KIR Effects in Autoimmune and Inflammatory Diseases

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Historically, the most robust disease associations with the highly polymorphic HLA class I/class II loci have been autoimmune in nature, and only very few infectious diseases have shown strong, consistent HLA associations (Cooke and Hill 2001; Gao et al. 2001). It would not be surprising if the strongest effects of KIR variation were also observed in autoimmune diseases. Some previously determined HLA associations with autoimmune diseases might actually be explained by synergistic interactions between KIR and alleles encoding their HLA class I ligands. An obvious hypothesis in this regard is that KIR genotypes expected to confer relatively strong activation to effector cells increase the risk of autoimmune disease. On the other hand, NK cell activation may be protective against some autoimmune disorders by suppressing or eliminating dendritic cells and monocytes (Shah et al. 1985; Gilbertson et al. 1986; Djeu and Blanchard 1988; Chambers et al. 1996; Geldhof et al. 1998; Carbone et al. 1999), cells known to stimulate the generation of cytotoxic T lymphocytes. NK cell activation may also confer protection by participating in clearance of the microorganisms that are instrumental in initiating autoimmunity. A rather substantial body of evidence has indicated deficiencies in NK cells (i.e., decreased numbers and activity) in several autoimmune diseases, including systemic lupus erythematosus (SLE), multiple sclerosis, and type 1 diabetes (reviewed in Baxter and Smyth 2002). It is not so clear whether the depressed NK cell activity observed among individuals with these autoimmune diseases is a cause or an effect of the disease, but given this phenotypic association, it will be of interest to test for potentially beneficial effects of activating KIR on these diseases.

A number of studies have investigated KIR expression in rheumatoid arthritis (RA). The frequency of CD8+ cells expressing CD158a (this specificity includes both KIR2DL1 and its activating counterpart, KIR2DS1) was decreased among patients with RA relative to healthy controls, and there was significantly less IL-2-induced upregulation of CD158a+ CD16+ cells from RA patients relative to healthy controls (Kogure et al. 2001). In another study of RA patients, KIR2DS2 expression in the absence of inhibitory KIR was observed on CD4+ CD28nuU T cells, expansion of which is characteristic in this disease (Namekawa et al. 2000). Antibodies to both KIR2DL1 and KIR2DL3 (which should also recognize KIR2DS1 and KIR2DS2) were identified in sera of some RA patients, as well as patients with SLE and Behcet disease (Mat-sui et al. 2001) but not in healthy donors, a situation that could disrupt an appropriate balance between effector cell inhibition and activation. Collectively, these studies raised the possibility that abnormal KIR expression may be involved in development of RA.

RA was also the first disease in which an effect of KIR genotype was observed. In a subset of RA patients with vascular complications, KIR2DS2 molecules were frequently observed on CD4+CD28nuU T cells, a cell type thought to be involved in endothelial damage (Yen et al. 2001) and expansion of which is particularly high in RA vasculitis patients (Martens et al. 1997). These investigators went on to show a significant increase in the genomic presence of KIR2DS2 among patients with RA vasculitis relative to either healthy controls or patients with RA in the absence of vasculitis. Because KIR2DS2 binds group 1 HLA-C alleles (those with N80), the association between KIR2DS2 and RA vasculitis should theoretically increase with the additional presence of HLA-C group 1. Although the HLA-C group 1 allele HLA-Cw*03 frequency was increased among RA vasculitis patients, this was not a general pattern for all group 1 alleles (indeed, HLA-Cw*07, another group 1 allele, showed borderline protection against vasculitis, and HLA-Cw*05, a group 2 allele that does not bind KIR2DS2, showed significant susceptibility to vasculitis) (Yen et al. 2001). Sample size limited the power of these analyses (n=30 for RA vasculitis), so an association between RA vasculitis and group 1 alleles as a whole cannot be ruled out, but the investigators alluded to the interesting possibility that KIR2DS2 may recognize HLA-Cw*03 in the context of a specific epitope generated in the disease process, rather than nonspecif-ically binding the entire set of group 1 allotypes. This is conceivable, given previous observations of peptide specificity in KIR binding to HLA class I ligand (Peruzzi et al. 1996a,b; Mandelboim et al. 1997; Rajagopalan and Long 1997; Zappacosta et al. 1997; Hansasuta et al. 2004).

The presence of CD4+CD28nuU T cells in the inflammatory infiltrate of atherosclerotic plaques has implicated these cells in acute coronary syndromes (ACS) as well (Nakajima et al. 2003). As in RA vasculitis, CD4+CD28nuU T cells from ACS patients express KIR2DS2, conveying the ability of these cells to kill in the absence of T cell receptor triggering. These studies, along with others, highlight the influence of KIR molecules expressed on T cell subsets in disease pathogenesis.

KIR2DS2 is in strong LD with KIR2DL2 (and therefore negative LD with KIR2DL3) and is rarely found on a KIR haplotype in the absence of KIR2DL2 (see Fig. 2) among individuals of European descent. Nevertheless, the unusual KIR profile, KIR2DS2+/KIR2DL2-, was observed at a frequency of nearly 12% among a group of German scleroderma patients (relative to 2% in controls) (Momot et al. 2004). All other activating KIR tested were also found at ahigher frequency in the patient group compared to controls (although generally not significantly), except for KIR2DS4, which is always present on A haplotypes. KIR2DS2 in combination with HLA-C group 1 alleles also appears to be more frequent among individuals with type 1 diabetes (van der Slik et al. 2003), putting this gene in contention for the autoimmune KIR variant, as has been described for the HLA haplotype HLA-A1-B8-DR3.

