Immune system dysregulation during spaceflight: clinical risk for exploration‐class missions

In the past 30 years, a great many investigations have been conducted to determine the effects of spaceflight on human immunity. Probably more than in any other space-life sciences discipline, many qualifiers must be considered related to the published evidence. These include whether studies involved actual spaceflight or ground analogs of flight, whether animal or humans were the subjects, differing vehicles and mission durations, which of the immune cell subpopulations were monitored, and which types of functional assays were used. These qualifiers aside, the current review by Gueguinou et al. [1] in this issue does an admirable job of summarizing the current knowledge base. The authors thoroughly describe the factors that will affect humans during prolonged, explorationclass space missions, the expected dysregulation of immune parameters based on the current evidence, and potential clinical risks. When considering the evidence to date, it cannot yet be firmly concluded that a clinical risk related to immune dysregulation actually exists for exploration-class spaceflight. This is primarily due to a lack of data about human immunity during long-duration spaceflight. Post-flight data have the potential to be influenced by landing and readaptation stress. Shortduration, in-flight data may not reflect immune status, as it equilibrates during long-duration spaceflight. For example, Pierson et al. [2, 3] have demonstrated reactivation of latent herpesviruses during short-duration flight, and frequency and magnitude of reactivation are much higher than observed terrestrially in analog conditions. It is currently unknown if this reactivation persists for the duration of a 6-month ISS mission or is transiently related to launch stress and early adaptation to the flight environment. Data derived from ground-based analogs, although valuable, must be interpreted with caution. Analogs, despite high fidelity with certain aspects of flight, often fail to replicate other aspects. Obviously, factors such as radiation and microgravity cannot be ground-replicated for human subjects. The closest ground analogs for immune dysregulation are likely those that replicate remote deployment, mission stress, environmental hazards, prolonged isolation, and disrupted circadian rhythms. Immune dysregulation has been reported during bed rest, closed chamber confinement, undersea missions (NASA Extreme Environment Mission Operations), and deployment to the Arctic and Antarctic [4–9]. Given the extreme isolation conditions experienced during Antarctic winter-over, this analog may be the closest on Earth for flight-associated immune changes. Without question, all of the published evidence has contributed greatly to our knowledge base about expectations for immune changes, potential mechanisms, monitoring strategies, and likely countermeasures. However, firm conclusions about clinical risk for humans minimally require in-flight human data collected during long-duration spaceflight. In a series of recent internal and external science program reviews associated with the advent of the Constellation Program, NASA has defined specific potential risks for lunar and Mars missions. These risks and other supporting documents are listed in the Program Requirements Document (PRD) for the NASA Human Research Program and are publicly available (http://humanresearch.jsc.nasa.gov/elements/smo/ nra.asp). The potential for adverse health events related to prolonged immune dysregulation is one of the listed risks; however, a specific magnitude and direction for immune dysregulation are not identified. Instead, the potential for immune hyperactivity resulting in risks such as hypersensitivities or autoimmunity is discussed, as is the potential for immune hypoactivity with corresponding risks for infectious diseases and persistent viral reactivation. Thus, multiple possible adverse health events are listed. For each adverse event, ample terrestrial data exist to correlate dysregulated immunity with clinical disease [10, 11]. Studies by Glaser and others [12, 13] have thoroughly connected physiological stress to changes in specific immune parameters associated with spaceflight [14].