Clinical and Basic Immunodermatology Clinical and Basic Immunodermatology

Edited by Anthony A. Gaspari, MD Department of Dermatology University of Maryland School of Medicine Baltimore, MD USA Stephen K. Tyring, MD, PhD Department of Dermatology University of Texas Medical School at Houston Houston, TX USA Editors Anthony A. Gaspari, MD University of Maryland School of Medicine Baltimore, MD USA

Stephen K. Tyring, MD, PhD University of Texas Medical School at Houston Houston, TX USA

ISBN 978-1-84800-164-0 e-ISBN 978-1-84800-165-7 DOI 10.1007/978-1-84800-165-7

British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library

Library of Congress Control Number: 2008923739

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9 8 7 6 5 4 3 2 1 springer.com Preface

In 1981, the first edition of Clinical Immunodermatology was published, with Dr. Mark Dahl as the editor and sole contributor. This textbook filled a real need for residents in training, as the focus of this textbook was immuno- logically mediated skin disease. It certainly was critical and highly enjoyable reading for me when I began my dermatology residency in 1982 at Emory University. Its second edition in 1985 and the third and final edition in 1996 saw further improvements in this outstanding textbook. It has been a tremen- dous asset for all of those interested in the immune system, and how it plays a protective and pathologic role in skin diseases. The critical features of this textbook were its concise nature, simple diagrams, and clear and direct style of delivering fundamental information about the role of the immune system and its relevance to skin diseases. All of these features made this textbook well appreciated by residents and clinicians. This textbook really was the brainchild of Dr. Mark Dahl, and reflected well his lucid approach to teaching, organizing information, and presenting a complex topic in such a high-quality product. Fortunately for our specialty, Dr. Dahl remains active in academic dermatology, teaching, patient care, and publishing. Over the past twelve years, much has changed, stimulating Steve Tyring and I to revisit this important subject. There has been an explosion of information in the fields of cellular, molecular, innate, adaptive immunity, and immuno- pharmacology. In parallel, these advances have been applied to and translated to a better understanding and treatment of a number of common and less common dermatologic diseases. There are also a number of new therapeutic agents that are targeted therapies, or have an immune mechanism. All of these developments have occurred during the blossoming of the information age. Thus, we decided that it was no longer possible to present a single or even a dual authored/edited textbook. Steve Tyring and I decided to pursue the recruitment of national and international experts to author chapters on their respective areas of expertise. Hence, our approach for this important endeavor is that of a multiauthored collection of chapters that would be integrated into this book. Despite the different approach, our goal is to present the latest information related to fundamentals of the skin immune system, as well as a disease-focused textbook in the same concise, readable, and easily digested format that was initially developed by Dr. Dahl. We thank Dr. Dahl for his vision and his original book, which has had pro- found influence on generations of dermatologists. We have strived to enhance the teaching of cutaneous immunology, particularly as related to skin disease, to the next generations of young dermatologists who will be caring for patients

v vi Preface afflicted with immune-based skin diseases. We would be delighted if our text- book triggered the kind of interest in immunology that was stimulated in Steve and I during our training.

