Skin immunity

Last updated August 19, 2023

Skin immunity is a property of skin that allows it to resist infections from pathogens. In addition to providing a passive physical barrier against infection, the skin also contains elements of the innate and adaptive immune systems which allows it to actively fight infections. Hence the skin provides defense in depth against infection.

The skin acts as a barrier, a kind of sheath, made of several layers of cells and their related glands. The skin is a dynamic organ that contains different cells which contains elements of the innate and the adaptive immune systems which are activated when the tissue is under attack by invading pathogens. Shortly after infection, the immune adaptive response is induced by dendritic cells (Langerhans cells) present in the epidermis; they are responsible for the capture, processing, and presentation of antigens to T lymphocytes in local lymphoid organs. As a result, T lymphocytes express the cutaneous lymphocyte antigen (CLA) molecule, a modified form of P-selectin glycoprotein ligand-1.^[1] Lymphocytes move to the epidermis where they reside as memory T cells, they will thus be activated and will trigger an inflammatory response. Dysregulation of these mechanisms is associated with inflammatory diseases of the skin.^[2]

Afferent and efferent phases of the immune system of the skin

Some humoral and cellular components of the skin pass through the vessel lymph to get to the circulation. This circulation net has a big importance, it's the way of direct communication between the specific site of the skin and the lymph cells found inside the lymph node and the systematic tissues. The epidermis antigens are connected with some cells of the skin. Among them there are the APC, antigen presenting cells (Langerhans, dentritic and cutaneous). They capture the antigen, they process it and they present it on their surface as being associated with the MHC-II. Keratinocytes produce TNFα and IL-1 which act on the Langerhans cells, inducing an increase of the expression of histocompatibility complex and cytokine secretion. Moreover, they induce their migration from the skin to the paracortical areas of the lymph nodes. Once there, these cells can provide the necessary stimulus for the lymphocytes T, who will proliferate and express the cutaneous receptor recruitment and to various chemo attractants that promote the accumulation of dermal micro vascular endothelial cells of inflamed skin to finally enter the skin tissue. Once the activated lymphocytes arrive, they get in contact with the antigen, they proliferate and develop their effector functions in order to neutralize or eliminate the pathogen. The Langerhans cells promote and permit the start of the cellular immune response of lymphocytes through the skin and are recruited from the peripheral blood. Antigen presentation may occur in peripheral lymphoid tissues.^[3]

Antigenic presentation from the Langerhans cells to the lymphocytes

The Langerhans cells, once they are activated, rapidly migrate to the lymph nodes where they will accumulate in the paracortex and show the antigen of the skin to the lymph nodes via efferent lymph vessels. The Langerhans cells induce a vast proliferation of the naïve lymphocytes T and they participate in the immunoestimulation phase of the immune response, converting the lymphocytes in T helper cells. Recently, it has been shown that Langerhans cells can express an antigenic peptide associated to MHC-I capable of inducing a response from the cytotoxic LT and effector functions, such as the production of cytokines.^[3]

Microbiota and skin immunity

Skin microbiota plays an important role in tissue homeostasis and local immunity.^[4]^[5]^[6]^[7] Skin microbial communities are highly diverse and can be remodeled over time or in response to environment challenges.^[8]^[9]^[10]

From around 2005 on, the scientific community has thoroughly developed the concept of human microbiome^[11]^[12] and begun the systematic study to establish the relationship between the microbiome and human physiology in health and disease.^[13] We^{[ who? ]} begin to understand that gut microbiota helps modulating host immunity at a systemic level.^[14]^[15] However, gut microbiome does not affect skin immunity significantly, instead, skin immunity is modulated by skin microflora according to the results obtained by Naik et al.^[5] Analyzing immunologic changes of germ-free (GF) mice with reconstituted gut microbiota showed a recovery of Il-17A and IFN-γ levels up to those observed in the gastrointestinal tract of specific pathogen free (SPF) mice but gut microbiome restoration did not affect skin immunity. Comparing GF and SPF mice showed a decrease in the skin production of IFN-γ and IL-17A. To evaluate the functional consequences of the absence of skin microbiota Leishmania major was introduced intradermally and the lesions were evaluated. L. major lesions in GF mice were significantly smaller and less severe than in SPF mice, however, the number of parasites after infection was significantly higher in GF mice. These results clearly indicate that GF mice have an impaired capacity of response in front of infections compared to SPF mice. Finally, mono-association of GF mice with S. epidermidis clearly restored immunity function which in the case of skin is mediated by IL-1 which is key for the restoration of IL-17A and IFN-γ levels. Thus skin commensals exert their effect by enhancing IL-1 signaling and amplifying responses according to local inflammatory milieu. As IL-1 has been implicated in the etiology and pathology of psoriasis and other cutaneous disorders,^[16] it is likely that skin commensals are important drivers and amplifiers of skin pathologies.

