Objective. The expression of autoimmunity in mice deficient in programmed death 1 (PD-1) suggests that PD-1 is a candidate gene involved in the development of human autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). We therefore tested the potential association between PD-1 and the development of SLE and RA by conducting case-control genetic-association studies.Methods. Ninety-eight SLE patients, 84 RA patients, and sex-matched control subjects for each disease group were recruited and genotyped for a singlenucleotide polymorphism, C؉872T, in the human PD-1 gene. The significance of the association of the PD-1 gene with SLE or with RA was analyzed by statistical tests for the difference in genotype distribution between disease and control groups.Results. The human PD-1 gene was found to be significantly associated with disease development in RA patients, but not SLE patients. The risk of RA development appeared to be significantly increased by carriage of the T allele (odds ratio 3.32, P < 0.0001) or the C/T genotype (odds ratio 3.52, P < 0.00005).Conclusion. The PD-1 gene is significantly associated with RA susceptibility, suggesting the possibility that PD-1 may contribute to the pathogenesis of RA.Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are two human autoimmune diseases that are mediated by damaging immune overreactivity to self antigens. Although the pathogenesis of SLE and RA remains unclear, it is possible that dysregulated lymphocyte activation initiates the breakdown of tolerance and predisposes the patient to the development of these autoimmune diseases, because lymphocyte activation appears to be governed by immunostimulatory and immunoinhibitory signals that are delivered through lymphocyte surface receptors. More solid evidence to support this hypothesis comes from the fact that autoimmune diseases can develop in mice that have either an overexpression of a stimulatory receptor or a deficiency of an inhibitory receptor. However, further efforts toward establishing a correlation between each immunoregulatory receptor and human autoimmune diseases are still needed in order to gain more insight into the disease pathogenesis and to develop better therapeutic strategies.Programmed death 1 (PD-1), which was originally identified in a T cell line undergoing activationinduced cell death, is a CD28 family member that contains a cytoplasmic immunoreceptor tyrosine-based inhibitory motif and is expressed on the surface of activated T cells and B cells (1-5). As an immunoinhibitory receptor, PD-1 has been shown to inhibit lymphocyte activation and cytokine production after interacting with its ligands PDL-1 (B7-H1) and PDL-2 (B7-DC) (6-10). The immunoinhibitory function of PD-1 was further supported by the observation that mice deficient in PD-1 expression developed autoimmune diseases, despite having distinct phenotypes on different genetic backgrounds. C57BL/6 mice with PD-1 deficiency had an increased incidence of progressive glomerulonephrit...

Key Points• Highly electronegative LDL (L5), which is elevated in patients with STEMI, induces platelet activation and aggregation through LOX-1.• L5 may have a role in promoting thrombogenesis that leads to STEMI.Platelet activation and aggregation underlie acute thrombosis that leads to ST-elevation myocardial infarction (STEMI). L5-highly electronegative low-density lipoprotein (LDL)-is significantly elevated in patients with STEMI. Thus, we examined the role of L5 in thrombogenesis. Plasma LDL from patients with STEMI (n 5 30) was chromatographically resolved into 5 subfractions (L1-L5) with increasing electronegativity. In vitro, L5 enhanced adenosine diphosphate-stimulated platelet aggregation twofold more than did L1 and induced platelet-endothelial cell (EC) adhesion. L5 also increased P-selectin expression and glycoprotein (GP)IIb/IIIa activation and decreased cyclic adenosine monophosphate levels (n 5 6, P < .01) in platelets. In vivo, injection of L5 (5 mg/kg) into C57BL/6 mice twice weekly for 6 weeks shortened tail bleeding time by 43% (n 5 3; P < .01 vs L1-injected mice) and increased P-selectin expression and GPIIb/IIIa activation in platelets. Pharmacologic blockade experiments revealed that L5 signals through plateletactivating factor receptor and lectin-like oxidized LDL receptor-1 to attenuate Akt activation and trigger granule release and GPIIb/IIIa activation via protein kinase C-a. L5 but not L1 induced tissue factor and P-selectin expression in human aortic ECs (P < .01), thereby triggering platelet activation and aggregation with activated ECs. These findings indicate that elevated plasma levels of L5 may promote thrombosis that leads to STEMI. (Blood. 2013;122(22):3632-3641)

SummaryThe role of naturally occurring regulatory T cells (Treg), known to be phenotypically heterogeneous, in controlling the expression of systemic lupus erythematosus (SLE) is incompletely defined. Therefore, different subpopulations of CD4 + FoxP3 + Tregs in patients with active or inactive SLE were investigated and compared with those of healthy subjects and patients with ankylosing spondylitis (AS). Characterization of different subsets of circulating CD4 + FoxP3 + Tregs was examined using flow cytometry. CD4 + CD25 high T cells were sorted and examined for suppressive activity in vitro. The results showed first that a significant decrease in the frequency of CD4 + CD25 high FoxP3 + T cells was present in patients with active SLE (n = 58), compared with healthy controls (n = 36) and AS patients (n = 23). In contrast, the frequencies of CD25 low FoxP3 + and CD25 ) FoxP3 + CD4 + T cells were significantly increased in patients with active SLE by comparison with the control subjects. The elevation of these two putative Treg subpopulations was associated with lower plasma levels of complement C3 and C4 in patients with SLE. In addition, the ratios of the three subsets of CD4 + FoxP3 + Tregs versus effector T cells (CD4 + CD25 + FoxP3 ) ) were inversely correlated with the titer of antidouble-stranded DNA IgG in patients with inactive, but not active, SLE. These results suggest that the pathogenesis of SLE may be associated with a defect in the homeostatic control of different Treg subsets.