Sepsis is a syndrome with hyperactivity of TH17-like innate immunity and hypoactivity of adaptive immunity
SSepsis is a syndrome with hyperactivity of TH17-like innate immunity and hypoactivity of adaptive immunity
By Wan-Chung Hu* *Postdoctorate Genomics Research Center Academia Sinica No 128 Academia Road section2 Nangang 115, Taipei, Taiwan
Current Institutes:
Department of Neurology Shin Kong Memorial Hospital Taipei, Taiwan bstract
Currently, there are two major theories for the pathogenesis of sepsis: hyperimmune and hypoimmune. Hyperimmune theory suggests that cytokine storm causes the symptoms of sepsis. On the contrary, hypoimmune theory suggests that immunosuppression causes the manifestations of sepsis. By using microarray study, this study implies that hyperactivity of TH17-like innate immunity and failure of adaptive immunity are noted in sepsis patients. I find out that innate immunity related genes are significantly up-regulated including CD14, TLR1,2,4,5,8, HSP70, CEBP proteins, AP1(JUNB, FOSL2), TGF-β, IL-6, TGF-α, CSF2 receptor, TNFRSF1A, S100A binding proteins, CCR2, formyl peptide receptor2, amyloid proteins, pentraxin, defensins, CLEC5A, whole complement machinery, CPD, NCF, MMP, neutrophil elastase, caspases, IgG and IgA Fc receptors(CD64, CD32), ALOX5, PTGS, LTB4R, LTA4H, and ICAM1. Majority of adaptive immunity genes are down-regulated including MHC related genes, TCR genes, granzymes/perforin, CD40, CD8, CD3, TCR signaling, BCR signaling, T & B cell specific transcription factors, NK killer receptors, and TH17 helper specific transcription factors(STAT3, RORA, REL). In addition, Treg related genes are up-regulated including TGFβ, IL-15, STAT5B, SMAD2/4, CD36, and thrombospondin. Thus, both hyperimmune and hypoimmune play important roles in the pathophysiology of sepsis.
Introduction
Despite of the discovery of antibiotics, mortality rate of sepsis is still very high. Most important of all, the exact pathophysiology of sepsis is still unclear. Currently, there are two dominant theory to explain the etiology of sepsis: hyperimmune theory and hypoimmune theory. However, these two theories are contrary with each other. Hyperimmune theory was proposed by Dr. Lewis Thomas. In his classical paper in NEJM 1972, he proposed that hyperactivation of proinflammatory cytokines, the cytokine storm, is the actual cause of sepsis symptoms. These uncontrolled cytokines destruct and cause multiple organ failure. His theory is the mainstream theory of sepsis etiology. Based on this theory, therapeutic strategy such as antibody neutralizing TNFα was tested in septic patients in clinical trials. However, these antibodies did not improve the survival rate of septic patients. Further, anti-TNFα increased the mortality rate of septic patients in several clinical trials. That makes people to doubt the hyperimmune theory. Thus, another theory-hypoimmune theory emerges. Based on the observation that immunosuppressive patients are prone to get sepsis, hypoimmune status was suggested to be the etiology of sepsis. However, the hypoimmune theory cannot successfully explain the proinflmmatory cytokines torm noted in sepsis. Both hyperimmune theory and hypoimmune theory have clinical and experimental evidences. However, they are contrary with each other. Here, I use the microarray study of whole blood of septic patients to propose a new theory: Sepsis is a syndrome of hyperactivity of innate immunity and hypoactivity of adaptive immunity. This new theory solves the above controversy.
Material and Methods
Results
RMA analysis of whole blood from healthy normal control The RMA analysis was performed for RNA samples from whole blood of healthy ontrol of the lung adenocarcinoma dataset. Raw boxplot, NUSE plot, RLE value plot, RLE-NUSE multiplot, and RLE-NUSE T2 plot were generated. Then, sample was included and excluded by using these graphs(Figure 1A, 1B, 1C, 1D, 1E). Because of the strong deviation in the T2 plot, the sample GSM506435 was removed for the further analysis. RMA analysis of whole blood from septic patients The RMA analysis was performed for RNA samples from whole blood of sepsis patients dataset. Raw boxplot, NUSE plot, RLE value plot, RLE-NUSE multiplot, and RLE-NUSE T2 plot were generated. Then, sample was included and excluded by using these graphs(Figure 2A, 2B, 2C, 2D, 2E). GSM265024 and GSM265030 are removed due to above criteria. Toll-like signaling and heat shock protein expression in septic patients According to the microarray analysis, Toll-like receptors 1, 2, 4, 5, 8 are up-regulated in sepsis.(Table 1) CD14 molecule and downstream signaling such as IRAK4 and TAB2 are also up-regulated. TLR1, 2, 4, 5, 8 are mediating anti-bacterial immune response. Thus, TH17-like proinflamatory cytokines such as IL-6 will be triggered. However, the egative TLR regulator-IRAK3 is 21 fold up-regulated. Thus, TLR 1, 2, 4, 5, 8 signaling may not successfully trigger proinflammatory cytokines. Other pathway such as CD14 may act as an important alternative pathway to trigger IL-6 and other TH17-like cytokines. Other pattern recognition receptors such as formyl peptide receptors (FPR)which can recognize specific bacterial antigen to trigger innate immunity are also differentially expressed. FPR1 is 7.6 fold down-regulated, but FPR2 is 4.7 fold up-regulated. In table 2, we can see that many heat shock protein genes are up-regulated. Fever is a usual manifestation of sepsis. Thus, it is not surprising that heat shock proteins are expressed during sepsis. Among them, heat shock protein 70 (HSPA1A/1B) is 7 fold up-regulated. HSP70 can bind to TLR4 to trigger anti-bacterial TH17-like innate immunity. It is worth noting that HSP90AA1 is 13 fold down-regulated. HSP90 can bind to steroid receptor and prevent its action. If HSP90 is down-regulated, the action of steroid cannot be stopped. Thus, steroid related immune regulatory effect may be initiated during sepsis. Antigen processing and antigen presentation genes in sepsis In table 3 and table 4, we can see many cathepsin and proteasome genes are up-regulated. Up-regulated cathepsin genes include CTSA, CTSD, CTSC, CTSG, and TSZ. But, CTSO and CTSW are down-regulated. Cathepsin W (CTSW) is related to CD8 T cell activation.