**4. Effects on antigen-presenting cells and lymphocytes**

Specific or adaptive immunity is the second line of defense against the entry of foreign substances, particles, or cells into the organism. It involves natural and specific immune cells (antigen-presenting cells and lymphocytes) that will cooperate to develop a response specifically directed against the intruder.

APCs are a heterogeneous group that treat and present antigens in the form of peptides to CD4+ T lymphocytes unable to recognize a native antigen via their TCR. These cells are crucial in triggering an immune response. This group includes dendritic cells, monocytes/macrophages, and B lymphocytes.

Even though the antigen presentation function is an essential immune process, very little information is available on the impact that environmental conditions encountered during spaceflights could have on this function. Only one study has been published on dendritic cells and revealed that microgravity reduces their production, their phagocytic capacities, and the surface expression of costimulatory/ adhesion molecules involved in the presentation of antigenic peptides [58]. These data suggest that certain functions of antigen-presenting cells, required for the development of an effective immune response, may be disrupted in microgravity.

On the other hand, numerous studies have shown a significant reduction in T-cell activity under both real and simulated microgravity. This lower activity [59] results from spaceflight-induced modifications of the expression of genes essential for the proper functioning of T cells such as those encoding interleukin-2 and its receptor [60], translation of mRNAs [61], cell-cell interactions [62], alterations of the structure of the cytoskeleton [63–66], signal transduction enabling T-cell activation [67–69], and cell cycle regulation [70].

B lymphocytes are another cell type that acts in synergy with T lymphocytes to ensure optimal protection of the individual. These cells, at the maturation stage called plasmocyte, produce large quantities of antibodies, which, by binding specifically to the antigen, contribute to its elimination. Antibodies and B lymphocytes constitute humoral immunity whose modulation by spatial conditions has been much less studied than that of T lymphocytes. For many years, researchers have been satisfied with the quantification of antibodies present in the serum/

plasma of astronauts, but these studies generated conflicting results. For example, Konstantinova et al. [71] reported increased levels of serum IgA and IgM, while Rykova et al. [40] indicated that the amounts of serum IgA, IgG, and IgM were not affected after prolonged space missions. Subsequently, further studies were conducted to determine how changes in gravity affect humoral immunity and demonstrated that stresses encountered during spaceflight quantitatively and qualitatively affect the production of antibodies in response to antigenic stimulation. Changes in the expression of VH gene segments, encoding a large part of the antibody binding sites, have been observed in adult *P. waltl* immunized on board the Mir space station [72, 73] as well as a twofold decrease in the frequency of somatic hypermutations (SHM) that enable the diversification of antibody binding sites, in order to improve their affinity for the antigen [74] (**Figure 5**). Very recently, changes in the use of the gene segments required to create the antibody repertoire have also been observed in immunized mice subjected to anti-orthostatic suspension [75]. The antibody repertoire is therefore most likely modified under either real or simulated microgravity. In addition, a decrease in the expression of several effectors involved in immunity was observed 7 days after landing in mice that had been on board the BION-M1 biosatellite for 30 days [26]. This observation confirms the negative effect of spaceflight on the immune system and demonstrates that this impairment persists for at least 7 days after the return to Earth. This conclusion is in line with the studies that revealed disruptions in the production of antibodies in *P. waltl* still visible 10 days after landing [72–74].

Finally, it has been shown that the proliferative responses of B and T lymphocytes are reduced when mice are subjected to gravity changes (anti-orthostatic

#### **Figure 5.**

*Somatic hypermutations (SHM) are nucleotide substitutions whose purpose is to improve the affinity of antibody binding sites. The frequency of these mutations was determined in adult P. waltl immunized on board the Mir space station and in adult P. waltl immunized with the same antigen on Earth. This study showed that the frequency of these mutations is two times lower when animals are immunized on board the space station [74]. IE, P. waltl immunized on Earth; IS, P. waltl immunized in space; NI, not immunized.*

**43**

*Spaceflight-Associated Immune System Modifications DOI: http://dx.doi.org/10.5772/intechopen.88880*

these two variables are cumulative.

**6. Conclusion and perspectives**

gravity change.

suspension or 2 G hypergravity) for 3 weeks [76, 77]. However, the responses from these lymphocytes were not altered after 3 weeks of exposure to the model mimicking socio-environmental stressors encountered in flight [34]. These data suggest that the lower reactivity in lymphocytes induced by spaceflight is mainly due to

Note that there is a break in the adaptation of mice at 3 G, which results in an increase in the serum corticosterone concentration and the level of anxiety [76]. These changes persist beyond 2 weeks after the return to normal gravity. This demonstrates that the hypergravity model should be used with caution if the effects of hypergravity are to be distinguished from those of a stress response. From 3 G,

