Page 61 - Clinical Immunology_ Principles and Practice ( PDFDrive )

46 ParT ONE Principles of Immune Response

ILC1 ILC2 ILC3
ILC
Cell type:

Transcriptional T-bet GATA-3 RORγt
regulator:

Cytokines IFNγ IL-4, 5, 13 IL-2, 17, 22
produced: TNFα, GM-CSF,
LIF

Biological Cancer Helminth immunity Mucosal immunity
significance: immunosurveillance Immune regulation psoriasis?
Wound healing
Atopic disorders?
FIG 3.3 Developmental Regulation and Functions of Innate Lymphoid Cells. The development
of innate lymphoid cells (ILCs) is regulated by master transcriptional regulators, including T-bet,
GATA-3, and RORγt. Three subsets are recognized: ILC1, ILC2, and ILC3. ILC play roles in tumor
immunosurveillance, immune regulation, wound healing, mucosal immunity, atopic disorders,
psoriasis, and mucosal immunity.

cells. Postnatal ILC3 cells influence tissue homeostasis and host pleiotropism (e.g., the ability to act on multiple cell types) and
defense against extracellular organisms. ILC3-produced IL-22 redundancy. Cytokines can function locally and distantly and
induces expression of APPs by intestinal epithelial cells. Produc- can affect the production of other cytokines. Exposure to cytokines
tion of IL-17 by ILC3 cells likely contributes to host defense can induce changes in gene expression that affect cell function
against Candida. ILC3 cells can also produce IL-2, GM-CSF, (e.g., enhanced microbicidal activity or proliferation). Secretion
TNF-α, and leukemia inhibitory factor (LIF). Production of of cytokines (IL-1β, IL-6, TNF-α) is a transient event, thereby
GM-CSF by splenic ILC3 cells is believed to promote survival limiting potential destruction of host tissue. However, severe
and activation of splenic neutrophils. A significant population infections (e.g., bacteremia and sepsis) can lead to overproduction
of ILC3 cells has been found in lesional skin of patients with of TNF-α, IL-1β, and IFN-γ, which leads to vascular collapse,
psoriasis. 44 disseminated intravascular coagulation, and metabolic distur-
Mast cells (Chapter 23) are components of innate immunity bances (septic shock), which are often fatal.
that are also commonly found at the interface between host and Cytokine synthesis is a transient process because the messenger
environment. They are derived from progenitors in bone marrow RNA of most cytokines is unstable, thus limiting cytokine produc-
and circulate as immature precursors to the periphery. Mast cells tion. Production of certain cytokines is also regulated by a
take up residence and mature in skin, airways, and the GI tract. posttranslational process. For example, TNF-α is a membrane-
They are positioned to be first responders to environmental bound protein that is proteolytically cleaved by a membrane-
45
stimuli, including infectious agents. Stem cell factor (SCF, also associated metalloproteinase. IL-1β is a 33-kDa protein that is
known as c-kit ligand) is their main survival and developmental proteolytically processed by the IL-1β-converting enzyme
factor. Mast cells express TLR-1 through TLR-9 and therefore caspase-1 to generate the biologically active, 17-kDa, mature
are capable of responding to a wide variety of pathogens. TLR- IL-1β (described below).
induced mast-cell activation leads to production of proinflam- TNF-α and IL-1β can recruit PMNs and monocytes to sites
matory cytokines and chemokines. Murine models of peritonitis, of infection and enhance their ability to eliminate microbes.
such as cecal ligation and puncture, demonstrate that mast cells TNF-α and IL-1β induce expression of adhesion molecules
46
enhance resistance to bacterial infection. Mast cells are also (Chapter 11), such as selectins (P-selectin, E-selectin) and the
well known for mediating allergic reactions through IgE-bound integrin ligands ICAMs (intercellular adhesion molecules) and
allergens that are anchored by FcεRI on the mast-cell surface. VCAMs (vascular cell adhesion molecules) on vascular endothelial
Ligation of FcεRI leads to release of tryptase, histamine, leukot- cells near the sites of infection. Expression of selectins on vascular
rienes, prostaglandins, and cytokines, which cause type 1 endothelium induces leukocyte rolling on endothelium. Che-
hypersensitivity reactions (Chapter 42). mokines, such as CXCL8, activate PMNs and monocyte integrins
and increase their affinity for ligands (ICAMs, VCAMs) on
ACTIVATING INNATE IMMUNITY vascular endothelium, allowing migration of PMNs and mono-
cytes through endothelium to sites of infection. TNF-α and IL-1β
The innate immune response is initiated when cells of the innate both induce prostaglandin synthesis in the hypothalamus, which
immune system encounter pathogens and recognize them by induces fever.
means of PRRs binding to microbial molecules (e.g., lipopolysac-
charide, DNA, RNA). These interactions activate signaling PATTERN RECOGNITION RECEPTORS
pathways that lead to the production of secreted factors involved
in the inflammatory response, including cytokines (Chapter 9) Our understanding of the mechanisms by which pathogens are
and chemokines (Chapter 10). Characteristics of cytokines include detected has increased greatly over the past decade. Pathogen