Key features B_ The major purpose of the immune system is protection against harmful organisms, which is achieved by a rapid “primitive” reaction, called the innate immune response, and a more highly developed specific reaction, called the adaptive immune response. B_ The characteristics of an adaptive immune response are specificity and the accumulation of memory thus enabling improvement with each successive encounter with a particular antigen mS The key event in an adaptive immune response is antigen presentation, yielding either a cell-mediated or a humoral response. The cellular response involves primarily T cells, whereas the humoral response involves B cells that ultimately mature into antibody-secreting plasma cells = Immune responses are not always protective and can even be pathogenic ifthe response induces severe tissue destruction ors directed against an autoantigen mAs a barrier organ to the outside environment, the skins endowed ‘with the capacity and the necessary cellular components to mount an immune response {TRODUCTION .e skin is in a sense a defense organ, since it represents a major crier against the outside environment, As such, itis constantly con- mnted with microbial, chemical and physical insults, Within the past ree decades, there has been a greater appreciation for the fact that ¢ skin not only functions as a mechanical barrier to the outside world, t also uses the immune system for protection. Accordingly, the skin endowed with the capacity to generate an immune response, which ve rise to the term “skin-associated lymphoid tissues” [SALT The classical immune response, also referred t0 as the adaptive mune response, is characterized by specificity that is due to immu- logic memory (specific immunity|’. Innate immunity is 2 more imitive defense system that acts in a rapid but less specifie manner. th types of responses can be generated in the skin. Adaptive immune sponses in the skin, however, are not always protective but can also ‘harmful in nature, e.g. allergic or autoimmune reactions. Numerous in diseases are caused by T lymphocytes and are therefore immuno- ically mediated. Consequently, many dermatoses respond favorably immunosuppressive therapy administered either systemically or cally INATE IMMUNE RESPONSE nate immune responses are characterized by a lack of immunologic emory, These immune reactions are less complicated than adaptive sponses and developed earlier in evolution’. Nevertheless, failures in ese “primitive” immune responses may be associated with severe, cn fatal, health problems. Essential components of the innate sponse are neutrophils, eosinophils, natural killer cells, mast cells, cokines, complement and antimicrobial peptides. The innate response more rapid and less conttolled than the adaptive immune response, omplement ,e complement system plays an important role in innate immunity consists of at least 20 serum glycoproteins what are activated by an Immunology A Thomas Schwarz enzymatic amplifying cascade (see Ch. 60]. Three pathways can trigger this cascade, The classical pathway is stimulated by antigen-antibody complexes, the alternative pathway by polysaccharides derived from microbial cell walls, and the more recently identified lectin pathway by the interaction of microbial carbohydrates with mannose-binding pro- teins. All three pathways lead to activation of the central C3 component and, finally, the generation of a number of immunologically active substances. For example, C3b, the cleavage product of C3, binds to the surface of microbes. Since phagocytic cells express receptors for C3b, phagocytosis of the microorganisms is enhanced. In addition, comple- ‘ment components bind to antigen-antibody immune complexes, which helps complement receptor-bearing antigen-presenting cells to target these immune complexes Ca is a powerful attractant for neutrophils. C3a, C4a and C5a, also called anaphylatoxins, induce the release of inflammatory mediators from mast cells. This increases vascular permeability, thereby enabling proteins (e.g. antibodies) to enter the tissue. Assembly of the comple- ment components C5b, C6, C7, C8 and C9 forms the membrane attack complex {MAC}, which generates pores in cell membranes, tcausing death by osmotic lysis. Human cells are much less susceptible to killing by complement than are microbes, since human cells express the complement receptor type 1 (CRI, CD35}, decay-accelerating factor (DAF, CD55) and membrane cofactor protein (MCP. CD46\, which Inhibit C3 convertase and thereby block progression of the complement