(3) Up-regulated proteasome genes include PSMD13, PSMC6, PSMD12, PSMD5, PSMB6, and PSMD10. Down-regulated proteasome genes include PSMF1, PSMC2, and PSME4, Among them, PSMF1 is a proteasome inhibitor. Both cathepsins and proteasomes are important in the antigen processing pathways. We can see antigen processing after bacterial infection is intact. In table 5, however, we can see all MHC related genes are down-regulated in leukocytes of septic patients. These down-regulated genes include HLA-DPB, HLA-DQA, HLA-DRB, HLA-DOB, HLA-DRA, HLA-DQB, Tapasin, MHC I related transcripts, HLA-B, and HLA-DPA. Among them, HLA-B is more than 11 fold down-regulated. MHC genes are keys to the antigen presentation to trigger adaptive immune reaction such as B cell or T cell activation. Since all the MHC related genes are down-regulated, antigen presentation during sepsis is likely to be impaired. This matches previous observations.(4) TH17-like innate immune transcription factors in sepsis In table 6, many immune related transcription factors are differentially regulated uring sepsis. First of all, many innate immunity related transcription factors are up-regulated in septic patients. These include AP1(JunB and FosL2), NFIL3, ARNT, and CEBP(CEBPA, CEBPG, and CEBPD) genes. Aryl hydrocarbon receptor nuclear translocator(ARNT) plays an important role in the activation of TH17-like innate immunity. CEBP family genes are related to the activity of myeloid cells and granulocytes. CEBP genes are also related to the activation of acute response proteins. In addition, the inhibitor of NFkB, NFKBIA, is down-regulated in sepsis. It means that the activity of NFkB, an key innate immunity mediator, is up-regulated in septic patients. It is worth noting that two important transcription factors: High Mobility Group Box(HMGB) and Hypoxia inducible factor alpha(HIFα) are also up-regulated during sepsis. HMGB, a vital innate immunity mediator, is greater than nine fold up-regulation. STAT1, a key transcription factor for TH1 and THαβ immunity, is down-regulated in sepsis. In addition, TBX21(T-bet), a key TH1 immune response driver, is also down-regulated. (Table 25) In addition, MafB which can suppress IFNαβ in THαβ immunity is up-regulated(5). Other TH2 related key transcription factors such as GATA3 and C-MAF are also down-regulated.(6) It means that TH1, TH2, and THαβ are down-regulated in sepsis. Surprisingly, key TH17 related transcription factors are also own-regulated including REL, STAT3, and RORA.(7) Besides, SOCS3, a negative regulator of the central TH17 transcription factor STAT3, is up-regulated. It means that TH17 helper cells cannot be successfully triggered. On the other hand, Treg and TGFβ signaling are up-regulated including STAT5B, IL-15, SMAD2, and SMAD4.(8, 9) TH17 and Treg associated aryl hydrocarbon receptor nuclear translocator(ARNT) is also up-regulated in sepsis.(10) Thus, Treg cells are likely to be activated in sepsis. This matches the previous observations that Treg cells are up-regulated during sepsis. TH17-like and Treg related cytokines are up-regulated during sepsis In table 7, many TH17-like and Treg related cytokines are up-regulated in septic patients. The whole TGFβ activation machinery is up-regulated including thrombospondin, CD36, and TGFβ itself. TGFA and IL-15 are also up-regulated. Besides, IL-6 is also up-regulated in sepsis. Thus, both key TH17 driven cytokines, TGFβ and IL-6, are activated in septic patients. However, full activation of TH17 helper cells also need a TCR signaling. IL-32, a TH1 related macrophage differentiation factor, is down-regulated.(11) TH22 mediators, IL1A is down-regulated and IL1RN (IL1 receptor antagonist is up-regulated. It means that TH22 is not activated in sepsis. In table 8, cytokine receptors are differentially regulated in sepsis. On the contrary with cytokine, cytokine in a certain immunological pathway is usually down-regulated. Thus, since TH17-like immunity is activated. TGFBR3, IL6R, and IL17RA are all down-regulated. TGFβ receptor 3 is greater than 11 fold down-regulated, and interleukin 6 receptor is greater than 16 fold down-regulated. Treg is also triggered in sepsis, so TGFBR3, IL2RB, and IL7R are also down-regulated. TH1 related cytokine receptors, IFNGR1 and IFNGR2, are up-regulated. TH2 cytokine receptor, IL4R, is also up-regulated. As for THαβ immunity, IFNAR1 is up-regulated but IFNAR2 is down-regulated. TH22 cytokine receptors, IL1R1 and IL1R2, are up-regulated. Thus, TH1, TH2, THαβ, and TH22 are not activated during sepsis. In table 9, important CSF receptors are up-regulated. These include CSF2 (GM-CSF) receptor α and β. GM-CSF can promote the proliferation of monocyte and granulocyte lineages. In table 10, many TNF related genes are differentially regulated. Up-regulated TNF related genes include TNFAIP6, TNFAIP8, TNFRSF1A and TNFSF10. Down-regulated TNF related genes include TNFRSF10C, TNFRSF9, and TNFSF14. TNFRSF1A is the major receptor of TNFα. Thus, both IL-1 receptor and TNFα receptor are up-regulated during sepsis. TNFSF10(TRAIL) is a pro-apoptotic factor, and NFRSF10C is a receptor to prevent TRAIL induced apoptosis. Thus, TRAIL induced apoptosis pathway is activated in sepsis. TNFRSF9(4-1BB) and