Robert Clancy

Salivary IgA levels and infection risk in elite swimmers

UNLABELLED The effects of exercise on the immune system has been shown to be dependent on the level of fitness of the subjects, the degree of intensity, and the duration of the exercise. A reduction in salivary IgA levels occurs after individual sessions of exercise. PURPOSE The purpose of this study was to assess the relationship between changes in salivary IgA and training volume, psychological stress, and infection rates in a cohort of 26 elite swimmers over a 7-month training period and to compare the changes with a group of 12 moderately exercising controls. METHODS Salivary IgA concentrations were measured by an electroimmunodiffusion. Exercise gradings were assessed by a standardized aerobic-anaerobic rating system. Psychological stress/anxiety was evaluated by the Spielberger State-Trait Anxiety Inventory. Infections were physician-verified. RESULTS Salivary IgA levels showed an inverse correlation with the number of infections in both elite swimmers and moderately exercising control subjects. The pretraining salivary IgA levels in swimmers were 4.1% lower for each additional month of training and 5.8% lower for each additional infection. The posttraining salivary IgA levels in swimmers were not significantly correlated with infection rates but were 8.5% lower for each additional 1 km swum in a training session and 7.0% lower for each additional month of training. The number of infections observed in the elite swimmers was predicted from regression models by the preseason (P = 0.05) and the mean pretraining salivary IgA levels (P = 0.006). The trends in pretraining salivary IgA levels over the 7-month season, calculated as individual slopes of pretraining IgA levels over time, were also predictive of the number of infections (P = 0.03) in the swimmers. CONCLUSIONS These results indicate that measurement of salivary IgA levels over a training season may be predictive for athletes at risk of infection.

The effect on immunity of long‐term intensive training in elite swimmers

The impact of long‐term training on systemic and mucosal immunity was assessed prospectively in a cohort of elite swimmers over a 7‐month training season in preparation for national championships. The results indicated significant suppression (P < 0.05) of serum IgA. IgG and IgM and salivary IgA concentration in athletes associated with long‐term training at an intensive level. There was also a trend towards lower IgG2 subclass levels in serum in athletes compared with controls (P= 0.07). There were no significant changes in numbers or percentages of B or T cell subsets, but there was a significant fall in natural killer (NK) cell numbers and percentages in athletes over the training season (P < 0.05). After individual training sessions there was a significant decrease in salivary IgA levels for athletes compared with controls (P= 0.02). In athletes there was a downward trend in salivary IgA levels over the 7‐month training period in both the pre‐exercise (P= 0.06) and post‐exercise samples (P= 0.04). There were no significant trends in salivary IgG levels over the study period in either athletes or controls. The only significant change in salivary IgM levels was an increase in detection rate in the pre‐competition phase in athletes (P= 0.03). The study suggests that training of elite athletes at an intensive level over both short‐ and long‐time frames suppresses both systemic and mucosal immunity. Protracted immune suppression linked with prolonged training may determine susceptibility to infection, particularly at times of major competitions.

GM‐CSF, IL‐1α, IL‐β, IL‐6, IL‐8, IL‐10, ICAM‐1 and VCAM‐1 gene expression and cytokine production in human duodenal fibroblasts stimulated with lipopolysaccharide, IL‐1α and TNF‐α

The role of mucosal fibroblasts in intestinal inflammatory reactions is not known. In this study, we demonstrate that fibroblasts grown from histologically normal human duodenal biopsy tissues expressed mRNA genes for granulocyte‐macrophage colony‐stimulating factor (GM‐CSF). IL‐lα, IL‐1β, IL‐6, IL‐8, IL‐10, intercellular adhesion molecule‐I (ICAM‐I) and vascular cell adhesion molecule‐1 (VCAM‐i) when stimulated with lipopolysaccharide (LPS) or IL‐1α. The increased mRNA expression of GM‐CSF, IL‐1α IL‐1β IL‐6 and IL‐α in response to IL‐1α and LPS stimulation was time‐ and dose‐dependent. In contrast. IL‐10 was weakly expressed when fibroblasts were stimulated with LPS. IL‐1α or tumour necrosis factor‐alpha (TNF‐α), but the expression was enhanced in the presence of cycloheximide combined with optimal concentrations of LPS. IL‐1α or TNF‐α. IL‐1α was a more potent stimulator than LPS for GM‐CSF. IL‐6, IL‐8 and I L‐10 expression, but not for IL‐1α and IL‐1β. Increased GM‐CSF. lL‐6 and IL‐8 gene expression was associated with the production of cytokine proteins in culture supernatant, but IL‐1α and IL‐1bL remained undetectable. Dexamethasone suppressed both gene expression and protein production of GM‐CSF. IL‐6 and IL‐8 when fibroblasts were exposed to IL‐1α. TNF‐α stimulated the release of GM‐CSF. IL‐6 and IL‐8 and, combined with IL‐1α. cytokine production was enhanced synergistically. Finally, both LPS and IL‐1ã up‐regulated ICAM‐I and VCAM‐1 gene expression. These findings implicate duodenal fibroblasts in the initiation and/or regulation of intestinal inflammation.

