2 Immunodermatology                                                                                Eric Huang, MD, PhD    ...
Committed to Your Future       For practice exam questions and interactive study         tools, visit the Dermatology In-R...
2.1   THE INNATE AND ADAPTIVE IMMUNE SYSTEMS    It is helpful to divide the immune system into two complementary branches ...
Adaptive Immunity    • Delayed response (initially)    • Memory (stronger elicitation responses upon re-exposure)    Recep...
Mast Cells     •  Provide protection against bacteria and parasites     •  Express high levels of FcεRI (receptor for IgE)...
T Cells     • Progenitors arise in the bone marrow, but migrate to thymus for maturation     • Subdivided into functionall...
CD8+ T Cells      • Kill by releasing granules containing perforin and granzymes, which induce apoptosis      • May also i...
2.3 CYTOKINES     Cytokines are a structurally diverse group of molecules that have important local and sys-temic effects ...
TH2 Cytokines     • IL-4: Differentiation toward TH2 cells; isotype switching to IgE and IgG4, inhibition of       macroph...
Table 2-2. Cytokine Activities (cont.)    Cytokine     Produced by           Target cells             Action    IL-12     ...
• Cervarix vaccine directed against HPV 16, 18. Approved for females 10-25 years old   • Zostavax indicated for prevention...
binding lectin. All act via sequential recruitment, proteolytic activation and assembly,with the ultimate endpoint being f...
   • HAE type II is less common, due to normal levels of non-functional C1 INH     • Acquired angioedema (AAE) is due to ...
• Chronic Idiopathic Urticaria: HLA-DR4, HLA-DRB4 53, HLA-DQ8    • Herpes gestationis: HLA-DR3, HLA-DR4    • Pemphigus: HL...
Other   Ustekinumab (Stelara)   •	 Human monoclonal antibody that binds p40 subunit of IL-12 and IL-23   •	 Mechanism of a...
13.	 Garcia Bracamonte B, Ortiz de Frutos FJ, Iglesias Diez L. Occupational allergic contact dermatitis due to     formald...
37. Yancey KB, Kirtschig G, Yee C, Lazarova Z. Studies of patients with anti-epiligrin cicatricial pemphigoid. J     Derma...
NOTES48  2011/2012 Dermatology In-Review l Committed to Your Future
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  1. 1. 2 Immunodermatology Eric Huang, MD, PhD William R. Levis, MD Georgia B. Schuller-Levis, PhDC o n t e n t s2.1 The Innate and Adaptive Immune Systems . . . . . . 332.2 Cells of the Innate and Adaptive Immune System . . . 342.3 Cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 382.4 Antibodies and Complement . . . . . . . . . . . . . . . . . . . . 402.5 Major Histocompatibility Complex and HLA Disease Associations . . . . . . . . . . . . . . . . . . . . . . 432.6 Non-Steroidal Immunologic Therapies . . . . . . . . . . 44 Immunodermatology 31
  2. 2. Committed to Your Future For practice exam questions and interactive study tools, visit the Dermatology In-Review Online Practice Exam and Study System at DermatologyInReview.com/GaldermaSponsored by
  3. 3. 2.1 THE INNATE AND ADAPTIVE IMMUNE SYSTEMS It is helpful to divide the immune system into two complementary branches based upon theplasticity of their responses. The innate immune system is often ascribed non-specific recep-tors, but it is more accurate and useful to understand that it uses pre-determined receptors thatspecifically recognize non-self pathogens but not self antigens. In contrast, the adaptive immunesystem relies upon gene rearrangement to produce receptors specific for individual antigens, andthese receptors may potentially bind both non-self and self antigens. The immune system is composed of both cellular and non-cellular components. Keratinocytesand mucosal epithelia provide a physical barrier against pathogens and can also secrete cytokinessuch as TNF and IL-1. Soluble factors such as antimicrobial peptides and canthelicidins, comple-ment, cytokines, and antibodies assist the cellular components (leukocytes). Leukocytes aresubdivided by function into granulocytes (neutrophils, eosinophils, mast cells, basophils), lympho-cytes (B cells, T cells, natural killer cells), and monocytes (called histiocytes in tissue; Langerhanscells in the epidermis).Innate Immunity u TIP • Rapid response, “first line of defense” aTLR7 binds imiquimod; native • Lack of memory: Repeated exposure does not change the ligand is ssRNA response • Provides initial inflammatory signals which recruit lymphocytes (adaptive immunity) • Lack of innate inflammatory signal may induce tolerance by adaptive immunity Receptors • No gene rearrangement, limited antigen recognition repertoire • Germline-encoded, distinguish non-self from self u TIP •  attern recognition receptors include toll-like receptors (TLR) P a - and nucleotide oligomerization domain receptors (NODs); these Decreased expression of anti microbial peptides in atopics receptors recognize PAMPs (pathogen-associated molecular vs. psoriatics may explain increased cutaneous infection patterns) in the former • TLR family has 13 members. Highest expression levels are found in monocytes, dendritic cells, and B cells • TLR7 binds imiquimod, expressed on melanocytes, native ligand is ssRNA • TLR7 activation results in pleiotropic responses, including u TIP antigen presenting cell (APC) activation and cytokine aCytokines: particularly TNFα, production (IL-12, IFNα, TNFα) IL-1, IL-10, IL-12, IFNα, IFNβ • TLR2 may be activated in inflammatory acne • TLR2 and TLR9 polymorphisms associated with atopic dermatitis Non-Cellular Components • Antimicrobial peptides: defensins and canthelicidins are u TIP produced by phagocytes and keratinocytes and directly kill aDEFB4 implicated in genetic bacteria, fungi, and viruses association studies with development of psoriasis • DEFB4 encodes β-defensin 2 • Complement: see below Cellular Components • Macrophages, neutrophils, natural killer cells, mast cells, eosinophils, intraepithelial lymphocytes Immunodermatology 33
  4. 4. Adaptive Immunity • Delayed response (initially) • Memory (stronger elicitation responses upon re-exposure) Receptors • Gene rearrangement leads to randomly generated receptors with ability to recognize millions of antigens  •  o not distinguish self from non-self D • Require antigen presentation in context of MHC molecules Non-Cellular Components u TIP • Antibodies: see below aCytokines: particularly IL-2, Cellular Components IL-4, IL-5, IFNγ, TGFβ • T cells, B cells, Langerhans cells2.2  CELLS OF THE INNATE AND ADAPTIVE IMMUNE SYSTEMPhagocytes (Macrophages and Neutrophils) • Identify microbes using receptors for mannose, opsonins, and TLRs • Ingest pathogens •  estroy pathogens by producing reactive oxygen intermediates via phagocyte oxidase, D nitric oxide via inducible NO synthase, and lysosomal enzymes such as lysozyme, elastase, and collagenase • Activated by CD4+ and CD8 + T cells through IFNγ and CD40L u TIP • Phagocytes are unable to kill intracellular organisms (screening aDefect in phagocyte oxidase leads to chronic granuloma- test nitroblue tetrazolium reduction assay) tous disease Mononuclear Phagocytes • Once localized in tissues, are called macrophages • In addition to phagocytosis, macrophages degrade foreign antigens or cells into peptide antigens for presentation to T cells • Express Fc receptors for IgG • Produce cytokines which recruit other inflammatory cells Neutrophils • The most abundant leukocyte • Major function is phagocytosis • Have receptors for IgG and complement • Have many storage granules • Hereditary deficiencies of neutrophil function lead to overwhelming bacterial infection, which can be fatalGranulocytes •  Neutrophils, eosinophils, mast cells, and basophils are collectively known as granulocytes Eosinophils •  Provide protection against helminths •  Function through antibody-dependent cell-mediated cytotoxicity via IgG and IgE (independent of complement) • Release major basic protein (toxic to all cells, but particularly helminths) and leukotrienes • Activated by IL-534  2011/2012 Dermatology In-Review l Committed to Your Future
