etas_02 immuno

Immunodermatology 31

2 Immunodermatology

Eric Huang, MD, PhD

William R. Levis, MD

Georgia B. Schuller-Levis, PhD

C o n t e n t s

2.1 The Innate and Adaptive Immune Systems . . . . . .33

2.2 Cells of the Innate and Adaptive Immune System . . 34

2.3 Cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .38

2.4 Antibodies and Complement . . . . . . . . . . . . . . . . . . . 40

2.5 Major Histocompatibility Complex and

HLA Disease Associations . . . . . . . . . . . . . . . . . . . . . . 43

2.6 Non-Steroidal Immunologic Therapies . . . . . . . . . . 44

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2.1 THE INNATE AND ADAPTIVE IMMUNE SYSTEMSIt is helpful to divide the immune system into two complementary branches based upon the

plasticity 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 that specifically recognize non-self pathogens but not self antigens. In contrast, the adaptive immune system relies upon gene rearrangement to produce receptors specific for individual antigens, and these receptors may potentially bind both non-self and self antigens.

The immune system is composed of both cellular and non-cellular components. Keratinocytes and mucosal epithelia provide a physical barrier against pathogens and can also secrete cytokines such as TNF and IL-1. Soluble factors such as antimicrobial peptides and canthelicidins, comple-ment, cytokines, and antibodies assist the cellular components (leukocytes). Leukocytes are subdivided by function into granulocytes (neutrophils, eosinophils, mast cells, basophils), lympho-cytes (B cells, T cells, natural killer cells), and monocytes (called histiocytes in tissue; Langerhans cells in the epidermis).

Innate Immunity• Rapid response, “first line of defense”• Lack of memory: Repeated exposure does not change the

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• Pattern recognition receptors include toll-like receptors (TLR)

and nucleotide oligomerization domain receptors (NODs); these receptors recognize PAMPs (pathogen-associated molecular patterns)

• 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

antigen presenting cell (APC) activation and cytokine production (IL-12, IFNα, TNFα)

• TLR2 may be activated in inflammatory acne• TLR2 and TLR9 polymorphisms associated with atopic dermatitis

Non-Cellular Components• Antimicrobial peptides: defensins and canthelicidins are

produced by phagocytes and keratinocytes and directly kill bacteria, fungi, and viruses

• DEFB4 encodes β-defensin 2• Complement: see below

Cellular Components• Macrophages, neutrophils, natural killer cells, mast cells, eosinophils, intraepithelial

lymphocytes

uTIPa TLR7 binds imiquimod; native

ligand is ssRNA

uTIPa Cytokines: particularly TNFα,

IL-1, IL-10, IL-12, IFNα, IFNβ

uTIPa

Decreased expression of anti-

microbial peptides in atopics vs. psoriatics may explain increased cutaneous infection in the former

uTIPa DEFB4 implicated in genetic

association studies with development of psoriasis

34 2011/2012 Dermatology In-Review l Committed to Your Future

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

• Do not distinguish self from non-self• Require antigen presentation in context of MHC molecules

Non-Cellular Components• Antibodies: see below

Cellular Components• T cells, B cells, Langerhans cells

2.2 CELLS OF THE INNATE AND ADAPTIVE IMMUNE SYSTEMPhagocytes (Macrophages and Neutrophils)

• Identify microbes using receptors for mannose, opsonins, and TLRs• Ingest pathogens• Destroy pathogens by producing reactive oxygen intermediates via phagocyte oxidase,

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• Phagocytes are unable to kill intracellular organisms (screening

test nitroblue tetrazolium reduction assay)

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 fatal

Granulocytes • 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-5

uTIPa Cytokines: particularly IL-2,

IL-4, IL-5, IFNγ, TGFβ

uTIPa Defect in phagocyte oxidase

leads to chronic granuloma-tous disease


Mast Cells• Provide protection against bacteria and parasites• Express high levels of FcεRI (receptor for IgE)• Release histamine, prostaglandins, leukotrienes, cytokines, tryptase (elevated in serum of

patients with mastocytosis)• Central cell in immediate-type hypersensitivity

through IgE-mediated release of histamine• Many cases of idiopathic urticaria have circulating

autoantibodies directed against the chain of high affinity IgE receptor on the mast cell surface

Monocytes 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• Express surface marker CD1a• Adhesion to keratinocytes mediated by e-cadherin• Express B7 molecules (CD80 or CD86) only after activation

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

expression

Lymphocytes These cells are primarily responsible for the specificity of the immune response. Lymphocytes

are triggered by a specific antigen to produce antibodies (B cells), cytokines (CD4+ T cells) or cause direct cytotoxicity (CD8+ T cells).

