A comparison of prehension force control in young and elderly individuals

Age-related changes were investigated in the control of precision grip force during the lifting and holding of objects with slippery (silk) and nonslippery (sandpaper) surface textures. Two groups of active elderly adults comprising individuals aged 69–79 years (n = 10), and 80–93 years (n = 10) together with a group of young adults aged 18–32 years (n = 10) participated in the study. Each subject lifted a free weight (3N) during which time gripping and lifting forces were monitored. The elderly subjects, especially the individuals in the 81–93 year group, had a larger number of fluctuations in the grip force rate curve and longer force application time than the younger subjects during lifting. The effect of prior experience with one surface on the following different surface was more pronounced in the younger subjects than the elderly subjects. These results suggest a decline in programmed force production capacity with increased age. The fingers of the elderly subjects were more slippery and they exhibited a greater safety margin of the grip force while holding the object than the younger adults. The overall results demonstrated that precision grip force control capacity declines with advancing age. It is suggested that this decline is due mainly to age-related changes in skin properties, and cutaneous sensibility functions, and in part to central nervous system function.     

Single cell analysis of antigen-specific T cell responses in HIV-infected individuals

Antigen-specific and polyclonally induced T cell responses were analyzed in 10 HIV-infected individuals and in 14 controls by enumerating the numbers of tetanus toxoid (TT)-specific and phytohemagglutinin (PHA)-induced IFN-gamma-secreting cells (SC) and IL-4-SC using an enzyme-linked immunospot assay. Whereas the numbers of IFN-gamma-SC in HIV-infected patients were not different from those of the controls in response to an in vitro stimulation with PHA, they were significantly decreased in response to an in vitro stimulation with TT, both before and after a TT booster. Cell depletion experiments indicated that this difference was related to an impairment of CD4(+) T-cell-mediated TT-specific IFN-gamma secretion. Concerning IL-4, the numbers of both polyclonally induced IL-4-SC and TT-specific IL-4-SC were significantly lower in HIV-infected patients than in the controls. It is concluded that secretion of antigen-specific cytokines of both Th1 and Th2 types is depressed in HIV-infected patients.     

Polyclonal B cell responses to conserved neutralization epitopes in a subset of HIV-1-infected individuals

A small proportion of HIV-infected individuals generate a neutralizing antibody (NAb) response of exceptional magnitude and breadth. A detailed analysis of the critical epitopes targeted by broadly neutralizing antibodies should help to define optimal targets for vaccine design. HIV-1-infected subjects with potent cross-reactive serum neutralizing antibodies were identified by assaying sera from 308 subjects against a multiclade panel of 12 "tier 2" viruses (4 each of subtypes A, B, and C). Various neutralizing epitope specificities were determined for the top 9 neutralizers, including clade A-, clade B-, clade C-, and clade A/C-infected donors, by using a comprehensive set of assays. In some subjects, neutralization breadth was mediated by two or more antibody specificities. Although antibodies to the gp41 membrane-proximal external region (MPER) were identified in some subjects, the subjects with the greatest neutralization breadth targeted gp120 epitopes, including the CD4 binding site, a glycan-containing quaternary epitope formed by the V2 and V3 loops, or an outer domain epitope containing a glycan at residue N332. The broadly reactive HIV-1 neutralization observed in some subjects is mediated by antibodies targeting several conserved regions on the HIV-1 envelope glycoprotein.     

Physiological and subjective responses to low relative humidity in young and elderly men