  5. 5. Mast Cells •  Provide protection against bacteria and parasites •  Express high levels of FcεRI (receptor for IgE) •  elease histamine, prostaglandins, leukotrienes, cytokines, tryptase (elevated in serum of R patients with mastocytosis) u TIP •  Central cell in immediate-type hypersensitivity a dult mastocytosis most frequently A through IgE-mediated release of histamine related to activating mutations in c-kit •  Many cases of idiopathic urticaria have circulating tyrosine kinase (but not childhood disease) autoantibodies directed against the chain of high affinity IgE receptor on the mast cell surfaceMonocytes Langerhans Cells • Immature dendritic cells found in epidermis and mucosa • Migrate to regional lymph nodes upon Ag capture, undergoing maturation to become antigen presenting cell (APC) • Present processed peptide associated with MHC II to T cells (primarily CD4+), resulting in T cell activation u TIP •  xpress surface marker CD1a E a irbeck granules (characteristic B • Adhesion to keratinocytes mediated by e-cadherin racket shape on EM) are part of • Express B7 molecules (CD80 or CD86) only after activation endosomal recycling compartment by antigen or other exogenous stimuli • TGFβ upregulates e-cadherin expression and maintains Langerhans cells in immature state • Adjuvants work through APCs to increase costimulatory molecule expression and cytokine expressionLymphocytes These cells are primarily responsible for the specificity of the immune response. Lymphocytesare triggered by a specific antigen to produce antibodies (B cells), cytokines (CD4+ T cells) orcause direct cytotoxicity (CD8+ T cells). Natural Killer Cells • dentify virally-infected or transformed (tumor) host cells via their down-regulation of self- I MHC I • Possess activating and inhibitory receptors • Activating receptors bind ligands common to self • Inhibitory receptors identify self-MHC I; if stimulated, dominantly inhibit NK cell activity • Destroy cells via perforins and granzymes (same as T effector cells) • Activated by IL-12 and IL-15, secrete IFNγ • Mediate antibody-dependent cellular cytotoxicity B Cells •  rogenitors in the bone marrow develop into immature B lymphocytes that express an P antigen-specific receptor • Interaction between the antigen and the surface bound antibody (receptor) initiates B cell activation • Express MHC II molecules, receptors for complement, and Fc receptor •  ithin lymph node, located in lymphoid follicle W • In the presence of particular cytokines, undergo isotype switching of antibodies Immunodermatology 35
  6. 6. T Cells • Progenitors arise in the bone marrow, but migrate to thymus for maturation • Subdivided into functionally distinct populations of helper (CD4+) and cytotoxic (CD8+) T cells • Respond to stimulation by production of cytokines or causing cell lysis • Require two signals for activation u TIP • Signal 1 comprised of T cell receptor binding to MHC a ocated in paracortex of lymph nodes L molecule on APC • Signal 2 involves CD28 on T cell interacting with B7 molecule located on APC • MHC/TCR engagement in absence of costimulation results in anergy CD4+ T Cells • CD4+ T cells (helper T cells) may be divided into four subtypes: TH1, TH2, TH17, Treg • TH1 cells augment T cell-mediated immunity, activate macrophages, and downregulate TH2 responses via IFNγ •  H2 cells suppress macrophage activity, activate eosinophils, induce isotype switching to T IgE and IgG4, and downregulate TH1 responses via IL-10 u TIP •  H17 cells are proinflammatory; implicated in the patho- T a H2 diseases: atopic dermatitis, CTCL, T genesis of psoriasis and other autoimmune diseases such lepromatous leprosy, disseminated as RA, MS, and IBD cutaneous (chronic) leishmaniasis •  H17 cells secrete IL-17A, IL-17F, IL-21, IL-22, IL-23, and T TNFα • TH17 differentiation induced by TGFβ. Proliferation and survival mediated by IL-23 • Treg cells are important in down-regulation the immune response, and likely play a role in diseases associated with autoimmunity, immune dysregulation, and tumor biology • Treg cells express high levels of CD25 (IL-2 receptor alpha chain) and are characterized by expression of transcription factor FOXP3 • Treg cells suppress immune response through direct contact inhibition, secretion of IL-10, or TGFβ • Mutation of FOXP3 results in absence of Treg and is the cause of IPEX syndrome (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-Linked syndrome) IL-10 IL-4 IL-5 IL-10 Treg TH2 TGFb IL-4 CD4+ TGFb+ IFNg IL-6 IL-12 IL-1 TH17 IL-21 TH1 IL-17 IL-2 IL-22 IFNg Figure 2-1. CD4+ T Cell Differentiation and Associated Cytokines36  2011/2012 Dermatology In-Review l Committed to Your Future
