Aging and immune response to exercise

Human immune function undergoes adverse changes with aging. The T cells, which have a central role in cellular immunity, show the largest age-related differences in distribution and function, with thymus involution as the apparent underlying cause. The immune responses to acute exercise and training have not been studied extensively in the elderly. The natural killer (NK) cell response to a single exercise challenge is normal in older individuals, but immediately after exercise the elderly subjects manifest less suppression of phytohemagglutinin (PHA)-induced lymphocyte proliferation than younger individuals. In contrast, a strenuous exercise seems to induce a more sustained postexercise suppression of cellular immunity in older individuals than in their young peers. A few cross-sectional comparisons of immune status between physically fit elderly individuals and young sedentary controls suggest that habitual physical activity may enhance NK cell activity, checking certain aspects of the age-related decline in T cell function, such as reduced mitogenesis in response to plant lectins and decreases in the production of certain types of cytokine. The clinical implications, however, remain to be clarified by future study.     

Physical fitness, physical activity, and functional limitation in adults aged 40 and older

PURPOSE: A cohort of middle-aged and older men and women were followed for an average of 5.5 yr to examine the association between physical fitness, physical activity, and the prevalence of functional limitation. METHODS: The participants received medical assessments between 1980 and 1988 and responded to a mail-back survey regarding functional status in 1990. RESULTS: Among 3495 men and 1175 women over 40 yr of age at baseline, 350 (7.5%) reported at least one functional limitation in daily or household activities at follow-up. The prevalence of functional limitation was higher among women than men. Physically fit and physically active participants reported less functional limitation than unfit or sedentary participants. After controlling for age and other risk factors, the prevalence of functional limitation was lower for both moderately fit (odds ratio = 0.4, 95% CI = 0.2-0.6) and high fit men (odds ratio = 0.3, 95% CI = 0.2-0.4), compared with low fit men. Corresponding figures for women were 0.5 (0.3-0.7) and 0.3 (0.2-0.5) for moderately fit and high fit women. The association between physical activity and functional limitation was similar to the data for physical fitness. CONCLUSIONS: These data support a protective effect of physical fitness and physical activity on functional limitation among older adults and extend this protective effect to middle-aged men and women.     

Critical role of IL-12 in dendritic cell-induced differentiation of naive B lymphocytes

Dendritic cells (DC) are potent APCs initiating immune responses. In a previous report, we demonstrated that DC directly enhance both proliferation and differentiation of CD40-activated naive and memory B cells. The present study deciphers the molecular mechanisms involved in DC-dependent regulation of B cell responses. Herein, we have identified IL-12 as the mandatory molecule secreted by CD40-activated DC that promote the differentiation of naive B cells into plasma cells secreting high levels of IgM. In fact, IL-12 synergizes with soluble IL-6R alpha-chain (sgp80), produced by DC, to drive naive B cell differentiation. IL-12 is critical for the differentiation of naive B cells into IgM plasma cells, whereas IL-6R signaling mainly promotes Ig secretion by already differentiated B cells. The differentiation of naive B cells in cocultures of B cells, T cells, and DC is IL-12 dependent, definitely demonstrating that the role of DC in humoral responses is not confined to the activation of T cells and further extending the physiologic relevance of DC/B cell interaction. Finally, this study also identifies differential requirements for DC-dependent naive and memory B cell differentiation, the latter being IL-12 independent. Altogether these results indicate that, in addition to prime T cells toward Thl development, DC, through the production of IL-12, may also directly signal naive B cell during the initiation of the immune response.     