T cells and microbiota in skin immunity

Recent studies have demonstrated that specific components of the microbiota, as well as their metabolites, selectively promote the activation and the expansion of different T cell subsets under normal and/or pathological conditions.^[17] For example, colonization with Staphylococcus epidermidis may have diverse effects, as promote the growth of IL-17A+ CD8+ T cells that reside in the epidermis. This, would limit pathogen invasion improving innate immune barrier in an IL-17 dependent manner. According to an investigation led by US researchers, skin-resident CD11b+ dendritic cells would be the ones to orchestrate a specific response after interacting with commensal bacteria stimulating the proliferation of IL-17A+ CD8+ T cells through their capacity to produce IL-1. This activation mechanism is commensal specific and clearly belongs to the adaptive immune system; however, it strikingly improves innate immune protection as shown after challenging gnobiotic mice with Candida albicans. Indeed, mono-association of gnobiotic mice with S. epidermidis significantly improves innate protection against C. albicans. The connection between the innate and the adaptive system is driven in this case by the production of alarmins S100A8 and S100A9 known to elicit microbicidal responses and as potent chemoattractants for neutrophils.^[18]

The majority bacteria tested increased the number of skin T cells. Interactions between T cells and specific microbiota components may represent evolutionary outcome by which the skin immune system and the microbiota provide heterologous protection against invasive pathogens and calibrate barrier immunity through the use of chemical signals. This shows that the skin immune system is a highly dynamic environment that can be rapidly and specifically remodeled by certain commensals.^[18]

Finally, studying microbiota interactions and skin T cells can help to detect the cause of various diseases and possible cures for these. The increasing development of tools for personalized medicine will undoubtedly help to this goal, because each person has a different microbiota.

Related Research Articles

The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinters, distinguishing them from the organism's own healthy tissue. Many species have two major subsystems of the immune system. The innate immune system provides a preconfigured response to broad groups of situations and stimuli. The adaptive immune system provides a tailored response to each stimulus by learning to recognize molecules it has previously encountered. Both use molecules and cells to perform their functions.

A DNA vaccine is a type of vaccine that transfects a specific antigen-coding DNA sequence into the cells of an organism as a mechanism to induce an immune response.

A dendritic cell (DC) is an antigen-presenting cell of the mammalian immune system. A DC's main function is to process antigen material and present it on the cell surface to the T cells of the immune system. They act as messengers between the innate and adaptive immune systems.

The human microbiome is the aggregate of all microbiota that reside on or within human tissues and biofluids along with the corresponding anatomical sites in which they reside, including the skin, mammary glands, seminal fluid, uterus, ovarian follicles, lung, saliva, oral mucosa, conjunctiva, biliary tract, and gastrointestinal tract. Types of human microbiota include bacteria, archaea, fungi, protists, and viruses. Though micro-animals can also live on the human body, they are typically excluded from this definition. In the context of genomics, the term human microbiome is sometimes used to refer to the collective genomes of resident microorganisms; however, the term human metagenome has the same meaning.

A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include T cells, B cells, and Innate lymphoid cells (ILCs), of which natural killer cells are an important subtype. They are the main type of cell found in lymph, which prompted the name "lymphocyte". Lymphocytes make up between 18% and 42% of circulating white blood cells.

Gut-associated lymphoid tissue (GALT) is a component of the mucosa-associated lymphoid tissue (MALT) which works in the immune system to protect the body from invasion in the gut.