TNFSF14(CD258) are both important lymphocyte co-stimulatory molecules. Thus, lymphocyte costimulation is likely to be impaired at sepsis. TH17 related chemokine up-regulation during sepsis In table 11, we find out that TH17 related chemokine are up-regulated in septic patients. These chemokines include S100 binding proteins (S100A11, S100A8, S100A9, and S100P), CCR2(neutrophil chemokine receptor), hyaluronan-mediated motility receptor (HMMR), and chemokine-like factor(CKLF). THαβ related chemokine factors such as CX3CR1, XCL1, and XCL2 for NK cell recruitment are down-regulated. TH1 related chemokine factors such as CCL4 and CCR1 for macrophage/monocyte recruitment are also down-regulated. Besides, TH2 chemokine receptor CCR3 for eosinophil recruitment is also down-regulated. It is worth noting that CCR7, the chemokine receptor for central memory T cells, is greater than 5 fold down-regulated in sepsis. Thus, the generation of central memory T cell is likely to be impaired during sepsis. In table 12, many prostaglandin and leukotriene genes are differentially regulated. rostaglandins and leukotrienes are important chemotaxis mediators. The key enzyme: leukotriene A4 hydrolase for synthesizing leukotriene B4, a potent PMN chemoattractant, is up-regulated. Besides, leukotriene B4 receptor is also up-regulated. Besides, the receptor of PGD2, a TH2 related effector molecule, is 10 fold down-regulated. Prostangin D synthetase is also down-regulated. In addition, the gene 15-hydroxyprostaglandin dehydrogenase (HPGD), which is responsible for shutting down prostaglandin, is 16 fold up-regulated. Key molecules including phospholipase A 2 and arachidonate 5-lipoxygenase to initiate leukotriene synthesis are also up-regulated in sepsis. Th17-like innate immunity related effector molecule up-regulation in sepsis In table 13, many acute response proteins are up-regulated. These acute phase proteins are up-regulated by IL-6 and CEBP proteins. These genes include amyloid proteins (APP and APLP2), pentraxin(PTX3), transferrin receptor(TFRC), CLEC (CLEC5A and CLEC1B), and defensins (DEFA1, DEFA1B, DEFA3, and DEFA4). These above proteins are innate immunity effector proteins to attack bacterial antigens non-specifically. Defensin A4 is greater than 6 fold up-regulated. In table 14, the whole set complement machinery, an important effector component f innate immunity, is up-regulated. These include CD59, CD55, C1QB, ITGAM, CR1, CD46, C3AR1, ITGAX, C1QA, C1RL, C5AR1, and CD97. Thus, complement molecules are activated during sepsis. These complement molecules attack bacterial cell walls and membranes to cause their damage. However, complements may also cause harmful effect to the host. In table 15, certain genes related to PMN phagocytosis and bacteria killing are up-regulated. Neutrophil cytosolic factor 1&4, the subunit of NADPH oxidase for ingested bacteria killing, are up-regulated in sepsis. Carboxypeptidase D (CPD), which can up-regulate nitric oxide, is also up-regulated during sepsis.(12) Nitric oxide is also a key effector molecule for ingested bacteria killing. CPD is greater than 6.9 fold up-regulated. In table 16, PMN matrix metallopeptidases(MMP) and elastase are up-regulated. These protein enzymes can digest bacterial antigens as well as extracellular matrix. These genes include MMP8, MMP9, MMP25, and ELANE(elastase). In addition, tissue inhibitor of MMP, TIMP2, and serum inhibitors of elastase or proteinase, SERPINA1, SERPINB1, and SERPINB2, are also up-regulated. It means that PMN proteinases are dysregulated. It is worth noting that MMP8 is 32 fold up-regulated and MMP9 is 10 fold up-regulated. In table 17, apoptosis machinery is up-regulated during sepsis. Up-regulated genes nclude casapase3, FAS, caspase5, program cell death 10(PDCD10), caspase 1, caspase4, and TRAIL. Down-regulated genes include CFLAR and FAIM3, both of which are apoptosis negative regulators. Thus, apoptosis is activated at sepsis. It matches previous observations that there is massive leukocyte-lymphocyte apoptosis during sepsis. In table 18, many Fc receptor genes which mediate macrophage and neutrophil phagocytosis are up-regulated. These genes include IgG Fc receptor IIa(FCGR2A), IgE Fc receptor Ig(FCER1G), IgA Fc receptor(FCAR), IgG Fc receptor IIc(FCGR2C), IgG Fc receptor Ib, and IgG Fc receptor Ia/Ic(FCGR1A/1C). Besides, TH2 immunity related IgE Fc receptor Ia is 3.8 fold down-regulated. In addition, THαβ immunity related CD16 IgG Fc receptor expression is unchanged. TH17-related innate immunity is mediated by IgG(IgG2/IgG3) and IgA. Thus, TH17-like innate immunity with enhanced phagocytosis is noted during sepsis. In table 19, many CD molecules are up-regulated or down-regulated during sepsis. These CD molecules are important immune response mediators. Among them, up-regulation of CD36, the thrombospodin receptor, means that TGFβ molecule is also up-regulated. Down-regulated CD2 molecule means that T cell activation pathway is impaired. In addition, down-regulation of CD40 means that activation of antigen presenting cells such as B cells is impaired. Besides, CD24 is usually own-regulated in memory B cells. However, during sepsis, CD24 is strongly up-regulated. Coagulation , glycolysis, acidosis, and vasodilation gene dysregulation in sepsis In table20, many coagulation related genes are dysregulated during sepsis. Actually, disseminated intracellular coagulopathy is a common manifestation of sepsis. Up-regulated coagulation genes include F13A1, F5, F8, GP1BB, PROS1, PLAUR, MCFD2, TFPI, F2RL1, ITGA2B, PDGFC, ITGB3, and THBD. Both coagulation factors and inhibitors are dysregulated in sepsis. The whole glycolytic pathway enzymes are up-regulated during sepsis.