Cellular Components of Cutaneous Innate Immunity

Introduction

The skin harbors a remarkable diversity of immune cells that collectively form the Skin-Associated Lymphoid Tissue (SALT) or Skin Immune System (SIS). These resident and recruited cells work in concert to detect threats, mount appropriate responses, and maintain tissue homeostasis.

This chapter provides a detailed exploration of the cellular players in cutaneous innate immunity, from tissue-resident sentinels to rapidly recruited effector cells.

Dendritic Cells: Professional Antigen-Presenting Cells

Dendritic Cell Subsets in Skin

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Langerhans Cells: Epidermal Sentinels

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LC Functions: Beyond Presentation

Function	Mechanism	Clinical Relevance
Antigen presentation	MHC II + costimulation	Adaptive immunity initiation
Cross-presentation	MHC I presentation of exogenous Ag	CTL responses
Tolerance induction	Immature state, Treg induction	Contact sensitivity tolerance
HIV transmission	Langerin binds HIV (usually protective)	Sexual transmission
Leishmaniasis	Parasite hijacks LCs	Dissemination

Dermal Dendritic Cells

Subset	Markers	Key Function
cDC1	CD141 (BDCA-3), XCR1, CLEC9A	Cross-presentation → CTL, Th1
cDC2	CD1c (BDCA-1), CD11b, SIRPα	Th2, Th17 polarization
pDC	CD123, CD303 (BDCA-2), CD304	Type I IFN production (antiviral)
IDEC	CD1a, CD11b, FcεRI	Recruited in inflammation (AD)

Plasmacytoid Dendritic Cells (pDCs)

pDCs are the "type I interferon factories":

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Mast Cells: Tissue Alarm System

Mast Cell Phenotype and Distribution

Feature	Mucosal Mast Cells	Connective Tissue Mast Cells
Location	Mucosal surfaces	Dermis, around vessels
Protease content	Tryptase	Tryptase + Chymase
IgE dependency	High	Variable
T cell dependency	Yes	Partial
Skin relevance	Limited	Major population

Mast Cell Activation Pathways

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MRGPRX2: Drug Reaction Receptor

MRGPRX2 (Mas-related G protein-coupled receptor X2) mediates IgE-independent mast cell activation:

Ligand Class	Examples	Clinical Presentation
Drugs	Fluoroquinolones, vancomycin, opioids	Anaphylactoid reactions
Neuromuscular blockers	Rocuronium, atracurium	Perioperative reactions
Contrast agents	Iodinated contrast	Contrast reactions
Venoms	Wasp, bee venom	Local reactions
Neuropeptides	Substance P	Neurogenic inflammation

Macrophages: Tissue Guardians

Dermal Macrophage Heterogeneity

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Macrophage Functions in Skin

Function	Mechanism	Disease Relevance
Phagocytosis	PRR-mediated engulfment	Infection clearance
Antigen presentation	MHC II	T cell activation
Wound healing	Growth factors, matrix remodeling	Chronic wounds (M1/M2 imbalance)
Efferocytosis	Apoptotic cell clearance	Resolution of inflammation
Iron recycling	Hemoglobin processing	Post-bruising
Fibrosis	TGF-β, alternatively activated	Keloids, scleroderma

Neutrophils: First Responders

Neutrophil Recruitment

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Neutrophil Effector Functions

Function	Mechanism	Products
Phagocytosis	Receptor-mediated ingestion	—
Oxidative burst	NADPH oxidase	O₂⁻, H₂O₂, HOCl
Degranulation	Granule fusion	Elastase, MPO, defensins
NETosis	DNA extrusion	NETs (DNA + histones + granule proteins)

Neutrophilic Dermatoses

Diseases characterized by neutrophil accumulation without infection:

Disease	Histology	Association
Sweet syndrome	Dermal neutrophils, edema	Malignancy, IBD, drugs
Pyoderma gangrenosum	Ulceration, neutrophils	IBD, rheumatoid arthritis
Subcorneal pustular dermatosis	Subcorneal neutrophils	IgA gammopathy
Bowel-associated dermatosis-arthritis	Neutrophilic pustules	Bowel surgery, IBD
Behçet disease	Vasculitis, pathergy	HLA-B51

Natural Killer (NK) Cells

NK Cell Biology

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NK Cells in Skin Disease

Context	NK Role	Clinical Relevance
Melanoma	Tumor surveillance	Immunotherapy enhancement
Herpes infections	Antiviral	NK deficiency → severe HSV
Contact dermatitis	CHS memory	NK-mediated memory
Psoriasis	NKT cells in lesions	IL-17 production

Innate Lymphoid Cells (ILCs)

ILC Classification

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ILC2 in Atopic Dermatitis

ILC2s are pivotal in AD pathogenesis:

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ILC3 in Psoriasis

ILC3s contribute to IL-17/IL-22 production in psoriasis, particularly in early lesions before T cell infiltration.

Skin-Resident Memory and Innate Memory

Tissue-Resident Memory Concepts

Even innate cells can develop "trained immunity":

Cell Type	Memory-like Feature	Clinical Example
NK cells	Hapten-specific recall	Contact hypersensitivity
Macrophages	Trained immunity (epigenetic)	BCG protection beyond TB
ILC2	Allergen memory	Allergic inflammation
Epidermal γδ T cells	Rapid re-expansion	Wound healing

Summary: Cellular Orchestra

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Key Clinical Pearls

Topic	Pearl
Langerhans cells	CD1a+, Langerin+; decline with age and UV exposure
pDCs	Rare in normal skin; accumulate in psoriasis, lupus; major IFN-α source
MRGPRX2	Explains immediate non-IgE drug reactions
M1/M2 balance	Crucial for wound healing; chronic wounds stuck in M1
ILC2	Drive type 2 inflammation independent of T cells; key in AD
NETs	Important in vasculitis; source of autoantigens in lupus
Neutrophilic dermatoses	Sterile neutrophil infiltration; often associated with systemic disease

Cross-References

Volume 05, Chapter 1.1: Innate Immunity Overview
Volume 05, Chapter 2: Adaptive Immunity
Volume 13: Inflammatory Dermatoses - AD, psoriasis
Volume 27: Vascular Diseases - Vasculitis