Anthony A. Gaspari Stephen K. Tyring Contents

Preface ...... v

Section I Concepts of Fundamental Importance for Understanding Skin Disease

1 Cytokines and Chemokines ...... 3 Oliver A. Perez and Brian Berman

2 Innate and Adaptive Immunity ...... 17 Jan D. Bos and Marcel B.M. Teunissen

3 Neuroimmunology ...... 31 Erica Lee and Richard D. Granstein

4 Stress and Immunity ...... 45 Francisco A. Tausk, Ilia Elenkov, Ralph Paus, Steven Richardson, and Marcelo Label

5 Toll-Like Receptors ...... 67 Donna Bilu Martin and Anthony A. Gaspari

6 Conventional and Unconventional T Cells ...... 85 Scott Roberts and Michael Girardi

7 Complement System ...... 105 Kim B. Yancey and Zelmira Lazarova

8 Cutaneous Dendritic Cells in Health and Disease ...... 119 Mark C. Udey

9 Antimicrobial Peptides ...... 131 H. Ray Jalian and Jenny Kim

10 Photoimmunology ...... 147 Christopher Hansen, Justin J. Leitenberger, Heidi T. Jacobe, and Ponciano D. Cruz, Jr.

11 Angiogenesis for the Clinician ...... 157 Benjamin A. Lefkove, Levi E. Fried, and Jack L. Arbiser

vii viii Contents

Section II Common Skin Diseases

12 Contact Dermatitis: Allergic and Irritant ...... 171 Donald V. Belsito

13 Atopic Dermatitis ...... 193 Thomas Bieber and Julia Prölss

14 Psoriasis ...... 207 Frank O. Nestle

15 The Immunology of Acne ...... 217 Guy F. Webster and Jenny Kim

16 Nonmelanoma Skin Cancer ...... 223 Fergal J. Moloney and Gary M. Halliday

17 Immunobiology and Immune-Based Therapies of Melanoma ...... 245 Mariah R. Brown, John C. Ansel, and Cheryl A. Armstrong

18 Drug Eruptions ...... 263 Craig K. Svensson

19 Cutaneous Vasculitis ...... 277 Sherrif F. Ibrahim and Carlos H. Nousari

20 Immunodermatology and Viral Skin Infection ...... 297 Natalia Mendoza, Anita Arora, Cesar A. Arias, Aron J. Gewirtzman, and Stephen K. Tyring