In order to compare the physiological and the subjective responses to low relative humidity of elderly and young men, we measured saccharin clearance time (SCT), frequency of blinking, hydration state of the skin, transepidermal water loss (TEWL), sebum level recovery and skin temperatures as physiological responses. We asked subjects to evaluate thermal, dryness and comfort sensations as subjective responses using a rating scale. Eight non-smoking healthy male students (21.7+/-0.8 yr) and eight non-smoking healthy elderly men (71.1+/-4.1 yr) were selected. The pre-room conditions were maintained at an air temperature (Ta) of 25 degrees C and a relative humidity (RH) of 50%. The test-room conditions were adjusted to provide 25 degrees C Ta and RH levels of 10%, 30% and 50%. RH had no effect on the activity of the sebaceous gland or change of mean skin temperature. SCT of the elderly group under 10% RH was significantly longer than that of the young group. In particular, considering the SCT change, the nasal mucous membrane seems to be affected more in the elderly than in the young in low RH. Under 30% RH, the eyes and skin become dry, and under 10% RH the nasal mucous membrane becomes dry as well as the eyes and skin. These findings suggested that to avoid dryness of the eyes and skin, it is necessary to maintain greater than 30% RH, and to avoid dryness of the nasal mucous membrane, it is necessary to maintain greater than 10% RH. On the thermal sensation of the legs, at the lower humidity level, the elderly group felt cooler than the young group. On the dry sensation of the eyes and throat, the young group felt drier than the elderly group at the lower humidity levels. From the above results, the elderly group had difficulty in feeling dryness in the nasal mucous membrane despite being easily affected by low humidity. On the other hand, the young group felt the change of humidity sensitively despite not being severely affected by low humidity. Ocular mucosa and physiology of skin by dryness showed no difference by age. In the effect of longer exposure (180 min.) to low RH, only TEWL showed a slight decrease after 120 minutes in 30% RH, and all the measured results showed no noticeable differences compared with the result at 120 minutes.     

Immunological responses to ultraviolet light B radiation in Black individuals.

Immunological factors are important participants in the pathogenesis of experimental skin tumors. We therefore studied cutaneous immune responses in subjects with either low natural incidence (Black individuals), or a high frequency rate (White individuals) of skin cancer. We performed whole body irradiation with a low dose of ultraviolet light B (UV-B) and evaluated peripheral lymphocytes. UV-B irradiation was associated with small but significant changes in lymphocyte phenotype frequency. In White subjects this consisted of an increased number of CD19 (B cells) and CD 4/29 (inducer of helper T cells); Black subjects had a slight decrease in CD3 (T cells). Natural killer activity, not affected by UV-B in White subjects, increased significantly in Black subjects. UV-B was devoid of immunological effects in vitro for any of the parameters tested. As expected, the low UV-B dose used in this study induced increases of serum vitamin D3 concentrations in White subjects, with lack of response in the Black subjects. We conclude that Black individuals selectively exhibit an increase in Natural Killer activity in response to irradiation with low dose UV-B. This race group-specific immune response to ultraviolet radiation appears to require mediation by the skin. Enhanced Natural Killer activity could underlie at least partly the resistance in Black individuals to the development of photodependent skin cancer.     

Lacrimal gland-directed B cell responses

Although it is accepted that IgA plasma cells predominate in the lacrimal gland, the factors leading to this prevalence are not known. A series of 4-day LPS-driven co-culture experiments performed with dissociated lacrimal gland and lymphoid cell populations was employed to study the direct effect of lacrimal gland cells on B cell differentiation. Lacrimal gland cells, when co-cultured with spleen or mesenteric lymph node cells, were found to suppress differentiation of cells to IgA, IgG, and IgM production. Furthermore, suppression of IgG and IgM responses occurred after co-culture of lacrimal gland cells with Peyer's patch cells. However, these Peyer's patch co-cultures led to a stimulation of the IgA response, a condition that was abrogated by removal of Peyer's patch T cells before co-culturing. Pretreatment of lacrimal gland cells with mitomycin C eliminated the suppression and stimulation previously observed. These results demonstrate the effects of lacrimal gland, both directly and indirectly through T cells, on B cell differentiation. These findings explain in part the preferential accumulation of IgA-plasma cells within the gland.     

Differences in HIV-specific T cell responses between HIV-exposed and -unexposed HIV-seronegative individuals

HIV-1-specific T lymphocyte responses in individuals exposed to HIV-1 but who remain persistently seronegative (HESNs) have been reported in some but not all previous studies. This study was designed to resolve unequivocally the question of whether HESNs make HIV-1-specific T cell responses. We performed a blind investigation to measure HIV-1-specific T cell responses in both HIV-1-serodiscordant couples and HIV-1-unexposed seronegative controls (HUSNs). We found low-frequency HIV-1-specific T cells in both HESNs and HUSNs but show that the response rates were higher over time in the former (P = 0.01). Furthermore, the magnitudes of the HIV-1-specific T cell responses were significantly higher among responding HESNs than among HUSNs over time (P = 0.002). In both groups, responses were mediated by CD4 T cells. The responses were mapped to single peptides, which often corresponded to epitopes restricted by multiple HLA-DR types that have previously been detected in HIV-1-infected patients. HIV-1-specific T cell responses in HUSNs and some HESNs likely represent cross-reactivity to self or foreign non-HIV-1 antigens. The significantly greater T cell responses in HESNs, including in two who were homozygous for CCR5Δ32, demonstrates that HIV-1-specific T cell responses can be induced or augmented by exposure to HIV-1 without infection.     

