Waning and boosting of antibody Fc-effector functions upon SARS-CoV-2 vaccination.

Since the emergence of SARS-CoV-2, vaccines targeting COVID-19 have been developed with unprecedented speed and efficiency. CoronaVac, utilising an inactivated form of the COVID-19 virus and the mRNA26 based Pfizer/BNT162b2 vaccines are widely distributed. Beyond the ability of vaccines to induce production of neutralizing antibodies, they might lead to the generation of antibodies attenuating the disease by recruiting cytotoxic and opsonophagocytic functions. However, the Fc-effector functions of vaccine induced antibodies are much less studied than virus neutralization. Here, using systems serology, we follow the longitudinal Fc-effector profiles induced by CoronaVac and BNT162b2 up until five months following the two-dose vaccine regimen. Compared to BNT162b2, CoronaVac responses wane more slowly, albeit the levels remain lower than that of BNT162b2 recipients throughout the entire observation period. However, mRNA vaccine boosting of CoronaVac responses, including response to the Omicron variant, induce significantly higher peak of antibody functional responses with increased humoral breadth. In summary, we show that vaccine platform-induced humoral responses are not limited to virus neutralization but rather utilise antibody dependent effector functions. We demonstrate that this functionality wanes with different kinetics and can be rescued and expanded via boosting with subsequent homologous and heterologous vaccination.

Waning and boosting of functional humoral immunity to SARS-CoV-2.

Since the emergence of the SARS-CoV-2 virus, we have witnessed a revolution in vaccine development with the rapid emergence and deployment of both traditional and novel vaccine platforms. The inactivated CoronaVac vaccine and the mRNA-based Pfizer/BNT162b2 vaccine are among the most widely distributed vaccines, both demonstrating high, albeit variable, vaccine effectiveness against severe COVID-19 over time. Beyond the ability of the vaccines to generate neutralizing antibodies, antibodies can attenuate disease via their ability to recruit the cytotoxic and opsinophagocytic functions of the immune response. However, whether Fc-effector functions are induced differentially, wane with different kinetics, and are boostable, remains unknown. Here, using systems serology, we profiled the Fc-effector profiles induced by the CoronaVac and BNT162b2 vaccines, over time. Despite the significantly higher antibody functional responses induced by the BNT162b2 vaccine, CoronaVac responses waned more slowly, albeit still found at levels below those present in the systemic circulation of BNT162b2 immunized individuals. However, mRNA boosting of the CoronaVac vaccine responses resulted in the induction of significantly higher peak antibody functional responses with increased humoral breadth, including to Omicron. Collectively, the data presented here point to striking differences in vaccine platform-induced functional humoral immune responses, that wane with different kinetics, and can be functionally rescued and expanded with boosting.

Wfs1-deficient animals have brain-region-specific changes of Na+, K+-ATPase activity and mRNA expression of α1 and ß1 subunits.

Mutations in the WFS1 gene, which encodes the endoplasmic reticulum (ER) glycoprotein, cause Wolfram syndrome, a disease characterized by juvenile-onset diabetes mellitus, optic atrophy, deafness, and different psychiatric abnormalities. Loss of neuronal cells and pancreatic ß-cells in Wolfram syndrome patients is probably related to the dysfunction of ER stress regulation, which leads to cell apoptosis. The present study shows that Wfs1-deficient mice have brain-region-specific changes in Na(+),K(+)-ATPase activity and in the expression of the α1 and ß1 subunits. We found a significant (1.6-fold) increase of Na-pump activity and ß1 subunit mRNA expression in mice lacking the Wfs1 gene in the temporal lobe compared with their wild-type littermates. By contrast, exposure of mice to the elevated plus maze (EPM) model of anxiety decreased Na-pump activity 1.3-fold in the midbrain and dorsal striatum and 2.0-fold in the ventral striatum of homozygous animals compared with the nonexposed group. Na-pump α1 -subunit mRNA was significantly decreased in the dorsal striatum and midbrain of Wfs1-deficient homozygous animals compared with wild-type littermates. In the temporal lobe, an increase in the activity of the Na-pump is probably related to increased anxiety established in Wfs1-deficient mice, whereas the blunted dopamine function in the forebrain of Wfs1-deficient mice may be associated with a decrease of Na-pump activity in the dorsal and ventral striatum and in the midbrain after exposure to the EPM.

Differences between familial and sporadic cases of vitiligo.

BACKGROUND: Most cases of vitiligo are sporadic, but about 10-36% of the patients have positive family history. OBJECTIVE: The aim of our study was to describe differences between familial and sporadic cases of vitiligo. METHODS: A total of 186 adult vitiligo patients were examined, in 173 of whom the level of thyroid peroxidase antibodies, gastric parietal cell antibodies (PCA), antinuclear antibodies (ANA), anti-adrenal cortex antibodies and rheumatoid factor in blood was measured. All patients were divided in two groups: the cases with positive family history of vitiligo (51) and the sporadic cases (135). RESULTS: The risk of onset of the disease up to 20 years of age was higher in the familial group (P=0.008). Patients in familial group showed more widespread depigmentation compared with sporadic cases [body surface area (BSA) over 10%: P=0.004; BSA over 50%: P=0.001]. In familial group, patients had darker skin phototype (P=0.045) and the disease had started more often as a vulgar vitiligo (P=0.008). In sporadic vitiligo group, female gender was a risk factor for more widespread depigmentation (BSA over 10%, P=0.001). Extensive depigmentation was associated with reported triggering factors and mucosal involvement in both groups and with leukotrichia only in familial group. Widespread depigmentation related to the risk of presence of autoantibodies (P=0.03) in sporadic cases of vitiligo (especially of PCA: P=0.04 and ANA: P=0.0002). CONCLUSIONS: In this study, we demonstrated first time that patients with familial vitiligo have a higher risk for vulgar type at the beginning of the disease and female gender increases the risk for more extensive depigmentation in sporadic cases.

