脓毒症免疫炎症反应紊乱机制及治疗对策

Where can we look for markers of immunoparalysis?
Immunoparalysis in the PICU
A state of prolonged immunoparalysis was associated with increased relative risks for the development of adverse outcomes in children with MODS:
The innate immune response and death
Ex-vivo TNF production in patients with sepsis
Hall MW. Pediatric Research 2007;62:597-603
免疫麻痹的发生机制
1.单核细胞分泌细胞因子减少 2.单核细胞人类白细胞抗原DR减少； 3.免疫应答反应类型的转变； 4.细胞凋亡 ：各种免疫活性细胞以及 胃肠道黏膜上皮细胞。
单核细胞人类白细胞抗原DR （HLA-DR）
HLA-DR是抗原呈递细胞处理抗原过程中 主要的参与分子。 单核细胞上HLA—DR表达水平>20％，才能 正常行使细胞免疫功能，而HLA-DR低水平 表达常导致免疫抑制。
ADVANCES IN SEPSIS Vol 4 No 2 2005
Immune Effector Cells in Spleen Tissue
24-48 hours
Early mortality ≈20%
Anti-inflammatory Response
Immunostimulation interventions /Pro-inflammatory drugs ?
Time
Late Mortality ≈80%
In some patients, CARS is pathologically exaggerated and prolonged (beyond 48 hours)→Immunoparalysis
Increased
Th1, Th 17
Decreased
Th2, Treg
Adaptive immune cell types
Simplified description of systemic pro- and anti-inflammatory immune responses over time after septic shock: Time matters!! Pro-inflammatory Response Anti-inflammatory interventions The anti-inflammatory surge is termed the compensatory anti-inflammatory response syndrome (CARS)
细胞凋亡与免疫麻痹
凋亡是基因控制的程序性细胞死亡。
脓毒症时大量的获得性免疫细胞，主要是 淋巴细胞（B细胞、CD4+T细胞）、树突 状细胞以凋亡的形式死亡。 表现为外周血淋巴细胞计数的减少。
清除原发感染的能力遭到破坏,易于发生院内感染
T-cell counts
JAMA, December 21, 2011-Vol 306, No. 23
HLA-DR < 30 % (n = 21)
100 μg Interferon-γ inhalation 3/day x 7 days
Placebo (n = 10) Infection II : 5
50 %
Interferon-gamma (n = 11) Infection II : 1
9% ↑ PAF, phospholipase A2, IL-1β and AM HLA-DR ↓ IL-10
脓毒症免疫功能紊乱机制 及治疗对策
中国人民解放军第309医院重症医学科
张玉想
15810550308@163.com
机体的免疫系统及调节途经
STRESS Physical stress Emotional stress Hypoglycemia Cold exposure Pain Sepsis Trauma Shock Surgery
52 pts with severe trauma (ISS>16) HLA-DR of alveolar macrophages at days 2 or 3 Immunoparalysis was detected in 21 pts (40%) who were older and sicker.
脓毒症可以看作是病原体 与宿主免疫反应之间的竞赛
Opportunistic infections in ICU patients
• CMV infection • HSV infection • Invasive aspergillosis
Viral Infections in Septic Shock (VISS-Trial)– Crosslinks Between Inflammation and Immunosuppression
Annual Review of Immunology, Volume 20 ，2002 (www.annualreviews.org)
Immune effector cells
Immune Function Analysis of Cell Populations
树突状细胞 巨噬细胞 单核细胞 自然 杀伤细胞
Monocyte activation
SEPTIC SHOCK
TNF- IL-1ß IL-6 IL-8 PAF iNOS COX2
IL-1 ra IL-10 sTNFr-1/11 TGF- IL-4
Monocyte deactivation
PROINFLAMMATORY
ANTI-INFLAMMATORY + CELL HYPORESPONSIVENESS /
Assay Methods
（Innate ） 先天性免疫
Flow cytometry, immunohistochemistry
（Adaptive） 获得性免疫
T cells (CD4 and CD8)
免疫麻痹的概念
Tilting toward immunosuppression
Proinflammatory Response
Anti-Inflammatory Response
Characteristic cytokines
TNF α IL-1 β IL-6 IL-8 IL-17
IL-10 TGF β IL-1ra sTNFr
IFN-γ
IL-2
Innate immune function: phagocytosis, intracellular killing, antigen presentation
细胞因子微环境的变化 (IL-12\IL-10), 决定CD4+T细胞的 功能性分化
Th1

