Page 438 - Clinical Immunology_ Principles and Practice ( PDFDrive )

418 ParT ThrEE Host Defenses to Infectious Agents

Fungi *C. albicans *C. albicans *C. albicans *Candida spp. *Candida spp.
*C. glabrata *C. glabrata *P. brasiliensis *Malassezia spp. *A. fumigatus
*Coccidioides spp. *Paracoccidioides *Saccharomyces spp. *Chrysosporium
*H. capsulatum brasiliensis tropicum
*P. jirovecii
PAMP β-glucan α-mannan β-mannan ? N-mannan

CLR Dectin-1 Dectin-2 Galectin-3 MINCLE DC-SIGN

Plasma membrane

TNFα TNFα IL-1β TNFα IL-6
Gene expression IL-1β IL-1β IL-6 IL-6 IL-10
output IL-23 IL-23 IL-10 IL-10 IL-12
IL-1β
IL-2
IL-6
TNFα
IL-10 IL-10 TGFβ IL-23
IL-6
IL-12

FIG 29.3 C-Type Lectin Receptors (CLRs) and Fungal Immunity. CLRs recognize fungal PAMPs
and trigger downstream signaling that leads to cytokine production.

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promotes acidification and maturation of phagosomes. Patients
with mutations in dectin-1 are more susceptible to IFIs, which Collaboration Between TLRs and CLRs
demonstrates the essential role of dectin-1 in mediating fungal Although most cognate ligands found on the fungal cell wall are
immunity. 23 carbohydrates that preferentially trigger CLRs, experimental
Upon dectin-1 binding to β-1,3 glucan, a tyrosine residue evidence indicates that CLRs can collaborate with TLRs on the
within the cytoplasmic hemi–immunoreceptor tyrosine-based cell surface to coordinate cytokine production. Dectin-1 can
activation motif (ITAM) domain of dectin-1 is phosphorylated collaborate with TLR2 and TLR4 to induce synergistically
by Src family kinases, which leads to the recruitment and activa- cytokines, including TNF-α, IL-10, and IL-23. This collaboration
tion of Syk. Syk triggers the activation of the caspase recruitment has been used clinically for management of clinical disease.
domain family member 9–Bcl-10– mucosa-associated lympho- Fonsecaea pedrosoi is the fungus that causes chromoblastomycosis,
reticular tissue 1 (MALT1) complex, inducing nuclear factor a skin infection that is difficult to treat. The CLR Mincle recognizes
(NF)-κB and production of cytokines, including IL-1β, IL-6, this pathogen. If costimulation of both CLR and TLR pathways
IL-10, IL-112, IL-23, and TNF-α. Dectin-1 can signal through are not engaged, the inflammatory response is defective. Exog-
a Syk-independent pathway via activation of the serine/threonine enous administration of imiquimod, purified TLR7 ligand,
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kinase, Raf-1, that phosphorylates p65, a subunit of NF-κB. facilitated pathogen clearance in mouse models and humans.
Cytokines produced in response to canonical (via Syk) and This signaling requires both Syk/CARD9 and MyD88. Imiquimod
noncanonical (via Raf-1) NF-κB signaling are essential for the is a synthetic compound with potent antiviral and antitumor
activation of Th1 and Th17 cells (Fig. 29.4). activity that stimulates the innate immune system through TLR7
Syk also triggers recruitment and activation of NADPH oxidase, activation. When applied to the lesions of four patients with
which stimulates production of ROS, elaboration of proinflam- chromoblastomycosis, there was a rapid resolution of the infec-
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matory cytokines, and ultimately fungal killing. Syk appears to tion. This provides proof of concept that multiple signaling
be a master controller for phagosomal maturation and recruitment pathways are necessary for optimal activation of the innate
of light chain 3 (LC3), a protein associated with autophagy. immune system against fungal pathogens.