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. 2001 May 21;193(10):1159-67.
doi: 10.1084/jem.193.10.1159.

Major histocompatibility complex class I-recognizing receptors are disease risk genes in rheumatoid arthritis

J H Yen  1 , B E Moore, T Nakajima, D Scholl, D J Schaid, C M Weyand, J J Goronzy
Affiliations

Major histocompatibility complex class I-recognizing receptors are disease risk genes in rheumatoid arthritis

J H Yen et al. J Exp Med. .

Abstract

Rheumatoid arthritis (RA) is a heterogeneous syndrome of which a subset of patients develops vascular inflammation. The genetic determinants that confer risk for rheumatoid vasculitis are not known, but patients with vascular complications are known to have an expansion of CD4(+)CD28(null) T cells, a cell population potentially involved in endothelial damage. CD4(+)CD28(null) T cell clones isolated from RA patients with vasculitis were found to express killer cell immunoglobulin-like receptors (KIRs) with the stimulatory KIR2DS2 often present in the absence of opposing inhibitory receptors with related specificities. To test the hypothesis that the KIR2DS2 gene is involved in the development of vasculitis, association studies were performed. The KIR2DS2 gene was significantly enriched among patients with rheumatoid vasculitis compared with normal individuals (odds ratio 5.56, P = 0.001) and patients with RA but no vasculitis (odds ratio 7.96, P = 0.001). Also, the distribution of human histocompatibility leukocyte antigen (HLA)-C, the putative ligand for KIRs, was significantly different in patients with rheumatoid vasculitis in comparison with the control populations. These data suggest that HLA class I-recognizing receptors and HLA class I genes are genetic risk determinants that modulate the pattern of RA expression. Specifically, KIR2DS2 in conjunction with the appropriate HLA-C ligand may have a role in vascular damage by regulating CD4(+)CD28(null) T cells.

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Figures

Figure 1
Figure 1
CD4+CD28null T cells express MHC class I–recognizing receptors. Peripheral blood CD4 T cells were analyzed by three-color flow cytometry for the expression of MHC class I–recognizing receptors. A representative experiment from a patient with rheumatoid vasculitis is shown. CD158b (encompassing KIR2DS2, KIR2DL2, and KIR2DL3) was exclusively expressed on CD28null but not on CD28+CD4+ T cells. CD158a (KIR2DS1 and KIR2DL1) was infrequently expressed and high expression of CD94/NKG2 dimers was absent (data not shown). Background staining with isotype-matched control antibodies is shown as shaded areas.
Figure 2
Figure 2
Repertoire of MHC class I–recognizing receptors expressed by CD4 T cells. CD4+CD28null T cell clones established from three patients with rheumatoid vasculitis (top panel) and three controls were characterized for the expression of inhibitory (A) and stimulatory KIR (B) isoforms by RT-PCR. Two controls were healthy individuals (middle panel), one had an acute coronary syndrome (bottom panel). The expression patterns were not random but favored the inhibitory KIR2DL4, KIR2DL2, KIR2DL3, and KIR3DL2. Expression of stimulatory receptors was highly restricted to KIR2DS2 in the patients with RA and the patient with acute coronary syndrome (*not done).
Figure 2
Figure 2
Repertoire of MHC class I–recognizing receptors expressed by CD4 T cells. CD4+CD28null T cell clones established from three patients with rheumatoid vasculitis (top panel) and three controls were characterized for the expression of inhibitory (A) and stimulatory KIR (B) isoforms by RT-PCR. Two controls were healthy individuals (middle panel), one had an acute coronary syndrome (bottom panel). The expression patterns were not random but favored the inhibitory KIR2DL4, KIR2DL2, KIR2DL3, and KIR3DL2. Expression of stimulatory receptors was highly restricted to KIR2DS2 in the patients with RA and the patient with acute coronary syndrome (*not done).
Figure 3
Figure 3
Coexpression of MHC class I–recognizing receptors on CD4 T cell clones. KIR2DS2+ T cell clones from Fig. 2 were analyzed for the coexpression of the inhibitory KIR2DL2 and KIR2DL3 receptors, which have a highly homologous extracellular domain to KIR2DS2 and which may recognize the same HLA-C ligands. Approximately one-third of the clones in the patients with rheumatoid vasculitis or acute coronary syndrome (ACS) expressed the stimulatory KIR2DS2 receptor unopposed by any of these two inhibitory receptors whereas such clones were not found in the CD4+CD28null control T cell clones from the healthy individuals.
Figure 4
Figure 4
Costimulatory function of KIR2DS2. A CD4+CD28null T cell clone that expressed KIR2DS2 but not KIR2DL2 or KIR2DL3 was unstimulated (A) or stimulated with an optimal concentration of anti-CD3 (B), suboptimal concentration of anti-CD3 (C), GL183 alone (D), a suboptimal concentration of anti-CD3 plus control Ig (E), or plus GL183 (F). Cells were harvested after 18 h and transcription of IFN-γ was assessed by RT-PCR. Results are representative of three experiments and are shown in comparison with β-actin transcripts after separation on agarose gels (top panel) or as mean ± standard deviation of IFN-γ transcripts after semiquantification on a Light Cycler.
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