Background/Purpose: In subjects with lupus nephritis (LN), tissue injury due to local immune activation involving persistently activated macrophages in the renal parenchyma is limited by non-classical natural killer (NK) cells. This protective pathway, based on a genetic effect related to the NK ligand Human Leukocyte Antigen (HLA)-C, was recently shown to limit activation of macrophages and dendritic cells by immune stimuli in vitro. A risk phenotype of HLA Class I, termed the Lys variant, or the C2 epitope or Asn80Lys, rs17408553, leads to a hypo-responsive NK cell which is secondary to high affinity of ligand by variant and an inhibitory NK receptor. The clinical impact of these pathways is understudied; the aim of this study, therefore, is to evaluate associations of clinical outcomes among subjects carrying the risk genotype in two cohorts of SLE patients.

Methods: Patients were included if there was confirmation of a diagnosis of SLE as per the ACR and access to chart review along with DNA for genotyping. There were 2 patient subsets: 96 lupus nephritis (LN) patients who were selected from SLE cohorts from the ALMS trial (27 LN) and the NYU Specimen and Matched Phenotype Linked Evaluation (SAMPLE, 69 LN), and the second subgroup was SLE absent lupus nephritis (NN) (SAMPLE, 33 NN). LN were adjudicated for response to induction therapy and DNA specimens were genotyped at rs17408553 using a Pyrosequencing assay (ADS9525-RS) and the result is reported as minor allelic frequency (MAF). While pyrosequencing is performed in the usual way, it is noteworthy that the PCR fragment of HLA-C containing the rs17408553 SNP was designed to exclude the very similar HLA-B gene by the specificity of the PCR primers, which can be monitored by one nucleic acid that differs between HLA-C and HLA-B within the PCR amplicon.

Results: Demographic characteristics of LN and NN were matched for age, gender, and ethnicity. LN biopsies encompassed all ISN/RPS classes, the majority of which were proliferative forms. For LN, 35% had hypertension, 47% had nephrotic range proteinuria, and a majority were given an induction therapy consisting of steroids plus mycophenolate mofetil. At six months, 14 LN patients were non-responders, 8 were partial responders and 74 were complete responders. For MAF at rs17408553, the C2 allele was enriched in LN patients compared to controls (0.45 vs 0.37, SLE (LN+NN) vs control; OR 1.40, P=0.01). However, for a comparison of LN and NN, the frequencies of C2 were found to be similar (0.45 vs 0.45, LN vs NN, P=1). While LN spot prot/cr ratios were similar in C1/C1 and C2/N groups at the end of induction (3.86 ± 3.02 vs 4.64 ± 3.30, P=0.52), there was an association of an increase in variant allele and LN patients with no response at induction (0.73 vs 0.41, LN non-response vs LN response, P=0.0149). The association of variant at HLA-C and subjects with non-response was observed in both LN cohorts (ALMS trial and SAMPLE).

Conclusion: Using two distinct and well-characterized cohorts, there was an association of variant at HLA-C and subjects with non-response to induction therapy. These data support the speculation that hypo-responsive NK cells adversely influence the course of nephritis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/association-of-the-variant-form-of-rs17408553-at-human-leukocyte-antigen-c-supports-evidence-that-hypo-responsive-natural-killer-cells-adversely-influence-the-course-of-nephritis/