Stress hormones and the immunological responses to heat and exercise

This review focuses on the response of "stress" hormones to heat, exercise (single or repeated bouts), and combinations of these stimuli, with particular reference to their impact upon immune function. Very hot conditions induce a typical stress response, with secretion of catecholamines and cortisol. The catecholamines induce a demargination of leukocytes, and cortisol subsequently causes cells to migrate to lymphoid tissue. Sustained exercise, even in a thermally comfortable environment, induces a larger hormonal response than moderate thermal stress. With moderate exercise, increases in leukocyte numbers are related mainly to plasma norepinephrine concentrations, but with more intense exercise epinephrine concentrations assume a major importance. As exercise continues, plasma cortisol levels also rise, inducing an influx of neutrophils from bone marrow and an efflux of other leukocyte subsets. A combination of exercise and heat stress augments both hormonal and leukocyte responses. But these changes seem to be reversed if temperatures are clamped by exercising in cold water. If a second bout of exercise is performed with an inter-test interval of 30-45 min, neither hormone concentrations nor immune responses show any great cumulative effect under temperate conditions. However, in a hot environment the second exercise bout induces a larger and more persistent neutrophilia. Training influences these various responses mainly by decreasing the stress imposed when exercising at a given absolute work-rate.     

Humoral immunity due to long-lived plasma cells

Conventional models suggest that long-term antibody responses are maintained by the continuous differentiation of memory B cells into antibody-secreting plasma cells. This is based on the notion that plasma cells are short-lived and need to be continually replenished by memory B cells. We examined the issue of plasma cell longevity by following the persistence of LCMV-specific antibody and plasma cell numbers after in vivo depletion of memory B cells and by adoptive transfer of virus-specific plasma cells into naive mice. The results show that a substantial fraction of plasma cells can survive and continue to secrete antibody for extended periods of time (>1 year) in the absence of any detectable memory B cells. This study documents the existence of long-lived plasma cells and demonstrates a new mechanism by which humoral immunity is maintained.     

Norepinephrine response to exercise at the same relative intensity before and after endurance exercise training

It is well documented that endurance exercise training results in a blunted norepinephrine (NE) response to exercise of a given absolute exercise intensity. However, it is not clear what effect training has on the catecholamine response to exercise of the same relative intensity because previous studies have provided conflicting results. The purpose of the present study was, therefore, to determine the catecholamine response to exercise of the same relative exercise intensity before and after endurance exercise training. Six women and three men [age 28 +/- 8 (SD) yr] performed 10 wk of training. Maximal O2 uptake (VO2 max) was determined during treadmill exercise. Fifteen-minute treadmill exercise bouts were performed at 60, 65, 70, 75, 80, and 85% of VO2 max before and after training. VO2 max was increased by 20% (from 39.2 +/- 7.7 to 46.9 +/- 8.1 ml. kg-1. min-1; P < 0.05) in response to training. Plasma NE concentrations were higher (P < 0.05) during exercise at the same relative intensity after, compared with before, training at 65-85% of VO2 max. Differences between heart rates and plasma epinephrine concentrations after, compared with before, training were not statistically significant. These results provide evidence that the NE response to exercise is dependent on the absolute as well as the relative intensity of the exercise.     

Plasma fibrinogen levels in healthy postmenopausal women: physical activity and hormone replacement status

BACKGROUND: Fibrinogen is a major component of the coagulation system and a powerful independent risk factor for cardiovascular disease in postmenopausal women. Regular physical activity has been recommended as an effective clinical approach to lowering plasma fibrinogen levels; currently, however, there are little or no data to support a relationship between habitual exercise status and plasma fibrinogen levels in healthy postmenopausal women who either use or do not use hormone replacement therapy (HRT). METHODS: Plasma fibrinogen levels were measured in 20 physically active (56 +/- 1 yr) and 31 sedentary (58 +/- 1 yr) healthy postmenopausal women. Nine (45%) physically active and 15 (48%) sedentary women had been using HRT for > 1 year; the others were nonusers of HRT. RESULTS: Plasma fibrinogen levels were approximately 15% lower (p = .001) in the physically active women (2.48 +/- .08 g/L) than the sedentary controls (2.92 +/- .06 g/L) and approximately 7% lower (p = .04) in the users (2.65 +/- .08 g/L) versus nonusers (2.84 +/- .08 g/L) of HRT. Moreover, the lower (0.4 g/L) plasma fibrinogen levels associated with regular physical activity were evident in both the users (2.39 +/- .11 vs 2.80 +/- .08 g/L, p = .001) and nonusers (2.56 +/- .11 vs 3.03 +/- .08 g/L, p = .006) of HRT. Stepwise multiple regression analysis revealed that percent body fat was the primary determinant of plasma fibrinogen levels, accounting for 30% of the variability. CONCLUSIONS: Regular physical activity is associated with lower plasma fibrinogen levels in postmenopausal women; the lower plasma fibrinogen levels associated with regular physical activity are evident in both users and nonusers of HRT; and plasma fibrinogen levels are positively related to percent body fat in postmenopausal women differing in physical activity and HRT status. Lower plasma fibrinogen levels in physically active postmenopausal women may contribute to their lower risk of cardiovascular disease.     

