Photoneuroimmunology: Modulation of the Neuroimmune System by UV Radiation

Introduction

  • Sunlight contains
    • visible light (400–700 nm)
    • ultraviolet radiation (UVR)
      • UVA radiation as 400–320 nm ~95%
      • UVB radiation as 320–290 nm ~5%
      • UVC radiation as 290–200nm ~0% (blocked by ozone)
  • UVR is immunomodulatory
    • immune responses in neuropeptide-depleted mice are not suppressed by UVR
    • Caspaicin (w/in 48hr of UVR) reversed effect
    • Neuropeptides and neuroendocrine hormones both contribute to UV-induced immunomodulation, as well as to adaptive responses of skin to UV.

Photoneuroimmunology, Health, and Disease

  • Tumors develop in mice treated with a carcinogenic dose of UVR
    • UVR induces DNA damage and also modulates the immune system
    • Being on immunosupressants make UVR damage worse for predisposing your to cancer
    • UVR-induced immunomodulation protects against over-zealous responses to nuclear antigens exposed by UVR-killed (sunburn) cells
  • UVR is used to treat psoriasis
    • It can suppress the immune system – affects response to vaccines and infectious agents
    • individuals living at low latitudes may have an enhanced susceptibility to infectious diseases (since there is more UV)
    • living at higher latitudes have an enhanced incidence of multiple sclerosis and other autoimmune (b/c there’s a reduction in immunosuppressive UV radiation)
  • UVR increases 1,25 (OH)2 vitamin D3
  • UVR-induced local immunosuppression – involve modified antigen presentation by UVR-damaged Langerhans cells or immature dermal dendritic cells
  • systemic immunosuppression – erythemal amounts of UVR are required
  • Dermal mast cells in UV radiation – essential for UV-induced local immunosupression (and suppression of delayed type hypersensitivity responses to allogeneic spleen cells)
    • prevalence of mast cells correlates directly with their susceptibility to UV-induced systemic immunosuppression
    • There are larger concentrations of dermal mast cells (when cells carry Uvs1, a major locus for susceptibility to UV-induced immunosuppression)
    • Being mast cell-depleted, makes you non-susceptible to UV-induced systemic immunosuppression
  • Mast cells produce chemokines (such as TNFa, IL10 and Histamine)
    • Histamine can induce immunomodulation
      • It stimulates Prostaglandin E2 production
      • Prostaglandin E2 can work locally or systemically on epidermal cells in lymph nodes
      • Prostanoids are responsible for at least 50% of the systemic suppression of contact hypersensitivity responses caused by UV irradiation
      • Histamine modulates the maturation and activation of dendritic cells
    • neuropeptides are the major mechanism of IgE-independent mast cell activation

Skin Photoreceptors for UVR. Links to the Neuroimmune System

  • Very little UVB radiation penetrates skin beneath the epidermis
    • cellular DNA damage
      • cyclobutane pyrimidine dimers is the predominant DNA lesions in whole human skin exposed to UVA and UVB radiation
      • UVR damage makes LCs worse at presenting antigens (in lymph nodes) – suppressing immunity to the antigen and inducing regulatory cells and tolerance to antigens
    • oxidation of membrane proteins
      • UVR causes the oxidation of phosphatidylcholine in the membranes of irradiated skin cells
        • oxidized phosphatidylcholine binds to, and activates:
          • receptors for platelet activating factor on cells
          • Which activates MAP kinases, phospholipases, and gene transcription
    • alterations to intracellular signaling events
  • trans-urocanic acid (Trans-UCA [deaminated histidine]) – molecular species located superficially in the stratum corneum of skin
    • It is converted to its more soluble cis isomer, when exposed to UVR
    • Helps cause immunosuppression by UVR
    • UCA isomers in human urine may be a biomarker of recent UVA/UVB radiation exposure
    • cis-UCA also modulates the immune system in UV-induced cells

Stimulation by cis-Urocanic Acid of Neuropeptide Release from Peripheral Sensory Nerves

  • cis-UCA, but not trans-UCA, can activate sensory nerves in skin to release neuropeptides
    • cis-UCA increases microvascular (blood) flow
    • cis-UCA relies on neuropeptides, substance P, and calcitonin gene-related peptide (CGRP), or else it is not immunomodulatory
    • cis-UCA can reduce immune response to hapten
    • cis-UCA binds competitively to receptors for γ-amino-butyric acid(GABA), but doesn’t change blood flow
    • cis-UCA binds a histamine receptors, but doesn’t change blood flow
    • cis-UCA binds to the 5-hydroxytryptamine (5-HT)2A receptor
    • cis-UCA suppresses lipopolysaccharide-induced TNFα production by human monocytes

Immunoregulatory Properties of UVR/ cis-Urocanic Acid-Induced Neuropeptides – Calcitonin Gene-Related Peptide

  • UVR-induced CGRP is responsible (CRITICAL) for some suppressive properties of UVB on local contact hypersensitive responses
    • CGRP can reduce Ia-positive epidermal antigen presenting cells
    • CGRP reduces immunoregulation caused by a single (and multiple) erythemal dose of UV
    • CGRP downregulates LCs (major antigen presenting cells of the epidermis)
      • increases production of cyclic AMP by adenylate cyclase and augmentation of lipopolysaccharide- and granulocyte-macrophage colony stimulating factor-induced IL-10 production
      • IL-10 downregulates CD86 and inhibits antigen presentation by Langerhans cells

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