Cytokines and inflammation

Human papillomavirus (HPV) is recognized as the primary cause of cervical cancer. In women living with HIV, HPV infection is associated with a 3- to 4-fold increased risk of developing cervical intraepithelial neoplasia and cancer compared to HIV-negative women, even with effective combination antiretroviral therapy. The host immune response is crucial in determining the course of HPV infection, as cytokines and chemokines play a key role in antiviral defense, shaping the immune response type and influencing the clinical progression of the disease.

The aim is to analyze studies assessing cytokine concentrations in the cervical mucosa and their impact on the progression of HPV infection in HIV-positive women.

A systematic review was conducted, including studies that evaluated cytokine and chemokine levels in HIV-positive women of reproductive age (≥18 years). Both cohort and cross-sectional studies were considered.

This review examines cytokine and chemokine levels in biopsy samples and cervical scrapes from women co-infected with HIV and HPV. The analysis highlights distinct cytokine profile characteristics, including interferon-gamma (IFN-γ), interleukin-10 (IL-10), tumor necrosis factor (TNF), interleukin-6 (IL-6), and macrophage inflammatory protein (MIP).

Understanding immune processes and their impact on HPV infection in HIV-positive women contributes to a better understanding of the disease pathogenesis and improves diagnostics, prevention, and treatment strategies. Given the increased risk of acquiring HPV infection and the subsequent development of cervical precancerous lesions and cancer in HIV-positive women, strengthening preventive measures and early detection efforts for HPV infection in this population should be considered.

Despite significant advancements in extending average life expectancy, challenges persist in enhancing the quality of life for elderly and senile individuals, preventing and treating age-associated diseases and managing geriatric syndromes. The immune system plays a crucial role in aging, undergoing extensive functional changes collectively referred to as immunosenescence. Cellular aging within the immune system is associated with telomere shortening, proteostasis loss, mitochondrial dysfunction, DNA damage, and oxidative stress. Senescent cells are characterized by resistance to apoptosis, cell cycle arrest, and abnormal production of pro-inflammatory cytokines, leading to chronic low-grade inflammation. Concurrently, the effector mechanisms of the immune response become depleted, resulting in a reduced ability of the immune system to adequately respond to antigenic stimuli. Thymic atrophy, depletion of bone marrow niches, a shift in hematopoiesis toward the myeloid lineage, and alterations in lymphocyte subpopulation ratios occur. Additionally, the effector functions of neutrophil granulocytes are impaired. However, the nature of these functional changes in immunosenescence remains insufficiently studied, requiring further research to determine the specific dysfunctions of neutrophil granulocytes in aging.

BACKGROUND: The search for additional diagnostic markers that reflect the dynamics of disease progression remains a necessary and relevant task. Inflammation, as a key component of the pathogenesis of many diseases, is one of the main factors contributing to an increased level of extracellular DNA (ecDNA) in the blood plasma of affected patients.

AIM: To determine the fragmentation index of ecDNA, the quantitative content of mitochondrial ecDNA (mt-ecDNA) within the total ecDNA pool, and the level of membrane-bound ecDNA in the blood of patients with rheumatoid arthritis and bronchial asthma to assess the potential diagnostic value of these parameters in evaluating inflammatory activity and therapeutic effectiveness.

METHODS: The total ecDNA pool was measured using the Quant-IT™ PicoGreen reagent for double-stranded DNA. The amount of mt-ecDNA and the ratio of long to short ecDNA fragments in blood plasma were assessed by real-time quantitative polymerase chain reaction.

RESULTS: The ecDNA fragmentation index was significantly lower in both patients with bronchial asthma (Me=0.42; p <0.001) and rheumatoid arthritis (Me=0.34; p <0.001) compared to the donor group (Me=0.81). The prescribed therapy had no substantial effect on the fragmentation index, which remained nearly unchanged from the time of admission: Me=0.49 in the bronchial asthma group and Me=0.35 in the rheumatoid arthritis group. In patients with bronchial asthma, a moderate correlation was observed between mt-ecDNA levels and C-reactive protein (ρ=0.34; p >0.05). In patients with rheumatoid arthritis, similar correlations were found between mt-ecDNA and DAS-28 (ρ=0.36; p >0.05), as well as C-reactive protein (ρ=0.28; p >0.05). The membrane-bound ecDNA fraction was significantly lower in patients with rheumatoid arthritis compared to healthy donors (18.7 ng/mL vs. 55.6 ng/mL; p <0.01). A decrease in membrane-bound ecDNA fraction was also observed in patients with bronchial asthma compared to the donor group (19.4 ng/mL; p <0.01).

CONCLUSION: The ecDNA fragmentation index and mt-ecDNA levels cannot serve as markers of inflammatory activity or indicators of the pathological shift in the Th1/Th2 balance in various immune system disorders. This is supported by the fact that diseases with differing levels of inflammatory activity, such as rheumatoid arthritis and bronchial asthma, result in a similar reduction in the ecDNA fragmentation index relative to healthy donors and do not lead to any significant difference in mean mt-ecDNA levels between these patient groups.

BACKGROUND: The mTOR/S6K metabolic intracellular signaling cascade plays a key role in regulating the activation and differentiation of Th17/Treg lymphocyte populations. Pathogens can disrupt T-lymphocyte differentiation programs and weaken immune responses through arginine depletion mechanisms.

AIM: To evaluate the effect of bacterial arginine-hydrolyzing enzyme arginine deiminase on the balance of Th17/Treg helper T-cell polarization in vitro.

MATERIALS AND METHODS: Experiments were conducted using mononuclear leukocytes from healthy donors. Lymphocyte activation and differentiation were induced with activating antibodies and a cytokine cocktail. Recombinant Streptococcus pyogenes arginine deiminase was used. The enzyme’s arginine-hydrolyzing activity was confirmed by a modified Sakaguchi method. Mitochondrial oxidative phosphorylation activity was analyzed via MTT assay. The proportion of Th17, Treg, and IL-17A⁺/Foxp3⁺ transitional lymphocyte populations was assessed using monoclonal antibodies and flow cytometry.

RESULTS: The enzyme caused a significant sevenfold decrease in arginine concentration in mononuclear leukocyte cultures. The arginine deficiency induced by arginine deiminase activity could not be compensated even by supplementing supraphysiological concentrations of the amino acid. Differentiation was accompanied by a significant reduction in oxidative phosphorylation (p <0.001). Arginine deiminase inhibited mitochondrial respiration in both intact (p <0.001) and differentiated cells (p <0.05). The enzyme’s activity suppressed Th17 cell differentiation (p <0.05) but did not affect IL-17A⁺/Foxp3⁺ transitional cells, Treg lymphocytes, or the Th17/Treg ratio.

CONCLUSIONS: Arginine deiminase may disrupt adaptive immune development and diminish the effectiveness of protective immune responses.