chuka_lis (chuka_lis) wrote,

В поисках отличий

Работа в правильном направлении. Попытка разобраться, что на самом деле является факторами риска тяжелого заболевания. Почему чаще и выраженее болеют старики и мужчины.

Old age and male sex are important risk factors for COVID-19 severity. Several studies have  investigated whether immune responses during SARS-CoV-2 infection are influenced by  demographic factors such as age and sex [18, 19]. Although they identified immune profiles  associated with severe COVID-19, they could not assess whether these were secondarily induced by  the disease, or due to a-priori immune differences between different groups. In the present study,  we show that the immune characteristics associated with severe COVID-19, such as specific changes  in cell populations and circulating inflammatory proteins, are already present in healthy elderly and  men. Interestingly, while the season did not impact the immune response to SARS-CoV-2 stimulation
in the entire group, there was a clear difference in the responses between the young and old. Young  individuals, but not the elderly, improve their IFN  responses to SARS-CoV-2 during the summer.  COVID-19 progression to a severe clinical picture is related to the depletion of several immune cell types, including naïve CD4+ and CD8+, and CD56 high NK cells. Our study demonstrates the age-related  decline of these cells in healthy individuals even before the infection, which likely contributes to  their incapacity to eliminate the virus. These data are supported by studies suggesting that some of  these cell types are scarcer in uninfected elderly and males [20, 21]. Naïve B lymphocyte numbers  were also reduced with advanced age, which would undermine the development of adaptive  immunity and antibody production upon infection [22]. The aging process does not only alter cell  numbers, but also the functions ) [23]. All these might cumulatively disrupt the response  against SARS-CoV-2 infection.
We showed that one of the striking differences in immune cell types between males and females  was the number of CD4+ T cells. Although we cannot rule out that significant differences in cell  populations might not determine the disease severity, SARS-CoV-2-specific CD4+ T cells were  strongly linked with milder COVID-19, unlike antibodies and CD8+ T cell numbers [24]. Fast induction of CD4+ T cells was related to a milder disease, while defects in inducing SARS-CoV-2-specific CD4+ T  cells were associated with severe or fatal COVID-19.  An exaggerated systemic inflammation has been associated with severe COVID-19, mirrored by high  circulating concentrations of pro-inflammatory mediators [25]. Among those, IL-8, IL-18, and MCP-1  have been frequently reported, and the first two characterize the immune response of men with a  severe outcome [8]. Notably, their concentrations are already higher in both men and the elderly in  our healthy cohorts. Another protein displaying the same pattern is HGF, acting on epithelial and T  cells promoting migration [26], which has higher concentrations in the circulation of severe patients  [27]. The circulating HGF concentrations are higher in men, but also increases with age in women.
Chemokines are critical inflammatory mediators, and MCP-2, CCL3, CCL4, CCL19, and CXCL10 are all  more abundant in males. ENRAGE (S100A12), produced by neutrophils and monocytes, is also higher  in healthy males than females. Monocytes expressing high S100A12 and IL-8 are linked to COVID-19  severity [28]. Additionally, anti-inflammatory proteins IL-10 and PD-L1 are elevated in healthy males  and severe COVID-19. Initially considered a negative feedback mechanism for infection-induced  inflammation, there are arguments suggesting these proteins as biomarkers of immune exhaustion,  which is likely to play a substantial role in the pathophysiology of COVID-19 [29, 30]. Notably, the  association of early IL-10 production with COVID-19 severity supports this idea [31].  Severity markers increasing with old age, but not affected by sex, include IL-6 and OPG. IL-6 secreted by hyperactive monocytes contributes to low HLA-DR expression and lymphopenia in severe COVID- 19 [32]. TNF-family cytokine receptor OPG, abundant in ICU patients, increases with old age in our  healthy cohorts [9]. High OPG concentrations in females are likely due to estrogen's effects  promoting OPG expression to inhibit bone resorption [33]. Another TNF-family member, TRANCE (RANKL), which is lower in severe COVID-19 cases, also declines with advancing age in healthy  individuals. T cells are one of the primary TRANCE sources, which might explain its scarcity in the  elderly and severe COVID-19 patients with lymphopenia [34].  Of note, concentrations of circulating IL-7 and IFNγ, which are increased in severe COVID-19, are  similar in men and women. Therefore, T cell numbers being higher in women is unlikely due to IL-7- induced lymphopoiesis, whereas higher T cell numbers do not necessarily lead to more circulating  IFNγ. An overview of the age- and sex-dependent immune profiles in healthy individuals potentially  predisposing to severe COVID-19 upon infection is provided in Figure 7.  Environmental factors are also known to affect immune responses.
Certain infections such as  influenza follow a seasonal pattern [35], and the evolution of the pandemic last year also suggested273that COVID-19 incidence might follow a seasonal variation [14]. Therefore, we questioned whether  this might be due to seasonal changes in the immune response to the virus. In the entire group, we found no clear seasonal response against SARS-CoV-2 , although this could be due to the limited sample size. Interestingly, young individuals improve their IFN  response to SARS-CoV-2 during the  summer, while the elderly do not. Further research with larger cohorts is required to validate seasonality's full impact on anti-SARS-CoV-2 host defense.  Our results indicate that the immune response upon in vitro SARS-CoV-2 stimulation varies depending on age and sex. The response of the elderly is characterized by low IFNγ and elevated IL- 1RA production. IFNγ is crucial for an effective response of T- and NK cells to viral infections, and its deficiency is associated with severe COVID-19 [36]. Depleted NK and T cell pools might explain why  the elderly areless capable of producing IFNγ upon SARS-CoV-2 stimulation. Poor IFNγ response,  especially in the fall, might put the elderly at higher risk for severe COVID-19. Men and women produce comparable amounts of IFNγ, although the T cell numbers are higher in women. Other roles  of T cells besides IFN  production may contribute to the better prognosis of women with COVID-19. One important point is that these defects are present in the whole population, not at the individual  level: while the elderly as a group have lower immune responses, there are certainly aged individuals  who have effective immune reaction. This inter-individual variability could be the reason why some 290elderly or some men have good responses against SARS-CoV-2 and develop only mild disease. In COVID-19, an overproduction of pro-inflammatory cytokines contributes to the pathophysiology late in the disease [37]. On the other hand, cytokines such as IL-1β might also be crucial for an early  anti-viral response. The deficiency of IL-1β or its receptor causes higher viral load and mortality in  murine models [38]. Furthermore, genetic variants in IL1B contribute to influenza susceptibility in  humans [39]. We observed higher IL-1β production in women in response to SARS-CoV-2 in vitro,  arguing that an initial potent anti-viral defense is essential to prevent severe disease. Moreover, IL- 1RA is an antagonist of IL-1 bioactivity, helping prevent excessive inflammation [40]. However, early  IL-1RA production in patients is associated with COVID-19 severity [31], while our finding of higher IL-1RA production in the elderly suggests that IL-1RA might be hindering their ability to mount an  optimal immune response against SARS-CoV-2. Alternatively, high IL-1RA production with increasing  age might mirror the general inflammatory profile of elderly individuals. In conclusion, our findings shed light on the immunological factors that might explain why men and  the elderly have a higher risk of developing severe COVID-19. These results also emphasize the  importance of the IL1β/IL-1RA axis and IFNγ in anti-SARS-CoV-2 response. We propose that intrinsically different immune characteristics, including plasma inflammatory mediators and immune  cell populations, in healthy people would influence their immune response upon SARS-CoV-2  infection and the severity of the disease. Results of this study inform prophylactic and therapeutic  efforts.
Tags: иммунитет, коронавирус, статьи
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