21 HIV Disease and AIDS ...... 323 Andrew Blauvelt

22 Bacterial Infections ...... 335 Carolyn Senavsky, Noah Craft, and Lloyd S. Miller

23 Parasitic Infections ...... 363 Sidney Klaus

24 Fungal Infections ...... 373 Nahed Ismail and Michael R. McGinnis

25 Cutaneous T-Cell Lymphoma ...... 411 Ellen J. Kim, Camille E. Introcaso, Stephen K. Richardson, and Alain H. Rook

26 Graft-Versus-Host Disease ...... 439 Edward W. Cowen Contents ix

27 Allergic Urticaria ...... 459 Laura M. Gober and Sarbjit S. Saini

Section III Immunopharmacology

28 Biologic Therapies for Inflammatory Disease ...... 481 Emily M. Berger and Alice B. Gotlieb

29 Topical Immune Response Modifiers:Adjuvants ...... 527 Annemarie Uliasz and Mark Lebwohl

30 Topical Immune Response Modifiers: Antiinflammatories ...... 539 Thomas A. Luger and Martin Steinhoff

31 Traditional Immune-Modulating Drugs ...... 551 Stephen E. Wolverton

32 Topical Corticosteroids ...... 561 Ulrich R. Hengge

33 Vaccines ...... 579 Anita Arora, Natalia Mendoza, Anne Marie Tremaine, and Stephen K. Tyring

34 Intravenous Immunoglobulins ...... 605 Doerte Bittner and Alexander Enk

Section IV Autoimmunity, Immunodeficiency, and Immune – Associated Dermatoses

35 Novel Approach to the Evaluation of Primary Immunodeficiencies ...... 617 Clemens Esche and Bernard A. Cohen

36 Iatrogenic Immunodeficiency and Skin Disease ...... 633 Brenda L. Bartlett and Jennifer Z. Cooper

37 Granulomatosis ...... 645 Kurt Q. Lu

38 Vitiligo Vulgaris ...... 661 James J. Nordlund, I. Caroline Le Poole, and Raymond E. Boissy

39 Alopecia Areata ...... 691 Richard S. Kalish and Amos Gilhar x Contents

40 Cutaneous Lupus Erythematosus ...... 703 David F. Fiorentino and Richard D. Sontheimer

41 Fibrotic Skin Diseases ...... 721 Irina G. Luzina and Sergei P. Atamas

42 Pemphigus Family of Diseases ...... 739 Masayuki Amagai

43 The Pemphigoid Spectrum ...... 751 Kelly Nelson, Ning Li, Zhi Liu, and Luis A. Diaz

44 Epidermolysis Bullosa Acquisita ...... 763 Julie Burnett, Jennifer Remington, Mei Chen, and David T. Woodley

45 Immunoglobulin A Dermatoses ...... 771 Todd V. Cartee and Robert A. Swerlick

Index ...... 789 Contributors

Masayuki Amagai, MD, PhD Department of Dermatology, Keio University School of Medicine, Tokyo, Japan

John C. Ansel, MD Department of Dermatology, University of Colorado at Denver and Health Sciences Center, Aurora, CO, USA

Jack L. Arbiser, MD, PhD Department of Dermatology, Emory University School of Medicine, Atlanta, GA, USA

Cesar A. Arias, MD, MSc, PhD Department of Dermatology, University of Texas Medical School at Houston, Houston, TX, USA

Cheryl A. Armstrong, MD Department of Dermatology, University of Colorado at Denver and Health Sciences Center, Aurora, CO, USA

Anita Arora, MD Department of Dermatology, University of Texas Health Science Center, Houston, TX, USA

Sergei P. Atamas, MD, PhD Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA

Brenda L. Bartlett, MD University of Maryland School of Medicine, Baltimore, MD, USA

Donald V. Belsito, MD Clinical Professor of Medicine (Dermatology), University of Missouri-Kansas City, Kansas City, MO, USA

Emily M. Berger, BA Tufts University School of Medicine, Boston, MA, USA

xi xii Contributors

Brian Berman, MD, PhD Department of Dermatology and Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA

Thomas Bieber, MD, PhD Department of Dermatology and Allergy, Friedrich Wilhelms University, Bonn, Germany

Donna Bilu Martin, MD Department of Dermatology, University of Maryland, Baltimore, MD, USA

Doerte Bittner, MD Department of Dermatology, University Hospital Heidelberg, Heidelberg, Germany

Andrew Blauvelt, MD Department of Dermatology and the Department of Molecular Microbiology and Immunology, Oregon Health and Science University and Dermatology Service, Portland, OR, USA

Raymond E. Boissy, PhD Department of Dermatology, University of Cincinnati College of Medicine, Cincinnati, OH, USA

Jan D. Bos, MD, PhD, FRCP Department of Dermatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

Mariah R. Brown, MD Department of Dermatology, University of Colorado at Denver and Health Sciences Center, Aurora, CO, USA

Julie Burnett, MD Department of Dermatology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

Todd V. Cartee, MD Department of Dermatology, Emory University School of Medicine, Atlanta, GA, USA

Mei Chen, PhD Department of Dermatology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

Bernard A. Cohen, MD Department of Dermatology, Johns Hopkins Outpatient Center, Baltimore, MD, USA

Jennifer Z. Cooper, MD University of Maryland School of Medicine, Baltimore, MD, USA Contributors xiii

Edward W. Cowen, MD, MHSc Dermatology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

Noah Craft, MD, PhD, DTMH Divisions of Dermatology and Adult Infectious Diseases, David Geffen School of Medicine at UCLA and Los Angeles Biomedical Research Institute, Torrance, CA, USA

Ponciano D. Cruz, Jr., MD Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX, USA

Luis A. Diaz, MD Department of Dermatology, University of North Carolina School of Medicine, Chapel Hill, NC, USA

Ilia Elenkov, MD Institute of Neurobiology and Molecular Medicine, Rome, Italy

Alexander Enk, MD, PhD Department of Dermatology, University Hospital Heidelberg, Heidelberg, Germany

Clemens Esche, MD Department of Dermatology, Johns Hopkins Outpatient Center, Baltimore, MD, USA

David F. Fiorentino, MD, PhD Assistant Professor of Dermatology and Medicine (Rheumatology), Stanford University School of Medicine, Stanford, CA, USA