cascade, CD59 is a protein that binds to C8 and inhibits insertion of C9 into the cell membrane. Toll-Like Receptors Innate immunity serves to recognize invading microorganisms and then induce a host defense response. Several families of pattern recognition receptors {PRRs} mediate responses to pathogen-associated molecular patterns (PAMPs} that are conserved among microorganisms. Toll-like receptors [TLRs; the mammalian homologues of the Toll receptors sdentfied in Drosophila) axe one such family of PRRs. Ten TLRs have been identified to date’ (Fig. 4.1), with the following specificities: TLR2 {in association with either TLRI or TLR6}, recognition of lipoproteins and peptidoglycans; TLR4, lipopolysaccharide, TLRS, flagellin [a com- ponent of bacterial flagellal, and TLR9, bacterial CpG DNA sequences. TLRs may also be involved in the recognition of viral components ‘The signaling pathway of TLRs is highly homologous to that of the receptor for interleukin-1 {IL-1}. Upon interaction with myeloid dif ferentiation factor 88 |MyD88}, IL-1 receptor-associated kinase |IRAK) 3s recruited, ultimately leading to activation of the transcription factor NE-xB (see'Fig. 4.1). Activation of TLRs can also result in the release ff interferons (IENs} via activation of interferon regulatory factor 3 URE-3) Dendritic cells express several types of TLRs. Upon activation of these receptors by microbial components, the dendritic cells mature and migrate to the lymph nodes, where they present pathogen-derive antigens to naive T cells and induce an adaptive immune response. TLRs thereby bridge the gap between the innate and adaptive immune systems’, These two systems constantly interact in the skin, and the innate immune system represents a potential target for modulating adaptive immune responses’. Cutaneous dendritic cells that ate stimu lated by the innate immune system not only instruct T cells to respond but also tell them how and where. Different PAMPs and danger signals polarize dendritic cells, giving them the ability to produce certain cytokines and to induce T cells to differentiate into particular subtypes. Many of these danger signals are provided by keratinocytes, which also express PRRs. In addition, TLRs expressed in the skin direct control of pathogens by the epithelium,booksmedicos.org Taya looprtens Diarylates Ioeptotens gin Tc op Guinclones RNA DNA Antimicrobial Peptides “To cope with an environment that is full of microorgenisms, plants and invertebrates produce a vanety of highly effective antimicrobial proteins. Human epithelia, including the epidermis, secrete such anti- microbial peptides as a mechanism of innate defense. The first anti- ricrobial peptide tobe found in human skin (specifically from psonatic scales) was human fedefensin-2 [hBD-2)" A number of other ant microbial peptides have subsequently been isolated [Table 4.1}. In addi- tion to antibacterial properties, some of these peptides. possess antimycotic and likely antiviral activities. As demonstrated for psoria- sin, which prevents Escherichia coli infection’, these peptides may protect the skin from bacterial infections. Expression of antimicrobial peptides can be induced by bacteria, bacterial products or proinflam- atory cytokines via TLRs and other mechanisms. Enhanced and decreased production of these peptides in psoriasis and atopic derma- iis, respectively, may explain why superinfections ate so Fare in the former disease and common in the latter'’. However, others have found enhanced expression of antimicrobial peptides in atopie skin, which may reflect disruption of the epidermal barrier, Ultraviolet {UV} B radiation has been show to indvce expression of antimicrobial peptides, potentially explaining the lack of UVB-related bacterial infec- tions despite its immunosuppressive effects (see Ch. 86". ‘Betasdefensins can also attract immature dendaie cells and memory T ells via the chemokine receptor [CCR)6, illustrating another link between innate epithelial defense and adaptive immunity'*. The antimicrobial peptide LL-37 (also known as cathelicidin antimicrobial peptide [CAMP]} mediates dendntic cell activation in psoriasis by bunding selEDNA and forming structures that sumulate TLRO and thereby induce IFN production". Cytokines Cytokines are a large, heterogeneous family of low-molecular-weight messenger substances that play 2 crucial role in intercellular commu- nication. Cytokines can be secreted by almost any cell type, and they may act in an autocrine, paracrine or endocrine manner. Cytokines ‘exert their biologic