  7. 7. CD8+ T Cells • Kill by releasing granules containing perforin and granzymes, which induce apoptosis • May also induce apoptosis by presenting FasL to Fas receptor on target cells γδ T Cells •  T Cells which possess a γδ T Cell receptor (TCR) as opposed to the more common αβ TCR (as seen in CD4+ and CD8+ T cells) • Primarily found in epithelia and appear to play a role in immunoregulation and immunosurveillance • Suppress TH1 cells through release of IL-10 • May play important roles in cancer surveillance and resistance to graft-vs.-host disease Table 2-1. T Cell Surface Receptors Receptor Location Binding Partner Location Effect TCR T cell Ag-MHC I or II APC Activation CD2 T cell LFA-3 Endothelial cells, Adhesion, activation APC CD4 T cell MHC II APC Activation CD8 T cell MHC I APC Activation CD28 T cell B7 (CD80, CD86) APC, target cell Activation (2nd signal) CTLA-4 Activated T cell B7 (CD80, CD86) APC Inhibition CD40L T cell CD40 APC, B cell Activation PD1 Activated T cell PD-L1, PD-L2 APC, normal tissue Inhibition LFA1 T cell ICAM-1 Endothelial cells, Migration, adhesion (CD18 + CD11a) APC Mac-1 Macrophages, ICAM-1 Endothelial cells, Migration, adhesion (CD18 + CD11b) neutrophils, NK APC *Mutation in CD18 cells causes leukocyte adhesion deficiency I Figure 2-2. T Cell - APC Interactions Immunodermatology 37
  8. 8. 2.3 CYTOKINES Cytokines are a structurally diverse group of molecules that have important local and sys-temic effects contributing to both innate and adaptive immunity. There are three major structuralfamilies: the hematopoietin family, which includes interleukins and growth hormones, the tumornecrosis factor (TNF) family, and the chemokine family. Most cytokines produced by T cells aregiven the name interleukin (IL) followed by a number. TH1 and TH2 cells release different but over-lapping sets of cytokines. TH1 cells secrete IFNγ, which is the main macrophage-activating cyto-kine, TNFα, and lymphotoxin. TH2 cells upregulate humoral immunity by secreting IL-4 and IL-5,and inhibit macrophage activation via IL-10. The main cytokine released by CD8+ effector cellsis IFNγ. u TIP • Small secreted proteins with pleomorphic effects, including a ajor producers are helper M cell growth and differentiation, inflammation and immunity T Cells and macrophages (phagocytosis, intracellular killing, effector function), and cell migration (chemokines) • Cellular response mediated by binding to specific receptors • Expressed in groups (skewing towards TH1 or TH2 responses)TH1 Cytokines • IFNγ: Differentiation toward TH1 cells; increased MHC I and II on APCs; enhanced macrophage activity • IL-2: Proliferation and activation of T cells (clonal expansion), B cells (antibody production), and NK cells • IL-12: Heterodimer of p40 and p35 subunits. Increased cytolytic activity and IFNγ production by T cells and NK cell. IL-12B encodes p40 Figure 2-3. IL-12 and IL-23 Cytokines and Receptors Share Similar Subunits38  2011/2012 Dermatology In-Review l Committed to Your Future
  9. 9. TH2 Cytokines • IL-4: Differentiation toward TH2 cells; isotype switching to IgE and IgG4, inhibition of macrophage activation • IL-5: Activates eosinophils + B Cell differentions • IL-6: Proliferation and differentiation of B cells • IL-10: Decreases expression of MHC II and costimulatory molecules on APCs; decreases IL-12 • IL-13: Related to IL-4; implicated in allergic inflammationTH17 Cytokines • IL-17: Family of cytokines that are proinflammatory, resulting in production of many cytokines including IL-6 and TNFα • IL-17 members include IL-17A and IL-17F, which are implicated in allergic and autoimmune inflammation as seen in asthma, SLE, and RA u TIP • IL-22: Members of IL-10 family that mediates inflammation a stekinumab targets p40 subunits U through STAT transcriptional activation pathway; stimulates of IL-12 and IL-23; approved for treatment of psoriasis keratinocyte proliferation • IL-23: Heterodimer of p40 (as in IL-12) and p19 subunits. u TIP Required for survival and proliferation of TH17; may be key a - cytokine in development of psoriasis. IL-23A encodes p19 IL-17 expression of antimicrobial cyte and IL-22 enhance keratino peptides, and IL-22 stimulates kera-Other tinocyte proliferation as seen in psoriasis •  TNFα: Primary mediator of acute inflammation, fever, hepatic production of acute phase reactants u TIP •  GFα expression inhibited by thalidomide T a NFα