Page 54 - Clinical Immunology_ Principles and Practice ( PDFDrive )

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Innate Immunity

Douglas R. McDonald, Ofer Levy

Innate immunity is the first line of host defense against infection. KEY CONCEPTS
All living organisms are continually exposed to microbes. For
example, the human gut is colonized by trillions of commensal The Innate Immune System
bacteria. The innate immune system must accommodate com- • The innate immune system provides the initial immune response to
mensal bacteria but be able to be activated by pathogens (e.g., pathogens.
Salmonella or Shigella). Potentially life-threatening infections • Although less specific than the adaptive immune system, the innate
can result from naturally occurring defects in the innate immune immune system must differentiate commensal from pathological
response (Chapter 36). microbes.
A defining characteristic of innate immunity is its existence • The innate immune system comprises barriers to the environment
before microbial exposure. Innate immune responses are initiated (e.g., skin, mucosa), antimicrobial peptides and proteins, cells (e.g.,
neutrophils, macrophages, monocytes), and soluble factors (i.e.,
rapidly by microbes and precede the development of adaptive cytokines, chemokines, complement).
immune responses. The adaptive immune system is characterized • Pathogen detection is mediated by a variety of germline-encoded
by the tremendous diversity of its receptors and its antigen ligands. pathogen recognition receptors (PRRs) that can recognize invariant
The innate immune system responds to a more constrained set microbial structures known as pathogen-associated molecular patterns
of antigens that are typically essential and invariant structural (PAMPs).
components specific to microbes. These microbial components • Activation of the innate immune system leads to subsequent activation
of the adaptive immune system.
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are known as pathogen-associated molecular patterns (PAMPs). • The innate immune system has a form of memory or “trained immunity”
They include microbial cell wall components and nucleic acids. such that innate immune activation can modulate innate immune
PAMPs are recognized by pattern recognition receptors (PRRs), responses to subsequent unrelated stimulus/infection.
and they are highly potent and effective in initiating inflammatory
responses.
“Trained immunity” is used to describe the phenomenon of
enhanced innate immune responses following microbial expo-
2,3
sure. This increase in host resistance to reinfection can provide responses to infection. Genetic disorders of the skin that com-
“cross-protection” against other infectious agents. For example, promise skin integrity, such as epidermolysis bullosa (Chapter
macrophages and natural killer (NK) cells can expand and contract 63), can result in life-threatening infections.
their cell populations, upregulate genes involved in pathogen Skin disorders that impair barrier function, such as atopic
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recognition and presentation, and secrete cytokines that augment dermatitis (AD) (Chapter 44) or eczema, are common. Filaggrin
the antimicrobial activity of bystander cells. Thus there is a (FLG) is a key a structural component of the outermost layer
growing appreciation that the adaptive and innate immune of the epidermis. Loss of function variants in filaggrin (R510X,
systems have certain similar characteristics. 2282del4) is estimated to be present in up to 50% of patients
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with AD. FLG mutations are a risk factor for the development
BARRIERS TO INFECTION of early-onset AD and thus for sensitization to food allergens
(Chapter 45), allergic rhinitis, and asthma (Chapter 72) (the
Skin and Mucosa atopic march). Eczematous skin can lead to reduced expression
The epithelial layers of the skin and the linings of the gastro- of APPs and increased susceptibility to cutaneous bacterial (e.g.,
intestinal (GI), genitourinary (GU), and respiratory tracts provide Staphylococcus, Streptococcus) and viral (e.g., herpes) infections. 5
a mechanical barrier to microbial entry and thus play an essential The luminal surfaces of the intestines are sites of continual
role in host defense. The stratum corneum of the skin is the first exposure to massive numbers of microbes. Intestinal epithelial
barrier encountered by microbes (Chapter 19). The skin is cells (IECs) (Chapter 20) protect against infection by forming
persistently colonized with numerous microbes. Thus an intact a physical barrier through tight junctions and by producing
physical barrier is essential to prevent activation of the immune mucus (goblet cells) and APPs. IECs express apical junction
system under nonpathological conditions. Key cellular compo- complexes, including E-cadherin, ZO-1, claudin, and occludin,
nents of the skin immune barrier include keratinocytes, dendritic which function to form a tight monolayer that prevents penetra-
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cells (DCs), macrophages, T lymphocytes, and mast cells. These tion by bacteria. A breakdown in epithelial gut homeostasis can
cells express a wide variety of pathogen recognition receptors lead to inflammatory bowel diseases (e.g., Crohn disease, ulcerative
and secrete a broad range of cytokines, chemokines, and anti- colitis) (Chapter 75) and increased susceptibility to bacterial
microbial proteins and peptides (APPs) that mediate inflammatory infection. 7

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