(Table21) These include lactate dehydrogenase A, phosphoglycerate kinase 1, pyruvate kinase, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3, hexokinase 2, glycogen phosphorylase, 2,3-bisphosphoglycerate mutase, hexokinase 3, glucose-6-phosphate isomerase, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2, glyceraldehyde-3-phosphate dehydrogenase, enolase 1, and phosphoglycerate kinase 1. In addition, the enzyme, pyruvate dehydrogenase kinase, which can stop pyruvate to form acetyl-CoA is up-regulated. The enzyme, pyruvate dehyrogenase phosphatase, which can facilitate pyruvate to form acetyl-CoA to enter aerobic citric cid cycle is down-regulated in sepsis. Thus, pyruvate can keep on forming lactate in anaerobic pathway during sepsis. Concurrently, H + -ATPases are also up-regulated during sepsis(Table22). In my previous article(paper in press), I find out the coupling between glycolytic enzymes and H + -ATPases during falciparum malarial infection. Here, I also find out up-regulated H + -ATPases including ATP6V0B, ATP6V0E1, ATP6AP2, ATP6V1C1, TCIRG1, ATP6V1D, ATP11B, and ATP11A. Besides, carbonic anhydrase IV & II, which can produce H CO , are up-regulated in sepsis. Thus, this can help to explain the acidosis during sepsis. Hypotension is a complication of sepsis. Septic shock is related to global vasodilation. In table 23, several key vasodilation genes are up-regulated. These genes including angiotensinase c (PRCP), adrenomedullin(ADM), and monoamine oxidase A(MAO-A). Angiotensin is a very strong vasopressor, and angiotensinase can metabolize angiotensin to inhibit its function. Adrenomedullin is a potent vasodilator. MAO-A can metabolize three key endogenous vasoconstrictors: dopamine, epinephrine, and norepinephrine. Thus, elevated MAO-A can prevent the effect of hypertensive agents. Thus, the findings can help to explain the etiology of septic shock. Failure of NK, B, T lymphocyte adaptive immunity during sepsis Lymphocytes play important roles in adaptive immunity. In sepsis, the three major lymphocyte populations: NK cells, T cells, and B cells are all down-regulated. Thus, lymphocyte adaptive immunity fails to induce during sepsis. This is very important is sepsis pathogenesis. In table 24, majority of NK cell related genes are down-regulated including NK cell killer receptors (NKTR, KLRK1, LAIR2, KLRD1, KLRG1, KLRB1, and KLRF1), granzymes (GZMA, GZMK, GZMB, and GZMH), and perforin (PRF1). Thus, NK lymphocytes are inactivated or even suppressed during sepsis. NK cells are very important in THαβ immunity, and it also implies that THαβ immunity is inhibited during sepsis. In table 25, many T cell related genes are also down-regulated. These down-regulated genes include TCR genes(TRAC, TARP, TRBC1/C2, TRD@, TRGC2, and TRDV3), CD costimulatory molecules(CD3E, CD8A, CD3G, LY9, CD3D,CD2), T cell specific transcription factors(IKZF1, TCF7, NFAT5, NFATC3, TCF7L2, NFATC2IP, TBX21, ID2, and ID2B), granzyme/perforin (GZMA, GNLY, GZMK, GZMB, GZMH, and PRF1), and TCR downstream signaling(ZAP70 and LCK)(13). Thus, the whole-set of T cell activation machinery is suppressed. Both CD4 helper T cells and CD8 cytotoxic T cells are inactivated and down-regulated in septic patients. n table 25, B cell genes are differentially regulated. Up-regulated B cell related genes include immunoglobulin light chain(IGK, IGJ, and IGKV1-5), immunoglobulin heavy chain(IGHG1/G2 and IGHA1/A2), and B cell suppressive transcription factors(BCL6 and IBTK)(14). Down-regulated genes include B cell stimulatory transcription factor (PAX5 and IKZF1), immunoglobulin heavy chain(IGHM), BCR signaling(FYN and LYN), and PI3K signaling(PIK3CB, PIK3IP1, PIK3CG, and PIK3R1)(15-17). The negative regulator of PI3K signaling, PTEN, is 4.6 fold up-regulated. BCL6 and IBTK can inhibit B cell differentiation and activation. PI3K signaling is the downstream stimulatory pathway of B cell activation. Thus, BCR signaling appears to be suppressed during sepsis. Although Ig light chain and IgA/IgG2 are up-regulated, this may be due to the isotype switch effect of up-regulated immunosuppressant TGF-β. The key immunoglobulin, IgM, for bacteria defense is down-regulated. It implies that B cell adaptive immunity is also impaired at sepsis. Discussion Despite of current antibiotics treatment, sepsis still causes a very high mortality. The pathophysiology of sepsis is still unclear.(18, 19) The most dominant theory for sepsis mechanism is hyperimmune.(20) Hyperimmunity with cytokine storm was observed n sepsis by Dr. Lewis Thomas.(21) He suggested the symptom and sign in sepsis is due to the overactivity of pro-inflammatory cytokines in a NEJM paper. His theory is widely accepted. Based on his hyperimmune theory, many therapeutic strategies were developed. Most famous approach is the anti-TNF agent in sepsis clinical trials. Because the pro-inflammatory cytokine TNFα is up-regulated in sepsis, use of anti-TNF agent should help to control sepsis. However, the result is opposite. Usage of anti-TNF agent increase the sepsis mortality rate.(22-24) Thus, the sepsis-hyperimmune theory is doubtful. The other sepsis pathophysiology theory emerged. This is the hypoimmune theory. Because immunocompromised patients are prone to develop sepsis, hypoimmune should be related to the cause of sepsis.(25) In addition, massive effector lymphocyte apoptosis, depletion of dendritic cells, and elevated Treg cells are noted during sepsis.(26-30) In previous reports, down-regulation of co-stimulatory molecules and MHC are noted in septic patients.(31) In addition, B cells play important roles in recovery from sepsis status.