We previously reported increased susceptibility to developing psoriatic arthritis (PsA) in the presence of the activating KIR2DS1 and/or KIR2DS2, most notably when ligands for the corresponding homologous inhibitory KIR were missing (Martin et al. 2002b). For example, individuals with KIR2DS1 were most strongly associated with PsA when KIR2DL1 ligands, HLA-C group

2, were absent. The same situation was true for KIR2DS2 in the absence of HLA-C group 1. This suggested that the absence of ligands for inhibitory KIR might lower the threshold for effector cell activation, increasing the risk of a potentially harmful activating signal (Fig. 3a). Any inhibitory KIR-HLA interaction, however, could potentially provide counteracting inhibition to an activating signal, including one that occurs through a heterologous inhibitory KIR relative to the activating KIR in question. Thus an activating KIR, such as KIR2DS1, might be detrimental in terms of developing PsA if the ligand for either KIR2DL1 or KIR2DL2/3 is missing (i.e., in homozygotes for either group of HLA-Cw ligands). NK cells are kept in check through constitutive dominant inhibitory receptors for class I ligands (Ljunggren and Karre 1990; Valiante et al. 1997), and effector functions occur only when activating signals outdo inhibitory signals (Cerwenka and Lanier 2001; Diefenbach and Raulet 2001; Lanier 2001a,b). This can be achieved either by enhanced activating receptor-ligand interactions, which are expected when activating KIR are present, or by weak inhibitory receptor-ligand interactions that impart a low threshold for activation, which are expected when ligand for inhibitory KIR are missing (unlike KIR2DS1 and KIR2DS2, inhibitory KIR2DL1 and KIR2DL2/3 are virtually always present) (Lanier 2001a). Based on this line of thought, we proposed a second model in which susceptibility to PsA increases progressively with increasing levels of KIR-mediated activation of NK cells as defined by the presence of KIR2DS1 and/or KIR2DS2 and homozygosity for HLA-C group 1 or 2 (Fig. 3b) (Nelson et al. 2004). The data showed a highly significant trend where compound activating KIR/HLA genotypes conferred the greatest level of susceptibility to PsA and, alternatively, genotypes associated with most inhibition were most protective. The PsA studies underscore the need to continually pursue credible models for the effects of KIR/HLA on disease, a process that will remain dynamic as long as KIR biology continues to unfold.

The involvement of KIR genotype in PsA, an inflammatory arthritis occurring in a subset of patients with psoriasis vulgaris (PV) (Gladman and Rahman 2001), raises the question as to whether KIR genotype specifically affects the development of arthritis in psoriasis patients or of psoriasis itself. Typing for the presence/absence of 14 KIR genes in a group of 96 Japanese PV patients revealed an increased frequency of KIR2DS1, a gene that was also associated with PsA (Suzuki et al. 2004). Other genes commonly found on B haplotypes were also found with increased frequency in these patients, a finding that is meaningful despite the small control sample studied (n=50) because the A haplotype frequency is exceptionally high in the Japanese population (Yawata et al. 2002). A strong association of KIR2DS1 with PV was also reported in a Polish cohort (Luszczek et al. 2004). These data suggest that

Fig. 3 Influence of KIR2DS and HLA-Cw group on PsA. a Old model: Frequency of individuals i with 2DS1 and/or 2DS2 who do not have ligand for the corresponding inhibitory KIR (upper bars), ii with 2DS1 and/or 2DS2 and ligand for the corresponding inhibitory KIR (middle bars), and iii missing both 2DS1 and 2DS2 (lower bars). (P for trend=2x10"5). b New model: There is a trend toward decreasing susceptibility to PsA with genotypes conferring decreasing KIR-mediated NK cell activation (going from upper bars to lower bars). C group hom refers to individuals who have two copies of group 1 alleles or two copies of group 2 alleles. C group het refers to individuals who are heterozygous for a group 1 and a group 2 allele. (P for trend=2x10-7)

Fig. 3 Influence of KIR2DS and HLA-Cw group on PsA. a Old model: Frequency of individuals i with 2DS1 and/or 2DS2 who do not have ligand for the corresponding inhibitory KIR (upper bars), ii with 2DS1 and/or 2DS2 and ligand for the corresponding inhibitory KIR (middle bars), and iii missing both 2DS1 and 2DS2 (lower bars). (P for trend=2x10"5). b New model: There is a trend toward decreasing susceptibility to PsA with genotypes conferring decreasing KIR-mediated NK cell activation (going from upper bars to lower bars). C group hom refers to individuals who have two copies of group 1 alleles or two copies of group 2 alleles. C group het refers to individuals who are heterozygous for a group 1 and a group 2 allele. (P for trend=2x10-7)

the KIR associations observed in PsA maybe attributable to psoriasis overall, a possibility that should be pursued further by testing the KIR-PsA model described above (Nelson et al. 2004) in the Japanese and Polish data sets.

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  • hildifons
    Do kir effect disease?
    4 years ago

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