Natural Killer Cells • Identify virally-infected or transformed (tumor) host cells via their down-regulation of self-

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• Progenitors in the bone marrow develop into immature B lymphocytes that express an

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

• Within lymph node, located in lymphoid follicle• In the presence of particular cytokines, undergo isotype switching of antibodies

uTIPa Birbeck granules (characteristic

racket shape on EM) are part of endosomal recycling compartment

uTIPa�Adult mastocytosis most frequently

related to activating mutations in c-kit tyrosine kinase (but not childhood disease)


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• Signal 1 comprised of T cell receptor binding to MHC 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 anergyCD4+ 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

• TH2 cells suppress macrophage activity, activate eosinophils, induce isotype switching to IgE and IgG4, and downregulate TH1 responses via IL-10

• TH17 cells are proinflammatory; implicated in the patho-genesis of psoriasis and other autoimmune diseases such as RA, MS, and IBD

• TH17 cells secrete IL-17A, IL-17F, IL-21, IL-22, IL-23, and 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

Treg

TGFb IL-4

TH2

IL-4IL-5IL-10

TH1TH17

CD4+

IFNgIL-12

IL-2IFNg

IL-1IL-21

TGFb+IL-6

IL-17IL-22

Figure 2-1. CD4+ T Cell Differentiation and Associated Cytokines

uTIPa Located in paracortex of lymph nodes

uTIPa TH2 diseases: atopic dermatitis, CTCL,

lepromatous leprosy, disseminated cutaneous (chronic) leishmaniasis


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, APC

Adhesion, activation

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 (CD18 + CD11a)

T cell ICAM-1 Endothelial cells, APC

Migration, adhesion

Mac-1 (CD18 + CD11b)

Macrophages, neutrophils, NK cells

ICAM-1 Endothelial cells, APC

Migration, adhesion *Mutation in CD18causes leukocyteadhesion deficiency I

Figure 2-2. T Cell - APC Interactions


2.3 CYTOKINESCytokines 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 structural families: the hematopoietin family, which includes interleukins and growth hormones, the tumor necrosis factor (TNF) family, and the chemokine family. Most cytokines produced by T cells are given 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 cells is IFNγ.

• Small secreted proteins with pleomorphic effects, including cell growth and differentiation, inflammation and immunity (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 Subunits

uTIPa�Major producers are helper

T Cells and macrophages


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 inflammation

TH17 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• IL-22: Members of IL-10 family that mediates inflammation through STAT transcriptional activation pathway; stimulates keratinocyte proliferation• IL-23: Heterodimer of p40 (as in IL-12) and p19 subunits. Required for survival and proliferation of TH17; may be key cytokine in development of psoriasis. IL-23A encodes p19

Other

• TNFα: Primary mediator of acute inflammation, fever, hepatic production of acute phase reactants

• TGFα expression inhibited by thalidomide

Table 2-2. Cytokine Activities

Cytokine Produced by Target cells Action

GM-CSF Helper T cells Leukocyte progenitors Growth and differentiation

IL-1 MacrophagesB cells

Helper T Cells

B Cells

Co-stimulation

Maturation and proliferation

IL-2 TH1 B, T, NK cells Growth, proliferation, and activation

IL-4 TH2 MacrophagesB CellsNaive CD4+ T Cells

Increase MHC II expressionProliferation, IgG4 and IgE T cells synthesisProliferation, differentiation to TH2

B Cells TH2, macrophages B cellsEosinophils

Proliferation and differentiation, IgA synthesisActivation

IL-5 TH2 B CellsNaive CD4+ T Cells

Differentiation to plasma cellsDifferentiation to TH17 cells

IL-6 MacrophagesB cells

MacrophagesB Cells

Inhibit cytokine productionActivation

IL-10 TH17 T CellsNaive CD4+ T Cells

Differentiation to effector T cellsDifferentiation to TH1 cells

uTIPa

IL-17 and IL-22 enhance keratino-

cyte expression of antimicrobial peptides, and IL-22 stimulates kera-tinocyte proliferation as seen in psoriasis

uTIPa�Ustekinumab targets p40 subunits

of IL-12 and IL-23; approved for treatment of psoriasis

uTIPa TNFα expression inhibited by

thalidomide


Cytokine Produced by Target cells Action

IL-12 TH17 T CellsNaive CD4+ T Cells

Differentiation to effector T cellsDifferentiation to TH1 cells

IL-17 TH17 Multiple targets Inflammation

IL-21 Activated APCs Naive CD4+ T Cells Differentiation to TH17 cells

IL-22 LeukocytesFibroblasts

Multiple targets Inflammation; keratinocyte proliferation

IL-23 TH1Cytotoxic T cellsNK cells

TH17 Survival and proliferation

IFNα, IFNβ LeukocytesFibroblasts

Multiple cell types Inhibit viral replication; increase MHC I expression

IFNγ TH1Cytotoxic T cellsNK cells

Macrophages

TH2B Cells

Increase MHC expression, killing

Inhibit proliferationSwitch to IgG2a

2.4 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 bind to 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.

