Genetic Variants Of The Host CD16a Antibody Receptor Are Associated With The Risk Of Severe COVID-19

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A new study by researchers from the Medical University of Vienna-Austria have found that genetic variants of the host CD16a antibody receptor are associated with the risk of severe COVID-19.

The study findings were published in the peer reviewed journal: Genetics in Medicine. 

https://www.gimjournal.org/article/S1098-3600(22)00722-5/fulltext

The role of antibody-mediated activation of NK cells in patients with COVID-19 has not been fully clarified so far, and it remains controversial whether SARS-CoV-2-specific ADCC responses increase COVID-19 severity or contribute to limitation of the disease.8,13,14

In this study, we now provide evidence that the SARS-CoV-2-specific antibody-mediated activation of NK cells in patients with COVID-19 is dependent on individual expression of genetically distinct FcγRIIIa variants, and that an overall higher SARS-CoV-2-specific ADCC response is associated with development of severe COVID-19.

In our study cohort, the FcγRIIIa-158-F/F variant was significantly less prevalent in hospitalized patients with COVID-19 and especially in patients with COVID-19 dying from SARS-CoV-2 infection than in nonhospitalized patients with mild infections. In contrast, a significantly higher proportion of patients expressing the FcγRIIIa-158-V/V receptor variant was hospitalized and died from COVID-19.

Further in vitro experiments subsequently showed on a functional basis that the stimulation with SARS-CoV-2-specific antibodies leads to a significantly higher activation of NK cells with FcγRIIIa receptors carrying a 158-V amino acid residue than the NK cells carrying the homozygous FcγRIIIa-158-F/F variant. An earlier in vitro study showed that, in general, the FcγRIIIa-158-V/V variant provides a significantly increased affinity to the Fc-part of IgG antibodies compared with the FcγRIIIa-158-F/F receptor variant.6 Our data are in agreement with this observation.

In addition, we showed that higher activation of NK cells carrying the FcγRIIIa-158-V/V variant may contribute to a severe clinical course of COVID-19.

This may be because of the fact that, as our data reveal, FcγRIIIa-158-V/V expressing NK cells show higher expression levels of the proinflammatory cytokines TNFα and IFNγ.

Especially TNFα was recently identified as a marker cytokine for hypercytokinemia in patients with severe COVID-19.2 In addition, TNFα and IFNγ are key factors in the pathogenesis of severe COVID-19, because especially TNFα is a potent chemoattractant for leukocytes and promote the expression of adhesion molecules on endothelial cells, thereby providing the functional basis for migration of leukocytes into the SARS-CoV-2-infected lung. Using a SARS-CoV-2 mouse model, others recently found that the combination of both TNFα and IFNγ induced inflammatory cell death and a lethal hypercytokinemia.15

The high potential of NK cell based immunological mechanisms, such as ADCC in the lung, is further underlined by other authors who showed overall decreased NK cell levels in the peripheral blood of severely diseased patients with COVID-19, and consequently hypothesized that NK cells migrate into the SARS-CoV-2-infected lung during severe infection.16

It seems thus likely that NK cells are an important source of TNFα and IFNγ in patients with COVID-19, and that NK cell-driven ADCC contributes, through these effectors, substantially to the course of COVID-19. These effects are, as we showed, to some extent dependent on the individual FcγRIIIa-158-V/F variant of the patients and may be is the one factor contributing to the individually different clinical severity of COVID-19.

We also found that NK cells that were stimulated with plasma from severely diseased patients with COVID-19 showed markedly increased activation levels of cytotoxicity markers compared with that from patients with COVID-19 with mild disease. This is in agreement with recently published ex vivo studies that found a higher NK cell activation status in severe than in mild COVID-19, which was hallmarked by the high-level expression of perforin and evidenced a status of NK cell exhaustion.9,17

Another ex vivo study analyzed the potential of peripheral blood mononuclear cells derived from patients with COVID-19 to induce an ADCC response against rituximab-coated Raji cells.18 The authors found a considerably defective ADCC response in hospitalized patients with COVID-19, which also shows exhaustion of ADCC mediating cells in these patients. Combined, these and our data show that the SARS-CoV-2-specific antibody-mediated ADCC responses may contribute to the immune exhaustion in patients with COVID-19.