Levi E. Fried, BA Department of Dermatology, Emory University School of Medicine, Atlanta, GA, USA

Anthony A. Gaspari, MD Department of Dermatology, University of Maryland School of Medicine, Baltimore, MD, USA

Aron J. Gewirtzman, MD Department of Dermatology, Center for Clinical Studies, Houston, TX, USA

Amos Gilhar, MD Skin Research Laboratory, Technion-Israel Institute of Technology, Haifa, Israel

Michael Girardi, MD Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA xiv Contributors

Laura M. Gober, MD Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Alice B. Gottlieb, MD, PhD Department of Dermatology, Tufts–New England Medical Center, Boston, MA, USA

Richard D. Granstein, MD Department of Dermatology, Joan and Sanford I. Weill Medical College of Cornell University, New York–Presbyterian Hospital, New York, NY, USA

Gary M. Halliday, BSc (Hons), PhD, DSc Dermatology Research Laboratories, University of Sydney, Sydney, New South Wales, Australia

Christopher Hansen, MD Department of Dermatology, University of Utah, Salt Lake City, UT, USA

Ulrich R. Hengge, MD, MBA Department of Dermatology, Heinrich-Heine University, Duesseldorf, Germany

Sherrif F. Ibrahim, MD, PhD Department of Dermatology, University of Rochester, Rochester, NY, USA

Camille E. Introcaso, MD Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

Nahed Ismail, MD, PhD Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA

Heidi T. Jacobe, MD Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX, USA

H. Ray Jalian, MD Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA

Richard S. Kalish, MD, PhD† Department of Dermatology, Stony Brook University Medical Center, Stony Brook, NY, USA

† Deceased. Contributors xv

Ellen J. Kim, MD Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

Jenny Kim, MD, PhD Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA

Sidney Klaus, MD Department of Dermatology, VA Medical Center, Dartmouth Medical School, White River Junction, VT, USA

Marcelo G. Label, MD Department of Dermatology, Hospital Ramos Mejía, Buenos Aires, Argentina

Zelmira Lazarova, MD Department of Dermatology, Medical College of Wisconsin, Milwaukee, WI, USA

Mark Lebwohl, MD Department of Dermatology, Mount Sinai School of Medicine, New York, NY, USA

Erica Lee, MD Department of Dermatology, Joan and Sanford I. Weill Medical College of Cornell University, New York–Presbyterian Hospital, New York, NY, USA

Benjamin A. Lefkove, BA Department of Dermatology, Emory University School of Medicine, Atlanta, GA, USA

Justin J. Leitenberger, BS Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX, USA

I. Caroline Le Poole, PhD Department of Pathology, Loyola University Medical Center Maywood, IL, USA

Ning Li, PhD Department of Dermatology, University of North Carolina School of Medicine, Chapel Hill, NC, USA

Zhi Liu, PhD Department of Dermatology, University of North Carolina School of Medicine, Chapel Hill, NC, USA

Kurt Q. Lu, MD Department of Dermatology, University Hospitals Case Medical Center Case Western Reserve University, Cleveland, OH, USA xvi Contributors

Thomas A. Luger, MD Department of Dermatology, University of Münster, Münster, Germany

Irina G. Luzina, MD, PhD Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA

Michael R. McGinnis, PhD, ABMM Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA

Natalia Mendoza, MD Department of Dermatology, Universidad El Bosque, Bogota, Colombia

Lloyd S. Miller, MD, PhD Division of Dermatology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA

Fergal J. Moloney, MD, MRCPI Dermatology Research Laboratories, University of Sydney, Sydney, New South Wales, Australia

Kelly Nelson, MD Department of Dermatology, University of North Carolina School of Medicine, Chapel Hill, NC, USA

Frank O. Nestle, MD St. John’s Institute of Dermatology, Division of Genetics and Molecular Medicine, Kings’ College London School of Medicine at Guy’s Kings’ College and St. Thomas Hospitals, London, UK

