Immune Circuits of the Skin

Innate Immunity

  • skin associated lymphoid tissue (SALT) and skin immune system (SIS)
  • The path the innate immunity takes is depended on a germ-line procedure
  • LPS (lipopolysaccaride) peptidoglycan and lipotechoic acid are essential for microbial function and not produced by humans
  • Mannan-binding lectins turn on the immune system against pathogens and trigger the classical complement cascade
  • Macrophage mannose and scavenger receptors make fluid around pathogens for clearance
  • Toll like receptors (TLR) are named for their recebmalnce to something in a fly’s immune system
    • TLRs, TLR4 discovered in 1997, respond differently to pathogens and help recognize pathogenic ligands derived from bacteria, vrisuses, fungi, and some nonpathogenic host proteins and synthetic compounds (like lectins in food?), for example TLR4 responds to gram-negative LPS, while TLR2 protects against gram-positive organisms
    • Activating TLRs triggers increased expression of genes coding for key components of the inflammatory response
  • IL1 leads to activation of NF-kB (a nuclear transcription factor responsible for the induction of chemokines, cytokines, costimulatory molecules, adhesion molecules, and major histocompatability complex (MHC) molecules)
  • TLR signaling pathways may also depend on MyD88
    • TLRs act on Langerhans cells, dermal dendritic cells, keratinocytes, and mast cells
  • Bone marrow-derived antigen presenting cells (APCs) are called Langerhans cells (LC) in the epidermis and dermal dendritic cells in dermis
    • LC are neural agenst and exhaust melanocytes
    • LC have Fe recebors (that bind immunoglobulin constant regions), C3 complement receptors, and MHC class II molecules
    • LC are phagocytic and help skin drain lymph nodes

Denditic Cells

  • APCs initiate and direct the adaptive immunity
  • TLR1, 2, 4, 5 and 9 make dendritic cells sensitive to bacterial LPS, lipoproteins, glycolipids, flagellin, and CpG DNA
  • Langerhans cells don’t bind via bacteria on TLR2, 4 and 5, but do on TLR7
    • Langerhans cells to LPS and viral antigens relative to splenic dendritic cells and peritoneal macrophages
    • Langerhans cells can not be stimulated to release interferon (IFN)-γ, important in recruiting type 1 helper (Th1) T cells, but were relatively prolific secretors of chemokines that promote the type 2helper (Th2) response
    • Langerhans cells may respond epidermal milieu (e.g., keratinocytes and cytokines), instead of initiating inflammation
    • Langerhans cells may downregulate the inflammatory response

Kerantinocytes

  • Keratinocyte cells create a network of tight, intercellular adhesions which are the initial barrier to exogenous injury and prevent dessication
    • Keratinocytes in the immune system can be triggered mechanically (e.g., through trauma), photochemically (e.g., by ultraviolet radiation (UVR) ), and chemically (via receptor-medi- ated response), serving to initiate inflammation and to couple the innate and adaptive arms of immunity.
    • They secrete pro-inflammatory cytokines, including interleukin(IL)-1α and tumor necrosis factor (TNF)-α.
  • UVR enhances TNFa release
  • IL-1α is upregulated by physical injury, resulting in the nuclear factor (NF)- κB-mediated activation of more than 90 known gene targets in skin
  • keratinocytes once stimulated by IL-1 can be then stimulated by GMCSF(ganulocyte-macrophage colony stimulating factor)
    • Keratinocytes can secrete IL-6, IL-7, IL-12, IL-15, and IL-18, all of which can promote and shape the adaptive immune response
  • IL-1 receptor antagonist (IL-1ra) is found in high concentrations in keratinocytes
  • IL-10 has also been shown to be inducible in keratinocytes exposed to UVB radiation

Mast Cells

  • They degranulate in response to the cross-linking of FcεR receptors by IgE, and releasing preformed histamine and TNF-α, prostaglandins, and leukotrienes
    • mast cells prolifically secrete cytokines – Th2-promoting interleukins, IL-4, IL-5, and IL-13, and Th1-related factors, including IFN-γ, IL-12, and IL-18, as well as numerous chemokines and growth factors
    • Mast cell-derived IL-1, TNF-α, and histamine have clear impact on the permeability of the vascular endothelium

The Integrated Innate Response

 