Epstein-barr virus reactivation and upper-respiratory illness in elite swimmers

PURPOSE The aim of this study was to investigate the relationships between latent viral shedding of Epstein-Barr virus (EBV) in saliva, upper-respiratory illness, and mucosal immune suppression in a cohort of highly trained swimmers undertaking intensive training. METHODS Saliva was collected before selected training sessions from 14 elite male swimmers during a 30-d period of intensive training. Prior infection with EBV was determined by EBV antibody serology. Salivary IgA concentrations were measured by enzyme linked immunosorbent assay (ELISA), and EBV viral shedding (EBV-DNA) was detected by polymerase chain reaction (PCR). Symptoms of upper-respiratory illness were recorded daily. RESULTS Eleven swimmers (79%) were seropositive for prior EBV infection. Seven EBV seropositive swimmers (64%) had EBV-DNA detected during the study period. Upper-respiratory symptoms (URS) were reported in six of seven swimmers in whom EBV-DNA was detected and in three of four swimmers with no EBV-DNA detection. No URS were reported in the EBV seronegative swimmers. There was a statistically significant relationship between EBV serology status and URS (P = 0.027). EBV-DNA was detected in saliva before the appearance of URS. Salivary IgA levels were significantly lower immediately before the URS (P = 0.01) compared with subsequent peak IgA levels and declined to pre-URS levels on average 11 d after the first appearance of URS. CONCLUSIONS The time course of appearance of EBV-DNA in relation to URS suggests latent viral EBV shedding may be a contributing factor in the URS. The low levels of salivary IgA detected before the URS indicated transient mucosal immune suppression in the study cohort. The viral shedding may alternatively be a reflection of the altered immune control mechanisms that occur in response to intensive exercise and unrelated to the URS.

ORAL IMMUNISATION WITH KILLED HAEMOPHILUS INFLUENZAE FOR PROTECTION AGAINST ACUTE BRONCHITIS IN CHRONIC OBSTRUCTIVE LUNG DISEASE

Fifty patients with chronic obstructive lung disease were randomly allocated to three groups, to assess whether an oral vaccine containing non-typable Haemophilus influenzae protected against acute bronchitis. The double-blind prospective study over a three-month winter period included two placebo groups and one test group. Oral immunisation with H influenzae induced a tenfold reduction in the incidence of infection (p less than 0.001). During the subsequent winter, without further immunisation, protection by the vaccine was no longer statistically significant. There was no clear correlation between clinical protection and either carriage of H influenzae or the level of antibody to H influenzae antigen in saliva.

Modifiers of the human mucosal immune system.

This review focuses on saliva as a measure of mucosal immunity in man. The review will cover studies of parameters that modify the early ontogeny patterns of mucosal immunity and the impact of infections and physiological variables on the human mucosal immune response. The most significant modifiers of human mucosal immunity are events that occur in the neonatal maturation period and, later in life, the interplay between the immune system and the neuroendocrine systems. IgA antibodies are the predominant isotype involved in the human mucosal immune response and are important for protection at mucosal surfaces. The level of IgA in mucosal secretions is modified by antigenic stimulation as well as by many physiological variables. Studies have also revealed that IgM plays a significant immunoregulatory role at mucosal surfaces, particularly during episodes of infection or stress. The detection patterns of IgD in saliva of neonates suggests a role for IgD in the initial maturation process of mucosal immunity. The role of IgG at mucosal surfaces is unclear and although IgG may play a compensatory role in IgA deficiency, the detection of high levels of IgG in saliva appears to be associated with periods of increased membrane permeability.

Innate versus adaptive immunity in Candida albicans infection

Candida albicans is a common opportunistic pathogen, causing both superficial and systemic infection. Clinical observations indicate that mucocutaneous infections are commonly associated with defective cell‐mediated immune responses, whereas systemic infection is more frequently seen in patients with deficiencies in neutrophil number or function. Analysis of mechanisms of host resistance against gastrointestinal and oral infection in mouse models has demonstrated an absolute dependence on CD4+ T cells, although clearance also involves phagocytic cells. Both IL‐12 and TNF‐α appear to be important mediators, but mouse strain‐dependent variations in susceptibility to infection may be related to T‐cell enhancement of production of phagocytic cells by the bone marrow. In murine systemic infection, the role of innate and adaptive responses is less well defined. Studies in immunodeficient and T‐cell‐depleted mice suggest that clearance of the yeast may be predominantly a function of the innate response, whereas the adaptive response may either limit tissue damage or have the potential to cause immunopathology, depending on the host genetic context in which the infection takes place.