James J. Nordlund, MD Department of Dermatology, Wright State Boonshoft School of Medicine, Dayton, OH, USA

Carlos H. Nousari, MD Department of Dermatology, University of Miami, Miami, FL, USA

Ralf Paus, MD Department of Dermatology, University Hospital Schleswig-Holstein, Luebeck, Germany; Department of Cutaneous Medicine, School of Translational Medicine, University of Manchester, Manchester, UK

Oliver A. Perez, MD Department of Dermatology and Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA

Julia Prölss, MD Department of Dermatology and Allergy, Friedrich Wilhelms University, Bonn, Germany Contributors xvii

Jennifer Remington, MD Department of Dermatology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

Stephen K. Richardson, MD Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

Steven Richardson, MD Oakwood Hospital, Dearborn, MI, USA

Scott Roberts, PhD Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA

Alain H. Rook, MD Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

Sarbjit S. Saini, MD Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Carolyn Senavsky, MD Division of Dermatology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA

Richard D. Sontheimer, MD Department of Dermatology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

Martin Steinhoff, MD, PhD Department of Dermatology, University of Münster, Münster, Germany

Craig K. Svensson, PharmD, PhD College of Pharmacy, Nursing and Health Sciences, Purdue University West Lafayette, IN, USA

Robert A. Swerlick, MD Department of Dermatology, Emory University School of Medicine, Atlanta, GA, USA

Francisco A. Tausk, MD Department of Dermatology and Psychiatry, University of Rochester School of Medicine, Rochester, NY, USA

Marcel B.M. Teunissen, PhD Department of Dermatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands xviii Contributors

Anne Marie Tremaine, MD Department of Dermatology, Center for Clinical Studies, Houston, TX, USA

Stephen K. Tyring, MD, PhD, MBA Department of Dermatology, University of Texas Medical School at Houston, Houston, TX, USA

Mark C. Udey, MD, PhD Dermatology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

Annemarie Uliasz, MD Department of Dermatology, Mount Sinai School of Medicine, New York, NY, USA

Guy F. Webster, MD, PhD Jefferson Dermatology Associates, Philadelphia, PA, USA

Stephen E. Wolverton, MD Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, USA

David T. Woodley, MD Department of Dermatology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

Kim B. Yancey, MD Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX, USA Section I Concepts of Fundamental Importance for Understanding Skin Disease 1 Cytokines and Chemokines