activities by binding to specific cell surface recep- tors" Althougia the vast majority of cytokines occur in a soluble form, ean Fig. 4.1 Tolliike receptors, ther ligands and signaling pathways. Toll-like receptors (TLRS) recognize pathogen-associated moleculer patterns andlor synthetic compounds in a specific fashion. TLR2/TLAI dimer recognizes triacyated lipoprotein and a TLR2/TRLS dimer interacts with diacylated Tipoproteins. TLRS recognizes fagelin and TLR4 recognizes lipopolysaccharide (.P5) These TLRs ae located on the cell membrane and are internalized {pon ligand interaction. TUR3,TLR7, TLRB and TLAS are located on intracellular membranes of tendosomes and lysosomes. TLR3 recognizes viral double-stranded RNA (dsRNA) TLR7 and TLRS viral single-stranded RNA (ssRNA, and TLRS bacterial an viral hypomethylated DNA (CpG mati) TLR7 and “TLRG also bind to synthetic compounds (imidazoquirolones) Al TLRs except TLRS utilize ryelold differentiation factor 88 (MyD88) for signaling, while TLR2 and TLR4 also require Tol. interleukin-l receptor domain-containing adaptor protein TIRAP). MyD88 signaling via IL receptor- associated kinase-4 (RAK) and tumor necrosis factor receptor-actvated factor-6 (TRAF-S) mostly results activation of nuclear factor xB (NF-KB), Lltimacely inducing transcription of genes encodin immunomodulatory and proinammatory molecu! TLRS and TLR signal via MRedomain-containing adapter-inducing interferon-B (TRF). The TRF pathway induces the production of interferons (FN Via interferon regulatory factor-3IRF3) Both the ligand and signaling pathway of TLR10 are still some can be membrane-bound, making the differentiation betwe cytokine and receptor difficult, Cytokanes in‘luence the proliferatio differentiation and activation of cells. Each cytokine exhibits multi activities, a fact that complicates strict categorization. Cytokines that are produced by leukocytes and exert effects prefere sally on other white blood cells are called interleukins |IL). Colon stimulating factors {CSE} are mediators that induce differentiation a proliferation of hematopoietic progenitor cells, while IFNs interi ‘with viral replication. Cytokines that have chemoattractant activity termed chemokines, and they play a crucial ole in leukocyte migratio ‘The main subgroups of chemokines are differentiated according to t position of two cysteine (C} residues compared with the other ami acid residues [XI, CXC fa-chemokines) and CC |p-chemokines| (Chemokines that reeruit leukocytes are termed inflammatory chemo ines, wheres those that regulate trafficking within lymphoid tissu are called lymphoid chemokines, Early innate immune responses are dominated by cytokines wi inflammatory (eg. IL-1, IL-6, IL-18, tumor necrosis factor-o: [TNF inflammatory chemokines) and antiviral (eg. EN-, LEN-S) capaci Induction of adaptive immune responses is critically dependent cytokines with immunomodulatory capacities [e.g IL-2, IL-4, IL-1 IL-13, IL-17, 1L-22, IL-23, IFN-). However, since most of these medi tors exiubit’ multiple and sometimes overlapping activities, a str separation into inflammatory and immunomodulatory cytokines is n possible. Due to structural similarities, some cytokines are group into families, eg the IL-6 family |IL-6, IL-11, oncostatin M, leaker inhibitory factor [LIF|), the IL-10 family {IL-10, IL-19, 1L-20, IL-2 11-24, 1-26) and the I-12 family (IL-1, 1L-23, 1L-27| Macrophages and Neutrophils Macrophages, phagocyte ells derived fom blood-borne rmonoey carry receptors for carbohydrates that are usually not expressed « ‘vertebrate cells (e.g. mannose). Through this mechanism, mactophag can discriminate between “foreign” and “self” molecules. Furthermor tracrophages possess receptors for anubodies and complement Hen IRictooranism that are coated with antbodics and/or complement more readily phagocytosed'’, After phagocytosis, the microorganisr ave exposed to a varegy of tone inuselular molecules, nellbooksmedicos.org \ntleukoprotease Keratinocytes AP) Airway epithelia ermcidin (OCD Sweatlands Hee luman B-defersin 43 Keratinocytes (HY et HED}? Aleway epithelia. Intestinal tract 903 52 Keratinocytes H+ He ‘Aleway epithelia. (80-4 60 Keratinogyes tt Ht Airway epithelia. (mana) srleatheledin 45 Keratinoeyes tt He imicrobial peptide ‘Airway epithelia. CAMPYYhuman Urogenital tact ationic antimicrobial Granulocytes eptide 18 (HCAPTS) ysozyme 147 Keratinocytes ++ 4 ‘Airway epithelia. srisin M14 Keratinocytes. Sebocytes Nase 145 Keratinocytes ate ote ‘Airway epithelia Ia gh concentrations Eco ces n high concerns peroxide