expression inhibited by T thalidomide Table 2-2. Cytokine Activities Cytokine Produced by Target cells Action GM-CSF Helper T cells Leukocyte progenitors Growth and differentiation IL-1 Macrophages Helper T Cells Co-stimulation B cells B Cells Maturation and proliferation IL-2 TH1 B, T, NK cells Growth, proliferation, and activation IL-4 TH2 Macrophages Increase MHC II expression B Cells Proliferation, IgG4 and IgE T cells Naive CD4+ T Cells synthesis Proliferation, differentiation to TH2 B Cells TH2, macrophages B cells Proliferation and differentiation, IgA Eosinophils synthesis Activation IL-5 TH2 B Cells Differentiation to plasma cells Naive CD4+ T Cells Differentiation to TH17 cells IL-6 Macrophages Macrophages Inhibit cytokine production B cells B Cells Activation IL-10 TH17 T Cells Differentiation to effector T cells Naive CD4+ T Cells Differentiation to TH1 cells Immunodermatology 39
  10. 10. Table 2-2. Cytokine Activities (cont.) Cytokine Produced by Target cells Action IL-12 TH17 T Cells Differentiation to effector T cells Naive CD4+ T Cells Differentiation to TH1 cells IL-17 TH17 Multiple targets Inflammation IL-21 Activated APCs Naive CD4+ T Cells Differentiation to TH17 cells IL-22 Leukocytes Multiple targets Inflammation; keratinocyte proliferation Fibroblasts IL-23 TH1 TH17 Survival and proliferation Cytotoxic T cells NK cells IFNα, IFNβ Leukocytes Multiple cell types Inhibit viral replication; increase MHC I Fibroblasts expression IFNγ TH1 Macrophages Increase MHC expression, killing Cytotoxic T cells NK cells TH2 Inhibit proliferation B Cells Switch to IgG2a2.4 ANTIBODIES AND COMPLEMENTAntibodies All antibodies have the same overall structure and are known collectively as immunoglobulins(Ig). Antibodies are produced by plasma cells in response to infection or immunization. They bindto and neutralize toxins or pathogens and prepare them for uptake and destruction by phago-cytes. Each antibody has a unique antigen-binding domain which recognizes the antigen epitope. •  ntibodies are divided into several classes based upon differences in the structure of the A heavy chain •  ntibody molecules in each class are defined as having the same isotype. The basic structure A of antibody molecules is similar between the various classes and is depicted in Figure 2 •  roteolytic cleavage with papain generates two basic functional domains: two Fab fragments P and one Fc fragment •  he Fab fragment consists of the light chain and the amino terminal half of the heavy chain, T bound to each other by disulfide bonds. The Fab fragment contains antigen-binding activity • The Fc domain functions in complement activation and opsonization mediated by Fc recep- tors on phagocytes Antibody Functions • Neutralization of microbes and toxins by direct binding (e.g., Staphylococcal toxin; children are more susceptible than adults due to lack of antibodies) • Enhance opsonization of microbes via Fc receptors on phagocytes or by fixing complement • Lysis of microbes and inflammation via complement activation • In typical humoral response, isotype switching occurs subsequent to exposure to antigen • Switching is regulated by T cell-derived cytokines (IgG by IL-4, IL-6, IL-2, and IFNγ; IgA by IL-5 and TGFβ; IgE by IL-4) • Gardasil vaccine directed against HPV 6, 11, 16, 18. Indicated in females 9-26 years old. Indicated in males 9-26 years old for prevention of genital warts caused by HPV 6 and 1140  2011/2012 Dermatology In-Review l Committed to Your Future
  11. 11. • Cervarix vaccine directed against HPV 16, 18. Approved for females 10-25 years old • Zostavax indicated for prevention of herpes zoster in men and women at least 60 years old Distinguishing Features of Isotypes • Opsonizing antibodies: IgG1 and IgG3 • FcgRI has highest affinity for IgG (isotype 1 and 3) and is located on macrophages, neutrophils, eosinophils, leading to phagocytosis u TIP • Neutralizing antibodies: IgA1 and IgA2 at mucosal surfaces, a yper IgE syndrome patients H IgG2 and IgG4 in tissue have constitutive high IgE levels, • Complement fixing antibodies: IgG1, IgG3, IgM deficient Th1 responses, and suffer from cold abscesses and • IgA primarily at mucosal surfaces, prevent colonization by eczematous dermatits pathogens, important neutralizing function • IgD functions