Cytokine Gene Variations and Illness Response
Approximately 10 years ago, Australian researchers Drs. Andrew Lloyd, Ian Hickie and Ute Vollmer-Conna began studying post-infection fatigue as a model to understand mechanisms of CFS. Infection with pathogens such as Epstein-Barr virus (EBV) were known to result in prolonged and chronic illness characterized by debilitating fatigue, allowing the opportunity to study the possible causes of incident cases of CFS.
Incidence refers to new illness, as opposed to prevalence, which accounts for all people suffering from CFS at a single point in time (including new cases and the people that have been sick for a long time). Therefore, studying incident CFS provides a powerful opportunity to identify early events directly linked to disease development.
In 2006, the Aussies published a paper titled “Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study.” This British Medical Journal publication found that CFS followed infection in roughly 12 percent of the cases and was predicted largely by the severity of the acute illness.
Since that time, the Australian team has worked to determine why some people would experience more severe illness following acute infection than others. And now Dr. Ute Vollmer-Conna and colleagues have published a paper in the December issue of Clinical Infectious Diseases titled; “Cytokine polymorphisms have a synergistic effect on severity of the acute sickness in response to infection” that provides some answers. The main finding is that polymorphisms (naturally occurring genetic variations) in interferon gamma (IFN gamma) and interleukin 10 (IL10) cytokine genes result in differences in the corresponding cytokine protein levels. IFN gamma is one of several pro-inflammatory cytokines and IL10 is one of several anti-inflammatory cytokines.The balance of pro- to anti-inflammatory response is crucial to an effective immune response. Infection activates the immune system to produce pro-inflammatory cytokines important for killing the invading pathogen. Once that pathogen is cleared, the immune system is calmed by anti-inflammatory cytokines. A sustained pro-inflammatory response can be harmful, so the challenge for the immune system is to mount a response that controls or eliminates the pathogen without causing damage to the person.
The investigators found that specific polymorphisms in IFN gamma and IL10 resulted in variations in cytokine levels produced by blood cells. High levels of IFN gamma and low levels of IL10 were the result of what was termed a “high risk genotype.” Individuals with this genotype were significantly more likely to experience severe acute illness following infection and were more likely to be symptomatic for a longer time.
It’s worth noting that these investigators have studied people infected with three distinct pathogens over the past 10 years; EBV, Coxiella burnetii (the causative agent of Q fever) and Ross River virus. So it appears that a variety of pathogens can trigger CFS and that perturbations or imbalance in the immune response sustains CFS. Further studies of host genetic variation as well as pathogen genetic variation will not only strengthen the ability to predict who is at risk for CFS, but will also improve the ability to customize interventions.
Vollmer-Conna U, Piraino BF, Cameron B, Davenport T, Hickie I, Wakefield D, Lloyd AR; Dubbo Infection Outcomes Study Group (Dunckley H, Geczy A, Harris R, Khanna R, Marmion B, Rawlinson B, Reeves WC, Vernon S). Cytokine polymorphisms have a synergistic effect on severity of the acute sickness response to infection. Clin Infect Dis. 2008 Dec 1;47(11):1418-25.
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