Temperature dependence of the sodium pump is altered in the cerebral cortex of CCK2 receptor-deficient mice.

Previously we have shown that the temperature dependence of the sodium pump (Na(+),K(+)-ATPase) is altered under different neuropathological conditions. In this study we compared temperature dependence of the Na(+),K(+)-ATPase in the fronto-parietal cortex of CCK(2) receptor-deficient (homo- and heterozygous) and normal (wild-type) mice. The Arrhenius plot for Na(+),K(+)-ATPase from wild-type brain is non-linear with a breakpoint at 20.3 +/- 0.4 degrees C. In case of the brain cell membrane of CCK(2) receptor-deficient mice (homo- and heterozygous) the breakpoint on Arrhenius plot was detected at 26.0 +/- 1.1 degrees C and 25.4 +/- 0.4 degrees C, respectively. The shift of the breakpoint on the Arrhenius plot established in CCK(2) receptor-deficiency as well as in case of some other pathological conditions confirms that such kind of alteration in the Na(+),K(+)-ATPase temperature dependence is likely related to the homeostatic adjustment of altered function of the sodium pump.

[The role of conformational changes in the functioning of brain Na,K-ATPase]. / O roli konformatsionnykh izmenenii v funktsionirovanii Na,K-ATFazy mozga.

In the experiments with enzyme preparations of Na,K-ATPase from normal brain tissue (NBT) and tumorous brain tissue (TBT) the following data were established: 1) the cooperativity of Na,K-ATPase with Na+ from NBT is temperature-dependent, the Hill coefficient (nH) at 37, 27.0-30.5 and 20-22 degrees C being 1.80 +/- 0.07, 1.30 +/- 0.09 and 1.10 +/- 0.08, respectively; the cooperativity of Na+ with Na,K-ATPase from TBT was absent; 2) the cooperativity for ouabain (nH-1.30 +/- 0.05) was revealed only in the case of Na-pump from TBT; 3) the protective effect of ATP against the inhibitory action of pCMB is temperature-dependent and differs significantly in enzyme preparations from NBT and TBT; 4) the parameters of the temperature inactivation of enzyme preparations at 45-52 degrees C, especially the change of entropy (delta S*) were different in the case of NBT and TBT; 5) a peptide fraction isolated from sheep brain differently inhibited the Na,K-ATPase from NBT and TBT. In conclusion, these data demonstrate that there are significant differences in functioning of Na,K-ATPase from NBT and TBT, and that besides lipid-protein interactions the local domenic conformational changes in the enzyme molecule may play a definite role in these differences.

[Features of temperature dependence of the Na+,K+-ATPase reaction in normal and tumorous brain tissue]. / Osobennosti temperaturnoi zavisimosti Na+,K+-ATP-aznoi reaktsii v normal'noi i opukholevoi tkani mozga.

It has been shown that in the enzyme preparations (EP) from normal brain tissue (NBT) a typical break on the Arrhenius plot appeared at 20-22 degrees C, nH for Na+ and K+ exceeding 1.7 and 1.4, respectively. In EP from tumoural brain tissue (TBT) no break on the Arrhenius plot at 20-22 degrees C was revealed, but it appeared at 27.5 + 30.5 degrees C. The nH for Na+ with Na+,K+-ATPase from TBT was only 0.9, but the cooperative binding of K+ was preserved (nH = 1.3). Electrophoregrams (EP) from TBT showed additional protein bands. The urea and digitonin treatment of EP from NBT induced a break on the Arrhenius plot at 27.5-30.5 degrees C. It is suggested that the break at 27.5-30.5 degrees C is, probably, accompanied by local changes in the conformation of protein components of the enzyme.

[Characteristics of cooperative binding of Na+ and K+ with Na+,K+-ATPase depending upon its oligomeric structure]. / Osobennosti kooperativnogo sviazyvaniia Na+ i K+ s Na+,K+-ATPazoi mozga v zavisimosti ot ee oligomernoi struktury.

It has been shown that the desensibilization of the enzymic preparations of Na+, K+-ATPase by urea, DS-Na, digitonin and CHAPS reduces differently the amount of alpha beta-protomer in the enzymic preparations and the Hill coefficients of Na+ and K+. The factors (urea, DS-Na) which cause a more pronounced decrease in the amount of beta-protomer reduce the nH of Na+ for Na+, K+-ATPase and nH of K+ for Na+, K+-ATPase and K+-pNPPase to unit. The analysis of the effects of ATP and pNPP indicates that ATP has a protective effect only in the case of urea and DS-Na, but this effect is not exerted by pNPP (nonallosteric substrate). A conclusion is drawn that cooperative interactions of Na+, K+-ATPase from the brain with Na+ require more higher level of the oligomeric structure of enzyme than cooperative interactions with K+. At the same time these cooperative interactions in the both cases need subunits interactions in the protomer and interactions between cation sites with relatively high affinity.