Physiological responses of young and elderly men to prolonged exercise at critical power

The critical power (CP) of a muscle group or individual may represent the highest rate of work which can be performed for an extended period. We investigated this concept in young (n = 13, 24.5 years) and elderly (n = 12, 70.7 years) active men by first determining CP and then comparing responses elicited by 24 min of cycle exercise at power outputs (omega) corresponding to CP. Values from the final 2 min of the 24-min ride were expressed relative to maximal values established in a ramp test. CP for the elderly was only 65% that for the young, but on a relative basis, it was significantly higher both in terms of omega (67 vs 62% of omega max) and oxygen consumption (VO2) (91.5 vs 85.2% of maximum oxygen consumption). There were no group differences in relative values for ventilation (VE), heart rate or respiratory exchange ratio (R). During the 24-min ride, VO2 and R achieved a plateau in both groups, while VE, blood lactate and arterial PCO2 continued to change in the young. It was concluded that CP can be determined in active elderly men, but that CP may not represent a true non-fatiguing work rate in either young or elderly men.     

Bromelain modulates T cell and B cell immune responses in vitro and in vivo

The ability to modulate immune responses is a major aim of many vaccine and immunotherapeutic development programs. Bromelain, a mixture of cysteine proteases, modulates immunological responses and has been proposed to be of clinical use. However, the identity of the immune cells affected by bromelain and the specific cellular functions that are altered remain poorly understood. To address these shortcomings in our knowledge, we have used both in vitro and in vivo immunological assays to study the effects of bromelain. We found that bromelain enhanced T cell receptor (TCR) and anti-CD28-mediated T cell proliferation in splenocyte cultures by increasing the costimulatory activity of accessory cell populations. However, despite increased T cell proliferation, bromelain concomitantly decreased IL-2 production in splenocyte cultures. Additionally, bromelain did not affect TCR and CD28-induced proliferation of highly purified CD4+ T cells, but did inhibit IL-2 production by these cells. In vivo, bromelain enhanced T-cell-dependent, Ag-specific, B cell antibody responses. Again, bromelain induced a concomitant decrease in splenic IL-2 mRNA accumulation in immunized mice. Together, these data show that bromelain can simultaneously enhance and inhibit T cell responses in vitro and in vivo via a stimulatory action on accessory cells and a direct inhibitory action on T cells. This work provides important insights into the immunomodulatory activity of bromelain and has important implications for the use of exogenous cysteine proteases as vaccine adjuvants or immunomodulatory agents.     

TLR signaling fine-tunes anti-influenza B cell responses without regulating effector T cell responses

Influenza is a ssRNA virus that has been responsible for widespread morbidity and mortality; however, the innate immunological mechanisms that drive the adaptive anti-influenza immune response in vivo are yet to be fully elucidated. TLRs are pattern recognition receptors that bind evolutionarily conserved pathogen-associated molecular patterns, induce dendritic cell maturation, and consequently aid the development of effective immune responses. We have examined the role of TLRs in driving effective T and B cell responses against influenza virus. We found TLR3 and its associated adapter molecule, Toll/IL-R domain-containing adaptor-inducing IFN-beta, did not play a role in the development of CD4(+) or CD8(+) T cell responses against influenza virus, nor did they influence influenza-specific B cell responses. Surprisingly, TLR7 and MyD88 also played negligible roles in T cell activation and effector function upon infection with influenza virus; however, their signaling was critical for regulating anti-influenza B cell Ab isotype switching. The induction of appropriate anti-influenza humoral responses involved stimulation of TLRs on B cells directly and TLR-induced production of IFN-alpha, which acted to reduce IgG1 and increase IgG2a/c class switching. Notably, direct TLR signaling on B cells or T cell help through the CD40-CD40L interaction was sufficient to support B cell proliferation and IgG1 production, whereas IFN-alpha was critical for fine-tuning the nature of the isotype switch. Taken together, these data reveal that TLR signaling is not required for anti-influenza T cell responses, but through both direct and indirect means orchestrates appropriate anti-influenza B cell responses.     