Immune tolerance, or immunological tolerance, or immunotolerance, is a state of unresponsiveness of the immune system to substances or tissue that would otherwise have the capacity to elicit an immune response in a given organism. It is induced by prior exposure to that specific antigen and contrasts with conventional immune-mediated elimination of foreign antigens. Tolerance is classified into central tolerance or peripheral tolerance depending on where the state is originally induced—in the thymus and bone marrow (central) or in other tissues and lymph nodes (peripheral). The mechanisms by which these forms of tolerance are established are distinct, but the resulting effect is similar.

Dysbiosis is characterized by a disruption to the microbiome resulting in an imbalance in the microbiota, changes in their functional composition and metabolic activities, or a shift in their local distribution. For example, a part of the human microbiota such as the skin flora, gut flora, or vaginal flora, can become deranged, with normally dominating species underrepresented and normally outcompeted or contained species increasing to fill the void. Dysbiosis is most commonly reported as a condition in the gastrointestinal tract.

Gamma delta T cells are T cells that have a γδ T-cell receptor (TCR) on their surface. Most T cells are αβ T cells with TCR composed of two glycoprotein chains called α (alpha) and β (beta) TCR chains. In contrast, γδ T cells have a TCR that is made up of one γ (gamma) chain and one δ (delta) chain. This group of T cells is usually less common than αβ T cells, but are at their highest abundance in the gut mucosa, within a population of lymphocytes known as intraepithelial lymphocytes (IELs).

Long-term close-knit interactions between symbiotic microbes and their host can alter host immune system responses to other microorganisms, including pathogens, and are required to maintain proper homeostasis. The immune system is a host defense system consisting of anatomical physical barriers as well as physiological and cellular responses, which protect the host against harmful microorganisms while limiting host responses to harmless symbionts. Humans are home to 10¹³ to 10¹⁴ bacteria, roughly equivalent to the number of human cells, and while these bacteria can be pathogenic to their host most of them are mutually beneficial to both the host and bacteria.

Microbiota are the range of microorganisms that may be commensal, mutualistic, or pathogenic found in and on all multicellular organisms, including plants. Microbiota include bacteria, archaea, protists, fungi, and viruses, and have been found to be crucial for immunologic, hormonal, and metabolic homeostasis of their host.

Mucosal immunology is the study of immune system responses that occur at mucosal membranes of the intestines, the urogenital tract, and the respiratory system. The mucous membranes are in constant contact with microorganisms, food, and inhaled antigens. In healthy states, the mucosal immune system protects the organism against infectious pathogens and maintains a tolerance towards non-harmful commensal microbes and benign environmental substances. Disruption of this balance between tolerance and deprivation of pathogens can lead to pathological conditions such as food allergies, irritable bowel syndrome, susceptibility to infections, and more.

The lung microbiota is the pulmonary microbial community consisting of a complex variety of microorganisms found in the lower respiratory tract particularly on the mucous layer and the epithelial surfaces. These microorganisms include bacteria, fungi, viruses and bacteriophages. The bacterial part of the microbiota has been more closely studied. It consists of a core of nine genera: Prevotella, Sphingomonas, Pseudomonas, Acinetobacter, Fusobacterium, Megasphaera, Veillonella, Staphylococcus, and Streptococcus. They are aerobes as well as anaerobes and aerotolerant bacteria. The microbial communities are highly variable in particular individuals and compose of about 140 distinct families. The bronchial tree for instance contains a mean of 2000 bacterial genomes per cm² surface. The harmful or potentially harmful bacteria are also detected routinely in respiratory specimens. The most significant are Moraxella catarrhalis, Haemophilus influenzae, and Streptococcus pneumoniae. They are known to cause respiratory disorders under particular conditions namely if the human immune system is impaired. The mechanism by which they persist in the lower airways in healthy individuals is unknown.

