9.1.3 Cutaneous Immunology

In addition to being a physical barrier that protects the body against external insults, the skin also forms an immunological barrier which is crucial for host defense as well as tissue homeostasis. The cutaneous immune system contains a network of immune cells of the innate and adaptive immune system. Besides skin-resident immune cells there is also a constant circulation of immune cells between the skin, lymph nodes and blood stream. It is also referred to as skin associated lymphoid tissue (SALT).

Several cells in the skin are part of the innate (non-specific, native) immune system.

Keratinocytes

Keratinocytes are the prominent cell type of the epidermis. They form the outermost barrier against potential infection. Damage to the skin leads to the secretion of numerous cytokines and chemokines (e.g. TNF, IL1, CXCL2, CXCL10) by keratinocytes which activate local immune cells and endothelial cells, initiate antigen-specific immune responses, and recruit various immune cells into the skin including T cells and Natural killer cells. In addition, keratinocytes secrete antimicrobial peptides (AMPs), such as beta-defensins and cathelicidin, which prevent the invasion of microbes by direct killing of pathogens, and activation of the innate immune system. Keratinocytes recognize invading viruses, parasites, bacteria, and fungi in the skin through Toll-like (TLR) and nucleotide-binding oligomerization domain- (NOD)-like receptors.

Epidermal and dermal dendritic cells

Epidermal dendritic cells (Langerhans cells) are important to maintain tissue homeostasis and immune tolerance. In the case of an insult, they can sense microbial antigens via Toll-like receptors. Langerhans cells process and present antigens to naïve T cells thereby inducing an antigen-specific immune response. Dermal dendritic cells are professional antigen-presenting cells (APC, plasmocytoid and myeloid subtypes) that are also crucial for the induction of adaptive immune responses.

Mast cells

Mast cells are mostly located in the dermis and around vessels and adnexal structures. They are of major importance for the induction and regulation of immune responses against various allergens as well as bacterial and parasitic infections. Mast cells express a variety of receptors on their surface including e.g., FcεRI receptors for binding of IgE, Toll-like receptors, IL-4 and IL-5 receptors. Upon stimulation they release a plethora of immune-activating mediators including histamine, heparin, tryptase or chymase. Consequences of mast cell activation are e.g. pruritic wheals, vasodilatation, and edema.

Macrophages

Macrophages are the most abundant cell type of skin resident immune cells. They maintain and restore homeostasis of the skin by eliminating invading pathogens (phagocytosis), sometimes resulting in granuloma formation with multinucleated giant cells (sarcoidosis, foreign body granuloma, rheumatism, erythema nodosum). Activated macrophages present antigens to naïve T cells and release cytokines (TNFα, IL1β, IL-6) which further drive inflammation and attract neutrophils to the site of insult.

Eosinophils and neutrophils

Upon the release of inflammatory cytokines and chemokines from e.g. keratinocytes or macrophages, neutrophils and eosinophils are recruited to the site of inflammation. Neutrophils release NETs (Neutrophil extracellular traps) to immobilize pathogens and directly phagocytose invading microorganisms (NETosis). They also release chemo-attractants to recruit more neutrophils into the skin.

Eosinophils are of major importance in the defense against parasites. Eosinophilia of the skin is also a typical feature of atopic dermatitis. Besides pro-inflammatory mediators they are also attracted to immunoglobulins such as IgE. Upon stimulation eosinophils release a wide range of immunomodulatory factors including more than 35 cytokines, growth factors, and chemokines and cytotoxic granules. Thereby they kill parasites and promote Th2 helper T cell differentiation. Recruited also in skin cancer. 

Immune cell compartment of the subcutaneous adipose tissue

Besides being a mechanical barrier, the subcutaneous white adipose tissue (SWAT) also acts as an immunological barrier. It contains mainly macrophages and T lymphocytes which help to secure tissue homeostasis and integrity.

The adaptive immune response takes longer to develop, and it is highly specific to particular pathogens. It includes both cell-mediated and humoral immunity.

CD8+ and CD4+ T cells

Cell-mediated immunity is mediated by T cells. Antigen-presenting cells like dendritic cells or macrophages present foreign peptides to naïve T cells which then differentiate into cytotoxic CD8+ T cells or CD4+ T helper (Th) cells. These then antigen-specific T cells migrate into the skin to the site of inflammation, e.g. as seen with, allergic contact dermatitis.

Cytotoxic CD8+ T cells are of major importance in attacking virally infected cells or cancer cells.

CD4+ T helper cells are central for activating B cells thereby inducing humoral immunity. T helper cells can be subdivided in Th1, Th2, Th17 and Th22 cells, with every subtype having a specific cytokine profile and different role in skin immunity.

Th1 cells produce IFN-γ, activate e.g., macrophages and induce  cell-mediated immune response to kill intracellular pathogens. They play a role in the course of psoriasis.

Th2 cells produce e.g., IL-4, IL-5, IL-6 or IL-10, and activate B cells as well as eosinophils.  They play a role in atopic eczema.

Th17 cells produce IL-17 and IL-22. They regulate bacterial and fungal infections. Th22 cells secrete pro-inflammatory mediators like IL-22 and TNFα. Th17 and Th22 cells are important in the pathogenesis of psoriasis.

Regulatory T cells

Regulatory T cells (Tregs) are one of the largest immune cell subsets in skin. They play a critical role in regulating the inflammatory immune response, prevent autoimmunity and support local tissue repair.

Memory T cells

Memory T cells (TRM) circulate between skin and blood stream or reside in the skin (tissue resident TRM). They are important for mediating a long-lasting protective immunity. See also chapter drug reactions, herpes induced erythema multiforme.

B cells

B lymphocytes are central for humoral immunity. Upon activation through cytokines and stimulatory signals from T cells they produce immunoglobulins that can bind to specific antigens. B cells also present antigens and produce pro- and anti-inflammatory cytokines themselves.