The evolution of the medical Sciences corresponded to the discovery of new classes of molecules, firstly the vitamins, then the hormones, then again the neurotransmitters, and finally the cytokines, and each discovery of new molecules allowed the possibility to definitively cure some human diseases. Unfortunately, the last discovery that of cytokines, has still substantially excluded from the common clinical practice. Therefore, it becomes essential to clinically introduce the new science of cytokines, that we could call as cytokinology, before from either a diagnostic, or a prognostic point of view, and after from a therapeutic one. This statement is justified by the fact that the cytokines produced by the activated immune cells do not regulate the only immune system, but all biological functions, being the main responsible for host biological response. The most synthetic and less expensive biomarker could be the same lymphocyte-to-monocyte (LMR), since the evidence of a progressive decline in LMR has been proven to predict a negative prognosis in both metastatic cancer and cardiovascular disorders, as well as to be related to the exacerbation phase of the autoimmune diseases. The occurrence of high blood levels of TNF-alpha, IL-6 and IL-17A has a negative prognostic significance in both advanced cancer and autoimmunity. On the contrary, the evidence of high concentrations of TGF-beta and IL-10 is associated with a negative prognosis in metastatic cancer and with a disease control in the autoimmune disorders.

Despite its great complexity, the immune functionless is the end-results of the interactions occurring between lymphocyte and monocyte-macrophage functions, with the dendritic cells as the link between old innate and new acquired immunity. Moreover, within the lymphocyte system, the immune regulation is mainly determined by three major subsets of T lymphocytes, consisting of TH1 lymphocytes (CD4+CD25-CD17-), regulatory T lymphocytes (T reg) (CD4+CD25+), and TH17 lymphocytes (CD4+CD17+) [1-3]. All lymphocyte subpopulations may release several proteins, the so-called cytokines, but from a clinical point of view it is important to remember the main factors involved in the regulation of the whole immune system, which are represented by IL-2 for TH1 cells, IL-17A for TH17 cells, and IL-10 and TGF-beta for T reg cells. On the other side, the differentiation of the monocyte-macrophage system into different sub-sets is more controversial [4-8]. However, it has been shown that monocyte count may reflect the functional status of the macrophage system [9]. Therefore, because of the great number of potential immune biomarkers and their different economic cost, it is fundamental to distinguish the most important ones from a clinical point of view to monitor the clinical course of the various systemic diseases from those useful for the only experimental researches. At this proposal and by taking into consideration that the immune status is depending on the lymphocyte-macrophage relationships the most simple and less expensive biomarker from a clinical point of view may be considered the lymphocyte-to-monocyte ratio (LMR) which has appeared to play a prognostic significance in all severe human systemic diseases, including cancer autoimmune diseases and cardiovascular disorders [10-13]. Finally, as far as systemic disease-related symptomatology is concerned, IL-1 beta would be the main responsible for fever TNF-alpha for cachexia and anorexia IL-6 for sepsis-related hypotension and multi-organ failure and IL-31 for pruritus. Unfortunately, most Clinicians do not seem to be interested in the investigation of the physiopathology of cytokines [14-17].

Since the pathogenesis of human systemic diseases may be reinterpreted as depending at least in part on an altered relation among the different T lymphocyte subsets, it becomes clinically important to quantify T cell subpopulations. In fact, the alterations in cytokine secretions occurring in the different systemic diseases would be the simple consequence of those involving the various T cell subsets. The progressive decline in TH1 cell count in association with an increase in T reg cell number and activity is the main advanced cancer-related immune alteration which would be due to macrophage-mediated chronic inflammatory status. Then, the progressive decline in TH1/T reg cell ratio occurring during cancer progression depends either on a diminished TH1 cell count, or an increased T reg cell number. Moreover, it has been shown that the decline in TH1/ T reg cell ratio positively correlates with a decline in LMR values. Then, LMR values could represent an adequate and less expensive biomarker to monitor the evolution of advanced cancer patents. As fare as the autoimmune diseases are concerned, until few years ago the increased activity of TH1 cells was considered the main event responsible for the onset of autoimmune processes. In contrast, it has been demonstrated that the autoimmune diseases are namely characterized by an increase in TH17 cell activity in association with a decline in T reg cell count since the main action of TH17 cells is the inhibition of T reg cell generation and function. Then, the evidence of an abnormally high values of TH17/T reg cell ratio, which is due to both TH17 cell increase and T reg cell decline, may be considered as the main biomarker with negative prognostic significance to monitor the clinical course of the autoimmune diseases. LMR values have also appeared to have a prognostic significance in the autoimmune pathologies, since it has been shown to be normal or a little increased during the remission phase of disease and abnormally low during the exacerbation phase in any case not due to a diminished lymphocyte production as well as in the metastatic neoplasms but probably to lymphocyte exit from the blood to infiltrate organ tissues. In addition, at least some autoimmune diseases may be also characterized by a decline in TH1/TH17 cell ratio, sine the increase in TH17 cell count would be superior to TH1 enhancement. The occurrence of a diminished TH1/TH17 could also characterized the advanced neoplastic pathologies, because of cancer-related decline in TH1 count, as well as a probable increase in TH17 cell number, even though the TH17 profile in cancer patients has been less investigated up to now [18,19]. In any case, according to the data available up to now, cancer progression would be characterized not only by an increased T reg cell function, but also by an enhanced TH17 cell activation. Moreover, IL-17, despite its potential favourable effect due to an inhibition of T reg cell system, may directly stimulate cancer cell proliferation, and IL-17-expression by cancer cells would enhance their malignant aggressiveness. Finally, a marked increase in TH17/T reg cell ratio has been shown to predict a risk of acute respiratory distress syndrome (ARDS) in patients with lung injury, or viral infections, including coronavirus infection.

Table 1: The main immune and neuroendocrine pathological and prognostic biomarkers to monitor the clinical course of the main systemic human diseases.

The two extreme mistakes are the almost complete lack of immune evaluation in patients with systemic diseases, including cancer and autoimmunity, and on the other side the detection of an excessive number of laboratory immune parameters, including cytokine blood levels and lymphocyte subsets. Then, the correct clinical behaviour would have to consist of the measurement of the only essential and synthetic immune biomarkers to establish the immune status of patients, in particular by avoiding the measurement of cytokines provided by the same pathological significance, such as the concomitant detection of IL-1 beta and IL-6, because of their positive correlation. Obviously, the choice of the fundamental immune parameters to be clinically detected requires a perfect knowledge of the physiopathology of the different human systemic diseases. In addition, the synthetic group of biomarkers to monitor the clinical course of the systemic diseases must include both parameters provided by physio-pathologic and prognostic significance. The main cytokine levels and T lymphocyte subsets provided by pathological or prognostic significance in the most important human systemic diseases are summarized in (Table 1). LMR: Lymphocyte/monocyte ratio; ANP: Atrial natriuretic peptide; ET-1: Endothelin-1; MLT: Melatonin, ADH: Vasopressin; OT: Oxytocin. 

A further future evolution of the medical Sciences will be achieved and realized only when the evaluation of the functionless of the cytokine network will be included within the commonly laboratory examinations to monitor the clinical course of the most important severe human systemic disease. 

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