• Antibodies are divided into several classes based upon differences in the structure of the heavy chain

• Antibody molecules in each class are defined as having the same isotype. The basic structure of antibody molecules is similar between the various classes and is depicted in Figure 2

• Proteolytic cleavage with papain generates two basic functional domains: two Fab fragments and one Fc fragment

• The Fab fragment consists of the light chain and the amino terminal half of the heavy chain, 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 receptors 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 11

Table 2-2. Cytokine Activities (cont.)


• 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• Neutralizing antibodies: IgA1 and IgA2 at mucosal surfaces,

IgG2 and IgG4 in tissue• Complement fixing antibodies: IgG1, IgG3, IgM • IgA primarily at mucosal surfaces, prevent colonization by

pathogens, important neutralizing function • IgD functions as antigen receptor on mature B cells • IgE binds allergens, stimulates mast cells; increased in atopic

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

papaincleavage

light chain

constant

Fc

Figure 2-4. Antibody Structure

ComplementComplement consists of a series of 25 serum and membrane proteins. These glycoproteins

act as effectors in both innate and adaptive immunity. The complement cascade system has two important 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-

uTIPa�Hyper IgE syndrome patients

have constitutive high IgE levels, deficient Th1 responses, and suffer from cold abscesses and eczematous dermatits

uTIPa IgG crosses the placenta


binding lectin. All act via sequential recruitment, proteolytic activation and assembly, with the ultimate endpoint being formation of membrane attack complex (MAC), which inserts into 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

• CR3 (CD11b/CD18 heterodimer) and CR4 (CD11c/CD18 heterodimer) are members of the beta-2 integrin family (remember CD11a/CD18 is also known as LFA-1) and bind ICAM-1

• Other receptors include C1qRP, C3aR, C4aR, and C5aR; the latter three mediate anaphylactic reactions

• Acquired deficiency of CR1 is associated with autoimmune disorders such as SLE

• Deficiencies in CR3 and CR4 are found in leukocyte adhesion deficiency (LAD) type 1

Complement Deficiencies

• Early defects (C1, 2, 3, 5) lead to susceptibility to encapsulated organisms, especially Pneumococcus

• Association of C1-5 deficiency with SLE may be due to genetic 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 function

uTIPa Late defects (C5-9) confer

susceptibility to Neisseria

uTIPa EBV utilizes the CR2 receptor

for cell entry and infection

uTIPa�LAD type 1 patients suffer from

mucositis, poor wound healing, and frequent skin infections without puss or inflammation that can resemble pyoderma gangrenosum


• 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 MAJOR HISTOCOMPATIBILITY COMPLEX & HLA DISEASE ASSOCIATIONS

The molecules that display peptide antigen to T cells are cell-surface glycoproteins named the major histocom-patibility complex (MHC). There are two types of MHC molecules, Class I and Class II. These differ in several subtle ways but share most of their major structural features. MHC Class 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 degraded in the cytosol (all cells) and MHC Class II molecules bind stably to peptides derived from proteins degraded in endocytic vesicles (APCs). The two classes of MHC are differentially recognized by the 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 and expresses several MHC I and II genes with different peptide-binding specificities.

Class I• Expressed on all nucleated cells (HLA-A, B, C)• Recognized by CD8 on cytotoxic T cells• Present intracellular proteins (e.g., viral peptides) to TCR

Class 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 TCR

Other• 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 cells

HLA Disease AssociationsClass 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 presentClass II• Behcet’s disease: HLA-B51• Lichen Planus, Oral: HLA-B8• Lichen Planus, Cutaneous: HLA-Bw35

uTIPa�HLA-Cw6 has the most definitive

genetic association with psoriasis


• Chronic Idiopathic Urticaria: HLA-DR4, HLA-DRB4 53, HLA-DQ8• Herpes gestationis: HLA-DR3, HLA-DR4 • Pemphigus: HLA-DR4 or DRw6Both Class I and Class II • Dermatitis Herpetiformis: HLA-B8, HLA-DR3, HLA-DQw2

2.6 NON-STEROIDAL IMMUNOLOGIC THERAPIESCalcineurin Inhibitors

T cell activation follows a complex cascade of intracellular signaling events after ligation of the 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 activityTacrolimus (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 cells

TNF InhibitorsEntanercept (Enbrel)• Human fusion protein of TNFα type II receptor and IgG1 Fc region

• Binds soluble TNFα, cannot 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)• Chimeric mouse/human IgG1 binds TNFα (monoclonal Ab)• 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 spondylitis

T 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 psoriasis

uTIPaBinds surface and soluble TNFα

uTIPa�Binds soluble TNFα, cannot

cause cell lysis


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

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NOTES