Page 155 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 9 Cytokines and Cytokine Receptors 137

There are seven mammalian STATs: STAT1, STAT2, STAT3,
STAT4, STAT5A, STAT5B, and STAT6. Stat knock-out mice Attenuation of Type-I and Type-II Cytokine Signaling
document the essential and specific functions of these transcrip- Perhaps as important as the triggers that initiate signal transduc-
−/−
44
tion factors in transmitting cytokine signals. Stat1 mice develop tion are the mechanisms for extinguishing the response. There
normally but have extreme susceptibility to viral and some are several families of proteins involved in downregulating
−/−
bacterial infections, consistent with the defects seen in Ifng and cytokine signaling. Among these are phosphatases, cytokine-
−/−
Ifngr mice. Humans with loss of function mutations of STAT1 inducible inhibitor molecules, and transcriptional repressors.
have increased susceptibility to Salmonella and mycobacterial The phosphatase SHP-1 interacts with cytokine receptors and
infections, whereas GOF mutations of STAT1 cause chronic downregulates signaling. Mice with the naturally occurring
mucocutaneous candidiasis (CMC). Gene targeting of Stat3 leads “moth-eaten” mutation in SHP-1 lack a functional SHP-1 protein
to early embryonic lethality, the lethality being related, in part, and die at an early age as a result of autoimmune disease.
to interference with Lif function. Conditional knock-outs of Another family of proteins that attenuate cytokine signaling
Stat3 in myeloid cells display exaggerated inflammatory responses is the suppressors of cytokine signaling (SOCS), which are
as a result of failure of IL-10 signaling. STAT3 is also essential alternatively termed JAB, SSI, and CSIS. These are SH2-containing
for Th17 cells, and mutations of STAT3 underlie the primary proteins that bind to either cytokine receptors or to JAKs and
immunodeficiency Hyper-IgE syndrome (HIES, or Job’s syn- inhibit signaling. There are at least eight members of this family.
drome) associated with impaired IL-17 production. Polymor- Largely as a result of systemic hyperresponsiveness to IFN-γ,
−/−
phisms of STAT3 are associated with IBD (Chapter 75). STAT4 Socs-1 mice die within a few weeks of birth. SOCS-2 has been
−/−
is activated by IL-12. Stat4 mice develop normally but have recently shown to regulate Th2 differentiation and allergic
defective Th1 differentiation and IFNγ production combined responses. Another family member, SOCS-3, is important in
with augmented Th2 development. controlling Th17 differentiation. 45-47
−/−
STAT6 is activated by IL-4. Stat6 mice have defective Th2
development with defective IgE responses following infection KEY CONCEPTS
with parasites. Lack of STAT6 dramatically attenuates allergic
and asthmatic disease in animal models of these diseases. IL-13 Properties of the Tumor Necrosis Factor (TNF)
also activates STAT6, and its responses are abrogated in Receptor Superfamily
−/−
Stat6 mice. • Activation of a TNF receptor can lead to a wide range of effects, from
STAT5A and STAT5B are highly homologous, but nonetheless proliferation to apoptosis.
−/−
have different functions. Stat5a mice have impaired mammary • Transduction of signals through TNF receptor–associated factors (TRAFs)
−/−
gland development and failure of lactation, whereas Stat5b mice leads to the enhancement of survival.
have defective sexually dimorphic growth and growth hormone– • Signaling through death domains leads to the induction of
dependent regulation of liver gene expression. Stat5a/5b doubly apoptosis.
deficient mice manifest increased perinatal lethality, decreased
size, female infertility, and impaired lymphocyte development. THE TNF CYTOKINE AND RECEPTOR SUPERFAMILY
−/−
Stat5 mice develop lymphoproliferative disease reminiscent
of IL-2- and IL-2R–deficient mice, related to loss of Tregs with This large family of structurally related ligands, receptors, and
expansion of Tfh and Th17 cells. inhibitory decoy receptors has various roles both within and
Patients with STAT5B mutations have short stature and outside the immune system. The first two members of this family
immune dysregulation. to be discovered were TNF and lymphotoxin-α (LTα; formerly
named TNF-β). These molecules are secreted principally by
activated myeloid and T cells. They have similar proinflammatory
CLINICaL rELEVaNCE functions and belong to a large family of related molecules that
Type I and II Cytokine Receptors includes CD30 ligand, CD40 ligand, FAS ligand, and TNF-related
apoptosis inducing ligand (TRAIL). Indeed, the TNF cytokine
• Mutations of genes encoding interleukin (IL)-7R, γc, and Janus kinase family now contains 18 ligands and 29 receptors, each of which
3 (JAK3) cause severe combined immunodeficiency (SCID). exhibits marked differences in tissue expression, ligand specificity,
• TYK2 and signal transducer and activator of transcription 3 (STAT3) receptor binding, and biological function (Fig. 9.4) This section
mutations cause hyper-IgE syndrome (HIES).
• STAT1 mutations cause autosomal dominant chronic mucocutaneous describes general aspects of TNF and TNF receptor (TNFR)
candidiasis (CMC) with increased susceptibility to mycobacterial and biology, with examples from three of the best-studied TNF-family
viral infections. members. More complete listings of TNF-family cytokines and
• Mutations of genes encoding IL-12, IL-12R, and interferon-γ receptor their receptors can be found in Table 9.2 and Table 9.3.
(IFN-γR) are associated with susceptibility to intracellular infections.
• Polymorphisms of IL-2R and IL-7R are associated with multiple sclerosis Ligand and Receptor Structure
(MS). Much of our understanding of the structural and functional
• Polymorphisms of IL-23R are associated with inflammatory bowel
disease (IBD). characteristics of the TNF ligand and receptor superfamilies has
• Polymorphisms of STAT4 are associated with rheumatoid arthritis come from the analysis of TNF (TNFSF2), LTα (TNFSF1), FASL
(RA) and systemic lupus erythematosus (SLE). (TNFSF6), and their receptors. Among these, TNF and LTα are
• Erythropoietin (EPO), granulocyte–colony-stimulating factor (G-CSF), closely related homotrimeric proteins (32% identity). Human
and thrombopoietin (TPO) are used to treat cytopenias. TNF is synthesized as a 233-amino acid glycoprotein. It contains
• Anticytokine and/or cytokine receptor monoclonal antibodies (mAbs) a long (76 residue) amino-terminal sequence that anchors it to
are used to prevent transplant rejection and treat several autoimmune
and inflammatory diseases. the cell membrane as a 25-kilodalton (kDa) type II membrane
protein. A secreted 17-kDa form of TNF is generated through