TNF-a、IL-2、IFN-r 漂移 IL-4 、IL-10
CD4+T细胞活化 Th2

抑制性细胞因子IL-4 、IL-10进一步增加
免疫麻痹的发生机制
1．单核细胞分泌细胞因子的不 平衡 （抗炎因子产生过多-促炎因子分泌过少） 2．单核细胞人类白细胞抗原DR减少； 3．免疫应答反应类型的转变； 4．细胞凋亡 ：各种免疫活性细胞以及胃肠 道黏膜上皮细胞。
Journal of Surgical Research -, 1–12 (2011)
HSV-1 Thirty-one patients (51.7%)
CMV
16 patients (26.7%)
住院时间 呼吸机应用时间显著延长
Journal of Surgical Research -, 1–12 (2011)
Nakos G et al. Crit Care Med 2002;30:1488-1494
p < 0.05
免疫麻痹的发生机制
1．单核细胞分泌细胞因子的不 平衡 （抗炎因子产生过多-促炎因子分泌过少） 2．单核细胞人类白细胞抗原DR减少； 3．免疫应答反应类型的转变； 4．细胞凋亡 ：各种免疫活性细胞以及胃肠 道黏膜上皮细胞。
JAMA, December 21, 2011-Vol 306, No. 23
JAMA, December 21, 2011-Vol 306, No. 23
WHAT IS THE GUT?
B细胞、CD4+T细胞
Clark et al SHOCK, 2007 384-393,
肠道是MODS的始动器官
脓毒症时间愈长,T细胞和B细胞的缺失愈加 明显,大部分患者死于长期的低免疫状态期。
------《新英格兰医学杂志》 The New England Journal of Medicine 2003; 348: 138-150. 2003; 348: 138- 150.
免疫麻痹的发生机制
1.单核细胞分泌细胞因子减少 2.单核细胞人类白细胞抗原DR减少； 3.免疫应答反应类型的转变； 4.细胞凋亡 ：各种免疫活性细胞以及 胃肠道黏膜上皮细胞。
The Open Inflammation Journal, 2011, 4, (Suppl 1-M8) 67-73
Sepsis
Trauma
Burns
Drugs
Surgery
Systemic temporary immunosupression
mild
severe
Prevents inflammation induced damage
Relation of HSV shedding and outcome
BALF (+) 99/308 ICU patients
Linssen CFM. Intensive Care Med 2008;34:2202-2209
Hartemink KJ. Intensive Care Med 2003;29:2068-2071 Four ICU patients without previous abnormal immune function
Impairs antimicrobial defense
homeostasis
High susceptibility to infections
临床表现
感染状态持续存在、感染病原不能有效清除、 对院内感染敏感。 频繁的无致病性（葡萄球菌、艰难梭状芽 孢杆菌）和多重耐药的细菌、病毒和真菌 病原体（不动杆菌属、假单胞菌属、念珠 菌属、肠球菌和巨细胞病毒）的感染
MLN的免疫功能抑制可以导致经过 肠淋巴途径易位的肠源性LPS 在 MLN 的滤过和灭活减少，造成大量 LPS 通过胸导管进入全身循环，引 起循环中本已升高的内毒素水平进 一步升高，通过诱导大量淋巴细胞 凋亡和抗炎因子产生，引发机体更 严重的免疫失衡，促进MODS 的发 生和发展。
Journal of Surgical Research -, 1–12 (2011)
Cytomegalovirus Reactivation in Critically Ill Immunocompetent Patients
JAMA, July 23/30, 2008—Vol 300, No. 4 413
JAMA, December 21, 2011-Vol 306, No. 23 2601
HLA-DR expression in patents with sepsis
百度文库
Monneret G. Intensive Care Med 2006;32:1175-1182
HLA-DR Quantification simple flow cytometry
Monneret et al, Intensive Care Med, 2006
Monocyte HLA-DR expression < 30% has been associated with adverse outcomes from sepsis-induced MODS in adults and children.
TNF- IL-1ß Clinical presentation IL-6 IL-8 PAF iNOS COX2
SIRS Evolution
Biologic sequelae
IL-1 ra IL-10 sTNFr-1/11 TGF- IL-4
Sepsis SIRS
PROINFLAMMATORY ANTI-INFLAMMATORY