1-5-09 The Immunology of the skin 1. Describe the major components of the immune system.

Describe the differences between the innate and adaptive immune responses. Delineate the components of the adaptive and innate immune systems of the skin and describe their methods of action. Understand differences between the cellular and humoral components of the immune system. Describe the different immunoglobulins active in the immunology of the skin. Recall that there is innate and adaptive immunity. Innate immunity is rapid and non-specific with no memory. It consists of: o Neutrophils: roll along the endothelium and phagocytose via hagolysosomes! where organisms are killed "y o#ygen-de endent and inde endent mechanisms. The o#ygen-de endent mechanism involves respiratory burst that roduces hydrogen ero#ide! hydro#yl radicals! and singlet o#ygen. The o#ygen-inde endent mechanisms involves cationic proteins and enzymes such as myelo ero#idase and lyso$yme %acra hages release G- !" and G#- !" to stimulate myeloid recursor division in the "one marrow! resulting in the release of millions of neutro hils into circulation. o $osinophils: rotect the host from infection "y arasites! which associate with antigen-s ecific Ig& 'eosino hils ( arasites and allergic reactions) &osino hils "ind to Ig& via low-affinity receptors called "c-epsilon-%&&. &osino hils are only weakly hagocytic 'unlike macro hages and neutro hils)! "ut can have a athologic role in allergic reactions. o N' cells: eliminate infected or malignant cells o #ast ells: mast cells are located in tissues! while "aso hils are in the "lood. *oth bind avidly to IgE via e# ression of high affinity rece tors for the anti"ody! called "c-epsilon-%&. *inding causes immediate allergic reactions! such as anaphylaxis and angioedema. That+s "ecause activated ,c-e silon-RI leads to degranulation and release of histamine! serotonin! prostaglandins! leukotrienes '*-! .-! /-! &-! and 01,)2which enhance vascular permeability! bronchoconstriction! and induction of inflammatory response. o omplement: involves 30 serum glyco roteins that result in enhanced phagocytosis and APC recognition. The roteins include the anaphylatoxins (a! )a! and *a4 all stimulate mast cells to increase vascular permeability to encourage antibodies to enter tissue. .5a is a strong chemoattractant. The #+ com le# is com osed of .5"! .5! .6! .7! .9. It unches holes in mem"rane causing death "y osmotic lysis. o antimicrobial peptides: includes defensins like human "eta-defensin 'h,D--) and catheliecidins o cytokines: low molecular eight messenger su"stances that can act autocrine! aracrine! or endocrine via "inding to cell surface rece tors. They include

interleukins 'I8) which are leukocyte oriented! colony-stimulating factors '.9,) that act as hematopoeitic progenitors! and interferons 'I,:) which interfere with viral replication o toll-like receptors: recognition of micro"ial and viral com onents. They "ridge the ga "etween innate and ada tive immunity. /endritic cells e# ress toll-like rece tors 1da tive immunity: defined "y memory 's ecificity! im rovement with each encounter) and antigen presentation '/.+s stimulating na;ve T cells! initiating rimary immune res onse). It consists of: o Dendritic cells: function in stimulating na;ve T cells and initiating a rimary immune res onse. They have to main locations: /.+s in the T cell areas of the spleen and lymph nodes are the most effective 10.s /.+s in the epidermis are known as .angerhans cells 8angerhans cells are derived from the *%! des ite their e idermal location. They can "e identified with electron microsco y or histochemical analysis that stains for A Pase and has anti"odies directed against 8. antigenic moieties ' D1a is the most useful marker). They are distinctive in having ,irbeck granules in histochem. Their 10. function in the skin allows for initiation of sensitization 'as evidenced "y the lack of contact sensiti$ation in skin devoid of 8angerhans cells de leted "y <=). In inflammation! 8angerhans cells actually migrate to lymph nodes. 1ntigen resentation occurs in lym h nodes! not in the skin. 1s usual! ./- T cells recogni$e antigens resented on %>. class II 'which resent exogenous antigens that result form endocytosis? rotein degradation in endolyso$omes)! while ./7 T cells recogni$e antigens resented on %>. class I 'which resent endogenous antigens that are either viral or tumor) o The %>.-II is critically dependent on dendiritic cells! " cells! and monocytes#macrophages unlike %>.-I o / cells: they develo in the *%! migrate to the thymus for selection. positive selection 'only T cells that recogni$e self %>. are allowed to survive) occurs in the corte# of the thymus. 95@ of T cells get selected out in ositive selection. negative selection 'T cells that recogni$e self e tides dis layed on self%>.s are eliminated) occurs in the medulla of the thymus Immature T cells e# ress "oth ./- and ./7 'the Adou"le- ositiveB stage). &ventually! one of the surface markers is lost! giving the T cell s ecificity to %>. II and %>. I! res ectively. T cell signaling reCuires two signals: "irst signal: T.R "inding to e tide-%>. com le# on 10.s '"asically the antigen "eing resented) o this determines specificity