Bioheat modeling of elderly and young for prediction of physiological and thermal responses in heat-stressful conditions

Exposure to hot and humid conditions results in physiological changes in metabolism, cardiac output and thermoregulation of the young adult and these changes deviate with elderly due to aging. The elderly population is more vulnerable than the healthy and young population due to age-weakened physiology and thermoregulatory functions. There are, however, limited bioheat models addressing such changes due to hot exposure in the young and the elderly. This paper develops robust bioheat models for young and elderly while incorporating the physiological changes under exposure to heat-stressful conditions for both age groups the age-related changes in physiology and thermoregulation to an elderly human. However, due to a large variability of thermoregulation among the elderly population, a sensitivity analysis revealed that the average elderly is characterized by metabolic rate and cardiac output, which are lower than those of the young by 21% and 14.4%, respectively. Moreover, the thresholds of the onset of vasodilation and sweating are delayed from those of young adults by 0.5 °C and 0.21 °C, respectively.The elderly and young bioheat models were validated with number of independent published experimental studies under hot exposures in steady and transient conditions. Model predictions of core and mean skin temperatures showed good agreement with published experimental data with a discrepancy of 0.1 °C and 0.5 °C, respectively.     

ACTH decreases the expression and secretion of apolipoprotein B in HepG2 cell cultures

Administration of adrenocorticotropic hormone (ACTH) has been shown to decrease plasma concentrations of apolipoprotein B (apoB) containing lipoproteins, including lipoprotein(a), in man. However, the mechanism behind this hypolipidemic effect is unknown. This study aimed at distinguishing between the main possibilities (increased elimination or decreased production of lipoproteins) using HepG2 cell cultures. Addition of ACTH to the cell culture medium selectively down-regulated apoB mRNA expression and apoB secretion in a dose-dependent manner. At 100 pmol/liter ACTH, the apoB mRNA level was about 40% lower than in the untreated cells, and the secretion of apoB into the medium was decreased to a similar extent. The expression and secretion of other apolipoproteins (apoA-I, apoE, and apoM), however, were not affected by ACTH. Under normal culture conditions the level of secretion of apoB from HepG2 cells is quite low. In the presence of 0.4 mmol/liter oleic acid secretion of apoB increased 3-fold, but this phenomenon was not seen in ACTH-treated cells. Binding and internalization of radiolabeled low density lipoprotein (LDL) by HepG2 cell, as well as LDL-receptor mRNA and scavenger receptor B-I mRNA levels, were not influenced by ACTH. In conclusion, ACTH directly and selectively down-regulated the production and secretion of apoB in HepG2 cell cultures, suggesting that a principal mechanism behind the cholesterol-lowering effect of ACTH in vivo may be a decreased production rate of apoB-containing lipoproteins from the liver.     

alpha-Glycerylphosphorylcholine administration increases the GH responses to GHRH of young and elderly subjects.

Growth hormone (GH) secretion is decreased during aging in humans and in rodents. This decrease may be due to increased hypothalamic somatostatin release, which is inhibited by cholinergic agonists, or to decreased secretion of GHRH. Alpha-glyceryl-phosphorylcholine (alpha-GFC) is a putative acetylcholine precursor used in the treatment of cognitive disorders in the elderly. In order to learn what effect alpha-GFC had on GH secretion, GH-release hormone (GHRH) was given to young and old human volunteers, with or without the addition of alpha-GFC. GH secretion was greater in the younger subjects than in the old individuals, and both groups had a greater GH response to the GHRH+alpha-GFC than to GHRH alone. The potentiating effect of alpha-GFC on GH secretion was more pronounced in the elderly subjects. These findings confirm the observation that aged individuals respond less well to GHRH than younger subjects, and provides further evidence that increased cholinergic tone enhances GH release.     

