Innate and Acquired Immunity

Innate immunity is the most ancient and common system for defense against microbial infections. It evolved a detection system, a limited set of receptors (e.g., Toll-like receptors; TLRs) against microbial signatures that remain invariant inside a class of microbes [33]. Given that epithelial cells lie at the interface between the host and the environment, the expression of TLRs on these cells provides the first line of defense against invading pathogens through the recognition of microbial motifs. Although termed PAMPs, these motifs are not restricted to distinct pathogens since they include structural molecules such as lipopolysaccharide (LPS), lipoteichoic acid (LTA), peptidoglycan (PGN), lipoarabinomannan (LAM), flagellin, zymosan or double-stranded (ds) RNA (Table 13.1), which are common to multiple species of

Table 13.1. Toll-like receptors (TLRs) expressed by keratinocytes and their ligands

Receptor

Ligand

Origin of ligand

TLR1

Triacyl lipopeptides

Bacteria and mycobacteria

TLR2

Lipoproteins and lipopeptides

Various pathogens

Phenol-soluble modulin

Staphylococcus epidermidis

Lipoarabinomannan

Mycobacteria

Lipoteichoic acid

Gram-positive bacteria

Atypical lipopolysaccharide

Leptospira interrogans and Porphyromonas gingivalis

Zymosan

Fungi

Heat-shock protein 70

Host

TLR3

Double-stranded RNA

Viruses

TLR4

Lipopolysaccharide

Gram-negative bacteria

Heat-shock protein 70

Host

TLR5

Diacyl lipopeptides

Mycoplasma

TLR6

Lipoteichoic acid

Gram-positive bacteria

Zymosan

Fungi

TLR9

CpG-containing DNA

Bacteria and viruses

bacteria, yeast or viruses, respectively. In addition, a number of endogenous ligands, such as heat shock proteins or p-defensins, are also TLR ligands (Table 13.1). These endogenous molecules are also called "danger signals" released from dying or dead cells in order to trigger an inflammatory response [33].

The innate immune network of the skin consists of a range of pre-existing, rapidly mobilized host defense components including kerati-nocytes, neutrophils, mast cells, eosinophils, macrophages, and sebocytes. The key cellular components of the pathophysiologic processes of the skin are the keratinocytes, cells that are in a unique position between the interface of the environment and the host organism [61]. The findings that keratinocytes, which form 95% of all epidermal cells, express TLRs and are a potent source of antimicrobial and antiviral peptides and cytokines/chemokines emphasize their key role in the innate immune responses of the skin [5, 6]. Epidermal keratinocytes express, in a constitutive or inducible manner, at least 7 out of 11 known TLRs (TLR1-TLR6 and TLR9) [4, 36, 49, 59, 66]. Recognition of PAMPs by TLRs initiates quick innate immune responses such as phagocytosis, and the production of antimicrobial compounds and inflammatory mediators resulting in the killing and elimination of microorganisms. In addition, these mediators link innate and adaptive immunity, as they also function as chemoattractants for the effector cells of the acquired immune response [61].

A rapid innate immune response in the skin results in cutaneous inflammation, leading to extravasation and the homing of cutaneous lymphocyte-associated, antigen-expressing (CLA+) memory T cells to the skin, permitting them to encounter and respond to appropriately presented antigen in the skin. The ability of T and also B cells to recombine antigen receptor genes during development provides an efficient and powerful acquired immune system with nearly unlimited specificity for antigen. Although a fundamental aspect of mammalian biology, immunologic memory is a relatively recent evolutionary event.

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