Hyphomycetes in morning dew of meadows

CD80 and CD86 (B7-1 and B7-2) are the ligands on antigen-presenting cells (APCs) which bind CD28 and deliver the costimulatory signals necessary for T cell activation. The reasons for the existence of two CD28 binding molecules are not well understood. We created a mutant version of CTLA4-Ig that could selectively bind CD80 and block CD28-CD80 interaction but leave CD28-CD86 binding intact. CD80 blockade prevented antigen-induced accumulation of eosinophils and lymphocytes in the lung of immunized mice, but did not block antigen induced systemic blood eosinophilia or IgE antibody production. No preferential expression of CD80 could be demonstrated on a population of lung APC consisting mainly of macrophages. These results indicate that CD80 costimulation is not necessary for the induction of Th2 immune responses but rather for the maintenance or amplification of lung inflammatory responses.     

Lipid reactivity to stress: II. Biological and behavioral influences.

This study examined behavioral and physiological influences on lipid concentrations during acute and chronic stressors. One hundred men (n?=?92) and women (n?=?8) were tested during a chronic stressor and during 2 acute stressors. During chronic stress, diet, physical activity, exercise, and sleep were examined. During the acute stressors, catecholamines, cortisol, plasma volume, and cardiovascular responses were examined. None of the behavioral influences could explain the lipid response to chronic stress. Responses of the atherogenic lipids to acute stressors were not solely reflecting hemoconcentration of the plasma but were moderately correlated with cardiovascular, epinephrine, and cortisol reactivity. Diastolic blood pressure reactors to the acute stressors had larger lipid responses to the chronic stressor than did nonreactors. Elevations in blood lipids during stress are not artifacts and may be clinically significant. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Interleukin 6 influences germinal center development and antibody production via a contribution of C3 complement component

Mice rendered deficient for interleukin (IL) 6 by gene targeting were evaluated for their response to T cell-dependent antigens. Antigen-specific immunoglobulin (Ig)M levels were unaffected whereas all IgG isotypes showed varying degrees of alteration. Germinal center reactions occurred but remained physically smaller in comparison to those in the wild-type mice. This concurred with the observations that molecules involved in initial signaling events leading to germinal center formation were not altered (e.g., B7.2, CD40 and tumor necrosis factor R1). T cell priming was not impaired nor was a gross imbalance of T helper cell (Th) 1 versus Th2 cytokines observed. However, B7.1 molecules, absent from wild-type counterparts, were detected on germinal center B cells isolated from the deficient mice suggesting a modification of costimulatory signaling. A second alteration involved impaired de novo synthesis of C3 both in serum and germinal center cells from IL-6-deficient mice. Indeed, C3 provided an essential stimulatory signal for wild-type germinal center cells as both monoclonal antibodies that interrupted C3-CD21 interactions and sheep anti-mouse C3 antibodies caused a significant decrease in antigen-specific antibody production. In addition, germinal center cells isolated from C3-deficient mice produced a similar defect in isotype production. Low density cells with dendritic morphology were the local source of IL-6 and not the germinal center lymphocytes. Adding IL-6 in vitro to IL-6-deficient germinal center cells stimulated cell cycle progression and increased levels of antibody production. These findings reveal that the germinal center produces and uses molecules of the innate immune system, evolutionarily pirating them in order to optimally generate high affinity antibody responses.     

Acute effects of aerobic exercise on mood.

