Innate Immunity 先天性免疫

Memory ?

colicins of E. colilactic acid from lactobacilli*antibiotic treatment

SP-A & D, defensin (opsonization)

The front line of host defense

Establish an infection

(macrophage)

(neutrophil)

Macrophages are activated

by pathogens and both engulf

them and initiate inflammatory

responses.

co-stimulatory molecules (B7)

Neutrophil : short-livedMacrophage : long-lived, continued to generate new lysosomes

Genetic deficiency of NADPH oxidase – chronic granulomatous disease

Mycobacteria

抑制酸化阻止融合

Macrophages are activated

by pathogens and both engulf

them and initiate inflammatory

responses.

co-stimulatory molecules (B7)

Pattern-recognition receptors : A. 直接辨識 pathogen ，引發吞噬 (phagocytic receptor)

Mannose-binding lectin (MBL) : free in plasma 與細菌細胞壁的 mannose 結合 細菌表面分子的相對位置很重要 opsonization Macrophage mannose receptor : 與細菌及一些病毒 ( 如 HIV) 上的 mannose 結合 Scavenger receptors ( 與老化 RBC 的清除亦有關 )

B. 傳遞訊號 (signaling receptor)

Toll-like receptor (TLR) : 10 種 gene

interferon

TNF-α, IFN-β

LTA TNF-α

adjuvant

Macrophages are activated

by pathogens and both engulf

them and initiate inflammatory

responses.

co-stimulatory molecules (B7)

Macrophages release cytokines and chemokines to initiate an inflammatory response

1. 血流量增多但變慢 ( 紅、熱 ) 3. 血管通透性增加 (腫、痛 )

發炎細胞的到達 1.WBC 2.Monocyte 3. Others (eosinophil, lymphpcyte)

Enzyme cascades : (trigger by tissue damage)

1. Kinin system : 產生影響血管的 peptides ( 如 bradykinin) ，使血管通透性增加， plasma proteins 進入”病灶“，阻止病原擴散。 造成疼痛2. Coagulation system : 形成 fibrin clot ，阻止病原進入血流。

The complement system :

由不同分子誘發，但產生相同的作用分子

3. pore2. phagocytosis1. chemoattractants

4. 清除有問題的細胞

Triggered-enzyme cascade

Classical pathway : initiation by activation of C1 complex

MB-lectin pathway

MASP-2: cleavage C4 and C2MASP-1: uncertain

缺乏 MBL 者，幼年期易受感染，此時 adaptive immunity 尚未成熟，移行抗體已下降。

*C3 的活化作用只發生在病原體表面，不會發生於 宿主細胞上。

因 C4b 會與病原表面的蛋白或醣類結合， 若無儘快結合，則 C4b 會發生水解，變成不可逆且不具活性，無法形成 C3 convertase 。 C3b 也需儘速結合於病原表面。

C2 只在與 C4b 結合時，才可被 C1s 切割。

Hydrolysis of C3 causes

initiation of the alternative

pathway

Fluid-phase C3 convertase

Amplification loop

Positive regulatory factor : 缺乏者易感染 Neisseria

Ingestion of complement-tagged pathogens by

phagocytes is mediated by receptors (CR) for bound

complement proteins.

6 types of complement receptors

Anaphylactic shock(anaphylatoxin)

The terminal complement proteins polymerize to

form pores in membranes that can kill the pathogens

membrane-attack complex

C8 = C8 (bind)

+C8- (insert)

Neisseria

Complement control proteins regulate all three pathways

and protect the host from its destructive effects

(serpin)

Hereditary angioneurotic edema excess cleaved C4 and C2 fragmentsC2b C2 kinin

Induced innate responses to infection local and distant effects

cysteine

CXCR1-6

CCR1-9

Chemokines 的功能及特性1. 一種 chemokine 可與一種以上的 receptor 結合，即可被 多種 receptor 辨識。2. 一種 chemokine 可由多種不同細胞產生且可影響多種細胞3. 引起趨化反應，藉由濃度梯度引導 effector cells 聚集於 感染部位。4. 有些種類與淋巴球的發育、移行及血管生成有關。

Adhesion molecules : 3 family

subunitTNF-

C5aTNF-LPS

Neutrophils leave the blood and migrate to sites of infection in a multistep process mediated through adhesive interactions.

fast

extravasation

往濃度高處移動

(peaks within first 6 hrs)

slow

TNF-α is an important cytokine that triggers local containment of

infection but induces shock when released systemically.

Blood pressure↓

clot

Septic shock

mice with mutant TNF-α receptor ?

endogenous pyrogens

leukocytosis

bind C1q

Acute-phase response

Pneumoncystis carinii

Intracellular pathogen

NK : release cytotoxic granules onto the target cell, the effector proteins penetrate the membrane and induce apoptosis.