These findings are of special interest because the immune exhaustion in convalescent patients with COVID-19 was recently proposed as a potential risk factor for “long-COVID,” a multi-symptomatic condition characterized by long-term sequelae appearing after the convalescence period of COVID-19.19

In our study, the frequency of FcγRIIIa-158-V/F variants in control patients was comparable to recently published European study cohorts.20 Whereas the FcγRIIIa-158-F/F and FcγRIIIa-158-V/F variants occur frequently, the high-affinity FcγRIIIa-158-V/V genotype occurs more rarely and was observed in our cohort in only 15% of control persons.

It was described that the FcγRIIIa-158-V/V genotype occurs somewhat more frequently in individuals of African American ancestry.21,22 Interestingly, recently published studies in British patients with COVID-19 identified Afro-American ancestry as an independent risk factor for severe disease and death due to COVID-19.23 It requires, however, further studies to analyze to what extent genetic risk factors and especially the FcγRIIIa-158-V/F variants may contribute to the increased risk for severe COVID-19 in patients of distinct ethnic backgrounds.

In our study, we identified FcγRIIIa-158-V/V variant as an independent risk factor for severe COVID-19, especially in patients aged <60 years. This finding may be associated with the pronounced shaping of NK cell repertoire by aging. In elderly, higher frequencies of the CD56dimCD16+ NK cells are detectable than in younger individuals, who show higher levels of CD56brightCD16+ NK cells.24 Although CD56dimCD16+ NK cells are highly cytotoxic, CD56brightCD16+ cells have a specialized role as abundant cytokine producers.25 It is thus reasonable that FcγRIIIa-158-V/V variant is an especially important risk factor for severe COVID-19 in younger individuals, because high-levels of CD56brightCD16+ cells may contribute to patients’ hypercytokinemia.

From this study it became apparent that the SARS-CoV-2-specific ADCC response is unlikely to contribute to an early defense against SARS-CoV-2, because patients with COVID-19 developed a detectable SARS-CoV-2-specific and NK cell-mediated ADCC response only starting from day 6 after the first onset of clinical symptoms. A previous study in Chinese patients with COVID-19, similarly showed that the overall increase in SARS-CoV-2-specific ADCC response in patients with COVID-19 peaked around 11 to 20 days after disease onset.8 This is different to other NK cell-driven responses, as we recently showed that early and potent NKG2C+ NK cell responses may prevent the development of severe COVID-19.7

Although we focused on the association between patients’ FcγRIIIa-158-V/F receptor variants and the extent of ADCC, others have analyzed individual antibody profile in ADCC and found a positive correlation between receptor binding domain-specific ADCC response and higher levels of inflammation and immune activation markers, including TNFα.13

In further studies, a combined evaluation of the individual antibody response and the NK cell FcγRIIIa-158-V/F receptor polymorphism of single patients may allow for judging more precisely a patients’ risk for severe COVID-19 infections. As a further limitation, we focused in our study only on the dynamics and extent of the NK cell-mediated ADCC responses.

Notably, FcγRIIIa is not only expressed on NK cells, but also to a lower extent on monocytes, macrophages, and neutrophils.26,27 The migration and high-level activation of monocytes, macrophages, and especially neutrophils was recently associated with severe progression of COVID-19.28,29 Further studies are therefore required to evaluate the ADCC response in FcγRIIIa-expressing cells beyond NK cell response.

In our study cohort, FcγRIIIa-158-F/F genotype was only overrepresented in nonhospitalized mildly diseased patients with COVID-19, whereas severely diseased hospitalized patients with COVID-19 and healthy controls showed a similar distribution of the FcγRIIIa-158-F/V variants. These results show that FcγRIIIa-158-F/F individuals have a lower risk for severe COVID-19.

Our results are of special interest as potential predictive markers for the COVID-19 disease severity are still scare. Further studies, also in prospective study cohorts, are however needed to further assess to what extent FcγRIIIa-158-F/F individuals are protected from severe COVID-19.

In conclusion, we show that a potent SARS-CoV-2-specific ADCC response is associated with the development of severe COVID-19 and that the FcγRIIIa-158-V/F polymorphism significantly contributes to the antibody-mediated activation of NK cell against SARS-CoV-2. Further studies are needed to evaluate the fine specificity of the ADCC responses against SARS-CoV-2 and to gain further insights into the impact ADCC has on the immune pathogenesis of COVID-19.

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