Oliver A. Perez and Brian Berman

Key Points antiinflammatory cytokines can lead to inflammatory cutaneous disorders. • Cytokines are soluble mediators (polypeptides) The CD4+ T-helper (Th) lymphocyte paradigm that act as messengers of the immune system. has also contributed to our understanding of inflam- • Cytokines are critical in fundamental processes such matory cutaneous disorders. CD4+ Th1 cells evoke as host defense, cell cycle control, inflammation, cell-mediated immunity and phagocyte-depend- cancer, fibrosis, wound healing, and angiogenesis. ent inflammation, while CD4+ Th2 cells evoke • Cytokines and chemokines have been implicated in strong antibody, or humeral, immune responses, the pathogenesis of a number of skin diseases, and including those of the immunoglobulin E (IgE) are now being targeted by specific biologic agents antibody class, and inhibit phagocytosis.6–10 Th2 produced by recombinant DNA technology. interleukins can also inhibit the development of • Chemokines are a structurally diverse collection the Th1 response.11 A predominant Th1 cytokine of bioactive molecules that include lipids, peptides, pattern is characteristic in diseases such as psoria- and small proteins of several classes. sis and contact dermatitis, while a Th2 cytokine • Chemokines play a critical role in the pathogenesis pattern is characteristic in diseases such as atopic wound healing, scarring of cell trafficking, cancer dermatitis and late-stage cutaneous lymphoma2,4 and inflammatory skin disorders. (Table 1.1). Cytokines are soluble low-molecular weight glyco- As important as the cytokine production profiles proteins or small polypeptides that act in an auto- of specific lymphocyte subsets during an immune crine or paracrine manner between leukocytes and response or disease process are the chemokines other cells. Cytokines have many biologic func- (chemotactic cytokines) released and their ulti- tions and are important for leukocyte growth and mate recruitment of other lymphocyte subsets. differentiation as well as activation and migration. Chemokines play an important role in angio- Cytokines orchestrate defense, growth, fibrosis, genesis, hematopoiesis, neural development, can- angiogenesis, inflammation, and neoplasm con- cer metastasis, and infection. Chemokines belong trol.1–3 They are synthesized by immunologic cells to a structurally diverse collection of bioactive such as lymphocytes and monocytes/macrophages molecules that include lipids (e.g., prostaglandin and by nonimmunologic cells such as keratinocytes D2 and leukotrienes), peptides (e.g., chemerin and endothelial cells. Proinflammatory cytokines nonamer), and small proteins of several classes include interleukin-1 (IL-1), IL-2, interferon-γ (e.g., defensins, chemokines, and nonchemokine (IFN-γ), and tumor necrosis factor-α (TNF-α), and cytokines such as granulocyte-macrophage colony- antiinflammatory cytokines include IL-1 receptor stimulating factor (GM-CSF) ). The crystal structure antagonist, IL-4, IL-10, and transforming growth of all chemokines share a disordered amino terminus, factor-β (TGF-β)4,5 (Fig. 1.1). The overexpression a β-pleaded sheet composed of three antiparallel of inflammatory cytokines or decreased levels of strands, a carboxyl-terminal α-helix, and two to

3 4 O.A. Perez and B. Berman

Th1 cells Th2 cells C terminus

Cytokines IL - 2 IL - 4 released IL - 10 IL - 5 IL - 12 IL - 6 IFNγ IL - 9 IL - 10 N-loop Helper B3 function Delayed - type Antibody hyper sensitivity response response B1 B2

Fig. 1.1. Th1 and Th2 cytokines, their interactions and their effect on the immune response Disulphide bridges

Table 1.1. Cytokine production profiles of CD4+ T- helper cell subtypes3,6–10 Th1 IL-2, IL-10, IL-12, IFN-γ, N-terminal domain TNF–α/ –β, GM-CSF Th2 IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, IL-25, GM-CSF GM-CSF – Granulocyte-macrophage Colony Stimulating Factor; N terminus IFN – Interferon; IL – Interleukin; TNF – Tumor Necrosis Factor Fig. 1.2. Crystal structure of a chemokine. Chemo- kines share a disordered amino terminus, a β-pleated three disulfide bonds that stabilize the core of the sheet composed of three antiparallel strands, a carboxyl- protein12 (Fig. 1.2). terminal α-helix and two to three disulfide bonds that During the last two decades, there has been an stabilize the core of the protein exponential increase in our understanding of the innate and adaptive immune systems and the role 13–15 cytokine and chemokine networks play in T-cell, protein production. It has three isoforms in β antigen-presenting cell (APC), and dendritic humans, and TGF- signaling involves the interac- cell (DC) activation and function. Consequently, tion of at least three different receptors (types I, there has been a radical increase in our under- II, and III) through a heteromeric protein kinase β standing of the pathogenesis of wound heal- receptor complex. The three TGF- receptors are ing, scarring, skin cancer, and inflammatory serine-threonine kinases with cysteine-rich extra- 16,17 dermatoses as well as improvements in their cellular domains. It has been shown that the β management and treatment. However, effective expression of TGF- receptors I and II as well as β cures for these dermatologic conditions remain specific TGF- isoforms are elevated in fibrotic to be developed. This chapter reviews the func- disorders characterized by excessive accumulation tion of cytokines and chemokines, their profiles of interstitial matrix material in the kidney, liver, 18–23 in these common dermatologic conditions, and lung, and skin. β how present and future therapeutics are targeting TGF- 1 has been identified by Northern analy- known cytokine and chemokine networks. sis and immunohistochemistry in hypertrophic scars, and hypertrophic scar fibroblasts have been shown to produce approximately twice as much TGF-β1 as do normal skin fibroblasts.21,24 When Cytokines Smith et al.25,26 examined the effect of exogenous β Transforming Growth Factor TGF- 2 on keloid fibroblasts, they found increased DNA synthesis. According to their findings, TGF- In the skin, TGF-β is produced by macrophages, β2 can induce a greater contraction of keloid fibroblasts, and epithelial cells, and has been fibroblasts than hypertrophic scar fibroblasts in shown to stimulate collagen gene expression and the fibroblast-populated collagen lattice model. 1. Cytokines and Chemokines 5

