Skin immune system
Our skin plays a vital role in protection from the external environment. Its roles include:
- Physical barrier
- Immune interface to shield us from infection and toxins
- Prevention of autoimmunity.
Peripheral lymphoid organs include spleen, lymph nodes and skin (also called skin-associated lymphoid tissue or SALT).
* Reprinted by permission from Macmillan Publishers Ltd: Nestle, F. O., Di Meglio, P., Qin, J., & Nickoloff, B. J. (2009). Skin immune sentinels in health and disease. Nature Reviews.Immunology, 9(10), 679-91.
Overview of the skin immune system
The skin immune systems are innate (non-specific) and adaptive (specific). Immune cells inhabit the epidermis and dermis.
The key immune cells in the epidermis are:
- Epidermal dendritic cells (Langerhan cells)
- Keratinocytes (skin cells).
The dermis has blood and lymph vessels and numerous immune cells, including:
- Dermal dendritic cells
- Lymphocytes: T cells, B cells, natural killer (NK) cells
- Mast cells.
There is continuous trafficking of immune cells between the skin, draining lymph nodes and blood circulation. The skin microbiome also contributes to the homeostasis of the skin immune system.
Innate immune response
The innate immune response is quick and is not dependent on previous immunological memory.
Keratinocytes are the predominant cells in the epidermis. They act as the first line of innate immune defence against infection. They express toll-like receptors (TLRs), which are pattern-recognition receptors (PRRs) that detect conserved molecules on pathogens and trigger an inflammatory response.
Keratinocytes communicate with the rest of the immune system through:
- Antimicrobial peptides (cathelicidins and β-defensins)
- Signalling cytokines (eg, IL-1β)
- Chemokines, which attract other immune cells to the epidermis
- Direct activation of primed T lymphocytes.
Macrophages and neutrophils
Macrophages are phagocytic cells that can discriminate between self and foreign molecules. After phagocytosis by macrophages, an invading pathogen is killed inside the cell. Activated macrophages recruit neutrophils to enter the circulation and travel to sites of infection or inflammation.
Neutrophils are the “first responders”. They directly attack micro-organisms by phagocytosis and by degranulation of toxic substances.
Epidermal and dermal dendritic cells are involved in both the innate and adaptive immune responses. In the innate response:
- Dendritic cells possess TLRs that can be activated by microbial components
- Plasmactyoid dendritic cells (pDCs) produce large amounts of interferon-γ (IFN-γ) in response to viral infection.
Natural killer cells
NK cells are cytotoxic lymphocytes that can eliminate virally infected cells and cancer cells without antigen presentation or priming.
- NK cells are activated by interferons or other cytokines released from macrophages.
- They can kill target cells using the perforin-granzyme pathway.
- NK cells express inhibitor receptors that recognise MHC class I and prevent undesirable attack on self.
Mast cells store pre-formed inflammatory mediators such as histamine within cytoplasmic granules. Mast cells possess a high-affinity surface receptor FcεRI that binds specific triggering signals. The cells degranulate upon contact with stimuli such as allergens, venoms, IgE antibodies, and medications.
The mediators can result in pruritic weals due to increased vascular permeability (urticaria). Mast cell activation can rarely lead to anaphylaxis, characterised by bronchoconstriction, dizziness and syncope.
Eosinophils enter the skin in pathologic conditions such as parasitic infestations and atopic dermatitis.
- Eosinophil cytoplasmic granules provide protection against parasitic infections (innate immune response).
- They promote Th2 helper T cell differentiation upon release (adaptive immune response).
The complement system is an enzymatic cascade of over 20 different proteins normally found in the blood. When an infection is present, the system is sequentially activated leading to events that help destroy the invading organism.
The complement system can also attract neutrophils to the site of infection.
Adaptive immune response
Compared to the innate immunity, the adaptive immune response is specific to a pathogen and takes a longer time to elicit. Adaptive immunity requires the production of specific T lymphocytes to identify an antigen with precision and B cells to produce specific antibodies that bind to the microbe in a “lock-and-key” fashion.
Dendritic cells (Langerhan cells and macrophages), or antigen presenting cells (APCs), identify antigens and present them to immature T cells. Epidermal Langerhan cells use their dendrites (arm-like projections) to survey the environment, especially the stratum corneum. The Langerhan cells bind pathogens to their TLRs, travel to draining lymph nodes, and present antigens to naïve lymphocytes. Antigen presentation requires internalisation of pathogen, processing inside the cell, and display of a short peptide on the surface of APC on a major histocompatibility complex (MHC) molecule.
There are two major types of MHC: MHC-I and MHC-II.
- MHC-I is found on all cells in the body and is used to display endogenous substances such as viral or tumour proteins.
- MHC-II is found on APCs (dendritic cells, monocytes/macrophages and B cells) and is used to display foreign non-self molecules.
The skin contains resident T cells and recruited circulating T cells. Effective antigen presentation allows for naïve T cells to differentiate into effector T cells:
- Cytotoxic CD8+ T cells
- Helper CD4+ T cells (Th).
T cells are unable to recognise pathogens directly. The receptor on the surface of a T cell binds to the peptide/MHC complex on the surface of the APC.
- Cytotoxic CD8+ T cells recognize MHC-I. They can directly kill the virally infected or tumour cells by perforin-granzyme pathway, Fas death receptor and cytokine-mediated pathways.
- Helper CD4+ T cells bind to MHC-II molecules. They activate B cells to produce specific antibodies. Upon re-exposure to the same antigen, memory T cells can respond quickly by division and clonal expansion.
Th cells include Th1, Th2, Th17 and Th22 subtypes. Each subtype is associated with specific signalling cytokines and effector functions.
Th1 cells produce a cell-mediated immune response to kill intracellular pathogens.
- Th1 cells produce IFN-g and can activate macrophages and stimulate NK cells.
- Th1 cells play a role in the pathogenesis of psoriasis.
Th2 cell activation leads to B cell stimulation and antibody production.
- Th2 cells produce cytokines IL-4, IL-5, IL-6 and IL-10.
- They can stimulate eosinophil activation.
- Th2 cells are involved in atopic eczema.
Th17 cells produce IL-17 and IL-22 and play a role in protection from bacterial and fungal infections. Th22 cells produce IL-22 and TNF-a. Both Th17 and Th22 cells play a role in the pathogenesis of psoriasis.
B lymphocytes are unique in having the ability to produce antibodies (immunoglobulins) that can bind to specific antigens. Antibody effector functions are:
- Neutralisation – antibody binds to pathogen and prevents adherence/infection
- Opsonisation – the coating of the antigen surface by antibodies and subsequent uptake by phagocytic cells
- Complement activation.
To produce antibodies, B cells require cytokine signalling and stimulatory signals from Th cells. This takes place in secondary lymphoid organs such as lymph nodes.
- The B-cell receptor (BCR) must bind to the T cell receptor along with co-stimulatory signals on T helper cells.
- B cell proliferation (somatic hypermutation) leads to production of a specific antibody.
- Isotype switch results in IgG, IgA or IgE types of immunoglobulin.
- This process allows for generation of memory B cells and long-lived plasma cells for long-lasting immunity from infection.
Upon re-exposure to the same antigen and follicular dendritic cells, B cells are activated to produce specific antibodies.