anions, hydroxyl radicals, hypochlorous acid, nitric oxide, jozyme and antimicrobial cationic proteins. Macrophages can also esent processed antigens to T and B cells, However, their T-cell mulatory capacity is less effective than that of dendritic cells Activated macrophages release granulocyte colony-stimulating factor CSF) and granulocyte-macrophage colony-stimulating factor (GM- 5F|. These two cytokines induce the division of myeloid precursors the bone marrow, releasing millions of neutrophils into the circula- 18. Under normal conditions, neutrophils circulate in the blood- eam, some rolling along the vascular endothelium’. To enter the site fan infection, neutrophils utilize a complex process that involves cinlammatory mediators, adhesion molecules, chemoattractants d chemokines [sce Ch. 26), The recruited neutrophils phagocytose ganisms and kill them within phagolysosomes by using oxygen- pendent and oxygen-independent mechanisms, The former, called ¢ respiratory burst, involves the production of hydrogen peroxide, droxyl radicals and singlet oxygen. The axygen-independent method lizes highly toxic cationic proteins and enzymes, such as mycloper- idase and lysozyme. Organisms that are coated with antibodies or mplement components bind to Fe and complement receptors, respec ely, on neutrophils jas well as macrophages} and are more effectively agocytosed and killed osinophils 4e major function of eosinophils is most likely to protect the host mm infections by parasites, particularly nematodes, Infections with ese organisms are associated with the production of antigen-specific P antibodies that coat the parasite. Via their low-afhnity receptors ERI, CD23), cosinophils bind to IgE antibodies and become acti- ted. in contrast to macrophages and neutrophils, eosinophil are ly weakly phagocytic. They harbor large granules that contain sor basi protein, eosinophilic eatin protein, eosinophil perox- se and cosinophil-derived neurotoxin (we Ch. 25). Upon activation, sinophils release these toxte products, which can kil parasitey, gether with prostaglandins, leukotrienes. and various cytokines” sinophils also play an important role in the pathogenesis of allergic tions ‘Table 4.1 Skin-derived antimicrobial peptides. Basophils and Mast Cells Basophils found in the blood) and mast cells (located within tissues} exhibit similar functional and morphologic characteristics”. At least too populations of mast cells exist, which can be differentiated by the enzymes they contain and by their tissue location, Mucosal mast cells contain only uypsin, while connective tissue mast cells contain both ‘trypsin and chymotrypsin (sce Ch. 118). In contrast to pulmonary, serine and tonsillar mast ces, cutaneous mast ccls express the recep” tor for C5a {CD88}, which implies that triggering of mast cells through the anaphylatoxin ‘5a results im eutangnts, but not systemic, reac- Gions" Basophils and mast cells express higheafinity receptors for IgE iFeekt) that avidly bind IgE [sce Ch. 18} When a specific antigen binds to mast cel-bound IgE, the Foe becomes activated, which leads to degranulation and release of pre- formed mediators, including histamine and serotonin. Other mediators such as prostaglandins, eukotrienes {By C,, D, and E,), and platelet activating factor are also released, and they enhance vascular permeabil- iy, bronchoconstriction and induction of an inflammatory response {see Ch. 18}, Hence, basophils and mast eels play an imporeant role sn immediate-ype allergic reactions such as urticaria and angioedema ‘There sal increasing evidence that mast calls ae involved in contact hypersensitivity reactions Natural Killer Cells ‘The major task of natural killer (NK) cells is to climinate virally infected or malignant cells”. NK cells can recognize their targets in two ways. Since they express Fe receptors that bind IgG (FeyRITI, CD16|, NK cells can adhere to and kill target cells that are coated with IgG. This killing process is referred to as anuibody-dependent cellular eyto- toxicity |ADCC|, the biological value of which remains unclear ‘The second recognition system involves killer-activating and killer- inhibitory receptors, Killer-activating receptors recognize molecules that are expressed by nucleated cells. This provides a signal for the NK cell to kill the target cell by secretion of perforins, which make holes inthe cell membrane through which granzymes are injected. Granzymes lyse target cells by activating the apoptotic caspase cascade. In addition, NK cells carry inhibitory receptors (KIR) on their surface