Relationship between various pathways of cellular death at distinct stages of ontogenesis in normal state and systemic diseases of connective tissue

Abstract

The aim of our research was to reveal quantitative ratios existing between the pathways of cellular death in normal state, as well as in immunocomplex pathology. The proportion of different pathways of cell death (autophagy, apoptosis, necrosis) in autoimmune (systemic connective tissue diseases (SDCT) – rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and systemic scleroderma (SSD) is a subject of age-related changes. On the one hand, aging process can be considered a genetically determined overall decrease in adaptive potential of the body, and a systemic age-related chronic inflammatory response, with a pronounced cytokine proinflammatory shift. On the other hand, a polygenic decrease in energy and information capacity of the cells, represent the basis of multisystem and multiorgan functional and metabolic disorders in SDCT. Blood plasma samples were analyzed in the patients of two age groups. The first group consisted of 10 SLE cases (4 men and 6 women, average age 43.8 years), 13 patients with RA (5 men and 8 women, average age 45.6 years), 7 SSD (women, average age 35.8 years), and 10 healthy donors (6 men and 4 women, average age 40.7 years). The second age group consisted of 9 SLE cases (2 men and 7 women, average age 69.8 years), 10 patients with RA (5 men and 5 women, average age 65.6 years), 5 patients with SSD (women, average age 65.7 years) and 12 healthy donors (normal biological aging – 7 men and 5 women, average age 64.7 years). The data presented in this paper were obtained with informed consent of the patients. When carrying out biomedical research, we followed internationally recognized ethical standards of the Helsinki Declaration (International Medical Association, 1996, revision 2013). The proportion of various cell death types (autophagy, apoptosis, necrosis) in autoimmune disorders (systemic diseases of connective tissue, SDCT), i.e., rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic scleroderma (SSD) proved to be subject to age-dependent changes. Close interaction were revealed between the ways of cellular death in SDCT (most pronounced in SLE), correlating with age changes and clinical manifestations of autoimmune process. In SDCT, the affected tissues exhibit all types of cellular death, however, degree of their expression depends on the disease nosology. Upon systemic diffuse pathology of connective tissue, autophagy (especially in case of SLE and RA) is directly involved in development of immune response and inflammatory process. In normal biological aging, like as in SDCT, one may observe a sharply increased activity of the metabolic trigger – AMP-activated protein kinase (AMPK), a sensor of intracellular energy, along with shifted acid-base equilibrium. The quantity of active oxygen radicals increases, oxidoreductive potential of the cells is changed, with activation of cellular destruction components. Activity of cytokine system in the organism is changed causing apoptosis regulation; expression of chaperons is decreased, and the immune-oxygenase homeostasis is also displaced. Inhibition of genetically determined process of death of cells (apoptosis) comprises the basis for development of autoimmune diseases. Transition of late apoptosis into secondary necrosis is accompanied by decrease of antioxidant protection and development of autoimmune pathology. The chaperon-mediated induction of immune response as the signaling mechanism of autophagy, being evolutionarily fixed in mammals only, may be the common central link and “the molecular switch” causing both development of autoimmune diseases of connective tissue, and aging processes.