(32) This hypothesis is not accepted by most scientists because it cannot explain the observed cytokine storm during sepsis. Thus, both theories have some evidence support and both are only partially correct. Thus, the third theory proposed. This is the sequence theory. There is hyperimmune irst during sepsis, and then hypoimmune follows. This theory tried to incoperate both theories. However, it is not clear why there will be such sequential immune response. There is no existing immunological mechanism to explain this sequential effect. Why does the hyperimmune happen first? Why does the hyperimmune become to be hypoimmune? In addition, immunodeficiency patients are easily get sepsis. Then, why do these immunodeficiency patients easily develop hyperimmune status first? Current sepsis theory cannot well explain this. In this study, I use microarray analysis to demonstrate that sepsis is actually a hyperactivity of innate immunity and hypoactivity of adaptive immunity. Thus, it can well explain the co-existence of hyperimmune and hypoimmune. The hypoimmune adaptive immunity explains why immunocompromised patients tend to suffer from sepsis easily. The hyperimmune innate immunity explains why pro-inflammatory cytokine storm is observed at sepsis. The adaptive immune dysfunction with lack of T helper cells is the key to sepsis pathogenesis. Thus, block TH17 related cytokines such as TNFα can further stop the successful generation of TH17 helper cells to initiate adaptive immunity to combat extracellular bacteria. Thus, it can explain why TNF blockade increase the mortality rate of sepsis patients. n the microarray study, I find out evidences to support my theory. The whole blood from septic patients can reflect the leukocyte expression patterns. I find out that innate immunity related genes are significantly up-regulated. These genes include CD14, TLR1,2,4,5,8, HSP70, CEBP proteins, AP1(JUNB, FOSL2), TGF-β, IL-6, TGF-α, CSF2 receptor, TNFRSF1A, S100A binding proteins, CCR2, formyl peptide receptor2, amyloid proteins, pentraxin, defensins, CLEC5A, whole complement machinery, CPD, NCF, MMP, neutrophil elastase, caspases, IgG and IgA Fc receptors(CD64, CD32), ALOX5, PTGS, LTB4R, LTA4H, and ICAM1. I also find out that majority of adaptive immunity genes are down-regulated including MHC related genes, TCR genes, granzymes/perforin, CD40, CD8, CD3, TCR signaling, BCR signaling, T & B cell specific transcription factors, NK killer receptors, and TH17 helper specific transcription factors(STAT3, RORA, REL). In addition, Treg related genes are up-regulated including TGFβ, IL-15, STAT5B, SMAD2/4, CD36, and thrombospondin. Up-regulated regulatory cells during sepsis are also shown in other previous studies. Up-regulated Treg related genes can also suppress the adaptive immunity in sepsis. These all support my sepsis pathogenesis. Sepsis is also related to several complications such as disseminated intravascular coagulation(DIC), hypotension/shock, and lactate acidosis.(33) In this microarray nalysis, I find out that many coagulation related genes are up-regulated during sepsis including factor5, factor8, facto13, protein S, plasminogen receptor, ITGA2B, ITGB3, and thrombomodulin. Thus, it can help to explain the mechanism of DIC during sepsis. Several hypotensive agents are also up-regulated in sepsis including angiotesinase C, adrenomodullin, and MAO-A. This can help to explain septic shock pathophysiology. The whole set of glycolytic enzymes are up-regulated during sepsis including LDHA, PGK1, PKM2, PFKFB3, HK2, PYGL, BPGM, HK3, PDK3, GPI, PFKFB2, GAPDH, and ENO1. In addition, glycolytic enzyme coupled H + -ATPase genes are also up-regulated. These can explain the lactate acidosis noted during sepsis. Bacteria have strategies to suppress host immunity for their survival, especially the adaptive immunity.(34) In conclusion, after knowing the pathogenesis of sepsis, we can develop better preventive and therapeutic agents to control sepsis. The impairment of adaptive immunity could be more important than the overactivation of innate immunity during sepsis. Thus, we may use medications to activate host adaptive immunity such as T helper cells to combat sepsis. In addition, we can also develop therapeutic strategies to cope with sepsis related complications such as DIC, hypotension, and lactate acidosis. Hopefully, the detrimental illness-sepsis will be overcome one day. uthor’s information Wan-Chung Hu is a MD from College of Medicine of National Taiwan University and a PhD from vaccine science track of Department of International Health of Johns Hopkins University School of Public Health. He is a postdoctorate in Genomics Research Center of Academia Sinica, Taiwan. His previous work on immunology and functional genomic studies were published at
Infection and Immunity
Viral Immunology
Malaria Journal
Figure 1A Figure 1-B Figure 1-C Figure 1-D Figure 1-E Figure 2-A Figure 2-B Figure 2-C Figure 2-D Figure 2-E able 1. TLR Probe ID Pvalue Arrow Fold Gene 201743_at 1.37E-04 up 2.176301 CD14 204924_at 1.45E-10 up 3.380896 TLR2 210166_at 9.16E-08 up 2.395743 TLR5 210176_at 0.001131 up 2.073326 TLR1 213817_at 3.14E-13 up 21.0364 IRAK3 219618_at 1.89E-09 up 2.692996 IRAK4 220832_at 4.76E-09 up 5.164016 TLR8 221060_s_at 6.62E-07 up 3.331681 TLR4 212184_s_at 2.03E-05 up 2.61743 TAB2 221705_s_at 8.46E-10 down 2.07506 SIKE1 205118_at 1.05E-10 down 7.612908 FPR1 210772_at 2.06E-08 up 4.776773 FPR2 210773_s_at 2.95E-06 up 4.516464 FPR2 able 2. HSP Probe ID Pvalue Arrow Fold Gene 200598_s_at 4.02E-04 down 2.112279 HSP90B1 200599_s_at 6.27E-04 up 2.143909 HSP90B1 200800_s_at 8.98E-09 up 2.664816 HSPA1A /1B 200941_at 1.29E-10 up 2.175182 HSBP1 200942_s_at 7.06E-08 up 2.197023 HSBP1 202557_at 1.10E-05 up 2.82175 HSPA13 202558_s_at 7.12E-05 up 2.112017 HSPA13 202581_at 1.98E-14 up 7.20045 HSPA1A/1B 202842_s_at 6.81E-06 up 2.73954 DNAJB9 