as antigen receptor on mature B cells u TIP • IgE binds allergens, stimulates mast cells; increased in atopic agG crosses the placenta I individuals • IgG is the predominant antibody in a secondary immune response, most abundant in serum, best for opsonization. Also neutralizes pathogens and fixes complement • IgM is the first antibody produced by B cells, secreted by plasma cells as a pentamer • IgM doesn’t enter tissue well due to size; most efficient Ig at fixing complement • High-affinity receptor for the Fc region of IgE expressed on mast cells, basophils and Langerhans cells Ag binding variable heavy Fab light chain papain cleavage constant Fc Figure 2-4. Antibody Structure Complement Complement consists of a series of 25 serum and membrane proteins. These glycoproteinsact as effectors in both innate and adaptive immunity. The complement cascade system has twoimportant effects on cells, opsoniza-tion and membrane damage. Biologic activities of comple-ment also include chemotaxis, anaphylaxis, immune complex solubilization, and B cell activation(provides second signal). The cascade has three pathways: the classical, alternate, and mannose- Immunodermatology 41
  12. 12. binding lectin. All act via sequential recruitment, proteolytic activation and assembly,with the ultimate endpoint being formation of membrane attack complex (MAC), which insertsinto lipid membranes and causes osmotic lysis of cells. Classical Pathway • Activated by antigen-antibody (IgM or IgG) complexes • The proteins of the classical pathway are C1, C2, C3, and C4 • C1 binds, recruits C2 and C4 forming C3 convertase, cleaves C3 and C5 • C1 INH prevents C1 protease activity • C3a: Neutrophil chemoattractant (inflammation) • C3b: Opsonin (binds to pathogen, enhancing phagocytosis) • C5a: Anaphylatoxin (chemotaxis, increased vascular permeability, mast cell activation) • C5b: Combines with C6,7,8,9 to form membrane attack complex Alternate Pathway • Activated by bacterial products, including lipopolysaccharide (LPS) from gram negative bacteria • Proteins in the alternate complement pathway are Factor B, Factor D, Factor H, properdin and C3 Mannose-Binding Lectin Pathway • Activated by inflammatory macrophage cytokines Complement Receptors • Eight receptors have been identified • CR1 (also known as CD35) in main receptor for C3b. Plays important role in mediating clearance of immune complexes, phagocytosis, and immune adherence of antibody- coated bacteria to erythrocytes • CR2 (also known as CD21) presents antigen to B cells and is a co-receptor for B cell signaling u TIP • CR3 (CD11b/CD18 heterodimer) and CR4 (CD11c/CD18 a BV utilizes the CR2 receptor E heterodimer) are members of the beta-2 integrin family for cell entry and infection (remember CD11a/CD18 is also known as LFA-1) and bind ICAM-1 u TIP • Other receptors include C1qRP, C3aR, C4aR, and C5aR; aAD type 1 patients suffer from L the latter three mediate anaphylactic reactions mucositis, poor wound healing, and • Acquired deficiency of CR1 is associated with frequent skin infections without puss or inflammation that can resemble autoimmune disorders such as SLE pyoderma gangrenosum • Deficiencies in CR3 and CR4 are found in leukocyte adhesion deficiency (LAD) type 1 Complement Deficiencies  •  arly defects (C1, 2, 3, 5) lead to susceptibility to encapsulated uTIP E organisms, especially Pneumococcus a ate defects (C5-9) confer L • Association of C1-5 deficiency with SLE may be due to genetic susceptibility to Neisseria linkage • Late defects (C5-9) confer susceptibility to Neisseria  • C3 deficiency associated with partial lipodystrophy • Hereditary angioedema (HAE) type I is most common, due to low levels of C1 INH with normal function42  2011/2012 Dermatology In-Review l Committed to Your Future