T and B cell responses to myelin-oligodendrocyte glycoprotein in multiple sclerosis

The pathogenesis of multiple sclerosis (MS) is believed to involve an autoimmune component directed against the myelin sheath. One potential target Ag for such autoimmune attack is the myelin-oligodendrocyte glycoprotein (MOG) because an anti-MOG mAb has profound influence on the course of experimental autoimmune encephalomyelitis, which to some extent represents an experimental model of MS. Using single cell assays, we have evaluated T and B cell reactivities to MOG in MS patients and controls. T cell reactivity was estimated by counting the number of cells that secreted IFN-gamma in response to MOG, whereas B cell reactivity was estimated by enumerating cells secreting antibodies that bound to MOG. MOG reactive T cells were detected in the peripheral blood of the majority of the 16 MS patients examined (mean 1/7299 mononuclear cells), but infrequently and at lower numbers in samples from neurologic controls. MOG-reactive T cells were more frequent among MS patients' cerebrospinal fluid (CSF) mononuclear cells (mean 1/450 cells). The T cell response to MOG was evidently MHC class II restricted, because Fab fragments of a rabbit polyclonal anti HLA-DR antibodies abrogated the Ag-induced increase in number of cells that secreted IFN-gamma, as analyzed on CSF and PBMC from three patients with MS. Anti-MOG IgG antibody-secreting cells were detected in blood in 8 of 16 MS patients (mean 1/25,641 cells), but they were also strongly accumulated in CSF, being detected in 8 of 10 MS patients examined (mean 1/265 cells), while rarely found in controls. The findings imply that MOG may represent a pathogenetically important target Ag in MS.     

Placental protein 14 regulates selective B cell responses

Placental protein 14 (PP14) is a glycoprotein of the lipocalin family that acts as a negative regulator in T cell receptor-mediated activation. In this study, we investigated PP14s potential role in regulating B cell activation. While PP14-inhibited B cell proliferation, IgM secretion and the surface expression of MHC class II, the expression of other surface molecules, such as CD69 and CD86, were unaffected. These observed effects were independent of the anti-IgM concentration used for stimulation, regardless of the presence of either T cells or IL-4, and persisted when B cells were stimulated by stimuli, which circumvent early events during B cell Ag receptor (BCR) activation, namely, protein kinase C activators in combination with Ca(2+) ionophore. Interestingly, we demonstrated that PP14s inhibitory characteristics are reminiscence of that achieved by independent ligation of CD19 using anti-CD19 mAb. Together with our previously reported effects on T cells, these findings identify PP14 as a soluble regulatory factor capable of interacting with both T and B cells in a carbohydrate-dependent manner and as a result it can affect both cellular and humoral immune responses.     

Modulation of B cell responses by Toll-like receptors

B lymphocytes are well known because of their key role in mediating humoral immune responses. Upon encounter with antigen and on cognate interaction with T cells, they differentiate into antibody-secreting plasma cells, which are critical for protection against a variety of pathogens. In addition to their antibody-production function, B cells are efficient antigen-presenting cells and express a variety of pathogen recognition receptors (PRRs). Engagement of these PRRs with their respective ligands results in cytokine and chemokine secretion and the upregulation of co-stimulatory molecules. These events constitute innate immune responses. Toll-like receptor (TLR) activation provides a third signal for B cell activation and is essential for optimal antigen-specific antibody responses. In some situations, TLR activation in B cells can result in autoimmunity. The purpose of this review is to provide some insights into the way that TLRs influence innate and adaptive B cell responses.     

Protective B cell responses to flu--no fluke!

The mechanisms regulating the induction and maintenance of B lymphocytes have been delineated extensively in immunization studies using proteins and hapten-carrier systems. Increasing evidence suggests, however, that the regulation of B cell responses induced by infections is far more complex. In this study, we review the current understanding of B cell responses induced following infection with influenza virus, a small RNA virus that causes the flu. Notably, the rapidly induced, highly protective, and long-lived humoral response to this virus is contributed by multiple B cell subsets, each generating qualitatively distinct respiratory tract and systemic responses. Some B cell subsets provide extensive cross-protection against variants of the ever-mutating virus, and each is regulated by the quality and magnitude of infection-induced innate immune signals. Knowledge gained from the analysis of such highly protective humoral response might provide a blueprint for successful vaccines and vaccination approaches.