202843_at 8.03E-07 up 2.087716 DNAJB9 206782_s_at 1.21E-09 up 2.374709 DNAJC4 208810_at 3.57E-04 up 2.196654 DNAJB6 209015_s_at 9.66E-09 up 2.548422 DNAJB6 209157_at 1.97E-10 up 2.893105 DNAJA2 210338_s_at 1.85E-05 down 2.06926 HSPA8 211936_at 1.05E-07 up 2.110743 HSPA5 211969_at 3.39E-17 down 13.51482 HSP90AA1 212467_at 1.01E-07 up 3.702917 DNAJC13 212911_at 1.88E-13 up 3.009307 DNAJC16 219237_s_at 2.18E-04 down 2.275608 DNAJB14 able 3. Cathepsin Probe ID Pvalue Arrow Fold Gene 200661_at 6.28E-10 up 2.550876 CTSA 200766_at 3.53E-12 up 3.746886 CTSD 201487_at 7.15E-06 up 2.584763 CTSC 203758_at 4.23E-08 down 2.3372 CTSO 205653_at 1.36E-04 up 3.234722 CTSG 210042_s_at 2.94E-07 up 3.044302 CTSZ 214450_at 2.16E-06 down 2.202781 CTSW able 4. Proteasome Probe ID Pvalue Arrow Fold Gene 201052_s_at 8.16E-06 down 2.218188 PSMF1 201067_at 3.68E-20 down 4.692738 PSMC2 201232_s_at 5.58E-11 up 2.577756 PSMD13 201699_at 2.88E-08 up 4.61153 PSMC6 202352_s_at 1.45E-08 up 2.49783 PSMD12 202353_s_at 1.04E-07 up 2.4536 PSMD12 202753_at 6.55E-08 up 2.001992 PSMD6 203447_at 1.23E-10 up 2.450336 PSMD5 208805_at 6.04E-05 up 2.094127 PSMA6 208827_at 4.41E-09 up 2.513269 PSMB6 212220_at 1.31E-09 down 3.309962 PSME4 219485_s_at 1.85E-07 up 2.271658 PSMD10 able 5. MHC Probe ID Pvalue Arrow Fold Gene 201137_s_at 5.80E-04 down 2.085101 HLA-DPB1 203290_at 2.56E-08 down 5.193201 HLA-DQA1 204670_x_at 6.77E-08 down 2.848446 HLA-DRB1/B4 205671_s_at 1.27E-04 down 2.016965 HLA-DOB 208306_x_at 1.53E-06 down 2.437791 HLA-DRB1 208894_at 8.06E-07 down 2.762713 HLA-DRA 209312_x_at 1.24E-06 down 2.674953 HLA-DRB1/B4/B5 209823_x_at 8.65E-04 down 2.083243 HLA-DQB1 210294_at 7.08E-10 down 2.247553 TAPBP 210528_at 1.28E-05 down 2.565486 MR1 210982_s_at 4.46E-05 down 2.140575 HLA-DRA 211944_at 5.60E-22 down 7.377162 BAT2L2 211947_s_at 9.14E-14 down 4.692785 BAT2L2 211948_x_at 3.66E-28 down 11.74736 BAT2L2 211990_at 5.10E-06 down 3.188215 HLA-DPA1 211991_s_at 1.47E-05 down 2.428313 HLA-DPA1 212384_at 8.83E-15 down 2.983359 HLABAT1 212671_s_at 0.002545 down 2.265915 HLA-DQA1/A2 213537_at 7.83E-05 down 2.338689 HLA-DPA1 214052_x_at 4.45E-14 down 2.404988 BAT2L2 214055_x_at 1.16E-24 down 9.415468 BAT2L2 215193_x_at 2.90E-06 down 2.522364 HLA-DRB1/B3/B4 221491_x_at 1.50E-06 down 2.247077 HLA-DRB1/B3/B4/B5 able 6. Transcription factor Probe ID Pvalue Arrow Fold Gene M97935_MA_at 1.92E-04 down 2.010955 STAT1 201473_at 3.65E-09 up 2.459731 JUNB 201502_s_at 9.16E-07 down 2.364327 NFKBIA 202527_s_at 5.77E-09 up 3.237444 SMAD4 203075_at 3.46E-06 up 2.133481 SMAD2 203077_s_at 4.90E-07 up 2.370214 SMAD2 203574_at 4.37E-10 up 5.176725 NFIL3 204039_at 4.62E-08 up 2.059098 CEBPA 204203_at 9.92E-07 up 2.172468 CEBPG 205026_at 1.66E-09 up 2.20184 STAT5B 205841_at 1.02E-13 up 4.655113 JAK2 205842_s_at 6.01E-07 up 2.878639 JAK2 206035_at 7.43E-10 down 2.106359 REL 206036_s_at 8.46E-12 down 4.746634 REL 206359_at 3.22E-07 up 2.092249 SOCS3 206363_at 9.68E-06 down 2.261549 MAF 208991_at 1.49E-13 down 3.223685 STAT3 209604_s_at 2.74E-19 down 6.546836 GATA3 209969_s_at 2.12E-08 down 4.748202 STAT1 210426_x_at 1.14E-12 down 6.358444 RORA 210479_s_at 5.21E-15 down 7.850211 RORA 212501_at 1.73E-07 up 2.169912 CEBPB 212549_at 7.00E-12 up 2.369991 STAT5B 212550_at 7.19E-10 up 2.522143 STAT5B 213006_at 6.03E-10 up 4.206962 CEBPD 218221_at 1.49E-11 up 2.349603 ARNT 218559_s_at 9.49E-07 up 3.354582 MAFB 218880_at 5.34E-11 up 3.750719 FOSL2 208808_s_at 1.07E-11 up 9.120556 HMGB 200989_at 1.17E-06 up 2.997033 HIF1A able 7. Cytokine Probe ID Pvalue Arrow Fold Gene 201108_s_at 2.84E-06 up 2.858913 THBS1 201109_s_at 3.87E-05 up 3.674066 THBS1 201110_s_at 2.02E-09 up 8.271206 THBS1 203085_s_at 1.57E-08 up 2.327314 TGFB1 203828_s_at 7.88E-05 down 2.130993 IL32 205016_at 8.33E-10 up 4.855893 TGFA 205992_s_at 4.40E-06 up 3.5756 IL15 208114_s_at 7.75E-20 down 5.849659 ISG20L2 208200_at 3.06E-11 down 4.80094 IL1A 212195_at 3.90E-06 up 2.667476 IL6ST 206488_s_at 1.04E-04 up 2.926877 CD36 209555_s_at 2.87E-05 up 3.18128 CD36 212657_s_at 2.96E-07 up 2.31195 IL1RN able 8. Cytokine receptor Probe ID Pvalue Arrow Fold Gene 201642_at 1.42E-09 up 2.315 IFNGR2 202727_s_at 1.44E-08 up 3.323753 IFNGR1 202948_at 5.77E-10 up 6.463163 IL1R1 203233_at 2.36E-10 up 3.270304 IL4R 204191_at 2.98E-07 up 2.05704 IFNAR1 204731_at 7.48E-21 down 11.93166 TGFBR3 204786_s_at 5.23E-19 down 6.864011 IFNAR2 205227_at 2.89E-05 up 2.68359 IL1RAP 205291_at 2.89E-08 down 2.442178 IL2RB 205403_at 1.87E-08 up 6.689801 IL1R2 205707_at 1.73E-09 down 2.408515 IL17RA 205798_at 2.48E-24 down 31.78504 IL7R 205926_at 1.06E-09 down 2.187688 IL27RA 205945_at 1.49E-22 down 16.68902 IL6R 206618_at 4.70E-09 up 12.92154 IL18R1 207072_at 5.22E-08 up 4.927116 IL18RAP 211372_s_at 1.76E-08 up 10.6815 IL1R2 211676_s_at 6.66E-09 up 4.607373 IFNGR1 217489_s_at 2.79E-14 down 3.546462 IL6R able 9. CSF Probe ID Pvalue Arrow Fold Gene 205159_at 1.17E-06 up 2.511396 CSF2RB 210340_s_at 4.36E-10 up 2.295372 CSF2RA able 10. TNF Probe ID Pvalue Arrow Fold Gene 202509_s_at 1.99E-12 down 2.4938 TNFAIP2 206026_s_at 7.48E-06 up 3.620447 TNFAIP6 206222_at 1.55E-06 down 2.076582 TNFRSF10C 207536_s_at 5.06E-07 down 2.86682 TNFRSF9 207643_s_at 3.72E-12 up 2.681254 TNFRSF1A 207907_at 9.40E-17 down 3.895788 TNFSF14 208296_x_at 2.21E-05 up 2.431529 TNFAIP8 210260_s_at 4.11E-05 up 2.505209 TNFAIP8 214329_x_at 1.19E-04 up 2.324046 TNFSF10 able 11. Chemokine Probe ID Pvalue Arrow Fold Gene 200660_at 9.23E-12 up 2.053883 S100A11 202917_s_at 2.79E-12 up 2.617102 S100A8 203535_at 3.98E-16 up 2.584441 S100A9 204103_at 3.51E-09 down 2.364728 CCL4 204351_at 7.20E-04 up 2.155134 S100P 205099_s_at 6.98E-05 down 2.455516 CCR1 205863_at 7.49E-14 up 4.166398 S100A12 205898_at 6.76E-04 down 2.496165 CX3CR1 206337_at 5.73E-08 down 5.099034 CCR7 