM) light to moderately intense unilateral leg resistance training (RES(O), n = 11) only or resistance training with simultaneous electro-stimulation (RES(E), n = 11, 100 Hz, biphasic symmetrical wave, 400 µs), maximal isometric strength of the knee extensors and flexors (45°, 90° knee angle) and dynamic (60-180°/s) knee-extensor strength was measured and compared with a control group (CON, n = 14). Functional mobility was evaluated using the Timed Get Up and Go, Timed 25 Foot Walk, Two-Minute Walk Test, Functional Reach and Rivermead Mobility Index. RESULTS: Maximal isometric knee extensor (90°, MID: +10 ± 3%, POST: +10 ± 4%) in RES(O) and knee flexor (45°, POST: +7 ± 4%; 90°, POST: +9 ± 5%) in RES(E) strength increased (p < 0.05) compared with CON but RES(O) and RES(E) did not differ. Also, impaired legs responded positively to resistance training (unilateral leg strength analysis) and functional reaching increased significantly in RES(O) (+18%) compared with CON. Dynamic muscle strength and the remaining functional mobility tests did not change. CONCLUSION: Long-term light to moderately intense resistance training improves muscle strength in persons with MS but simultaneous electro-stimulation does not further improve training outcome.

Exploring the effects of a 20-week whole-body vibration training programme on leg muscle performance and function in persons with multiple sclerosis.

OBJECTIVE: To investigate the acute effects of long-term whole-body vibration on leg muscle performance and functional capacity in persons with multiple sclerosis. DESIGN: A randomized controlled trial. SUBJECTS: Twenty-five patients with multiple sclerosis (mean age 47.9 ± 1.9 years; Expanded Disability Status Scale 4.3 ± 0.2) were assigned randomly to whole-body vibration training (n = 11) or to a control group (n = 14). METHODS: The whole-body vibration group performed static and dynamic leg squats and lunges on a vibration platform (25-45 Hz, 2.5 mm amplitude) during a 20-week training period (5 training sessions per 2-week cycle), and the control group maintained their usual lifestyle. PRE-, MID- (10 weeks) and POST- (20 weeks) knee-muscle maximal isometric and dynamic strength, strength endurance and speed of movement were measured using isokinetic dynamometry. Function was determined through the Berg Balance Scale, Timed Up and Go, Two-minute Walk Test and the Timed 25-Foot Walk Test. RESULTS: Leg muscle performance and functional capacity were not altered following 10 or 20 weeks of whole-body vibration. CONCLUSION: Under the conditions of the present study, the applied 20-week whole-body vibration exercise protocol did not improve leg muscle performance or functional capacity in mild- to moderately impaired persons with multiple sclerosis during and immediately after the training programme.

Predicting habitual walking performance in multiple sclerosis: relevance of capacity and self-report measures.

The objective was to establish the extent to which physical functioning capacity and self-report measures are able to predict the habitual walking performance in ambulatory persons with multiple sclerosis. Fifty persons with multiple sclerosis (Expanded Disability Status Scale, EDSS, 1.5-6.5) were tested on leg muscle strength as well as walking and balance capacity, and completed self-report indices on perceived physical functioning. Habitual walking performance, that is, the real amount of steps that is performed in the customary living environment, was registered by means of an ambulant accelerometer-based monitor during seven consecutive days. Mild (EDSS 1.5-4.0, n = 29) and moderate (EDSS 4.5-6.5, n = 21) multiple sclerosis subgroups were additionally distinguished as predictor variables and values were hypothesized to differ depending on multiple sclerosis severity and concomitant ambulatory function. Multiple regression analyses yielded a single most significant predictor for each (sub)group with other variables making no independent contribution to the variation in habitual walking performance. For the total study sample, this was the 6-Minute Walking Test (R(2) = 0.458, p < 0.01). In the mild multiple sclerosis subgroup, the 6-Minute Walking Test was again most predictive, yet to a modest degree (R(2) = 0. 187, p = 0.02). In the moderate multiple sclerosis subgroup, the 2-Minute Walking Test explained over half of the variance (R(2) = 0.532, p < 0.01). Habitual walking performance is best reflected by longer walking capacity tests. The extent to which it can be predicted based on clinical testing is larger in a multiple sclerosis patient sample with more severe walking disability. Ambulatory monitoring, however, includes aspects of community ambulation not captured in the clinic, and must be considered as an additional outcome for evaluating interventions in multiple sclerosis.

Natural naive CD4+CD25+CD127low regulatory T cell (Treg) development and function are disturbed in multiple sclerosis patients: recovery of memory Treg homeostasis during disease progression.

Patients with relapsing-remitting multiple sclerosis (RR-MS) show a suboptimal CD4(+)CD25(+) regulatory T cell (Treg) function, whereas no Treg alterations are observed in secondary progressive MS (SP-MS) patients. To clarify the difference in Treg activity between early and chronic disease stages in MS, we analyzed the functional capacity and homeostatic parameters of naive CD4(+)CD25(+)CD127(low)CD45RA(+) Tregs (nTregs) and their memory counterparts CD4(+)CD25(+)CD127(low)CD45RO(+) Tregs (mTregs) in untreated MS patients and healthy controls. Interestingly, whereas the suppressive capacity of FACS-sorted nTregs was impaired in both early and chronic MS patients, only the latter group showed a restored mTreg function. Consistent with this observation, chronic MS patients had increased numbers of mTregs as compared with age-matched early MS patients, whereas nTreg frequencies did not differ significantly. TCR excision circle numbers were reduced in nTregs of early MS patients, suggestive of a diminished nTreg thymic output. Moreover, a decreased number of CD31(+) mTregs were observed in early vs chronic MS patients, indicating that inflammatory processes drive the homeostatic turnover of mTregs during the early disease stage. Additionally, early MS patients showed a more restricted nTreg and mTreg TCR BV gene profile as compared with healthy controls and chronic MS patients. Finally, analysis of IFN-beta and glatiramer acetate-treated MS patients showed that these immunomodulatory drugs modify nTreg homeostasis. Taken together, this study provides strong evidence for a disturbed thymic nTreg development and function in MS patients. Moreover, memory Treg but not naive Treg homeostasis recovers during disease progression.