NK cell missing self in microvascular inflammation with and without donor-specific antibodies

Microvascular inflammation (MVI), a histological hallmark of antibody-mediated rejection (AMR), is typically associated with donor-specific antibodies (DSA), but can also occur in their absence. Evidence implicates Natural Killer (NK) cells in DSA-negative MVI, although the mechanisms underlying their activation remain unclear.

We retrospectively analyzed 165 kidney transplant biopsies, regarding biopsy-based diagnostic categories as competing events: (1) MVI+DSA+ (n=91), (2) MVI+DSA- (n=35), and (3) MVI-DSA+ (n=39). Recipients and donors were genotyped for KIR and HLA to assess "missing self" - the absence of donor HLA ligands for recipient inhibitory KIR. We also tested the moderating effect of NK cell functional polymorphisms in FCGR3A (V/F158), KLRK1 (LNK/HNK), KLRC2 (wt/del) and rs9916629. We used cumulative incidence functions and cause-specific Cox regression models to examine the association of genetic variants and the incidence of the competing biopsy-based diagnostic categories.

The presence of missing self was associated with a lower hazard of MVI-DSA+ occurrence (hazard ratio (HR) 0.37, 95% confidence interval (CI): 0.16-0.84, 0.017); adjusted HR 0.42, 95%CI: 0.181.00, p=0.051), while a trend suggested a higher incidence of MVI+DSA- diagnosis when missing self was present (HR: 1.43, 95%CI: 0.71-2.89, p=0.313; adjusted HR 1.53, 95%CI: 0.72-3.25, p=0.269). None of NK high functional polymorphisms had a moderating effect on the relation between missing self and biopsy-based diagnostic categories.

These findings suggest that missing self is unlikely to increase the probability of MVI per se. On the other hand, missing self decreases the likelihood of biopsy findings being free of MVI in patients who develop DSA. Given the selected, biopsy-based cohort and the absence of an MVI-DSA- comparison group, these findings are exploratory and require validation in larger, prospectively defined cohorts.