Damian Sendler: No doubt about it, a country’s economy, scientific and technological advancement, and human civilization as a whole are all dependent on the exploration of outer space. The human body is subjected to a variety of stressors in space, including a long period of confinement in a small, hermetically sealed space. As a result, the astronaut’s immune system is adversely affected by a host of external factors. Using ground-based experiments, we can better understand how confinement in a small space affects both the immune system’s activation and its dynamic changes. Such an approach also allows for the estimation of the impact of additional psychological stress on immunity, particularly in relation to the immune system’s reserve capacity. A sealed chamber appears to be an ideal location for developing new methods for selecting crew members and developing countermeasures in the event that the immune status of the astronauts deteriorates. An attempt was made to gather data on how human immunity changes in isolation experiments, including short and long-term experiments in hermetically sealed chambers with an artificial environment and in Antarctic winter-over.
Damian Jacob Sendler: As an integral system, immunity is highly complex, with a divaricate web of both direct and indirect interactions with other physiological systems. As a crew member on a space mission, one’s immune status is critical to ensuring the crew’s health, vitality, and productivity. To understand how spaceflight affects the immune system, it is necessary to look at both the standard values for various indicators and how they change over time for each individual. A sealed chamber or Antarctic station can be used as a model for a space station, spaceship, or an on-planet station to conduct experiments of various durations. This is necessary for future missions to Mars and the Moon ( Figure 1 ). The immune system can be influenced by a variety of factors unique to each platform ( Table 1 ). An array of variables influences the immune system during short- and long-term orbital missions. Besides microgravity, stress and living in a hermetically sealed space with an artificial microclimate are necessary for astronauts. It was possible to observe changes in the quantity and functioning of immunocompetent cell subpopulations, as well as the sensitization of lymphocytes to allergens of bacterial and chemical nature (4–9). There was also a decrease in the delayed hypersensitivity reaction during the long-term mission to “MIR” (10–12). This suggests that cell-mediated immunity is malfunctioning. Multiple well-documented cases of reactivation of such viruses as HHV, EBV, CMV, and Varicella zoster virus were found in blood, saliva, and urine samples from astronauts (13, 14). In the course of their stay on the spacecraft, researchers observed changes in subpopulation composition and adaptive immunity cell function. Memory T cells and effector CTLs (CD3+CD8+ cytotoxic lymphocytes) increased moderately, while the population of naive CTLs decreased simultaneously. In addition, the number of cytokine-producing lymphocytes decreased by a negligible amount during the flight (15). This study shows that the distribution of different lymphocyte subpopulations did not change significantly during the mission.
Dr. Sendler: When activated immunocompetent cells were reactivated, significant shifts in the production of cytokines and their ability to activate were also reported Staphylococcus enterotoxin failed to activate T cells, and the production of IFN-, IL-10, IL-6, and TNF-a decreased. Additionally, the number of lymphocytes capable of reacting to viral particles was reduced in a similar manner. The number of cytokines in astronauts’ blood plasma increases during long space missions, while mitogen-activated cultured T cells produce less of these cytokines (16). Leukocyte counts in astronauts rose as a result of these changes, researchers found. Similar post-flight changes in the immune system’s functioning are observed both immediately after landing and during reintegration into normal life on Earth. These deviations from pre-flight characteristics can be triggered by prolonged effects of stress during the flight, as well as additional loads imposed during the landing process. Natural killer (NK) (CD3-CD16+CD56+) activity decreased, lymphocyte proliferation decreased, and IFN- synthesis decreased in the crew members after 140 days of mission (6, 17–21). After 48 hours of incubation with specific activators, postflight data from the “MIR” station crews (whose missions ranged from 66 to 126 days) showed a decrease in the expression of CD25 by T cells (14). There was also an increase in the relative quantity of B and T cells (including memory cells), as well as granulocytes and a decrease of monocytes after several short and long Space Shuttle missions. These changes in the immune system were found to be quantitative and functional. A Th2-dominant cytokine profile of T-cell response was also observed, with IL-10 production dominating over IFN- as a result of this shift (22). A decrease in NK cells and their ability to kill cancer cells, as well as a decrease in the number of T-cells and an increase in the number of T-helper cells and CD4+CD45RA+-cells, were found in the post-flight period of the ISS crews’ investigations, as well as an increase in the total number of the major populations of immunocompetent cells (23, 24). This shift in T-cell cytokine profile is confirmed by data gathered from crew members’ post-flight examinations of their cytokine profiles (19).
