Crohn's disease (CD), like ulcerative colitis (UC), is an inflammatory bowel disease (IBD) with a prevalence ranging from 0.1–58 cases per 100,000 people, depending on the region1. More than 2 million people in North America and 3.2 million people in Europe suffer from this disease2. The epidemiology of CD has changed over the past decades, demonstrating a trend toward increased prevalence in the developing countries, while in developed countries, its incidence has stabilized3. CD is most common among people aged 20 to 30 years1,2. The incidence of CD in North America ranges from 0 to 20.2 cases per 100,000 person-years, and that in Europe – from 0.3 to 12.7 cases per 100,000 person-years. The highest incidence of CD among North American countries was recorded in Canada (319 cases per 100,000 population), and among European countries – in Germany (322 cases per 100,000 population).3 In the United Kingdom, the prevalence of CD increased from 220 to 400 cases per 100,000 population between 2000 and 2017 and amounted to 14.3 person-years per 100,000 population in 2017. Meanwhile, 0.35% of British men and 0.44% of women were diagnosed with CD in 20174.
The relevance of CD is not only because its prevalence is increasing annually but also since full-fledged treatment requires significant direct and indirect costs throughout the life of patients, not to mention the psychological and emotional distress of these people and the deterioration of their life quality 5 . For example, in the United States, the average lifetime cost of treating CD is $622,056, of which $273,056 is for outpatient care, $164,298 – for inpatient care, $163,722 – pharmacies, and $20,979 – for the intensive care units 6 .
CD is a heterogeneous inflammatory disease with a multifactorial etiology, including genetic and environmental factors, as well as intestinal microbiota disorders. This disease affects any part of the gastrointestinal tract (GIT) from the oral cavity to the anus and is characterized by chronic, segmental, and transmural granulomatous inflammation of the GIT with the formation of fistula, abscesses, and stenotic lesions1,7. At CD, the small intestine and the large intestine are affected most often8. Disorder of the small intestine is observed in 66% of people suffering from this disease. CD with the involvement of the upper gastrointestinal tract disorder occurs in 0.5-4% of cases in the adult population. Typically, lesions of the upper and lower gastrointestinal tracts in CD occur simultaneously.
The etiology of CD is not known exactly, but it is obvious that this disease has a multifactorial nature8,9. Currently, the main trigger factors of this disease are believed to be genetic. In particular, more than 30 loci have been identified in the chromosomes that play a direct role in the development of CD. The disease is predominantly associated with the HLA-DR1 haplotype and loci on chromosomes 2 and 6. The role of the HETD2/CARDI5 gene and the OKTN gene has also been studied10,11.
Among the microorganisms playing a potential role in the development of CD, scientists name Mycobacterium paratuberculosis, i.e., measles virus, but no convincing data confirm them as an etiological factor of this disease12. The role of intestinal microflora in the development of CD is also being studied. In this context, the intestinal microbiota is seen as a stimulus, which can lead to a pathological response of the immune system. Such an opinion is related to bacterial endotoxins (lipopolysaccharides, bacterial envelope oligopeptides) that provoke the production of inflammatory mediators, stimulating the migration of cellular elements to the focus of the inflammatory process9,13.
The importance of stress factors in the development of CD is also not confirmed. However, the practice of clinicians shows that patients with this pathology of the intestine are very sensitive to the action of stress and respond to it with exacerbation of the disease14. There is also no consensus among scientists regarding the influence of diet on the occurrence of CD. Nevertheless, this disease is known to be more common in people who eat less natural products and prefer semi-processed foods9,15.
Autoimmune reactions play a major role in the pathogenesis of CD, since autoantibodies to intestinal mucosal epithelial cells have been detected in such patients16,17. Due to the primary increase in the permeability of the intestinal epithelial barrier, in which the cytoskeleton of epithelial cells is damaged, the enterotoxins, i.e., protein substances with antigenic properties, penetrate the bloodstream from the intestine, which leads to sensitization of the body with the production of autoantibodies. A consequence of this is the disruption of the mucosal intestinal system functions like the production of suppressor cytokines and immune areactivity in relation to various mitogens and antigens17.
In recent years, more and more attention has been paid to the role of various cytokines in the pathogenesis of CD, including tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), IL-2, IL6, IL-8, IL-12, IL-18, and interferon-γ (IFN-γ)18–20. By their nature, cytokines are polypeptide molecules with a molecular weight in the range of 5–50 kDa. Their main biological function is the formation and regulation of the body's defense reactions19, 21. They are synthesized by almost all cells of the human body, after which they enter the extracellular space, then bind with receptors of corresponding cells, resulting in the initiation of some biological reactions. Cytokines regulate the differentiation and maturation of cells with immunocompetent properties by stimulating or, on the contrary, suppressing proliferation, migration, secretion, and/or expression of surface receptors and antigens. Besides, cytokines control cytotoxic activity and antibody production18, 20, 22.
ILs are a subfamily of cytokines being mediator proteins. In CD, proinflammatory cytokines dominate, which stimulate the synthesis of agitrogen monoxide by enterocytes and immune cells, leading to damage of enterocyte cytoskeleton and, as a consequence, an increase in the permeability of the intestinal wall.18,19 Among proinflammatory cytokines, TNF-α has the greatest significance in the development of CD. Its excess in the body is associated with a number of the following biological processes: activation of T- and B-lymphocytes, neutrophils with the induction of IL-2, INF-γ; activation of macrophages with the induction of IL-2, IL-6 synthesis; activation of free radical synthesis; synthesis of acute-phase proinflammatory proteins in the liver (seromucoid, C-reactive protein, α1-antitrypsin, etc.); development of inflammatory reactions (leukocytosis, sepsis, fever, weight loss); development of endotoxemia; increase in vascular wall permeability with subsequent migration of leukocytes to the inflammation focus; stimulation of adhesion molecules expression on endotheliocytes and leukocytes; inhibition of apoptosis of inflammatory cells. Also, TNF-α together with IL-1 and INF-γ that are involved in granuloma formation. In CD, the concentration of IL-1, IL-2, IL-6, IL-8, and TNF-α sharply increases, while the concentration of anti-inflammatory cytokines (IL4, IL-10, IL-11, etc.) decreases23.
The significant importance of cytokines in the pathogenesis of CD determines the necessity to perform detailed studies of their content depending on the course, stage, and pathogenesis of the disease. Given the features of the cytokine profile of a particular patient, their examination as predictors of the disease severity and markers of inflammatory process activity would allow developing individual therapy tactics, providing the predictive treatment of CD.
The aim of the study was to investigate the profile of the main proinflammatory cytokines in the serum of patients with Crohn's disease and establish their association with the severity and activity of the disease.