206366_x_at 1.36E-09 down 3.847104 XCL1 206978_at 7.29E-05 up 2.362277 CCR2 207165_at 6.52E-05 up 2.285972 HMMR 208304_at 4.88E-05 down 3.621386 CCR3 214370_at 5.04E-06 down 2.084171 S100A8 214567_s_at 8.06E-08 down 2.902829 XCL1 /// XCL2 221058_s_at 1.49E-09 up 2.15809 CKLF able 12. PGD LTX Probe ID Pvalue Arrow Fold Gene 203913_s_at 1.26E-08 up 16.54476 HPGD 203914_x_at 3.77E-08 up 14.66064 HPGD 204445_s_at 2.84E-06 up 2.076126 ALOX5 204446_s_at 1.01E-07 up 2.0434 ALOX5 204748_at 0.019719 up 2.109052 PTGS2 205128_x_at 5.85E-07 up 2.664767 PTGS1 207206_s_at 1.59E-04 up 2.531166 ALOX12 209533_s_at 3.14E-10 up 2.619734 PLAA 210128_s_at 9.02E-10 up 2.505719 LTB4R 210145_at 1.51E-12 up 3.476688 PLA2G4A 211548_s_at 4.38E-08 up 12.3211 HPGD 211549_s_at 3.53E-04 up 2.6726 HPGD 211748_x_at 1.56E-06 down 2.033312 PTGDS 214366_s_at 5.17E-10 up 3.681805 ALOX5 215813_s_at 1.01E-08 up 3.363031 PTGS1 215894_at 2.35E-14 down 10.40363 PTGDR 216388_s_at 9.35E-07 up 2.104241 LTB4R 208771_s_at 4.07E-08 up 2.455806 LTA4H able 13. Acute Response Protein Probe ID Pvalue Arrow Fold Gene 200602_at 3.75E-12 up 4.384286 APP 206157_at 8.31E-08 up 3.272863 PTX3 208248_x_at 2.42E-09 up 2.54326 APLP2 208691_at 0.001264 up 2.485756 TFRC 208702_x_at 7.55E-09 up 2.826174 APLP2 208703_s_at 1.26E-07 up 3.047052 APLP2 208704_x_at 1.61E-08 up 2.435629 APLP2 211404_s_at 4.34E-10 up 2.927751 APLP2 214875_x_at 1.32E-08 up 2.761566 APLP2 214953_s_at 8.93E-05 up 2.120433 APP 219890_at 1.43E-12 up 7.827181 CLEC5A 220496_at 2.59E-07 up 3.327139 CLEC1B 205033_s_at 1.17E-05 up 4.788064 DEFA1/A1B/A3 207269_at 2.87E-05 up 6.665461 DEFA4 able 14. Complement Probe ID Pvalue Arrow Fold Gene 200983_x_at 7.97E-09 up 3.370908 CD59 200984_s_at 9.06E-10 up 3.891589 CD59 200985_s_at 4.85E-11 up 6.593943 CD59 201925_s_at 2.14E-07 up 5.613841 CD55 201926_s_at 6.74E-09 up 3.830297 CD55 202953_at 7.01E-06 up 2.526228 C1QB 205786_s_at 5.02E-13 up 4.053864 ITGAM 206244_at 6.06E-12 up 6.759067 CR1 208783_s_at 0.004769 up 2.21095 CD46 209906_at 7.48E-09 up 4.336492 C3AR1 210184_at 1.17E-06 up 2.086657 ITGAX 212463_at 2.34E-09 up 2.845059 CD59 217552_x_at 5.04E-10 up 3.57143 CR1 218232_at 1.52E-08 up 3.972673 C1QA 218983_at 7.83E-08 up 2.636687 C1RL 220088_at 9.13E-08 up 2.491036 C5AR1 202910_s_at 3.42E-07 up 2.255245 CD97 able 15. NO/ NADPH oxidase Probe ID Pvalue Arrow Fold Gene 201940_at 9.58E-11 up 5.886338 CPD 201941_at 1.14E-09 up 5.264568 CPD 201942_s_at 6.35E-08 up 3.362135 CPD 201943_s_at 7.91E-12 up 6.937615 CPD 204961_s_at 7.26E-08 up 2.016737 NCF1/1B/1C 207677_s_at 5.88E-10 up 2.661943 NCF4 214084_x_at 1.31E-08 up 2.251172 NCF1C able 16. MMP Probe ID Pvalue Arrow Fold Gene 203167_at 1.02E-13 up 3.135463 TIMP2 203936_s_at 2.89E-16 up 10.59129 MMP9 206871_at 1.04E-06 up 5.3948 ELANE 207329_at 3.41E-11 up 32.06008 MMP8 207890_s_at 1.30E-11 up 3.108211 MMP25 202833_s_at 2.83E-09 up 2.778271 SERPINA1 204614_at 5.64E-08 up 3.074429 SERPINB2 212268_at 8.64E-11 up 5.643009 SERPINB1 213572_s_at 7.52E-11 up 5.130388 SERPINB1 able 17. Caspase Probe ID Pvalue Arrow Fold Gene 202763_at 1.22E-06 up 2.523658 CASP3 204780_s_at 1.71E-04 up 2.524168 FAS 207500_at 4.39E-06 up 2.385929 CASP5 208485_x_at 1.73E-08 down 2.568559 CFLAR 209508_x_at 1.14E-10 down 2.749778 CFLAR 210564_x_at 1.77E-07 down 2.357083 CFLAR 210907_s_at 7.22E-06 up 2.816621 PDCD10 211316_x_at 3.60E-13 down 3.914512 CFLAR 211317_s_at 1.10E-07 down 2.657199 CFLAR 211367_s_at 7.39E-06 up 2.2941 CASP1 211862_x_at 3.34E-08 down 2.575973 CFLAR 213596_at 4.92E-09 up 3.013394 CASP4 214486_x_at 3.71E-08 down 2.177017 CFLAR 215719_x_at 2.24E-06 up 3.678086 FAS 221601_s_at 1.49E-09 down 4.178467 FAIM3 221602_s_at 2.73E-12 down 3.899111 FAIM3 able 18. Fc receptor Probe ID Pvalue Arrow Fold Gene 203561_at 6.67E-09 up 2.023942 FCGR2A 204232_at 8.21E-11 up 2.713677 FCER1G 207674_at 8.78E-08 up 6.420722 FCAR 210992_x_at 1.24E-07 up 2.313229 FCGR2C 211307_s_at 8.29E-08 up 4.563443 FCAR 211395_x_at 1.20E-06 up 2.139768 FCGR2C 211734_s_at 3.84E-05 down 3.85882 FCER1A 211816_x_at 3.58E-05 up 2.405171 FCAR 214511_x_at 2.07E-05 up 3.075548 FCGR1B 216950_s_at 5.51E-08 up 5.08392 FCGR1A/1C able 19. CD molecule Probe ID Pvalue Arrow Fold Gene 200663_at 7.97E-10 up 2.446524 CD63 201005_at 4.83E-08 up 4.230153 CD9 202351_at 5.59E-10 up 3.163429 ITGAV 202638_s_at 7.74E-08 up 2.891012 ICAM1 202878_s_at 8.07E-06 up 2.265542 CD93 202910_s_at 3.42E-07 up 2.255245 CD97 203645_s_at 2.02E-09 up 9.129274 CD163 204306_s_at 2.48E-06 up 2.098005 CD151 204489_s_at 2.80E-09 up 2.832196 CD44 204490_s_at 3.30E-09 up 2.773283 CD44 204661_at 2.08E-04 down 2.102266 CD52 205173_x_at 8.14E-08 up 3.565981 CD58 205789_at 6.34E-06 up 3.14233 CD1D 205831_at 4.40E-10 down 3.924635 CD2 205988_at 3.64E-19 down 5.606748 CD84 206488_s_at 1.04E-04 up 2.926877 CD36 206761_at 5.72E-06 down 2.026305 CD96 208405_s_at 5.16E-06 up 2.167749 CD164 208650_s_at 7.29E-08 up 4.591438 CD24 208651_x_at 5.17E-10 up 3.761404 CD24 208653_s_at 1.98E-11 up 4.511797 CD164 208654_s_at 3.10E-07 up 5.153189 CD164 209555_s_at 2.87E-05 up 3.18128 CD36 209771_x_at 1.91E-08 up 4.956121 CD24 209835_x_at 3.82E-07 up 2.377499 CD44 210031_at 4.04E-09 down 3.14224 CD247 211744_s_at 7.96E-09 up 3.998247 CD58 211900_x_at 3.47E-14 down 2.437045 CD6 211945_s_at 2.07E-06 up 2.577267 ITGB1 212014_x_at 4.13E-07 up 2.48835 CD44 212063_at 5.59E-07 up 2.205469 CD44 213958_at 2.29E-08 down 2.119745 CD6 215049_x_at 6.80E-09 up 8.964883 CD163 216233_at 3.21E-06 up 4.34145 CD163 216379_x_at 6.81E-09 up 5.765379 CD24 216942_s_at 4.88E-06 up 3.031317 CD58 17523_at 4.41E-13 down 6.665958 CD44 219669_at 1.40E-13 up 34.68958 CD177 222061_at 6.85E-09 up 3.64802 CD58 222292_at 7.05E-11 down 2.150798 CD40 266_s_at 1.78E-10 up 6.956197 CD24 able 20. Coagulation Probe ID