32 female medical students (aged 18–23 yrs) completed 2 8-min trials of high-intensity exercise and 2 8-min trials of low-intensity exercise. One high- and 1 low-exercise trial were accompanied by music; the other 2 trials were accompanied by metronome. Mood was assessed with a modification of the Profile of Mood States before and immediately after each trial. Ss were divided into fit and unfit groups based on heart rate responses during high-exercise trials. High-intensity exercise led to increases in tension/anxiety and fatigue, whereas positive mood changes (vigor and exhilaration) were seen following low-intensity exercise only. No fitness group differences in mood responses were observed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Consequences of retirement activities for distress and the sense of personal control

Mink were infected with Aleutian Mink Disease Parvovirus (AMDV) and sacrificed at monthly intervals after infection. During this time humoral immune responses and leucocyte numbers in blood, mesenteric lymph node, spleen and thymus were monitored. Serum hypergammaglobulinaemia was observed together with elevated antibody responses to AMDV NS1 and VP1/2 proteins. In blood, a highly significant increase in CD8+ lymphocytes was observed. However, (presumed)CD4+ cells defined as CD3+CD8- cells, and B lymphocytes remained relatively constant throughout the study. The (presumed)CD4+/CD8+ ratio decreased significantly from greater than 2 to less than 0.5 and MHC-II+ blood leucocytes increased significantly during infection, a large proportion of these being CD8+. Similar changes were observed in the mesenteric lymph node and spleen. Immunohistology of lymph nodes showed a massive expansion of the paracortical area due to increased numbers of CD8+ cells. The staining intensity of B lymphocytes in lymph nodes with a CD79a reactive monoclonal antibody was decreased in the late infection, indicating a possible greater number of plasma cells. Thymic involution was observed during the AMDV infection, although relative increases in CD3high (presumed)CD4+ and CD3highCD8+ single positive cells were observed. These increases were countered by a corresponding reduction in the CD3low(presumed)CD4+CD8+ double positive cell population. Immunohistology of the thymus in normal mink showed that most of the matured CD3+ T cells were present in the inner medulla, while only few CD3+ cells could be found in the outer cortex. In severely infected mink the thymic structural organisation vanished, and CD3+ cells were found throughout the organ.     

Effect of eccentric exercise on natural killer cell activity

The effect of eccentric one-legged exercise on natural killer (NK) cell activity was studied in eight healthy males. To distinguish between local and systemic effects, blood samples were collected from veins in the exercising leg and resting arm. However, the results did not significantly differ between the leg and arm. To eliminate diurnal variations, the results were compared with a control group that did not exercise but had blood samples collected at the same time points. In the exercising group, plasma creatine kinase increased progressively during and up to 4 days after exercise. The percentage of CD16+ NK cells increased during exercise, which was paralleled by an increase in the NK cell activity per fixed number of blood mononuclear cells. The NK cell activity on a per NK cell basis did not change. The percentage of CD3+, CD4+, CD8+, CD19+, and CD14+ cells did not change significantly during exercise. The present study thus showed that eccentric exercise with a relatively small muscle mass (1 quadriceps femoris muscle) causes systemic effects on NK cells. It is suggested that the increase in plasma epinephrine during eccentric exercise is responsible for the observed increase in the percentage of CD16+ cells.     

Congenital erythrocytosis with elevated erythropoietin level: an incorrectly set "erythrostat"?

It is well documented that IL-6 plays a critical role in B cell terminal differentiation, and in mucosal sites it stimulates proliferation and large-scale secretion of immunoglobulin by B cells, especially those committed to IgA production. The close juxtaposition of IL-6 mRNA+ cells to plasma cells in the intestinal lamina propria supports the proposition that IL-6 production in situ is an important factor determining the outcome of antibody responses at that site. However, it has not been established previously whether exogenous IL-6 could boost antibody responses in the intestine if administered with a challenge antigen. Using a resected gut loop (Thiry-Vella loop) model, we have been able to demonstrate that in mice with double loops, antibody containing cell responses to lumenal administration of ovalbumin were 50% greater in loops given intralumenal recombinant IL-6 with the challenge antigen, than in loops challenged with antigen alone. This demonstrates the efficacy of IL-6 in promoting accumulation of antibody secreting cells in the gut, and suggests a potential therapeutic role for IL-6 to enhance responses to mucosal vaccines.     