Certain immunological changes observed in astronauts or rodents on space missions can also be found in the elderly. For example, thymus involution, increased susceptibility to infections, and decreased response to vaccines may be correlated with impaired development of B- and T-lymphocyte function in the elderly [78, 79]. This thymus involution and changes in the development and response of immune cells are also observed when the gravitational force is altered, as illustrated by the reactivation of latent viruses in astronauts and the elderly. In addition, a recent study suggests that long-term spaceflight could induce an increase in inflammation as in the elderly (inflammaging), which could increase the risk of allergies or autoimmune diseases in astronauts [80]. Finally, aging is accompanied by changes in antibody production similar to those observed in flight. There is a decrease in antibody affinity [78] and a change in the use of antibody VH gene segments [81] as observed in *P. waltl* immunized in flight [73, 74], which affects the diversity of the antibody repertoire. It therefore appears that stresses encountered during space

Studies conducted so far show that on average one out of two astronauts encounters immunological problems and that stressors encountered during spaceflights can affect all components of the immune system. It is therefore mandatory to understand in details how all immune cell types are affected by space conditions by unraveling the cellular and molecular mechanisms modified within these cells. Indeed, the impact of spatial conditions on certain cells and functions of the immune system have not yet been precisely determined. Furthermore, the impact of long-term missions is largely under-investigated. This is because, up to now, most scientific data are derived from space missions not exceeding 6 months in duration. In addition, the impact of spatial conditions on interconnections between the immune and other systems (such as the musculoskeletal, nervous, respiratory, and cardiovascular systems) should be studied using interdisciplinary approaches. All this knowledge is required (i) to gain a better understanding of the risks incurred during future long-duration space missions (such as planned mission to Mars), where the crew will be left to their own with no possibility of a rapid return to Earth, and (ii) to develop nutritional, psychosocial, and/or pharmacological countermeasures to reduce stress, preserve the immune system, and prevent the development or aggravation of diseases [82]. Another aspect that should be taken into account is in-flight monitoring of astronaut's health and diagnostic data using

**5. Spaceflight as a model of accelerated immunosenescence**

missions could lead to premature aging of the immune system.

### *Spaceflight-Associated Immune System Modifications DOI: http://dx.doi.org/10.5772/intechopen.88880*

*Beyond LEO - Human Health Issues for Deep Space Exploration*

visible 10 days after landing [72–74].

plasma of astronauts, but these studies generated conflicting results. For example, Konstantinova et al. [71] reported increased levels of serum IgA and IgM, while Rykova et al. [40] indicated that the amounts of serum IgA, IgG, and IgM were not affected after prolonged space missions. Subsequently, further studies were conducted to determine how changes in gravity affect humoral immunity and demonstrated that stresses encountered during spaceflight quantitatively and qualitatively affect the production of antibodies in response to antigenic stimulation. Changes in the expression of VH gene segments, encoding a large part of the antibody binding sites, have been observed in adult *P. waltl* immunized on board the Mir space station

[72, 73] as well as a twofold decrease in the frequency of somatic hypermutations (SHM) that enable the diversification of antibody binding sites, in order to improve their affinity for the antigen [74] (**Figure 5**). Very recently, changes in the use of the gene segments required to create the antibody repertoire have also been observed in immunized mice subjected to anti-orthostatic suspension [75]. The antibody repertoire is therefore most likely modified under either real or simulated microgravity. In addition, a decrease in the expression of several effectors involved in immunity was observed 7 days after landing in mice that had been on board the BION-M1 biosatellite for 30 days [26]. This observation confirms the negative effect of spaceflight on the immune system and demonstrates that this impairment persists for at least 7 days after the return to Earth. This conclusion is in line with the studies that revealed disruptions in the production of antibodies in *P. waltl* still

Finally, it has been shown that the proliferative responses of B and T lymphocytes are reduced when mice are subjected to gravity changes (anti-orthostatic

*Somatic hypermutations (SHM) are nucleotide substitutions whose purpose is to improve the affinity of antibody binding sites. The frequency of these mutations was determined in adult P. waltl immunized on board the Mir space station and in adult P. waltl immunized with the same antigen on Earth. This study showed that the frequency of these mutations is two times lower when animals are immunized on board the space station* 

*[74]. IE, P. waltl immunized on Earth; IS, P. waltl immunized in space; NI, not immunized.*

**42**

**Figure 5.**

suspension or 2 G hypergravity) for 3 weeks [76, 77]. However, the responses from these lymphocytes were not altered after 3 weeks of exposure to the model mimicking socio-environmental stressors encountered in flight [34]. These data suggest that the lower reactivity in lymphocytes induced by spaceflight is mainly due to gravity change.

Note that there is a break in the adaptation of mice at 3 G, which results in an increase in the serum corticosterone concentration and the level of anxiety [76]. These changes persist beyond 2 weeks after the return to normal gravity. This demonstrates that the hypergravity model should be used with caution if the effects of hypergravity are to be distinguished from those of a stress response. From 3 G, these two variables are cumulative.