  13. 13.  • HAE type II is less common, due to normal levels of non-functional C1 INH • Acquired angioedema (AAE) is due to consumptive processes, so C1 INH levels are low • To differentiate AAE and HAE, measure C1q (normal in HAE, low in AAE)2.5  AJOR M HISTOCOMPATIBILITY COMPLEX HLA DISEASE ASSOCIATIONS The molecules that display peptide antigen to T cells are cell-surface glycoproteins namedthe major histocom-patibility complex (MHC). There are two types of MHC molecules, Class I andClass II. These differ in several subtle ways but share most of their major structural features. MHCClass I and II molecules display protein antigens for recognition by CD4+ or CD8+ T cells. MHC Class I molecules bind stably to peptides derived from proteins synthesized and degradedin the cytosol (all cells) and MHC Class II molecules bind stably to peptides derived from proteinsdegraded in endocytic vesicles (APCs). The two classes of MHC are differentially recognized bythe two co-receptor molecules, CD8 and CD4. CD8+ T cells recognize MHC Class I/peptide. CD4+T cells recognize MHC Class II peptide complexes. Every individual is polygenic at the MHC andexpresses several MHC I and II genes with different peptide-binding specificities.Class I u TIP • Expressed on all nucleated cells (HLA-A, B, C) a LA-Cw6 has the most definitive H • Recognized by CD8 on cytotoxic T cells genetic association with psoriasis • Present intracellular proteins (e.g., viral peptides) to TCRClass II • Expressed on B cells, monocytes, dendritic cells, and are inducible on keratinocytes and endothelial cells (HLA-DR, DQ, DP) • Recognized by CD4 on helper T cells • Class II molecules complexed with antigen triggers helper T cells • Present peptides derived from extracellular pathogens taken up into vesicles to TCROther • Level of Class I and II molecule expression is regulated by cytokines • MHC III region encodes or soluble proteins of the complement cascade and the tumor necrosis family • The polygenic and polymorphic nature of the MHC contributes to the ability of the immune system to respond to the multitude of different and rapidly evolving pathogens • HLA associations seen in human skin disease reflect the ability of that particular MHC molecule to present a disease-relevant peptide to T cellsHLA Disease Associations Class I • Psoriasis: HLA-Cw6: relative risk 9-15 times normal. Mechanism postulated to be through antigen presentation to CD8+ T Cells leading to epidermal migration • Guttate psoriasis: HLA-Cw6 and HLA-B17 • Generalized psoriasis, Reiter’s: HLA-B27 • Psoriatic arthritis: HLA-B27, especially if spondylitis present Class II • Behcet’s disease: HLA-B51 • Lichen Planus, Oral: HLA-B8 • Lichen Planus, Cutaneous: HLA-Bw35 Immunodermatology 43
  14. 14. • Chronic Idiopathic Urticaria: HLA-DR4, HLA-DRB4 53, HLA-DQ8 • Herpes gestationis: HLA-DR3, HLA-DR4 • Pemphigus: HLA-DR4 or DRw6 Both Class I and Class II • Dermatitis Herpetiformis: HLA-B8, HLA-DR3, HLA-DQw22.6 NON-STEROIDAL IMMUNOLOGIC THERAPIESCalcineurin Inhibitors T cell activation follows a complex cascade of intracellular signaling events after ligation ofthe TCR. A key regulatory step is the activation of calcineurin via calmodulin. Calcineurin phos-phatase activity dephosphorylates NFATc, resulting in nuclear translocation and subsequent tran-scriptional activation of cytokine expression. Cyclosporine (Neoral, Sandimmune) • Forms complex with cyclophilin, which inhibits calcineurin activity Tacrolimus (Protopic) and Pimecrolimus (Elidel) • Forms complex with FK506 binding protein (FKBP12), which inhibits calcineurin activity • Effective topically due to their small size (as opposed to cyclosporine) • Tacrolimus is a macrolide; Pimecrolimus is a derivative of ascomycin • Both decrease pro-inflammatory cytokine release (e.g., TNFα) and histamine release from mast cellsTNF Inhibitors Entanercept (Enbrel) u TIP • Human fusion protein of TNFα type II receptor and IgG1 Fc region a inds soluble TNFα, cannot B • Binds soluble TNFα, cannot cause cell lysis cause cell lysis • Most common side effect is injection site reaction • Approved for treatment of psoriasis, psoriatic arthritis, RA, JRA, and ankylosing spondylitis Infliximab (Remicade) u TIP • Chimeric mouse/human IgG1 binds TNFα (monoclonal Ab) aBinds surface and soluble TNFα • Approved for psoriatic arthritis, RA, Crohn’s, UC, ankylosing spondylitis Adalimumab (Humira) • Human monoclonal Ab IgG1 against TNFα • Approved for treatment of psoriatic arthritis, RA, ankylosing spondylitisT Cell Function Inhibitors Alefacept (Amevive) • Human fusion protein of LFA-3 with Fc portion of IgG1 • Binds CD2 (receptor molecule) on CD45RO+ memory effector T cells (also found on NK cells) • LFA-3 found on endothelial cells; interaction provides cell-cell adhesion distinct from LFA-1/ ICAM1 • LFA-3 also on APCs for activating T cells • Blocks 2nd signal, causing apoptosis of T cells • Prevents T cell activation, reduces CD4+ and CD8+ T cell counts (need to monitor) • Approved for psoriasis44  2011/2012 Dermatology In-Review l Committed to Your Future
