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Innate and Adaptive Immunity-Complementary & Distinct Host Defenses
Innate and Adaptive Immunity-Complementary & Distinct Host Defenses
INNATE ADAPTIVE
Hard-wired Requires Priming
Immediate Delayed or Immediate
Cell bound receptors Soluble and Cellular
Pattern-molecule recognition Antigen Specific
Macrophages, NK, non-prof. APC B-cells, T-cells
Different ligands selectively activate different TLRs
Different ligands selectively Different ligands selectively activate different TLRs activate different TLRs
TLR4 alteration associated with IBDTLR4 alteration associated with IBD
Upregulation of mucosal TLR4 expression in active, human IBD
Association of TLR4D299G-polymorphism with IBD in selective populations
Murine TLR4-“gain-of-function”: spontaneous intestinal inflammation with TH1-excess
Murine TLR4-“loss-of-function”: increased susceptibility to DSS-colitis and gram─ infections
Flagellins stimulate aberrant intestinal immune reactions via TLR5 as dominant antigens in colitis Flagellins stimulate aberrant intestinal immune
reactions via TLR5 as dominant antigens in colitis
Lodes et al. JCI 2004;113:1296Lodes et al. JCI 2004;113:1296
••Marked Marked TT--cellcell reactivityreactivity againstagainst flagellinflagellin••FlagellinFlagellin--specificspecific T T cellscells induceinduce colitiscolitis in SCID in SCID micemice••SerologicalSerological responseresponse to to specificspecific flagellinsflagellins in CD in CD ptspts..
TLR4 mutant and knockout mice are highly susceptible to develop DSS colitis
TLR4 mutant and knockout mice are highly susceptible to develop DSS colitis
Cario et al. Gastroenterology 2004;127:224Cario et al. Gastroenterology 2004;127:224
XX--YY
ZOZO--11-- PC
SKPC
SK
ZZ
+ PC
SK+
PCSK
XX--YY
ZOZO--11
ZZ
IECIEC
Commensal compounds assist the host to confer intestinal epithelial barrier functionCommensal compounds assist the host to confer intestinal epithelial barrier function
Madsen, et al. Madsen, et al. Gastroenterology 2001;121:580Gastroenterology 2001;121:580
T84
Otte, Podolsky. Am J Physiol GastrointestOtte, Podolsky. Am J Physiol GastrointestLiver Physiol 2004;286:G613Liver Physiol 2004;286:G613
+LPS 10ng/ml+LPS 10ng/ml MMθθ CD4+ T cellsCD4+ T cells
in thein the absence of absence of TLR4, the onset of TLR4, the onset of chronic chronic enterocolitisenterocolitisis delayed,is delayed, and and activity of colitis is activity of colitis is improvedimproved
Kobayashi et al. JCI 2003;111:1297Kobayashi et al. JCI 2003;111:1297
Commensal-mediated TLR4 dysfunction contributes to the development of TH1-intestinal inflammation
Commensal-mediated TLR4 dysfunction contributes to the development of TH1-intestinal inflammation
Com
men
sals
Com
men
sals M
ucosaM
ucosaInvasion
TLRTH1TH1--typetype
CytokinesCytokines
Aberrant TLR4/MyD88 Aberrant TLR4/MyD88 signalingsignaling may may favorfavor chronicchronicintestinal inflammation through intestinal inflammation through commensalcommensal--mediated mediated
proinflammatoryproinflammatory TH1TH1--effects in the lamina effects in the lamina propriapropria