This review summarizes research discoveries within 4 areas of exercise immunology that have received the most attention from investigators: (1) acute and chronic effects of exercise on the immune system, (2) clinical benefits of the exercise-immune relationship, (3) nutritional influences on the immune response to exercise, and (4) the effect of exercise on immunosenescence. These scientific discoveries can be organized into distinctive time periods: 1900-1979, which focused on exercise-induced changes in basic immune cell counts and function; 1980-1989, during which seminal papers were published with evidence that heavy exertion was associated with transient immune dysfunction, elevated inflammatory biomarkers, and increased risk of upper respiratory tract infections; 1990-2009, when additional focus areas were added to the field of exercise immunology including the interactive effect of nutrition, effects on the aging immune system, and inflammatory cytokines; and 2010 to the present, when technological advances in mass spectrometry allowed system biology approaches (i.e., metabolomics, proteomics, lipidomics, and microbiome characterization) to be applied to exercise immunology studies. The future of exercise immunology will take advantage of these technologies to provide new insights on the interactions between exercise, nutrition, and immune function, with application down to the personalized level. Additionally, these methodologies will improve mechanistic understanding of how exercise-induced immune perturbations reduce the risk of common chronic diseases.

Sixteen experienced marathoners ran on treadmills for 3 h at ∼70% maximal oxygen consumption (V˙o _2 max) on two occasions while receiving 1 l/h carbohydrate (CHO) or placebo (Pla) beverages. Blood and vastus lateralis muscle biopsy samples were collected before and after exercise. Plasma was analyzed for IL-6, IL-10, IL-1 receptor agonist (IL-1ra), IL-8, cortisol, glucose, and insulin. Muscle was analyzed for glycogen content and relative gene expression of 13 cytokines by using real-time quantitative RT-PCR. Plasma glucose and insulin were higher, and cortisol, IL-6, IL-10, and IL-1ra, but not IL-8, were significantly lower postexercise in CHO vs. Pla. Change in muscle glycogen content did not differ between CHO and Pla ( P = 0.246). Muscle cytokine mRNA content was detected preexercise for seven cytokines in this order (highest to lowest): IL-15, TNF-α, IL-8, IL-1β, IL-12p35, IL-6, and IFN-γ. After subjects ran for 3 h, gene expression above prerun levels was measured for five of these cytokines: IL-1β, IL-6, and IL-8 (large increases), and IL-10 and TNF-α (small increases). The increase in mRNA (fold difference from preexercise) was attenuated in CHO (15.9-fold) compared with Pla (35.2-fold) for IL-6 ( P = 0.071) and IL-8 (CHO, 7.8-fold; Pla, 23.3-fold; P = 0.063). CHO compared with Pla beverage ingestion attenuates the increase in plasma IL-6, IL-10, and IL-1ra and gene expression for IL-6 and IL-8 in athletes running 3 h at 70%V˙o _2 max despite no differences in muscle glycogen content.

The influence of carbohydrate (1 l/h of a 6% carbohydrate beverage), gender, and age on pro- and anti-inflammatory plasma cytokine and hormone changes was studied in 98 runners for 1.5 h after two competitive marathon races. The marathoner runners were randomly assigned to carbohydrate (C, n = 48) and placebo (P, n = 50) groups, with beverages administered during the races in a double-blind fashion using color codes. Plasma glucose was higher and cortisol was lower in the C than in the P group after the race (P < 0.001). For all subjects combined, plasma levels of interleukin (IL)-10, IL-1 receptor antagonist (IL-1ra), IL-6, and IL-8 rose significantly immediately after the race and remained above prerace levels 1.5 h later. The pattern of change in all cytokines did not differ significantly between the 12 women and 86 men in the study and the 23 subjects ≥50 yr of age and the 75 subjects <50 yr of age. The pattern of change in IL-10, IL-1ra, and IL-8, but not IL-6, differed significantly between the C and the P group, with higher postrace values measured for IL-10 (109% higher) and IL-1ra (212%) in the P group and for IL-8 (42%) in the C group. In conclusion, plasma levels of IL-10, IL-1ra, IL-6, and IL-8 rose strongly in runners after a competitive marathon, and this was not influenced by age or gender. Carbohydrate ingestion, however, had a major effect in attenuating increases in cortisol and two anti-inflammatory cytokines, IL-10 and IL-1ra.

Anecdotal, survey, and epidemiological data suggest that endurance athletes are at an increased risk for upper respiratory tract infection (URTI) during periods of heavy training and the 1 - to 2-wk period after race events. The majority of athletes, however, who participate in endurance race events do not experience illness. Of greater public health importance is the consistent finding of a reduction in URTI risk reported by fitness enthusiasts and athletes who engage in regular exercise training while avoiding overreaching/overtraining. Although it naturally follows that infection risk should in some way be linked to acute and chronic exercise-induced alterations in immunity, attempts thus far to measure this association have been unsuccessful. There is growing evidence that for several hours subsequent to heavy exertion, several components of both the innate and adaptive immune system exhibit suppressed function. The immune response to heavy exertion is transient, however, and further research on the mechanisms underlying the immune response to prolonged and intensive endurance exercise is necessary before meaningful clinical applications can be drawn. Some attempts have been made through chemical or nutritional means (e.g., indomethacin, glutamine, vitamin C, and carbohydrate supplementation) to attenuate immune changes after intensive exercise to lower the risk of infection. No consistent relationship between nutritional interventions, exercise immunology, and alteration in URTI risk has yet been established.

To determine the influence of 2 wk of quercetin (Q; 1000 mg x d(-1)) compared with placebo (P) supplementation on exercise performance and skeletal muscle mitochondrial biogenesis in untrained, young adult males (N = 26, age = 20.2 +/- 0.4 yr, VO2max = 46.3 +/- 1.2 mL x kg(-1) x min(-1)). Using a randomized, crossover design with a 2-wk washout period, subjects provided blood and muscle biopsy samples presupplementation and postsupplementation periods and were given 12-min time trials on 15% graded treadmills after 60 min of moderate exercise preloads at 60% VO2max. Plasma Q levels rose significantly in Q versus P during the 2-wk supplementation period (interaction P value <0.001). During the 12-min trial, the net change in distance achieved was significantly greater during Q (2.9%) compared with P (-1.2%; 29.5 +/- 11.5 vs -11.9 +/- 16.0 m, respectively, P = 0.038). Skeletal muscle messenger RNA expression tended to increase (range = 16-25%) during Q versus P for sirtuin 1 (interaction effect, P = 0.152), peroxisome proliferator-activated receptor gamma coactivator-1alpha (P = 0.192), cytochrome c oxidase (P = 0.081), and citrate synthase (P = 0.166). Muscle mitochondrial DNA (relative copy number per diploid nuclear genome) increased 140 +/- 154 (4.1%) with Q compared with -225 +/- 157 (6.0% decrease) with P (P = 0.098). In summary, 1000 mg x d(-1) Q versus P for 2 wk by untrained males was associated with a small but significant improvement in 12-min treadmill time trial performance and modest but insignificant increases in the relative copy number of mitochondrial DNA and messenger RNA levels of four genes related to mitochondrial biogenesis.