Mucosal-associated invariant T cells make up a subset of T cells in the immune system that display innate, effector-like qualities. In humans, MAIT cells are found in the blood, liver, lungs, and mucosa, defending against microbial activity and infection. The MHC class I-like protein, MR1, is responsible for presenting bacterially-produced vitamin B2 and B9 metabolites to MAIT cells. After the presentation of foreign antigen by MR1, MAIT cells secrete pro-inflammatory cytokines and are capable of lysing bacterially-infected cells. MAIT cells can also be activated through MR1-independent signaling. In addition to possessing innate-like functions, this T cell subset supports the adaptive immune response and has a memory-like phenotype. Furthermore, MAIT cells are thought to play a role in autoimmune diseases, such as multiple sclerosis, arthritis and inflammatory bowel disease, although definitive evidence is yet to be published.

Innate lymphoid cells (ILCs) are the most recently discovered family of innate immune cells, derived from common lymphoid progenitors (CLPs). In response to pathogenic tissue damage, ILCs contribute to immunity via the secretion of signalling molecules, and the regulation of both innate and adaptive immune cells. ILCs are primarily tissue resident cells, found in both lymphoid, and non- lymphoid tissues, and rarely in the blood. They are particularly abundant at mucosal surfaces, playing a key role in mucosal immunity and homeostasis. Characteristics allowing their differentiation from other immune cells include the regular lymphoid morphology, absence of rearranged antigen receptors found on T cells and B cells, and phenotypic markers usually present on myeloid or dendritic cells.

The altered Schaedler flora (ASF) is a community of eight bacterial species: two lactobacilli, one Bacteroides, one spiral bacterium of the Flexistipes genus, and four extremely oxygen sensitive (EOS) fusiform-shaped species. The bacteria are selected for their dominance and persistence in the normal microflora of mice, and for their ability to be isolated and grown in laboratory settings. Germ-free animals, mainly mice, are colonized with ASF for the purpose of studying the gastrointestinal (GI) tract. Intestinal mutualistic bacteria play an important role in affecting gene expression of the GI tract, immune responses, nutrient absorption, and pathogen resistance. The standardized microbial cocktail enabled the controlled study of microbe and host interactions, role of microbes, pathogen effects, and intestinal immunity and disease association, such as cancer, inflammatory bowel disease, diabetes, and other inflammatory or autoimmune diseases. Also, compared to germfree animals, ASF mice have fully developed immune system, resistance to opportunistic pathogens, and normal GI function and health, and are a great representation of normal mice.

The microbiota are the sum of all symbiotic microorganisms living on or in an organism. The fruit fly Drosophila melanogaster is a model organism and known as one of the most investigated organisms worldwide. The microbiota in flies is less complex than that found in humans. It still has an influence on the fitness of the fly, and it affects different life-history characteristics such as lifespan, resistance against pathogens (immunity) and metabolic processes (digestion). Considering the comprehensive toolkit available for research in Drosophila, analysis of its microbiome could enhance our understanding of similar processes in other types of host-microbiota interactions, including those involving humans. Microbiota plays key roles in the intestinal immune and metabolic responses via their fermentation product, acetate.

ILC2 cells, or type 2 innate lymphoid cells are a type of innate lymphoid cell. Not to be confused with the ILC. They are derived from common lymphoid progenitor and belong to the lymphoid lineage. These cells lack antigen specific B or T cell receptor because of the lack of recombination activating gene. ILC2s produce type 2 cytokines and are involved in responses to helminths, allergens, some viruses, such as influenza virus and cancer.

Type 3 innate lymphoid cells (ILC3) are immune cells from the lymphoid lineage that are part of the innate immune system. These cells participate in innate mechanisms on mucous membranes, contributing to tissue homeostasis, host-commensal mutualism and pathogen clearance. They are part of a heterogeneous group of innate lymphoid cells, which is traditionally divided into three subsets based on their expression of master transcription factors as well as secreted effector cytokines - ILC1, ILC2 and ILC3.

Yasmine Belkaid is an Algerian immunologist and senior investigator at the National Institute of Allergy and Infectious Diseases (NIAID) and adjunct professor at the University of Pennsylvania. She is best known for her work studying host-microbe interactions in tissues and immune regulation to microbes. Belkaid currently serves as the director of the NIAID Microbiome program. On 29 March 2023, she was appointed as President of the Pasteur Institute for a six-year term, starting from January 2024.

References

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