Correlation of suppressor cell development in parental and F1 hybrid mouse strains with the growth of a parental tumor in vivo

Parental AKR/J, and AKB6F1 and AKD2F1 hybrid mice were injected subcutaneously with a spontaneously arising AKR/J tumor. The highly responsive AKB6F1 strain never exhibited any depression of immune functioning during the course of tumor growth and regression. The (AKR/J) intermediately responsive strain, while able to generate a successful anti-tumor response, did display a transient reduction of immunological capability, but only during the period tumor growth and not during tumor regression. Cells able to suppress antibody, but not cell-mediated responses, were found. The unresponsive AKD2F1 strain was characterized by both a marked depression of immune responsiveness, as well as the generation of suppressor cells to both antibody, and later, cell-mediated responses. Depression of immune responsiveness, and the generation of suppressor cells, appeared to correlate with the strength or weakness of the anti-tumor response in these strains of mice.     

CD40 cross-linking inhibits specific antibody production by human B cells

Ligation of CD40 on B cells is a co-stimulatory signal for proliferation, antibody secretion, heavy chain switching and rescue from apoptosis after somatic mutation in the germinal centre. The importance of these manifold responses to CD40 activation for humoral immunity is exemplified by the inability of boys with X-linked hyper IgM syndrome to make IgG, IgE or IgA due to a mutation in in the gene coding for CD40 ligand (CD40L). In the present study, we have investigated the effect of CD40 ligation on specific antibody production by human B cells to influenza virus. The antibody response was T cell dependent and specific for the strain of influenza virus used as antigen. Addition of either CD40 mAb or recombinant trimeric CD40L profoundly inhibited specific antibody production. Antibody production by unseparated tonsillar mononuclear cells and by T-depleted B cells stimulated with antigen in the presence of T cell replacing factor were equally inhibited with CD40 antibody showing that the effect was due to ligation of CD40 on B cells rather than blocking of T cell help. The specific antibody detected in these experiments was mostly IgG with little or no IgM and was obtained from surface IgM B cells consistent with activation of a secondary (memory) response. Co-stimulation of tonsillar B cells with CD40 antibody and anti-IgG induced proliferation of IgG+ B cells. These results suggest that CD40 ligation can inhibit specific antibody responses and stimulate proliferation in the same IgG+ (memory) B cell subpopulation. Addition of CD40 antibody during the first 24-48 h of the response was required for inhibition, suggesting that the effect was on early B cell activation and/or proliferation required for antibody production. There was no correlation, however, between the ability of CD40 mAb to stimulate proliferation and inhibit antibody production. We suggest that early activation of CD40 in the specific antibody response inhibits the formation of plasma cells and promotes instead the generation of memory cells.     

Functional properties of CD4+ CD28- T cells in the aging immune system

The aging immune system is characterized by a progressive decline in the responsiveness to exogenous antigens and tumors in combination with a paradoxical increase in autoimmunity. From a clinical viewpoint, deficiencies in antibody responses to exogenous antigens, such as vaccines, have a major impact and may reflect intrinsic B cell defects or altered performance of helper T cells. Here we describe that aging is associated with the emergence of an unusual CD4 T cell subset characterized by the loss of CD28 expression. CD28 is the major costimulatory molecule required to complement signaling through the antigen receptor for complete T cell activation. CD4+ CD28- T cells are long-lived, typically undergo clonal expansion in vivo, and react to autoantigens in vitro. Despite the deficiency of CD28, these unusual T cells remain functionally active and produce high concentrations of interferon-gamma (IFN-gamma) and interleukin-2 (IL-2). The loss of CD28 expression is correlated with a lack of CD40 ligand expression rendering these CD4 T cells incapable of promoting B cell differentiation and immunoglobulin secretion. Aging-related accumulation of CD4+ CD28- T cells should result in an immune compartment skewed towards autoreactive responses and away from the generation of high-affinity B cell responses against exogenous antigens. We propose that the emergence of CD28-deficient CD4 T cells in the elderly can partially explain age-specific aberrations in immune responsiveness.     

