**6. Some remarks**

**5.12. A role of SAA in the APR of murine septic inflammations**

In order to analyze the different steps necessary to overcome an infection by the hepatic APR, an experimental mouse model was applied and shown as an "anti-sepsis circle" (see **Figure 6**) [32]. Using polymicrobial sepsis induced by cecal ligation and puncture (CLP), the various actions begin with mice exposed to a bacterial overload that leads to the IL-6 induction, which is the dominant interleukin and major inductor of the APR. IL-6-deficient mice can still mount an APR, since IL-6 represents one member of a larger group of interleukins with redundant actions. The action of IL-6 is to initiate the intracellular signaling via the hepatic IL-6 receptor gp130 and further induction of STAT3, which is inevitable for developing the full hepatic APR in hepatic cells, including the synthesis of the dominant APP SAA. However, when mice with a deletion of gp130 or STAT3 are treated with CLP, the hepatic synthesis of SAA is not induced and these mice cannot mount an APR anymore and are thus defenseless, and mortality is greatly increased. The missing APR and the missing defense can be reversed by adding myeloid-derived suppressor cells (MDSCs), which are induced by a hepatic APR including SAA. SAA induces and activates the proliferation of bone marrow cells, which include MDSCs. These cells are accepted to be able to also act against the microbial infection. MDSCs are anti-inflammatory in cancer, cancer spread and metastases [27]. They home-in on different organs. In septic mice, they have been examined from spleen and increase their numbers when pg130 and STAT deficiency are overcome by an

*5.12.1. On the role of the APR and APPs in septic mice*

86 Infectious Process and Sepsis

**Figure 6.** Closing the sepsis loop to the "anti-sepsis circle" schematically.

### **6.1. The septic loop became an "anti-sepsis circle" as a basis for further work**

Some essential elements of the cooperative defense against the experimental multi-microbial infections became apparent as shown in **Figure 6**. The pathway from infection procedures passes, through IL-6, gp130 and STAT3, to the APR with the dominant SAA family and its network. This loop has been closed to a circle through the action of at least the SAA1 that assisted in inducing the growth of the MDSCs in the bone marrow. These cells are also shown to be essential in fighting bacterial infection. However, when gp130 or SAA was not available in this model and the "circle" was interrupted, with fatal consequences, the addition of the missing agents restored the circle with its function [29]. It should be an important goal to examine the SAA isotypes in different inflammatory states and diseases in relation to febrile temperatures (**Figures 3** and **4**) and to analyze the functions of all 20 invariant peptides (**Figure 5**) and the epitopes of the AA/SAA antibodies (**Table 1**) in order fortify it.

It is also important to define the febrile temperatures by which the individual SAAs separate from HDL (proven in vitro, **Figures 3** and **4**) and get activated to execute their function. A novel idea could be: therapeutical hypothermia below 37°C could inactivate SAA through binding to HDL, which can be called "hypothermic deactivation of SAA." This option could be considered (after complying with the strict rules for a novel therapy) in severe inflammatory states exemplified by sepsis, septic shock, genetic hyperthermia syndromes and similar diseases summarized in SIRS (systemic inflammatory response syndrome). Inversely, a temperature-dependent conformational change of SAA at above 38°C causing SAA release from HDL can induce a "hyper-thermic activation of SAA," which could be beneficial for patients having clinical syndromes with body temperatures of 36°C and below.

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### **6.2. Innate, humoral checkpoints for survival and application by industrial organizations**

The presented view summarizes peptides of SAA that are decisive for innate humoral functions in different systems. This view can be applied to many possible possible inflammatory and infectious diseases, including sepsis. These SAA peptides provide a functional innate humoral "stop and go" mechanisms located on SAA ("SAA checkpoints") related to survival. Stop, with generic (humanized) AA/SAA monoclonal antibodies or equivalent agents, and go, with the bio-identical SAA preparations, including SAA isotypes or related peptides with special SAA functions (**Figure 5**), which need to be further explored to find out their additional role in the SAA network. This examination can also be extended to other APPs.

### **6.3. European Patent EP No 2368564**

Due to its novelty within the field of innate immunity and the possibly far-reaching impact in medicine, in particular, in inflammatory diseases including sepsis, these discoveries by three inventors were in agreement with the two other inventors patented by the author [49, 50].
