**6. Immunology and hematology**

## **6.1 Space anemia**

The circulatory blood volume is 5 L on average and contains plasma and cellular components, including erythrocytes, leukocytes (neutrophils, eosinophils, basophils, and lymphocytes), and platelets [72–74]. Among them, reduction in cellular components, especially erythrocytes (RBC), is associated with anemia, whereas the function of leukocytes is related to immunological response.

In the early stages of space development, cases of "space anemia" (hematocrit reduction) were reported on Gemini, Apollo, Skylab, and Shuttle missions and in the cosmonauts in the Salyut and Mir missions. However, in spaceflight, microgravity causes cephalad fluid shift, meaning this "space anemia" was actually a misinterpretation of symptoms. The true effects of microgravity can be measured through the total RBC count calculated from the hematocrit and plasma volume measurements. In this way, "space anemia" corresponded to a reduction in the total RBC count.

After 10 days aboard Spacelab-1, the total RBC count was reduced by 9% and by 15% after several weeks. After returning to Earth, the total RBC count did not recover even after 6 weeks and, in the case of Skylab astronauts, had not recovered after more than 3 months.

This suggested that microgravity is responsible for "space anemia," and many investigations were carried out to reveal whether anemia is the result of an increase in RBC destruction or a decrease in their production. Using labeled RBC by the uptake of 14C glycine, RBC destruction was found to be three times greater in rats having flown aboard Cosmos-782 than in the control rats. On the other hand, reduced RBC production is unlikely because the number of stem cells measured by the number of cellular colonies that developed in vitro from samples of bone marrow taken from rats that flew aboard the Soviet Biosatellite—2044 for 14 days—was unchanged.

Human studies carried out by [75] on Shuttle missions for 9 to 14 days demonstrated that space anemia is due mainly to a lower production of RBC, causing increased plasma volume, reduced hemoglobin concentration, and increased serum erythropoietin. This reflects a decrease in the RBC life span and slower production.

Rizzo et al. [76] analyzed the cause of the shortened RBC life span and reported altered cell membrane composition and an increase in lipid peroxidation products. They suggested that antioxidant defense systems in the erythrocytes were induced, with a significant increase in glutathione content.

The mechanism underlying anemia was also confirmed by measuring the erythropoietin (EPO) level [77]. Radioimmunoassay revealed that the EPO level decreases after 24 hours of flight and is reduced by 30–40% on the third day compared with preflight levels. This low secretion of EPO will inhibit RBC maturation and cause hemolysis due to suppressed erythropoiesis.

Other changes in leukocytes (WBC) are in their polymorphonuclear characteristics. The composition of WBC is changed such that there is a slight increase in neutrophils and decrease in eosinophils. The percentage of lymphocytes, especially T cells, decreases, whereas that of monocytes slightly increases. These changes quickly disappear upon returning to 1 G on Earth.

## **6.2 Immunological changes during weightlessness**

Recent studies confirmed dysregulation of the immunological response in humans and the reactivation of latent herpes virus, which persisted for the duration of a 6-month orbital spaceflight [78]. Blood samples from ISS crew members demonstrated that long exposure to microgravity reduced their T lymphocyte counts, suggesting the attenuation of cytotoxic function and viral reactivation in the space environment.

As the immune system is highly sensitive to different types of stressors, including psychological, physical, and local environmental stressors (e.g., oxidative and radiation exposure), exposure to the space environment suppresses T helper cells, which leads to susceptibility to viruses.