  • Substance P is a vasoactive peptide
  • natural killer cells act on viral infections to identify and destroy affected host cells, which depend on immunogloublin receptors and molecules sensitive to the downregulation of MHC-I peptides on their host targets
  • Complement fragments (proteins that bind invading microorganisms, either perforating their cellular membranes or coating them for subsequent phagocytosis) are chemoattractive to neutrophils and stimulatory for degranu- lation of mast cells
    • Complement proteins/fragments active TLRs and Antimicrobial peptides(AMPs)
      • AMPs are genetically encoded molecules that contribute to the cutaneous “chemical barrier” protecting expose skin surface
      • human β-defensins (hBDs) and cathelicidins are both AMPs in the skin
      • Other cells can produce AMPs as well
  • hBDs and cathelicidins have been shown to attract dendritic cells, T lymphocytes, neutrophils, monocytes/macrophages, and mast cells
    • They also help in wound healing

The Interface between Innate and Adaptive Immunity

  • Cytokines of the innate immunity also develop/activate professional APCs
  • Relying on the NF-kB pathway, dendritic cells activated by keratinocyte-derived TNF-α, IL-1α, and IL-18 (or also activated by TLRs on APCs) are primed for effective antigen presentation to naïve T lymphocytes through a process that includes:
    • the enhancement of phagocytic activity
    • the upregulation of costimulatory molecules CD40, CD80, and CD86
    • increased cell-surface expression of class II MHC molecules
    • height- ened expression of chemokine receptors responsible for localizing dendritic cells to T cell-rich areas
    • the production of cytokines that aid in directing the T cell response (e.g., IL-12, IL-18, and IL-10)
  • T lymphocytes can bind almost any protein antigen (genetic recombination after T cells go from bone marrow to the thymus)
    • T cell receptors (TCRs) are membrane-bound heterodimers of either α/β or γ/δ subunits that recognize peptide fragments presented on MHC or MHC-like molecules
    • Most T lymphocytes express α/β TCRs
    • CD4 or CD8 on the surface of α/β T cells mediate TCR and MHC-antigen complexes
    • CD4+ cells interact with MHC class II molecules and CD8+ interacts with MHC-I (in viral infections)
    • In healthy epidermis, CD8+ cells outnumber CD4+ cells; in the dermis, these are more evenly distributed
    • CD4+ cells enhance the phagocytic attack on microbes and guides the flexible adaptive immune response
  • TLR- and cytokine- activated cutaneous dendritic cells downmodulate the expression of E-cadherin (surface adhesion molecule with high avidity for keratinocytes), then once mature bind and prime naïve CD4+ cells expressing appropriate TCRs

Completing the Cutaneous Immune Circuit

  • IL-12 and IL-23 stimulate the differentiation of activated CD4+ cells into Th1 cells (releasing IL2IFNgamma and TNFalpha, promoting T cell proliferation, reinforce the antimicrobial capacity of phagocytes, and induce the differentiation of cytotoxic lymphocytes)
  • IL-4 drives the conversion of activated T-helper cells into Th2 cells – these secrete IL-4, IL-5, IL-6, and IL-10, important in quelling inflammation, as well as in stimulating eosinophils and B cells (not present in healthy human skin)
    • Th2 cells fight parasites and are part of the allergic reaction usually
  • Some CD4+ cells don’t become effectors and instead become Memory T cells (enable a rapid secondary immune response in the setting of reinfection)
  • cutaneous lymphocyte- associated antigen (CLA) is a carbohydrate cell–surface receptor found on roughly 90% of cutaneous T cells during inflammation and only sparsely expressed on non-skin-homing T lymphocytes
    • CLA can bring about cytokines i.e. (CXCR2, CCR4, CCR6, CXCR3, and CCR10)
    • CLA-marked T cells are involved with skin diseases such as psoriasis, allergic contact dermatitis, atopic dermatitis, cutaneous graft-vs.-host disease, and cutaneous T-cell lymphoma
  • After pro-inflammatory cytokines are diluted, suppressive factors such as IL-10 and TGF-β predominate
  • dendritic cells support the differentiation of regulatory T-helper sub- types, including Treg and Tr1 cells
  • regulatory cells inhibit inflammation and T cell proliferation through both direct contact and secretion of IL-10 and TGF-β

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