Bio 347, Chapter 3
I. Innate versus adaptive or acquired immunity
a response time: minutes/hours versus days
b. diversity: limited # germ line genes versus large # germ line genes
c. Memory: none versus persistent memory
d. Self/nonself discrimination: perfect versus almost perfect
e. Soluble components: antimicrobial peptides and proteins versus antibodies
f. major cell types: phagocytes, neutrophils, NK, dendritic cells versus T, B, and APC
II. Connections between innate and adaptive immunity
1. Response to invasion:
a. sensors that detect the invasion: Innate: Restricted to molecular patterns of microbes
(i) recognize pathogen associated molecular patterns-PAMP (combinations of sugars,
proteins, lipoproteins, nucleic acid motifs)
b. response mechanisms
(i). soluble factors--complement (acute phase response proteins)
(ii). macrophages--cytokines (interleukin 1 and 6, tumor necrosis factor alpha (TNF-)
(iii). inflammation--chemokines, chemoattractants, proinflammatory cytokines, integrins
(iv) Leukocyte extravasation multistep process
(v) antimicrobial peptides
III. Receptors: Complement, MBL, CRP, LPS, NOD, SRs, TLRs
IV. Toll-like receptors (TLR's)
1. Three discoveries (1996, 1997, 1998)
(i) mutation in TLR involved in fruit fly (invertebrate) development ("weird anatomy or Toll in
German), susceptibility to fungus infection.
(ii) Identification of TLR4 in humans (homology to invertebrate TLR)
(iii) TLR gave resistance to lipopolysaccharide (endotoxin from gram-negative bacteria) in mice
2. What are TLR's?
(i) Membrane spanning proteins that share structural similarities
a. Extracellular-leucine rich binding domain
b. transmembrane domain
c. intracellular (Toll/IL-1 receptor or TIR domains that are highly conserved
among all TLR's and are referred to as Box 1, 2 and 3)
(ii) function as homodimers, heterodimers, or perhaps as monomers
(iii) 9 of 11 known TLR's are present in humans
(iv) detect highly conserved pathogen molecules
3. Signal transduction pathways
(i) initiation--ligand reacting with receptor
(ii) association with adaptor molecules (TIR--adaptor proteins)
(iii) protein kinase mediated phosphorylation
(iv) initiation of enzyme cascade (NF-kB usually associated with survival and MAPK
associated with survival or death)
(v) enters nucleus and activates transcription factors
IV. Evolutionary aspects of immune response system
(i) MHC involvement: graft rejection in sponges and earthworm
(ii) antibody production in cold-blooded vertebrates
(iii) GALT, thymus, spleen, bone marrow, lymph nodes, germinal centers