Understanding the role of natural killer cell receptors and their human leukocyte antigen ligands in multiple sclerosis.

Multiple sclerosis (MS) is a complex, multifactorial autoimmune disease causing tissue injury of the central nervous system. Although the etiology of MS is unknown, a genetic-environmental interaction is believed to negatively influence immunoregulation, which results in destruction of myelin and/or oligodendrocytes. Although the precise role of innate immunity in the pathogenesis of MS is unclear, several lines of evidence suggest that natural killer (NK) cells might contribute to susceptibility and/or protection from disease or disease progression. NK cells are highly versatile, critical regulators of innate and adaptive immunity. The multifunctional NK cells act as cytotoxic effectors and/or cytokine producers and regulators, engaging with macrophages, T cells, B cells, dendritic cells, and endothelial cells to control the immune response. NK cells can respond to (eg, interleukin [IL]-2, IL-12, IL-15, IL-21) or secrete (eg, interferon, tumor necrosis factor) an array of cytokines in the inflammatory response. NK cells have long been associated with an immunoregulatory role in susceptibility to or protection from autoimmune disease. Studies in animal models and humans suggest a role for NK cells, through cytotoxicity or immunoregulatory cytokine activity in self tissues, resulting in downregulation of MS disease progression or increased susceptibility and disease severity in conjunction with particular cytokines. The NK cells appear to play a pivotal role in the maintenance of a tuned immune response versus one that is autoimmune. The diverse NK population activity is regulated by different receptor systems that facilitate recognition of infectious disease pathogens and tumors. The evolutionarily younger and highly diverse killer immunoglobulin-like receptors (KIRs) work in conjunction with the older and more conserved lectin-like NKG2 cell surface receptor family to modulate the immune response. The KIR genes code for stimulatory or inhibitory receptors, which vary in number and allelic composition among individuals (Fig 1). Likewise, the KIR gene products are present to varying degrees on the surface of NK and several subsets of T cells, and act in concert to mediate NK cell and T-lymphocyte activation. Cognate ligands for the inhibitory KIRs are the ubiquitously expressed human leukocyte antigen (HLA) class I molecules, whereas ligands for the stimulatory KIRs are for the most part unknown. Recent analysis suggests that certain KIR and HLA class I ligand combinations may impact predisposition to several autoimmune diseases, including psoriatic arthritis, ankylosing spondylitis, type I diabetes, and Crohn disease, among others. The report by Lorentzen et al in this issue of Annals of Neurology is the first study to address the question of the role of KIRs and their HLA ligands in the development of MS. The study by Lorentzen and colleagues is population-based, using a large and clinically welldocumented Norwegian cohort of 631 MS patients (female:male ratio, 2.6) and 555 healthy control (female: male ratio, 1.9) samples from a bone-marrow donor registry. They found a significant deficit of HLA Bw4 in patients (odds ratio 1.76; pcorrected 3.2 10 ), independent of known HLA DRB1 associations. Thus, the presence of Bw4 appears to confer protection from MS in this population. The Bw4 specificity is defined by an isoleucine or threonine residue at position 80 in the C-terminal region of the alphahelix of HLA-B (and some alleles of HLA-A); Bw4 is part of a dimorphism in this region (Bw4/Bw6) that is present in all human populations and believed to be maintained by balancing selection. The authors have carefully adjusted for linkage disequilibrium to the well-known DRB1 risk factors. They have not, however, rigorously distinguished between an HLA-B allele effect and an NK receptor ligand (Bw4) effect. HLA Bw4 is the cognate ligand for the inhibitory receptor KIR3DL1, and in humans, recognition of self HLA-Bw4 helps to confer functional competence, or “licensing”, of NK cells with KIR3DL1 receptors. In this case, the NK cells with self-HLA Bw4 receptors may be licensed, that is, more readily activated, as compared to NK cells without self-HLA–specific receptors (unlicensed). A deficit in HLA Bw4 could thus decrease the functionality of NK, resulting in a diminished response to infectious disease, and increased susceptibility to MS. For example, Bw4 homozygotes provide very strong protection against human immunodeficiency virus infection compared with Bw4/Bw6 heterozygotes or Bw6 homozygotes. In addition to these effects, differences in affinity between the many Bw4 and KIR3DL1 allelic pairs could also influence the functional outcome. In the Lorentzen study, the KIR3DL1 locus was found at a slightly higher frequency in patients compared with controls. However, the many KIR3DL1 allelic variants have different expression patterns and abilities to recognize HLA-Bw4 ligand, with significant potential to effect disease, as for example found in the KIR3DL1/