The increased contraction of keloid fibroblasts was Fibroblast proliferation as well as collagen, decreased with the addition of anti–TGF-β2 anti- fibronectin, and glycosaminoglycan production body. Other in vitro studies have also shown that are decreased when IFNs bind to their receptors TGF-β1 and −β2 stimulate fibroblasts to produce on fibroblasts.21,34–36 Interferon-α activates dermal collagen and that neutralizing antibodies to TGF- fibroblast synthesis of collagenase and reduces the β1 and −β2 inhibit scar tissue formation.22,25–31 production of its natural inhibitor, tissue inhibitor However, TGF-β3 prevents scarring. Fibronectin of metalloproteinase-I (TIMP-I). In contrast, IFN-β and collagen types I and III deposition in the early has been shown to inhibit collagen production.21,37 stages of wound healing as well as overall scarring Interferon-γ inhibits fibroblast proliferation, chem- was reduced when exogenous TGF-β3 was added otaxis, and production of ECM macromolecules, to cutaneous rat wounds. By contrast, rat wounds including collagen and glycosaminoglycans.13,35–39 treated with TGF-β1 and −β2 have increased Interferon-γ has also been shown to decrease colla- extracellular matrix (ECM) deposition in the early gen gene expression and to downregulate collagen stages of wound healing.27,32 synthesis by reducing steady-state messenger RNA In the near future, Renovo Pharmaceuticals (mRNA) levels of type I, II, and III procollagen as (Manchester, UK) is planning the release of Justiva, well as to downregulate nuclear factor 1, a procollagen which is derived from recombinant human (rhu) gene-activating transcription factor.36,40–42 TGF-β3. Justiva has shown promise in a phase I Since IFNs have antifibrotic properties, their clinical trial and two phase II clinical trials com- effect has been studied in hypertrophic and keloid pleted in the United Kingdom. In these studies, scar fibroblasts. In vitro studies have shown that wounds treated with Justiva demonstrated a statisti- IFN-α-2b and IFN-γ inhibit normal and hyper- cally significant improvement in scar appearance, trophic scar fibroblast TGF-β mRNA expression with a response rate of over 70%. Safety data and protein production/secretion. Interferon-γ has analysis from over 1000 subjects has revealed that also been demonstrated to inhibit normal fibrob- Justiva is tolerable and safe in humans. Renovo last TGF-β–induced type I collagen production in Pharmaceuticals has ongoing clinical trials to study vitro.43–45 In a phase II trial by Tredget et al.46 the the effect of Justiva on scar improvement following effect of subcutaneous recombinant IFN-α-2b in surgical excision of benign head and neck nevi, bilat- nine subjects with severe hypertrophic scarring after eral breast augmentation and reduction, and varicose thermal injury was examined. After a 3-month IFN- vein removal. Although the results of these trials are α-2b treatment regimen, there was a significant pending, Renovo Pharmaceuticals is hopeful that improvement in scar assessment in seven subjects Justiva will soon be available on the market.33 (p <.01), with three of the nine subjects demon- strating a significant reduction in scar volume α Interferons (p <.05). Before the IFN- -2b treatment, the serum TGF-β concentrations in the nine hypertrophic Interferons (IFNs) are naturally occurring immune scar subjects were significantly higher than control response modulators produced by lymphocytes and fibroblasts. This family of cytokines demonstrates antiviral, antiproliferative, immune-enhancing, and Table 1.2. Classification of cytokines immune-differentiating properties. The IFN family Interferons (IFN) IFN-α, -β, -γ, -δ, -ε, -κ, -τ, -ω136 consists of type I IFN, IFN-α, and IFN-β, which Tumor necrosis factors TNF-α, -β, Lymphotoxin-β3 are produced by leukocytes and fibroblasts, respec- (TNF) tively, and type II IFN, or IFN-γ, which is produced Interleukins (IL) IL-1 to IL-33110 by T lymphocytes (Table 1.2). These two types of Soluble Receptors For example, CD23, sIL1–R, sIL4–R, sIL6–R, sTNF-R3,137 IFNs bind to different high-affinity tyrosine kinase Colony-Stimulating G-CSF, GM-CSF, M-CSF, PDGF, receptors from the Janus family of kinases. When Factors (CSF) erythropoietin, thrombopoietin3 activated, these kinases phosphorylate cytoplasmic G-CSF – Granulocyte Colony Stimulating Factor; GM-CSF – signal transduction proteins that bind to cis-acting Granulocyte-macrophage Colony-Stimulating Factor; M-CSF – elements and subsequently regulate cellular gene Macrophage Colony Stimulating Factor; PDGF – Platelet transcription rates.21,34 Derived Growth Factor; TNF – Tumor Necrosis Factor. 6 O.A. Perez and B. Berman

