KIR Gene Distribution in Hematologic Disorders.
Authors: Howe Evan C. , Wlodarski Marcin , Ball Edward J. , Maciejewski Jaroslaw P. 
Published: October 2019

Abstract
Killer immunoglobulin-like receptors (KIR) shape the response of NK cells and some CTL. At the genetic level, a KIR mismatch can occur in an individual if the ligand for a particular KIR is absent. The role that such mismatches and certain KIR gene constellations may play in regulation of pathologic immune responses has been rarely explored. It is possible that KIR/HLA combinations can influence disease susceptibility by altering surveillance against microbial agents or transformed cells or by predisposing to autoimmunity. In hematology, KIR/HLA donor/recipient mismatch can influence stem cell transplantation outcome, and dysregulated KIR expression is found in NK cell leukemia. Despite progress in understanding the immune pathophysiology of aplastic anemia (AA), the determinants of susceptibility to immune-mediated bone marrow failure remain unknown. We hypothesized that the immunogenetic background of a specific set of KIR and HLA genes could be involved in the pathophysiologic mechanisms (autoimmune CTL and NK response) in these disorders. Since a number of HLA class I alleles serving as ligands for KIR is known, it is possible to examine the frequency of ligand sets among patient populations. When we studied 282 patients with AA, 82 with PNH, 119 with MDS, and 38 with T-LGL leukemia, no difference in the frequency of KIR C1 & C2 and Bw4 & Bw6 ligand contellations was found between these cohorts. Since there is extensive diversity in the number and types of KIR genes carried by individuals in the population, we next compared the KIR profiles in patients typed by sequence-specific primer amplification of 14 KIR genes and 2 pseudogenes (for 3 KIR, allele specific PCR was performed) to control populations (published cohorts and control groups from our laboratory [N=65]). Since KIR can occur in stimulatory and inhibitory forms, the balance between these two KIR types can determine the quality of the effector cell response to specific targets and globally. Therefore, we analyzed the global ratio between activating and inhibitory KIR genes in patients and controls (AA, N=26; MDS, N=36; PNH, N=29 and LGL, N=22), but no significant differences were found. In addition, the frequency of “unopposed” KIR (absent HLA ligand) in patients did not differ. When the prevalence of individual KIR genes was compared, no differences were found between controls and MDS or T-LGL leukemia patients. However, AA and PNH patients had a decrease in KIR-2DS1 and KIR-2DS5 genes: KIR-2DS1 (Control = 35%, AA = 21% (p=.015), PNH = 19% (p=.014)); KIR-2DS5 (Control = 33%, AA = 14% (p=.038), PNH = 12% (p=.027)). To determine whether absence of 2DS1 and 2DS5 was associated with AA and/or PNH, all patients with a PNH clone and those with AA without a detectable PNH clone were compared; no difference in the frequency of these KIR genes was found. The reduced frequency of KIR-2DS1 and -2DS5 in AA and PNH patients suggests that KIR-positive effector cells may be involved in the pathophysiology of these diseases. Several possible mechanisms could be operative. These activating KIR may be involved in the clearing of a hypothetical agent that triggers a pathologic immune response in AA. Alternately, the absence of these genes may simply identify haplotypes that carry the actual disease predisposing genes. The nature of the KIR gene association aside, these results further support the close pathophysiologic relationship of AA and PNH.