Host response to injury and infection is IntroductionSerum amyloid A (SAA) is a major acute-phase protein released to circulation in response to infection and injury. Within the first 24 to 36 hours after infection or injury, the blood concentration of SAA can increase by as much as 1000-fold over basal level, reaching a concentration of 80 M or 1 mg/mL. 1,2 The liver is a major source of acute-phase SAA, but extrahepatic expression of SAA has also been documented and is known to involve cells of atherosclerotic lesions, that is, smooth muscle cells, endothelial cells, and monocytes/macrophages. 3,4 Inflammatory cytokines such as interleukin 1␤ (IL-1␤), tumor necrosis factor ␣ (TNF-␣), and IL-6 are potent inducers of SAA expression by hepatocytes and, to various degrees, by macrophages and synoviocytes. 2,[5][6][7] In circulation, SAA is associated with high-density lipoproteins (HDLs) at lower concentrations, but it dissociates from HDLs at higher concentrations. 8,9 Free SAA is also found in the inflammatory sites, 3,4 suggesting a role of SAA in local inflammation.The marked increase of SAA has been used as an important indicator for diagnosis and prognosis of inflammatory diseases. 7,10 In addition, SAA is implicated as both a beneficial and harmful factor in the inflammatory process. Potential beneficial roles include reverse transport of cholesterol at sites of inflammation, through its ability to displace cholesterol from HDL. 11,12 With respect to being a harmful factor, SAA is the precursor of amyloid A, the deposit of which causes amyloidosis. 7,13 The findings that SAA is produced locally in atherosclerotic lesions and in arthritic joints suggest a potential role of this acute-phase protein in chronic inflammatory diseases such as atherosclerotic and rheumatoid arthritis. [13][14][15] Despite these important findings, a precise function of SAA in acute inflammation has not been defined. It is notable that a number of studies suggest a link between SAA and leukocyte infiltration. SAA is chemotactic to leukocytes including monocytes, mast cells, and T lymphocytes at concentrations attained in the blood during an acute-phase response. [16][17][18] These early observations have led to the recent identification of a cell surface receptor that mediates SAA-stimulated chemotaxis in monocytes. 19 There is also accumulating evidence suggesting that SAA possesses cytokinelike activities and is able to induce the production of matrix metalloproteinases (MMPs), 20 cytokines, and cytokine receptors including IL-1␤, interleukin-1 receptor antagonist (IL-1ra), and soluble TNF-␣ type II receptor (sTNFr-II). 21 Neutrophils that are stimulated by SAA for 24 hours release TNF-␣, IL-1␤, and IL-8 into culture medium. 22 However, it is not clear whether this is a primary response to SAA or a secondary response to other secreted cytokines because of the long incubation time. The receptor that mediates this function of SAA has not been identified.In this study, we investigated whether SAA induces primary cytokine responses i...

• Pembrolizumab was first shown to be clinically active in CLL patients with RT.• PD-1 and PD-L1 expression in tumor microenvironment are promising biomarkers to select RT patients for PD-1 blockade.Chronic lymphocytic leukemia (CLL) patients progressed early on ibrutinib often develop Richter transformation (RT) with a short survival of about 4 months. Preclinical studies suggest that programmed death 1 (PD-1) pathway is critical to inhibit immune surveillance in CLL. This phase 2 study was designed to test the efficacy and safety of pembrolizumab, a humanized PD-1-blocking antibody, at a dose of 200 mg every 3 weeks in relapsed and transformed CLL. Twenty-five patients including 16 relapsed CLL and 9 RT (all proven diffuse large cell lymphoma) patients were enrolled, and 60% received prior ibrutinib. Objective responses were observed in 4 out of 9 RT patients (44%) and in 0 out of 16 CLL patients (0%). All responses were observed in RT patients who had progression after prior therapy with ibrutinib. After a median follow-up time of 11 months, the median overall survival in the RT cohort was 10.7 months, but was not reached in RT patients who progressed after prior ibrutinib. Treatment-related grade 3 or above adverse events were reported in 15 (60%) patients and were manageable. Analyses of pretreatment tumor specimens from available patients revealed increased expression of PD-ligand 1 (PD-L1) and a trend of increased expression in PD-1 in the tumor microenvironment in patients who had confirmed responses. Overall, pembrolizumab exhibited selective efficacy in CLL patients with RT. The results of this study are the first to demonstrate the benefit of PD-1 blockade in CLL patients with RT, and could change the landscape of therapy for RT patients if further validated. This trial was registered at www.clinicaltrials.gov as #NCT02332980. (Blood. 2017;129(26):3419-3427)

Induced secretion of acute-phase serum amyloid A (SAA) is a host response to danger signals and a clinical indication of inflammation. The biological functions of SAA in inflammation have not been fully defined, although recent reports indicate that SAA induces proinflammatory cytokine expression. We now show that TLR2 is a functional receptor for SAA. HeLa cells expressing TLR2 responded to SAA with potent activation of NF-κB, which was enhanced by TLR1 expression and blocked by the Toll/IL-1 receptor/resistance (TIR) deletion mutants of TLR1, TLR2, and TLR6. SAA stimulation led to increased phosphorylation of MAPKs and accelerated IκBα degradation in TLR2-HeLa cells, and results from a solid-phase binding assay showed SAA interaction with the ectodomain of TLR2. Selective reduction of SAA-induced gene expression was observed in tlr2−/− mouse macrophages compared with wild-type cells. These results suggest a potential role for SAA in inflammatory diseases through activation of TLR2.