Clinical examples of free radical antioxidant and immune function interactions

Examples of immune dysfunction associated with increased oxidative stress exemplify the interactions between the immune system and the oxidant/ anti-oxidant status of the individual.

Rheumatoid arthritis

Rheumatoid arthritis (RA), an autoimmune disease of unknown cause, is characterized by a chronic inappropriate immune response in articular joints, resulting in inflammation and destruction of joint tissues. At some point, the initial insult and inflammation becomes a chronic process. Infiltration of the fluid-filled joint space (synovium) with inflammatory neutrophils occurs and structural changes appear in the synovium, forming an inflamed layer called a pannus. Oxidative products reduce the viscosity of the synovial fluid, thus hindering joint movement further.

Animal models have documented the increased production of pentane in arthritic animals; vitamin E supplementation lowered the pentane exhalation as well as joint swelling. Breath pentane concentrations correlates with the severity of symptoms in RA patients and clinical improvement is associated with a significant decrease in breath pentane. Patients with RA have significantly lower values in the total radical-trapping anti-oxidant parameter ('Trap') assay, based on serum levels of anti-oxidant nutrients, than do control subjects.

With regard to intervention studies, vitamin E has been examined to the greatest extent in patients with RA and other arthritic conditions. Three studies in RA patients suggest that vitamin E at high levels, but not at dietary intake levels, reduced pain. Vitamin E supplementation produced significant pain relief in four other studies. There was also a consistent finding of vitamin E-related antiinflammatory activity, although the studies involved a limited number of subjects.

Aging

The cumulative effects of free radical damage throughout the lifespan are seen in the pigmented age spots of the elderly, which are a consequence of lipid oxidation. The overall increased oxidative stress associated with aging also adversely affects many aspects of immune responses. The consequences of suboptimal immune responses are particularly detrimental in the elderly who have an increased risk of infections as well as of autoimmune diseases.

The cell-mediated immune responses involving T lymphocyte functions (cytotoxicity, interleukin 2 (IL-2) production, proliferation) are the most sensitive to the age-related decline in immune responses. As a consequence, DTH responses to skin test antigens are diminished in the elderly, and can often result in complete loss of response to antigen challenge (anergy) in the most immunosuppressed. Clinical studies have shown that DTH can be used as a pre dictor of morbidity and mortality in the elderly; i.e. elderly with anergy had twice the risk of death from all causes as elderly who responded to the antigens. Moreover, in hospitalized elderly who had undergone surgery, anergy was associated with a greater than tenfold increased risk of mortality and a fivefold increased risk of sepsis.

Recently, in a placebo-controlled study, intake of a one-a-day type multivitamin/mineral supplement for 12 months significantly enhanced DTH in healthy-elderly. Because the multivitamin included fi-carotene, vitamin E, vitamin C and all other essential vitamins as well as several minerals, it is not possible to determine whether the anti-oxidants or the other components in the multivitamin supplement were responsible for the improved DTH responses. In another recent placebo-controlled intervention trial, elderly were given a multivitamin, daily for 1 year, which contained approximately eight times the standard level of intake of /3-carotene as well as higher levels of vitamins C and E. The supplemented group had significantly less infections than the placebo group. Responses to vaccines were also improved in the supplemented group.

With respect to individual anti-oxidants, an epidemiological study in an elderly population found that the higher the plasma vitamin E levels, the lower the number of infections. Two placebo-controlled, double-blind studies showed that vitamin H supplementation alone significantly enhanced DTH responses and/or T cell proliferative responses in the elderly. Lymphocyte vitamin E levels increased over threefold with supplementation and were correlated with enhanced IL-2 production and decreased prostaglandin E2 as well as decreased serum lipid peroxides.

Cigarette smoking

Approximately 30% of US adult women and 25% of adult men smoke. Cigarette smoke contains millions of free radicals per inhalation. Other harmful products in cigarette smoke can stimulate the formation of highly reactive molecules that further increase the free radical burden; smokers have significantly higher breath pentane levels than nonsmokers. The micronutrient most affected by cigarette smoking appears to be the anti-oxidant, vitamin C. Smokers require about four times as much vitamin C per day to reach the same blood levels as nonsmokers. In addition to vitamin C, serum levels of vitamin E, folic acid and /3-carotene, as well as lung vitamin E concentrations, are significantly lower in smokers compared to nonsmokers.

Cigarette smokers have depressed immune responses compared to nonsmokers, which may in part be due to the overproduction of immunosuppressive free radicals by neutrophils and macrophages in their lungs. The lung of the healthy non-smoker contains very few neutrophils. In smokers, there is a constant activation of neutrophils and a consequent overproduction of reactive oxygen species.

Supplementation with high levels of vitamin E resulted in a significant decrease in smoker breath pentane levels and significantly reduced the overproduction of oxidant radicals by their circulating phagocytic cells.

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