  15. 15. Other Ustekinumab (Stelara) • Human monoclonal antibody that binds p40 subunit of IL-12 and IL-23 • Mechanism of action probably mediated primarily through IL-23 blockade • Approved for treatment of psoriasis • Associated with Reversible Posterior Leukoencephalopathy syndrome (RPLS) Ipilimumab (Yervoy) • Human monoclonal antibody that binds CTLA-4 • Prevents inhibition of activated T cells through CTLA-4 • Metastatic melanoma patients treated with ipilimumab have demonstrated increased 1 year survival rates • 13% of patients suffered severe or fatal autoimmune reactions Rituximab (Rituxan) • Monoclonal Ab against CD20 (on B cells; not on B cell progenitors) • Approved for treatment of B cell NHL Denileukin Diftitox (Ontak) • Fusion of a fragment of diphtheria toxin and IL-2 • Binds to high affinity IL-2 receptor (CD25) on T cells; cells are killed when toxin is internalized • Approved for treatment of CTCL Cetuximab (Erbitux) • Chimeric monoclonal Ab against epidermal growth factor receptor (EGFR) • Approved for treatment of metastatic colorectal cancer • Other EGFR anti-cancer treatments include gefitinib (Iressa) and erlotinib (Tarceva) • All are associated with acneiform eruptions REF E R E NC E S1. Janeway et al. Immunobiology 5. New York: Garland Publishing, 2001.2. Robins P. Review Notes for Dermatology New York: Physicians Continuing Education, 20.3. Robert C and Kupper JS. Mechanisms of Disease: Inflammatory Skin Diseases, Surveillance. New Engl J Med 341: 1817–1828, 1999.4. Kupper JS. Immunologic Targets in Psoriasis. New Engl J Med 349: 1987–1990, 2003.5. Asadi AK. Relapsing polychonditis. Dermatol Online J. 2003; 9(4): 3.6. Burnett PE, Burgin S. Erythema elevatum Dermatol diutinum. Online J. 2003; 9(4): 37.7. Chen X, Wolin SL. The Ro 60 kDa autoantigen: insights into cellular function and J role. Mol Med 2004.8. Costedoat-Chalumeau N, Amoura Z, Le Thi Hong D, Georgin S, et al. Neonatal lupus syndrome: review of the literature. Rev Med Interne. 2003; 24(10): 659–71.9. Dang CV, LaDuca FM, Bell WR. Histidyl-tRNA synthetase, the myositis Jo–1 antigen, is cytoplasmic and unas- sociated with the cytoskeletal framework. Exp Cell Res. 1986; 164: 261–6.10. Ebo DG, Bridts CH, Hagendorens MM, De Clerck LS, Stevens WJ. The prevalence and diagnostic value of spe-cific IgE antibodies to inhalant, animal and plant food, and ficus allergens in patients with natural rubber latex allergy. Acta Clin Belg. 2003; 58(3):183–9.11. Fernandez-L A, Sanz-Rodriguez F, Blanco FJ, Bernabeu C, Botella LM. Hereditary hemorrhagic telangiectasia, a vascular dysplasia affecting the TGF-beta signaling pathway. Clin Med Res. 2006; 4(1):66-78.12. Galvani AP, Slatkin M. Evaluating plague and smallpox as historical selective pressures for the CCR5-Delta 32 HIV-resistance allele. Proc Natl Acad Sci U S A. 2003; 100:15276–9. Immunodermatology 45
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  17. 17. 37. Yancey KB, Kirtschig G, Yee C, Lazarova Z. Studies of patients with anti-epiligrin cicatricial pemphigoid. J Dermatol. 1995; 22(11): 829–35.38. Yiannias JA, el-Azhary RA, Gibson LE. Erythema elevatum diutinum: a clinical and histopathologic study of 13 patients. J Am Acad Dermatol. 1992; 26: 38–44.39. Zhu YI, Stiller MJ. Dapsone and sulfones in dermatology: overview and update. J Am Acad Dermatol. 2001; 45(3): 420–34.40. Kim J, Ochoa MT, Krutzik SR, Takeuchi O, Uematsu S, Legaspi AJ, Brightbill HD, Holland D, Cunliffe WJ, Akira S, Sieling PA, Godowski PJ, Modlin RL. Activation of toll-like receptor 2 in acne triggers inflammatory cyto- kine responses. J Immunol. 2002;169(3):1535–41.41. Leonardi C, Kimball A, Papp K, Yeilding N, Guzzo C, Wang Y, Li S, Dooley L, Gordon K. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). The Lancet. 2008;371(9625):1665-1674.42. Hodi FS et al. Improved survival with Ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010; 363:711-23. Immunodermatology 47
  18. 18. NOTES48  2011/2012 Dermatology In-Review l Committed to Your Future