o "inding of first signal without the second costimulatory signal results in anergy followed "y a o totic cell death !econd 0costimulatory1 signal: surface molecules and cytokines o ,unctions in romoting clonal expansion of T cell as well as T cell differentiation into effectors and memories T hel er cells './-) recogni$e foreign antigens and activate #& to eliminate athogens! as well as activating , cells. There are three ty es of hel er effector cells: /h2: precursor that e# resses I8-3! I,:gamma! T:,-"eta! I,:! I8--! I8-5! I8-5! I8-9! I8-1D 'won+t really "e tested) /h1: e# resses I,:-gamma! T:,-al ha! and I8-3 to induce a cell-mediated inflammatory res onse /h-: e# resses I8--! I8-5! I8-5! and I8-10 to favor antibody production! cause allergic disdease! cause atopic asthma! and systemic lupus erythematosus. I8-- in articular stimulates * cells to roduce Ig&! while I8-5 romotes eosino hils and I8-10 inhi"its Th1. .ytoto#ic T cells './7) focus on endogenous antiviral and antitumor res onses. They have two athways for killing: Inserting perforins into the cell mem"rane 1ctivating death receptor "as './95) via death ligand "as. './958) to trigger a o tosis o .ostimulator molecules include the ,3 family members '*6-1 aka ./70! or *603 aka ./75) 0ositively regulates D-4 rece tor on T cellscauses crosslinkinge# ression of antia o totic genes and roduction of cytokines like I83 o / cell receptors 0/ %s1: defined "y their diversity. 9 ecific rece tors for every ossi"le antigen are encoded "y fewer than -00 genesE This is made ossi"le "y recombination of varia"le region genes2 =aria"le '=) /iversity '/)2only in T.R and T.R loci Foining 'F) .onstant '.)

&ach T.R uses a different com"o! with additional nucleotides "eing inserted "y deo#yri"onucleotidyl-transferase The maGority never encounter their antigen o , cells and immunoglobulins: the maGor role of * cells is roduction of immunoglo"ulins. D15! D-2! and D-- are the main markers. 1ctivation leads to maturation! or the secretion of s ecific anti"odies. &ach Ig contains two identical light chains and two identical heavy chains. They are linked together "y disulfide "onds! and the :-terminal functions as the "inding site. The ./R region of Ig+s recogni$e e ito es! so no antigen presentation is re$uired. &#tensive gene rearrangement creates diversity. &g#: the largest Ig at 900 k/a .ontains one F chain Induces rimary immune res onse: romotes agglutination and activates classical com lement &gG: the most abundant Ig! com rising of 65@ of all anti"odies. There are - su"classes 'IgH1-IgH-)! with IgH1 and IgHD "eing activators of classical com lement. %oreover! autoimmune anti"odies are mostly mediated "y IgH. &g+: this is the mucosal Ig. It activates the alternative athway. There are 3 su"classes 'Ig11 and Ig13). Ig1 is res onsi"le for athogenesis of "ullous autoimmune diseases. &g$: this is the ana hylactic anti"ody! for immediate ana hylactic reactions. 0resence of Gust a few are needed for sensiti$ation. o U6, radiation '390-D30 nm) su resses the skin immune system and causes reactivation of herpes simplex virus. Trans lant atients have increased chance of skin cancer.