T Cells Augment Monocyte and Neutrophil Function in Host Resistance against Oropharyngeal Candidiasis

ABSTRACT The purpose of this study was to identify the cell populations involved in recovery from oral infections with Candida albicans. Monoclonal antibodies specific for CD4+cells, CD8+ cells, and polymorphonuclear leukocytes were used to deplete BALB/c and CBA/CaH mice of the relevant cell populations in systemic circulation. Monocytes were inactivated with the cytotoxic chemical carrageenan. Mice were infected with 108C. albicans yeast cells and monitored for 21 days. Systemic depletion of CD4+ and CD8+ T lymphocytes alone did not increase the severity of oral infection compared to that of controls. Oral colonization persisted in animals treated with head and neck irradiation and depleted of CD4+T cells, whereas infections in animals that received head and neck irradiation alone or irradiation and anti-CD8 antibody cleared the infection in a comparable fashion. The depletion of polymorphonuclear cells and the cytotoxic inactivation of mononuclear phagocytes significantly increased the severity of oral infection in both BALB/c and CBA/CaH mice. High levels of interleukin 12 (IL-12) and gamma interferon (IFN-γ) were produced by lymphocytes from the draining lymph nodes of recovering animals, whereas IL-6, tumor necrosis factor alpha, and IFN-γ were detected in the oral mucosae of both naı̈ve and infected mice. The results indicate that recovery from oropharyngeal candidiasis in this model is dependent on CD4+-T-cell augmentation of monocyte and neutrophil functions exerted by Th1-type cytokines such as IL-12 and IFN-γ.

Primary Role for CD4 T Lymphocytes in Recovery From Oropharyngeal Candidiasis

ABSTRACT Oropharyngeal candidiasis is associated with defects in cell-mediated immunity and is commonly seen in human immunodeficiency virus positive individuals and AIDS patients. A model for oral candidiasis in T-cell-deficient BALB/c and CBA/CaH nu/nu mice was established. After inoculation with 108Candida albicans yeasts, these mice displayed increased levels of oral colonization compared to euthymic control mice and developed a chronic oropharyngeal infection. Histopathological examination of nu/nu oral tissues revealed extensive hyphae penetrating the epithelium, with polymorphonuclear leukocyte microabscess formation. Adoptive transfer of either naive or immune lymphocytes into immunodeficient mice resulted in the recovery of these animals from the oral infection. Reconstitution of immunodeficient mice with naive CD4+ but not CD8+ T cells significantly decreased oral colonization compared to controls. Interleukin-12 and gamma interferon were detected in the draining lymph nodes of immunodeficient mice following reconstitution with naive lymphocytes. This study demonstrates the direct requirement for T lymphocytes in recovery from oral candidiasis and suggests that this is associated with the production of cytokines by CD4+ T helper cells.

Cellular and Cytokine Correlates of Mucosal Protection in Murine Model of Oral Candidiasis

ABSTRACT Host protection against Candida albicans infection in a model of oral candidiasis involving infection-prone [DBA/2 (H-2d)] and less infection-prone [BALB/c (H-2d)] mouse strains was analyzed in terms of antibody and cellular responses, and in terms of cytokine patterns from regional lymph node cells. There was a selective expansion of γ/δ+ T-cell receptor cells, which correlated with the patterns of colonization in both mouse strains, with higher numbers of γ/δ T cells detected in BALB/c mice. Antigen-induced T-cell proliferation was significantly higher in BALB/c mice than in DBA/2 mice. Higher levels of serum immunoglobulin G (IgG) and salivary IgA antibodies were detected in BALB/c mice than in DBA/2 mice, but only after the infection was cleared. The cervical lymph node cells from infected mice were assessed for interleukin-4 (IL-4), IL-12, and gamma interferon (IFN-γ) mRNA gene expression by reverse transcription-PCR and protein production in the culture supernatants following restimulation in vitro. In BALB/c mice, an early increase in levels of IL-4, IFN-γ, and IL-12 correlated with rapid elimination of C. albicans. In DBA/2 mice, where resolution of infection was delayed, IL-4 message expression was delayed and the IL-4 secretion level was lower. Neutralization of IL-4 by multiple injections of an anti-IL-4 monoclonal antibody in BALB/c mice resulted in increased carriage rate and delayed clearance of the yeasts. Collectively, the data suggest that the T-cell response to C. albicans in the regional lymph nodes which correlates best with rapid oral clearance ofC. albicans is a balanced Th0 cytokine response involving early secretion of both IFN-γ and IL-4.