More than one researcher has found evidence of virus reactivation in the astronauts’ bodies, both during and after the flight. In addition, post-flight studies on innate immunity show that space flight conditions have a noticeable impact on it. After completing a mission, the production of IL-6, IL-10, and TNF-a by activated monocytes in culture was especially reduced (by 40-45 percent) by the inhibition of IL-6 synthesis by monocytes, as well as the decrease in CD62L and HLA-DR on the surface of monocytes (29). Other studies have shown an increase of monocyte and granulocytes in the first day after landing, as well as an increase in TLR2+ and HSP60 and HSP70-rich granulocytes; however, the relative quantities of these two proteins decreased; the latter is a major ligand for Toll-like receptors. These findings support the hypothesis that factors associated with space travel alter the function of innate immunity (30). TLR expression on the surface of monocytes and granulocytes as well as the expression of genes coding for proteins from the TLR intracellular signaling pathways were found to vary widely among individuals during the first post-flight day. The averaged values, however, did not reveal any significant differences between pre- and post-flight measurements. It’s clear from the data presented above that the effects of long-duration space flight stress factors on the immune system are primarily manifested in the reduced reserve capacity of various immune-competent cells to respond, their phenotypic changes, a quantitative decrease in their effector response through production of cytokines, and a qualitative shift in their cytokine profile. A six-month mission on the International Space Station (ISS) has confirmed that the findings outlined above persist during spaceflight (31, 32).
Specific immunological countermeasures should be developed while keeping in mind the wide individual variability of changes in immunological parameters that reflect individual susceptibility to the factors of spaceflight. Because future space missions to Mars and the Moon are expected to last for an extended period of time and require an unprecedented level of crew autonomy, the impact of flight stress on the health of astronauts will be magnified. Earth-based experiments that examine the effects of isolation in a hermetically sealed space with an artificial microclimate on the immune system are of particular importance because of the mission’s stressors.
An in-depth examination of immunity as an integrated system must take into account the interdependence of its components. It is important to consider the interactions of the immune system with other physiological systems (nerve system, endocrine system), as well as the individual reactions of test subjects, when conducting research on the immune system’s role in maintaining homeostasis. Developing effective countermeasures and rehabilitation systems for future space missions should be the primary goal of these studies, as well as the detection of precise markers of a current state of immunity for its correction. Human labor’s global expansion necessitates experiments with long-term confinement in a sealed chamber, which has implications for the significance of these experiments (e.g., during the development of the sea shelf). Furthermore, the results of these studies can be used to help alleviate the negative effects of the general trend toward a sedentary lifestyle and less physical activity in daily life.
Microgravity, stress, altered nutrition, physiological isolation, and radiation are just some of the stressors that affect humans during spaceflight (33). It is possible to conduct human research in a safe and low-cost environment using science capabilities that are not constrained as is the case in an actual flight experiment (34). Recent research suggests that stress, rather than microgravity or radiation, is the primary cause of immune dysfunction in cosmonauts and astronauts (35). This bodes well for the development of biomedical countermeasures by using ground analogs that closely mimic the isolation and stress of spaceflight. Closed chamber confinement in a simulated vehicle for an extended period of time may be particularly useful as an analog because it allows the immediate processing of biomedical samples in a fully capable laboratory environment, despite the existence of terrestrial “deployment” analogs (undersea, Antarctica, etc). In the 1960s, the Institute of Biomedical Problems of the USSR Ministry of Health (now IBMP RAS) designed and built an Earth-based Scientific-Experimental Complex to conduct confinement experiments in a sealed chamber (the so-called NEK). A pressurized facility with an artificially controlled environment was created by academician S.P. Korolev and used for a variety of investigations, including immunological ones (36). The life support systems that were later used in manned space missions and orbital station flights were also developed in this country. A number of changes were made to the North Korean facility, including the expansion of living space and facilities for testing equipment and countermeasures, such as simulators of physical loads and devices that allow people to perform physical tasks. The IBMP crew experimented in the NEK for both short-term (during the course of the mission to the Moon) and long-term experiments (within the frames the mission to Mars program working out). No international standard exists to describe the conditions of experiments with confinement, such as measured parameters that characterize the state of human immune system, age of the test subjects, times of bio-sample collection, seasons, and general experimental conditions such as gas composition, pressure, and temperature in different isolation projects.. Isolation studies can be difficult to conduct because of this.