Pvalue Arrow Fold Gene 203305_at 2.16E-04 up 2.180403 F13A1 204714_s_at 1.87E-08 up 3.933558 F5 205756_s_at 2.79E-05 up 2.08411 F8 205871_at 7.54E-07 down 3.123419 PLGLA/B1/B2 206655_s_at 2.25E-08 up 5.369561 GP1BB/SEPT5 207808_s_at 6.30E-08 up 2.883896 PROS1 210845_s_at 2.55E-07 up 2.502571 PLAUR 211924_s_at 5.53E-07 up 2.325629 PLAUR 212245_at 6.18E-07 up 2.301938 MCFD2 213258_at 1.07E-06 up 2.352817 TFPI 213506_at 0.002877 up 2.349815 F2RL1 214415_at 1.30E-09 down 5.536361 PLGLB1/B2 214866_at 5.37E-10 up 2.031086 PLAUR 216956_s_at 4.64E-05 up 2.39087 ITGA2B 218718_at 2.79E-10 up 9.385749 PDGFC 204627_s_at 1.30E-06 up 4.180416 ITGB3 203887_s_at 8.66E-09 up 4.530585 THBD 203888_at 4.42E-08 up 2.810682 THBD able 21. Glycolysis Probe ID Pvalue Arrow Fold Gene 200650_s_at 2.02E-09 up 2.710678 LDHA 200737_at 2.94E-11 up 3.17309 PGK1 201030_x_at 9.45E-05 down 2.016562 LDHB 201251_at 2.51E-10 up 2.67251 PKM2 202464_s_at 6.45E-09 up 7.300454 PFKFB3 202934_at 9.80E-14 up 4.768903 HK2 202990_at 2.15E-12 up 4.196534 PYGL 203502_at 1.24E-04 up 3.670577 BPGM 205936_s_at 5.17E-12 up 4.987516 HK3 206348_s_at 9.53E-11 up 2.597892 PDK3 208308_s_at 3.92E-09 up 2.215685 GPI 209992_at 3.99E-09 up 11.77066 PFKFB2 213453_x_at 2.13E-12 up 2.175151 GAPDH 217294_s_at 3.28E-06 up 2.62132 ENO1 217356_s_at 4.20E-08 up 2.028929 PGK1 218273_s_at 1.01E-07 down 2.250674 PDP1 able 22. H-ATPase Probe ID Pvalue Arrow Fold Gene 200078_s_at 6.15E-13 up 2.530917 ATP6V0B 201171_at 4.49E-10 up 2.484021 ATP6V0E1 201443_s_at 5.84E-06 up 2.32877 ATP6AP2 201971_s_at 4.45E-13 down 5.207561 ATP6V1A 202872_at 1.95E-10 up 6.183733 ATP6V1C1 202874_s_at 6.99E-10 up 5.718367 ATP6V1C1 204158_s_at 5.14E-08 up 2.068726 TCIRG1 208898_at 2.66E-09 up 2.413653 ATP6V1D 213587_s_at 1.13E-08 down 2.067119 ATP6V0E2 206208_at 1.00E-11 up 3.51149 CA4 206209_s_at 4.18E-15 up 7.982899 CA4 209301_at 2.78E-06 up 3.422036 CA2 212536_at 4.38E-09 up 4.21056 ATP11B 213582_at 1.89E-08 up 2.241957 ATP11A able 23. Vasodilator Probe ID Pvalue Arrow Fold Gene 201494_at 1.01E-08 up 2.190291 PRCP 202912_at 1.20E-08 up 4.330455 ADM 212741_at 0.004196 up 2.027247 MAOA able 24. NK cell Probe ID Pvalue Arrow Fold Gene 202379_s_at 2.01E-30 down 26.43984 NKTR 205821_at 1.39E-12 down 3.985353 KLRK1 207509_s_at 7.71E-10 down 2.948439 LAIR2 207795_s_at 1.01E-09 down 3.216148 KLRD1 210288_at 1.62E-11 down 5.382525 KLRG1 210606_x_at 1.91E-09 down 3.341239 KLRD1 214470_at 1.11E-04 down 2.103258 KLRB1 215338_s_at 1.06E-24 down 14.54682 NKTR 220646_s_at 1.34E-04 down 2.386466 KLRF1 205488_at 1.01E-05 down 2.867692 GZMA 206666_at 1.84E-07 down 3.446082 GZMK 207460_at 3.78E-09 down 2.502287 GZMM 210164_at 8.91E-09 down 3.75597 GZMB 210321_at 8.94E-10 down 5.800327 GZMH 214617_at 2.22E-06 down 2.646147 PRF1 able 25. T cell Probe ID Pvalue Arrow Fold Gene 205039_s_at 2.79E-08 down 2.22558 IKZF1 205255_x_at 3.09E-08 down 2.955244 TCF7 205456_at 5.31E-08 down 2.877146 CD3E 205488_at 1.01E-05 down 2.867692 GZMA 205495_s_at 5.33E-10 down 4.378694 GNLY 205758_at 1.20E-07 down 3.258815 CD8A 206666_at 1.84E-07 down 3.446082 GZMK 206804_at 1.10E-15 down 5.118528 CD3G 207460_at 3.78E-09 down 2.502287 GZMM 208003_s_at 5.52E-18 down 12.03963 NFAT5 209670_at 5.21E-06 down 2.475029 TRAC 209671_x_at 3.58E-08 down 2.774547 TRAC 209813_x_at 1.49E-09 down 4.424708 TARP 210164_at 8.91E-09 down 3.75597 GZMB 210321_at 8.94E-10 down 5.800327 GZMH 210370_s_at 1.34E-07 down 2.482685 LY9 210555_s_at 1.02E-07 down 2.476832 NFATC3 210556_at 4.68E-08 down 2.850907 NFATC3 210915_x_at 6.23E-06 down 2.847533 TRBC1 210972_x_at 1.78E-07 down 2.875805 TRAC/J17/V20 211144_x_at 5.76E-08 down 3.696107 TARP/TRGC2 211796_s_at 6.35E-06 down 2.926207 TRBC1/C2 211902_x_at 8.99E-07 down 2.286838 TRD@ 212759_s_at 3.98E-16 down 3.926594 TCF7L2 212762_s_at 2.70E-09 down 2.376013 TCF7L2 212808_at 1.21E-21 down 5.549449 NFATC2IP 213193_x_at 2.53E-06 down 2.918569 TRBC1 213539_at 1.00E-08 down 3.193378 CD3D 213830_at 5.93E-08 down 3.51036 TRD@ 214617_at 2.22E-06 down 2.646147 PRF1 215092_s_at 1.36E-09 down 2.475134 NFAT5 215806_x_at 1.02E-08 down 4.078028 TARP/TRGC2 216191_s_at 4.71E-07 down 4.762182 TRDV3 216920_s_at 2.28E-10 down 5.341667 TARP/TRGC2 217143_s_at 1.26E-08 down 6.055404 TRD@ 217526_at 1.43E-12 down 3.846013 NFATC2IP 17527_s_at 2.12E-13 down 5.801224 NFATC2IP 220684_at 7.39E-09 down 2.077709 TBX21 220704_at 2.15E-10 down 5.686157 IKZF1 37145_at 9.67E-10 down 4.340701 GNLY 214032_at 6.60E-08 down 2.523588 ZAP70 204890_s_at 1.65E-07 down 2.638662 LCK 204891_s_at 4.58E-08 down 3.313788 LCK 205831_at 4.40E-10 down 3.924635 CD2 201565_s_at 8.13E-13 down 4.167651 ID2 213931_at 7.33E-08 down 3.546731 ID2/2B able 26. B cell Probe ID Pvalue Arrow Fold Gene 221969_at 9.96E-13 down 4.199424 PAX5 203140_at 3.09E-10 up 3.687249 BCL6 210105_s_at 9.37E-10 down 3.319013 FYN 210754_s_at 2.98E-10 down 3.545109 LYN 205039_s_at 2.79E-08 down 2.22558 IKZF1 211430_s_at 0.015735 up 2.830679 IGHG1/G2 211643_x_at 0.024398 up 2.10616 IGK 212592_at 0.017267 up 2.569312 IGJ 212827_at 0.008027 down 2.240154 IGHM 214677_x_at 0.031357 up 2.035694 IGLV1-44 214768_x_at 0.006798 up 2.374888 IGKV1-5 217022_s_at 5.28E-05 up 5.197489 IGHA1 /A2 210970_s_at 2.98E-06 up 2.298244 IBTK 217620_s_at 4.31E-12 down 2.785986 PIK3CB 221756_at 5.52E-10 down 2.616271 PIK3IP1 204053_x_at 1.57E-06 up 2.560581 PTEN 204054_at 2.56E-10 up 5.50691 PTEN 211711_s_at 2.54E-08 up 4.673204 PTEN 206370_at 2.95E-09 down 2.443374 PIK3CG 212240_s_at 4.29E-13 down 4.50699 PIK3R1 212249_at 1.96E-06 down 2.560644 PIK3R1 eferences 1. Howrylak JA, Dolinay T, Lucht L, Wang Z, Christiani DC, Sethi JM, Xing EP, Donahoe MP, Choi AM. Discovery of the gene signature for acute lung injury in patients with sepsis.
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