Association Between NK Cell Genetic Variants and the Development of Long COVID Associated- and Prepandemic Small Fiber Neuropathy

Abstract

Long coronavirus disease 2019 (COVID) (LC) symptoms including pain and autonomic dysfunction are in some patients associated with small-fiber neuropathy (SFN). The pathomechanisms underlying SFN are mostly unclear. Natural killer (NK) cells play a crucial role in immune regulation, viral clearance and nerve metabolism. The aim of this study was to identify associations between development of small-fiber dysfunction dependent and independent of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and human genetic markers associated with specific NK cell functions. The genetic markers assessed in all cohorts included: FCGR3A, IGHG1, HLA-E, NKG2C, and rs9916629. Genotyping was performed using TaqMan assays, Sanger sequencing and touchdown polymerase chain reaction. We assessed human cytomegalovirus (HCMV) IgG serostatus in all participants, and screened for anti-neuronal, anti-glial and anti-ganglioside autoantibodies in both patient cohorts. We included 50 LC patients with newly-emerged symptoms of small-fiber dysfunction after SARS-CoV-2 infection, 27 prepandemic SFN patients and 320 control persons. Markers associated with low NKG2C response, that is, deletion of the NKG2C gene and lack of prior HCMV infection (IgG seronegativity), occurred significantly more frequently in prepandemic SFN patients compared to LC patients and controls (p = 0.0109 and 0.0005, respectively). In conclusion, markers of impaired NKG2C pathways are associated with prepandemic SFN, but not with Long COVID-associated small-fiber dysfunction.

Keywords: NK cell; NKG2C; long COVID; small fiber neuropathy.

Figure 1

Genetic natural killer (NK) cell markers associated with antibody‐dependent cellular cytotoxicity (ADCC) and the rs9916629 polymorphism. Genotype distributions of (A) FCGR3A, (B) G1m and (C) rs9916629 in Long COVID patients (LC), prepandemic small fiber neuropathy (SFN) patients (prep SFN) and population controls (population). Comparisons of genotype distributions were performed by χ ² test.

Figure 2

Genetic natural killer (NK) cell markers associated with the NKG2C/CD94–HLA‐E axis. Genotype distributions of (A) HLA‐E and (B) NKG2C in Long COVID patients (LC), prepandemic small fiber neuropathy (SFN) patients (prep SFN) and population controls (population). For NKG2C genotyping, leftover material was available from 48/50 LC patients and from 21/27 prepandemic SFN patients. Brackets show statistically significant differences in genotype distribution as assessed by χ ² test.

Figure 3

Prevalence of patients with NKG2C high and low responses in the study cohorts. “NKG2C response high” indicates patients who are HCMV IgG seropositive and carry the NKG2C wt allele (wt/wt or wt/del). “NKG2C response low” indicates patients who are HCMV IgG seronegative, or who are HCMV IgG seropositive while displaying the NKG2C del/del genotype. Comparison between (A) Long COVID patients (LC) or (B) LC patients with skin biopsy confirmed small fiber neuropathy (SFN) (LC (confirmed)), respectively, and prepandemic SFN patients (prep SFN) as well as population controls (population). Brackets show statistically significant differences in genotype distribution as assessed by χ ² test.