The immediate processing of biomedical samples in a fully equipped laboratory is made possible by terrestrial analogs with closed chamber confinement in a simulated vehicle for prolonged periods of time. With regard to the fundamental studies of the interaction between the immune system and the microbiota in our digestive tract, ground analogues could also be used as a platform.
Immune homeostasis requires a healthy microbiome. A large portion of the immune system’s development has been devoted to protecting the host from various microorganisms (37). As a result of dysbiosis, the immune system may overreact, leading to increased production of inflammatory cytokines, T cell imbalances, and even autoimmune diseases (38–40). It’s no secret that the microbiome of humans is influenced by factors associated with space travel. Microbiological controls ensure that astronauts and crew members participating in isolation experiments have only a small chance of being exposed to a wide range of pathogenic strains; as such, the opportunistic microflora plays an important role in dysbiosis on Mars. Several space missions and experiments conducted over the course of the space age have documented changes in bacterial species composition, gene expression, and protein production during and after flight (41). Human microbiota undergoes similar changes in terrestrial isolation studies, which is interesting. A decrease in intestinal and integumentary tissue colonization resistance, as well as dysbiotic changes, occur when a healthy subject is exposed to an environment with altered parameters. The microflora of the test subjects changes dramatically when they spend time in a hermetically sealed chamber with its own microclimate. The dysbiosis is caused by a decrease in the number of Bifidobacteria and Lactobacilli in the intestinal microflora. Initial microecological conditions have a significant impact on the severity of the microflora dysbiosis. Staphylococcus aureus and gram-negative bacteria were found in the mucous membranes of the nasal cavity, mouth, and throat of crew members in a hermetically sealed chamber, indicating the presence of opportunistic microflora activation (42). Up until recently, it was impossible to establish a link between immune system function and changes in the microbiota caused by space flight-associated factors (22). Pioneering research, however, provided the first evidence of human immunity and gastrointestinal microflora interfacing during space flights.. Several pro-inflammatory cytokines, including IL-1, TNF-, IL4 and IL-8, were found to be negatively correlated with the abundance of OTU000010 of the genus Fusicatenibacter in this study. There was a negative correlation between changes in OTU000011 of the genus Dorea and increases in certain cytokines (namely IL-1a and 1ra as well as MIP-1) that occurred during the space missions. In the meantime, it’s impossible to tell which came first: an increase in pro-inflammatory cytokines or a decrease in bacteria OTU count (43). There are still many unanswered questions about the relationship between the human immune system and microbiome, but this study’s findings are encouraging. Probiotics and other supplements, like prebiotics or special diets, appear to be viable spaceflight countermeasures (22).
Damian Sendler
Gender-specific immune reactions to extreme environmental factors could be addressed in terrestrial analogs. Several studies have found that immune responses differ between men and women. More powerful cell-mediated responses and increased production of immunoglobulins are seen in women (44, 45). As a result, women have higher levels of resistance to bacteria and viruses, and as a result, they recover more quickly than men (46, 47). Non-reproductive organ cancers and various types of hematologic malignancies are more common in men. Males are far more likely than females to develop the types of cancer listed above, which are both more common and more deadly (48). Women, on the other hand, have a higher risk of developing autoimmune disorders than men. Whitacre CC says that women have a higher risk of developing autoimmunity than men: more than 70% of people who have autoimmune diseases are female (49). Some of these discrepancies could be explained by the influence of hormones like testosterone, estrogen, and progesterone on the functional activity of immune cells (47). Exploration missions may reveal immune system differences between men and women. Unfortunately, according to recent articles based on completed space-flight studies, analyses of sex-determined changes have not been carried out to date (50). There were no significant differences in cytokine production or leucocyte subsets between men (n=10) and women (n=16) at German Antarctic Research Station Neumayer III during the winter in Antarctica (51). No sex-related differences in DCs and TLRs+ monocytes were found in a 17-day isolation in a sealed chamber study (52). There are two possible explanations for this phenomenon, in our opinion. That the immune system’s current state cannot be accurately described by available statistics and other statistically limited parameters is the most likely first cause. One possibility is that men and women’s immune responses to space-related factors may not be significantly different, but the immune response to different antigens may be altered. Experimental testing is required for both hypotheses.