T cells within germinal centers are specific for the immunizing antigen

A normal antibody response to T cell-dependent Ag requires physical contact between Ag-specific B and T cells. Because such Ag-specific cells are rare in vivo, we sought to identify an in vivo site where they physically contact each other. We examined the Ag specificity of T cells in germinal centers (GC) in lymph nodes, where it is known that Ag-specific B cells proliferate and mature. We investigated the Ag specificity of GC T cells in situ by examining two characteristics: 1) expression of certain V alpha and V beta TCR families; and 2) incorporation of bromodeoxyuridine into T cell DNA after exposure to Ag as an index of Ag-induced proliferation. When GC were induced in mice with cytochrome c and myelin basic protein, the GC T cells were found to preferentially express V alpha 11 and V beta 8 TCR families, which are, respectively, the dominant TCR families in these two responses. Furthermore, GC T cells have proliferated upon exposure to the Ag that induced GC formation. Taken together, these results demonstrate that GC must recruit and retain Ag-specific T cells, thus implicating the GC as an in vivo site where Ag-specific T and B cells interact.     

Coca chewing for exercise: hormonal and metabolic responses of nonhabitual chewers

To determine the effects of acute coca use on the hormonal and metabolic responses to exercise, 12 healthy nonhabitual coca users were submitted twice to steady-state exercise (approximately 75% maximal O2 uptake). On one occasion, they were asked to chew 15 g of coca leaves 1 h before exercise, whereas on the other occasion, exercise was performed after 1 h of chewing a sugar-free chewing gum. Plasma epinephrine, norepinephrine, insulin, glucagon, and metabolites (glucose, lactate, glycerol, and free fatty acids) were determined at rest before and after coca chewing and during the 5th, 15th, 30th, and 60th min of exercise. Simultaneously to these determinations, cardiorespiratory variables (heart rate, mean arterial blood pressure, oxygen uptake, and respiratory gas exchange ratio) were also measured. At rest, coca chewing had no effect on plasma hormonal and metabolic levels except for a significantly reduced insulin concentration. During exercise, the oxygen uptake, heart rate, and respiratory gas exchange ratio were significantly increased in the coca-chewing trial compared with the control (gum-chewing) test. The exercise-induced drop in plasma glucose and insulin was prevented by prior coca chewing. These results contrast with previous data obtained in chronic coca users who display during prolonged submaximal exercise an exaggerated plasma sympathetic response, an enhanced availability and utilization of fat (R. Favier, E. Caceres, H. Koubi, B. Sempore, M. Sauvain, and H. Spielvogel. J. Appl. Physiol. 80: 650-655, 1996). We conclude that, whereas coca chewing might affect glucose homeostasis during exercise, none of the physiological data provided by this study would suggest that acute coca chewing in nonhabitual users could enhance tolerance to exercise.     

Cross-reactive and group-specific immune responses to a neutralizing epitope of the human respiratory syncytial virus fusion protein

Immune responses to a synthetic peptide corresponding to amino-acids 205-225 of the fusion protein from group B respiratory syncytial (RS) virus, were studied in mice and rabbits, and compared to a similar peptide from group A RS virus. Peptide 205-225 (B) was recognized by monoclonal antibody RS-348, and was immunogenic in both mice and rabbits, as was peptide 205-225 from the fusion protein of a group A strain. Peptide 205-225 (B) induced a proliferative T-cell response, demonstrating the existence of a T-cell epitope in this region of the fusion protein of group B viruses. Both peptides were able to induce a T-cell cross-reactive proliferation when mice were primed with either the homologous or the heterologous peptide. ELISA were performed using synthetic peptides or whole virus (from group A and B) as antigens. Mice anti-peptide sera recognized both homologous and heterologous peptides. A similar pattern was observed with RS virus strains. In indirect immunofluorescence assays, both anti-peptide rabbit sera recognized human nasal epithelial cells infected with A or B strains of RS virus. In contrast, while anti-peptide 205-225 rabbit serum from group A neutralized group A and B strains of RS virus, anti-peptide 205-225 rabbit serum from group B was unable to neutralize a group A virus, although it neutralized a group B strain. These results are similar to the immune response observed in children following primary RS virus infection.