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CHaPTEr 9 Cytokines and Cytokine Receptors 145

Some TNF-family receptors use other mechanisms to activate have hyperactive B cells, but in humans, dominant negative TACI
NF-κB. LTβ receptor activates the IKK complex via the serine– mutations have been found in patients with common variable
threonine kinase NIK, which was initially identified through its immunodeficiency affecting B-cell numbers and function (Chapter
ability to associate with TRAF2. A naturally occurring mouse 34), which argues that in humans TACI serves as a positive
mutation termed alymphoplasia (aly) is the result of a point modulator of B cells.
mutation of NIK. Aly/aly mice lack lymph nodes and Peyer
patches and also exhibit disorganized splenic and thymic struc-
tures. This mutation, and the phenotype of LTβR knock-out KEY CONCEPTS
mice, revealed the critical role of this receptor in normal lymph Properties of the Interleukin-1 Receptor/Toll-Like
node development and the formation of “tertiary” lymphoid
tissue in inflammation. Receptor (IL-1R/TLR) Family
When a single TNF-family ligand, such as TNF, binds both • IL-1 plays a key role in fever and acute-phase responses.
a death receptor (TNFR1) and a non–death receptor (TNFR2), • IL-18 augments T-helper 1 (Th1) cell differentiation.
a number of mechanisms regulate receptor signaling and the • TLRs modulate proinflammatory signals in response to bacterial
cellular outcome. Rather than functioning in cell death, the proteins.
physiological function of TNFR2 may be as a costimulator of
lymphocyte proliferation. 56
INTERLEUKIN-1/TOLL-LIKE RECEPTOR FAMILY
CLINICaL rELEVaNCE Ligand and Receptor Structure
Tumor Necrosis Factor Receptor (TNFR) The IL-1/TLR family of receptors comprises at least 11 members,
Superfamily Cytokines and Receptors including the IL-1RI, IL-1RII, IL-1R-associated protein (IL-
and Disease 1RAcP), IL-18R, IL-18RAcP, IL-1Rrp2, IL-1RAPL, IL-33R(T1/
59
ST2), TIGGIR, SIGGIR, and the mammalian TLRs. The ligands
• Dominant mutations of in the gene encoding TNFR1 are associated for these receptors include IL-1, IL-18, IL-33, and IL-1 F5–IL-36
with autosomal dominant periodic fever syndromes, known as TNFR1- α, β, and γ; IL-36RA; IL-33 and IL-37; and IL-38. 60
associated periodic syndromes (TRAPS).
• Loss-of-function mutations in the gene encoding CD40L are associated Family Members and Their Actions
with X-linked hyper-IgM syndrome (X-HIM).
• Dominant interfering mutations in TNFRSF6, encoding the Fas receptor Interleukin-1
are associated with autoimmune lymphoproliferative syndrome (ALPS). There are two cell surface receptors for IL-1, type I (IL-1R1)
• Rheumatoid arthritis (RA) often responds to therapeutic use of TNF and type II (IL-1R2). Both these bind ligand (see Fig. 9.4), but
antagonists. only IL-1R1 transduces signals. The extracellular domain of
IL-1R1 has three Ig-like domains and a 200-amino acid cyto-
plasmic domain. Upon ligand binding, IL-1R1 associates with
Clinical Relevance IL-1R accessory protein (IL-1RAcP), which is critical for the
Mutations affecting the TNFR1 protein are associated with periodic initiation of signaling. The IL-1R2 cytoplasmic domain is
fever syndromes (Chapter 60). Patients with the TNFR1-associated extremely short and has been suggested to be a “decoy” receptor,
periodic syndrome (TRAPS) have missense mutations in exons competing with IL-1RI for ligand binding and attenuating signal-
encoding the extracellular regions of TNFR1 that affect normal ing. Both IL-1Rs are susceptible to proteolytic cleavage near the
TNFR1 function, prompting the designation. The mutated TNFR1 membrane surface. Thus they can be found as soluble proteins
in TRAPS accumulates intracellularly and signals in a TNF- that can “buffer” IL-1 signaling. These soluble receptors are readily
independent fashion to amplify inflammatory responses through detectable in the circulation.
57
the wild-type TNFR1. Both TNF blockade with etanercept and There are three members of the IL-1 gene family: two agonists,
IL-1 blockade have efficacy in reducing symptoms in TRAPS. 58 IL-1α and IL-1β, and one antagonist, IL-1 receptor antagonist
The in vivo role of Fas signaling in the regulation of the (IL-1Ra). Both IL-1α and IL-1β are synthesized as precursor
immune system was confirmed when the naturally arising lpr proteins. IL-1α and IL-1β are structurally similar and have similar
and gld mouse strains were found to harbor homozygous muta- actions, but they are regulated differently. IL-1α is processed by
tions of Fas and Fas ligand, respectively. Both these mouse strains a calpain-like converting enzyme, but granzyme B and neutrophils
are characterized by lymphadenopathy and splenomegaly resulting and mast cell proteases can also cleave the precursor. The proform
−
−
from the accumulation of unusual CD4 CD8 T cells, as well as of IL-1α has biological activity, but cleavage results in increased
the production of autoantibodies. Heterozygous dominant biological activity. IL-1β is regulated at the levels of mRNA
negative mutations in the gene encoding Fas cause the autoimmune stabilization and translation, and it requires proteolytic activation.
lymphoproliferative syndrome (ALPS) (Chapter 35). Pro–IL-1β remains in the cytoplasm until it is cleaved by proteases,
The gene encoding CD40 ligand is defective in X-linked such as caspase-1. It is then transported out of the cell.
hyper-IgM syndrome (X-HIM), a rare inherited disorder in which The cleavage of IL-1β occurs in a multiprotein complex called
affected male children generate only IgM antibodies, many of the inflammasome. The key components of the inflammasome are
which are autoantibodies (Chapter 34). Patients with X-HIM caspase-1 and a recognition/assembly component nucleotide-binding
frequently suffer opportunistic infections, usually bacterial, and oligomerization domain (NOD)–like receptor (NLR). Another
have an increased susceptibility to cancer. The physiological role protein called ASC (a simple adapter protein containing both pyrin
of the B cell–activating factor (BAFF) receptor in mouse B-cell and CARD domains) is required to facilitate assembly. NLR proteins
development is illustrated by BAFF-R mutations in the A/WySnJ are intracellular pattern-recognition receptors that contain three
mouse, which lacks peripheral B cells. TACI knock-out mice domains: (i) a segment with multiple leucine-rich repeats, whose