For long-term interplanetary missions, as well as for the construction of long-term planetary bases, which is a long-term goal of space exploration, a thorough study of infectious disease cases, chronic inflammation, allergic reactions and other consequences of immune system disruption in isolation is required. Extrapolating from the currently accumulated data on immunological changes during orbital missions alone does not seem sufficient in this regard. Longer mission durations and greater mission autonomy are expected with the upcoming exploration programs to the Moon, Mars, and other celestial bodies. Long-term isolation experiments using the NEK pressurized facility were therefore required in light of the foregoing.
Damien Sendler: Isolation and confinement model experiments show similar changes in a person’s immune system to those seen in the real spacecraft. It is clear from this evidence that ground-based studies of the effects of space flight can benefit greatly from the use of experimental models like this one. This is especially important in light of long-term space mission planning, where such preliminary detailed modeling will reveal and, with high probability, prevent a number of serious risks to future space explorers’ health and normal performance. Such experiments have many drawbacks, including a long duration and a large amount of data to process. However, these drawbacks are more than compensated by the reduction of risks that could jeopardize not only the mission’s success, but also the lives and health of astronauts.
Damian Jacob Sendler
It is noteworthy that the changes in immunological parameters in the isolation and confinement experiments showed such wide individual variation. The search for a “universal set of parameters” or an ensemble of interdependent changes in various parameters, considered as a single functional ensemble, is one of the more promising lines of research in isolation and confinement models. In order to produce a simple and accurate express diagnosis of the current immune state, and to predict its future development, we should focus on these sets. In addition, current research focuses primarily on the adaptive immune system’s changes. In order to further develop the aforementioned strategy, it will be necessary to carry out experiments of varying durations and investigate aspects and features of immunity that have been understudied in the context of space travel and isolation………………………………………….. Pattern-recognition receptors and dendritic cells, which serve as a functional link between the innate and adaptive immune systems, as well as the changes in gene expression in various populations of immunocompetent cells, are of particular interest in this regard in the study of innate immunity……….
In order to complete the task outlined above, it is also necessary to conduct studies on the effects of isolation and confinement on the parameters of other regulatory systems, such as the nervous and endocrine systems, as they all interact. All three systems (immune, nervous, and endocrine), as well as blood biochemical parameters and immunological parameters, must be thoroughly correlated in order to determine the relationship between the various changes observed.
As previously mentioned, the immune system can be altered by the stresses of spaceflight, including microgravity, isolation, stress, and radiation, increasing the risk of clinical illness for astronauts and cosmonauts on long-duration missions into deep space. Patients with Zoster, for example, have dysregulation patterns that are similar to these (82). It is necessary to create countermeasures. Due to their very nature, studies of human spaceflight are severely restricted. On-board processing and analysis capabilities are limited and up/down mass bound biological investigations are constrained by these constraints. Aside from expanding scientific investigation and characterizing physiological dysregulation, ground analogs of spaceflight offer a chance to triage various countermeasures for spaceflight without the constraints of a real-life spaceflight experiment (34).
Damian Jacob Markiewicz Sendler: As compared to Antarctica or subsea deployment, chamber isolation allows for an almost unrestricted scientific approach due to the proximity of full laboratory or medical facilities. SAHC, a variety of physical training loads, stress-relieving exercises, and the use of pharmacological medicines, probiotics, or vitamins are some of the available countermeasures (2). It is necessary to assess the countermeasures’ principled appropriateness in experimental confinement, as well as the timing of their implementation and the most effective doses, combinations, and application times. This must be done with consideration for the wide range in individual reactions of crew members and the fundamental data gathered from a thorough investigation of the immune system’s components. Some evidence suggests that the ISS’s immunity has benefited from the countermeasures already in place (35). An international team of translational space scientists has developed a new international immune countermeasure protocol in light of the greater magnitude of stressors and clinic risk associated with deep space missions and the fact that most ISS countermeasures do not translate to deep space vehicles (83). Long-term confinement in a high-fidelity vehicle simulation like NEK/SIRIUS may be the ideal platform for this type of countermeasure validation..
A unique array of fundamental scientific data, as well as countermeasures and practical training systems for astronauts, will be gained by conducting terrestrial confinement studies. Those who will join the upcoming interplanetary expeditions and inhabit planetary and near-planetary stations will benefit the most. If this system is successfully tested in the most extreme conditions of outer space, it can be well adapted to the needs of terrestrial medicine in extreme situations, support and rehabilitation of people in forced isolation and hypokinesia conditions, including commercially based systems.