**3. Effects on phagocytic and NK cells**

Natural or innate immunity is the body's first line of defense against a pathogen after the skin and epithelial surfaces. It enables a non-specific response to be implemented, involving various types of immune cells such as neutrophils, monocytes,

and macrophages, to destroy pathogens by phagocytosis and the release of microbicide substances.

Several studies have been conducted to understand how the space environment affects this immunity. For instance, an increase in the level of blood neutrophils in both humans and animals has often been observed after landing and can be attributed to the stresses encountered during this phase. Indeed, stress can induce the mobilization of these cells stored in the bone marrow [36, 37]. However, other explanations are also possible, such as changes in the expression of adhesion molecules [38]. It has also been shown that spatial conditions decrease the phagocytic and oxidative functions of neutrophils [39, 40] and induce, in monocytes, dysregulation in cytokine production, a reduced capacity to engulf *Escherichia coli* as well as lower reactive oxygen species (ROS) production and degranulation [41, 42]. Lower cytotoxicity of natural killer cells that provide immunological resistance and defense against foreign microorganisms but also against cells transformed because of, for example, a viral infection was observed [43, 44]. In addition, the reactivation of latent herpes viruses has frequently been reported. For example, Varicella-zoster virus (VZV) DNA has been detected in the saliva of astronauts during and immediately after a flight, while no VZV DNA was detected before launch [45]. Additional studies have revealed the presence of VZV in the saliva of 50% of astronauts during short spaceflights [46] and have shown that this percentage can increase up to 65% during long-duration missions [47]. Significantly, a few cases resulted in the development of shingles [45]. These viral reactivations are frequently coupled with

#### **Figure 4.**

*Stressors encountered during space missions can induce the production of glucocorticoids, catecholamine, and endocannabinoids. Numerous immune cell types have receptors for these molecules. Their functions can therefore be directly affected by the binding of these molecules on these receptors. GR, glucocorticoid receptor; ADRB2, beta-2 adrenergic receptor; CNR2, cannabinoid receptor type 2.*

**41**

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

nervous and immune systems).

of peptides to CD4+

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

ate to develop a response specifically directed against the intruder.

dendritic cells, monocytes/macrophages, and B lymphocytes.

activation [67–69], and cell cycle regulation [70].

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 cooper-

APCs are a heterogeneous group that treat and present antigens in the form

TCR. These cells are crucial in triggering an immune response. This group includes

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/

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

T lymphocytes unable to recognize a native antigen via their

a decrease in the production of interferons (cytokines constituting a first response in the event of viral infection) and to a higher level of stress hormones known to be able to regulate immune functions. Indeed, a variety of immune cells expresses glucocorticoid receptors, cannabinoid receptors, and adrenergic receptors (**Figure 4**). Thus, molecules produced in response to stressing events can directly affect immune cells and can be responsible for the reactivation of latent viruses [48–53]. Furthermore, virus reactivation could be a good biomarker of immunity weakening [54]. In support of this neuromodulation of the immune system, studies conducted on humans subjected to acute- (parabolic flight), medium- (1–2 weeks on board the ISS), or long-duration (4–7 months on board the ISS) gravitational stress demonstrated that there is a shift from an alert state of natural immune cells after acute gravitational stress to a decrease of their activity after spaceflight [55–57]. These changes were associated with changes in stress response, with a predominance of sympathetic nervous system responses after short flights, whereas long flights were characterized by glucocorticoid-induced changes. These data demonstrate that beside gravity change, stress responses are an important contributor to spaceflight-associated immune changes and once again highlight the importance of taking into account interconnections between physiological systems (here the

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

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

cide substances.

and macrophages, to destroy pathogens by phagocytosis and the release of microbi-

*Stressors encountered during space missions can induce the production of glucocorticoids, catecholamine, and endocannabinoids. Numerous immune cell types have receptors for these molecules. Their functions can therefore be directly affected by the binding of these molecules on these receptors. GR, glucocorticoid receptor;* 

*ADRB2, beta-2 adrenergic receptor; CNR2, cannabinoid receptor type 2.*

Several studies have been conducted to understand how the space environment affects this immunity. For instance, an increase in the level of blood neutrophils in both humans and animals has often been observed after landing and can be attributed to the stresses encountered during this phase. Indeed, stress can induce the mobilization of these cells stored in the bone marrow [36, 37]. However, other explanations are also possible, such as changes in the expression of adhesion molecules [38]. It has also been shown that spatial conditions decrease the phagocytic and oxidative functions of neutrophils [39, 40] and induce, in monocytes, dysregulation in cytokine production, a reduced capacity to engulf *Escherichia coli* as well as lower reactive oxygen species (ROS) production and degranulation [41, 42]. Lower cytotoxicity of natural killer cells that provide immunological resistance and defense against foreign microorganisms but also against cells transformed because of, for example, a viral infection was observed [43, 44]. In addition, the reactivation of latent herpes viruses has frequently been reported. For example, Varicella-zoster virus (VZV) DNA has been detected in the saliva of astronauts during and immediately after a flight, while no VZV DNA was detected before launch [45]. Additional studies have revealed the presence of VZV in the saliva of 50% of astronauts during short spaceflights [46] and have shown that this percentage can increase up to 65% during long-duration missions [47]. Significantly, a few cases resulted in the development of shingles [45]. These viral reactivations are frequently coupled with

**40**

**Figure 4.**

a decrease in the production of interferons (cytokines constituting a first response in the event of viral infection) and to a higher level of stress hormones known to be able to regulate immune functions. Indeed, a variety of immune cells expresses glucocorticoid receptors, cannabinoid receptors, and adrenergic receptors (**Figure 4**). Thus, molecules produced in response to stressing events can directly affect immune cells and can be responsible for the reactivation of latent viruses [48–53].

Furthermore, virus reactivation could be a good biomarker of immunity weakening [54]. In support of this neuromodulation of the immune system, studies conducted on humans subjected to acute- (parabolic flight), medium- (1–2 weeks on board the ISS), or long-duration (4–7 months on board the ISS) gravitational stress demonstrated that there is a shift from an alert state of natural immune cells after acute gravitational stress to a decrease of their activity after spaceflight [55–57]. These changes were associated with changes in stress response, with a predominance of sympathetic nervous system responses after short flights, whereas long flights were characterized by glucocorticoid-induced changes. These data demonstrate that beside gravity change, stress responses are an important contributor to spaceflight-associated immune changes and once again highlight the importance of taking into account interconnections between physiological systems (here the nervous and immune systems).
