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304 Part IV: Molecular and Cellular Hematology Chapter 20: Innate Immunity 305

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protein antigen in guinea pigs infected with Mycobacterium tuberculosis. mutations affecting IFN-γ, IL-12 and its receptor, 130,131 defects of
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Freund and McDermott demonstrated that heat-killed mycobacteria granule formation, and defects of nicotinamide adenine dinucleotide
were capable of eliciting an exaggerated antibody response as well when phosphate (NADPH) oxidase. 133
coadministered with a protein antigen, indicating that molecular com-
ponents of microbes (rather than infection per se) were responsible for
adjuvanticity. LPS was shown to be endowed with adjuvant activity in THE GENERAL STRATEGY OF INNATE
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1955, and by 1975 the Lps locus was shown to be required for this IMMUNE RESPONSES AND THE
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effect of LPS (as it is required for all other cellular effects of LPS). By
deduction, the positional cloning of Lps thus revealed the essential role CONCEPT OF FORWARD FEEDBACK
of TLR4 in LPS-mediated adjuvanticity. 7
Activation of an adaptive immune response to a specific anti- LOOPS IN AUTOIMMUNITY
gen has long been known to depend upon two signals that occur in Although the term “autoimmunity” is reserved for inappropriate adap-
the course of antigen presentation. First, the T-cell receptor must be tive immune responses that damage tissues of the host, the innate
activated. In addition, costimulatory molecules upregulated on the immune system may also cause injury or death, and typically does so
antigen-presenting cell (e.g., CD40, CD69, CD80, and CD86) are known when systemic activation occurs in the course of a serious infection.
to interact with receptors (or in some cases ligands) on the T cell. An Innate immune responses, which entail cytokine-mediated inflamma-
exchange of signals occurs over a period of approximately 12 hours, tion and coagulation, evolved to contain small inoculates of microor-
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ultimately leading to autonomous expansion of the T-cell clone and, in ganisms by encouraging the influx of granulocytes to engulf and destroy
turn, activation of specific B cells. Some of these signals are well charac- these pathogens, and by stimulating the development of an adaptive
terized. For example, CD80 and CD86 both engage CD28 and cytotoxic immune response. The mechanisms that are employed to these ends can
T-lymphocyte antigen (CTLA) on the T-cell surface, and abrogation of be lethal if they are generalized rather than focal. In several examples,
signaling via these costimulatory receptors is known to substantially the importance of microbes as drivers of inflammation has been cited,
attenuate the adaptive immune response. 119 and forward-feedback loops may perpetuate inflammation or auto-
Upregulation of costimulatory molecules (UCM) is therefore immunity. It has been reported, for example, that endogenous DNA,
essential, although not by itself sufficient, for activation of the adap- signaling via TLR9, is responsible for the generation and perpetuation
tive immune response. LPS depends upon TRIF (and specifically, upon of antinucleoprotein antibodies in a mouse model of systemic lupus
TRIF-mediated type I IFN gene expression) to elicit UCM 42,60,120 ; absent erythematosus. The involvement of TLRs 3 and 7 may also be
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TRIF, LPS cannot exert an adjuvant effect. TRAM is also required for important.
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UCM. Although MyD88 does not elicit UCM, it does contribute to In hemophagocytic lymphohistiocytosis (HLH), an amplification
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LPS-induced adjuvanticity in an experimental setting. It is likely that loop involving a microbial driver, CTL expansion, and IFN-γ driven
IL-12, a cytokine that is largely MyD88-dependent, also contributes to myeloid expansion has been well described in mice. In SHP1 defi-
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the adjuvant effect, along with other proteins yet to be identified. ciency in mice, autoimmunity and inflammation also depend upon a
Even though several publications initially suggested that TLR microbial driver and activation of TIR domain signaling pathways.
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signaling is required for adaptive immune responses to occur, it has NOMID and other mutations capable of activating the NLRP3 inflam-
been observed that mice lacking all TLR signaling are quite capable of masome have been mentioned earlier in this chapter. Beyond this, the
mounting adaptive immune responses, including antibody responses innate immune system may also contribute to sterile inflammation
and recall responses to defined antigens administered with diverse (autoinflammatory disease), as witnessed in many human diseases that
adjuvants. It is now evident that there is much redundancy in adaptive have so far eluded etiologic decipherment.
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immune responses, and several innate immune pathways can indepen-
dently trigger such responses.
REFERENCES
DISEASES CAUSED BY INNATE 1. Pancer Z, Amemiya CT, Ehrhardt GR, et al: Somatic diversification of variable lympho-
cyte receptors in the agnathan sea lamprey. Nature 430:174, 2004.
IMMUNE DEFECTS 2. Cooper MD, Alder MN: The evolution of adaptive immune systems. Cell 124:815, 2006.
3. Pfeiffer R: Untersuchungen über das Choleragift. Z Hyg Infektionskr 11:393, 1892.
Premature death from infection is strongly heritable in humans. 4. Raetz CR, Whitfield C: Lipopolysaccharide endotoxins. Annu Rev Biochem 71:635,
122
Defects of the innate immune sensing apparatus are expected to cause 2002.
hypersusceptibility to infection in humans as they clearly do in mice, 5. Galanos C, Luderitz O, Rietschel ET, et al: Synthetic and natural Escherichia coli free
lipid A express identical endotoxic activities. Eur J Biochem 148:1, 1985.
and specific examples of such mutations have recently come to light 6. Rosenstreich DL, Weinblatt AC, O’Brien AD: Genetic control of resistance to infection
including the NLR disorders discussed above (see “Sensors of the in mice. CRC Crit Rev Immunol 3:263, 1982.
NOD-Like Receptor Family”). Missense mutations of TLR4 that are 7. Poltorak A, He X, Smirnova I, et al: Defective LPS signaling in C3H/HeJ and
C57BL/10ScCr mice: Mutations in Tlr4 gene. Science 282:2085, 1998.
rare among the normal white population are quite common in patients 8. Anderson KV, Bokla L, Nusslein-Volhard C: Establishment of dorsal-ventral polarity in
with systemic meningococcal disease, and have been assigned a role in the Drosophila embryo: The induction of polarity by the Toll gene product. Cell 42:791,
123
susceptibility on this basis. A nonsense mutation of TLR5 was found 1985.
to be overrepresented in patients who developed Legionnaire disease 9. Lemaitre B, Nicolas E, Michaut L, et al: The dorsoventral regulatory gene cassette spätzle/
Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86:973,
as compared to a comparably exposed population that remained dis- 1996.
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ease-free. Mutations of IRAK4 and MyD88 create susceptibility to 10. Hemmi H, Takeuchi O, Kawai T, et al: A Toll-like receptor recognizes bacterial DNA.
Nature 408:740, 2000.
suppurative Gram-positive infections. 44,125 In humans, both TLR3 and 11. Takeuchi O, Kaufmann A, Grote K, et al: Preferentially the R-stereoisomer of the
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UNC93B1 mutations cause susceptibility to recurrent Herpes simplex mycoplasmal lipopeptide macrophage-activating lipopeptide-2 activates immune cells
virus encephalitis, and presumably to other diseases as well. through a Toll-Like receptor 2- and MyD88-dependent signaling pathway. J Immunol
On the effector side, examples of immunocompromise from innate 164:554, 2000.
immune defects are far better known, and include diseases caused by 12. Takeuchi O, Sato S, Horiuchi T, et al: Cutting edge: Role of Toll-like receptor 1 in medi-
ating immune response to microbial lipoproteins. J Immunol 169:10, 2002.

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