(p <.05). However, serum TGF-β levels fell signifi- International Units (IU).61,62 However, when used cantly within 2 months of IFN-α-2b therapy and for aggressive forms of BCC, this protocol has remained within the normal range 1 month after resulted in the cure rate of only 27% of treated the IFN-α-2b therapy was stopped (p <.05). A later patients.63 Therefore, IFN treatment of BCCs study by Tredget et al.44 also demonstrated signifi- remains an alternative only for patients with cantly lower TGF-β serum levels after IFN-α-2b low-risk nodular or superficial BCC. Although int- therapy in subjects with hypertrophic scars. ralesional recombinant IFN-α-2b has been shown Interferons have also been shown to have antineoplas- to be effective in the treatment of squamous cell tic properties and to be effective in the treatment of carcinoma (SCC) and actinic keratosis (AK) when melanoma and nonmelanoma skin cancers, Kaposi’s administered at a dose of 1.5 million IU three times sarcoma (KS), and cutaneous T-cell lymphoma weekly for 3 weeks, its use has been limited by the (CTCL).47–58 Adjuvant, high-dose IFN therapy has pain of injections and the multiple follow-up visits become the standard of care in the United States necessary.64 for melanomas with a high risk of recurrence. The The FDA has also approved the use of IFN-α-2a U.S. Food and Drug Administration (FDA) has and -2b for the treatment of KS in patients with approved the use of IFN-α-2b for the treatment of acquired immune deficiency syndrome (AIDS) sec- patients with melanomas thicker than 4 mm and ondary to human immunodeficiency virus (HIV). lymph node metastasis. In a study by Rusciani The recommended dosages for IFN-α-2a and -2b et al.,59 stage II melanoma IFN-α-2b–treated sub- are 36 and 30 million IU subcutaneously three jects were compared to stage II untreated controls. times per week, respectively. However, the average The results of this study demonstrated a metastasis response rate of KS to high-dose IFN-α therapy rate of 19.6% (10 of 51 treated subjects) vs. 60% has been approximately 30%. In many cases, tumor (18 of 30 untreated controls) at 3-year follow-up, recurrence has been observed within 6 months after (p <.0001), and a metastasis rate of 25% (4 of 16 discontinuation of treatment, and response to sub- treated subjects) vs. 63% (12 of 19 untreated con- sequent treatments has not been reliable. This has trols) at 5-year follow-up (p <.005). However, the led to indefinite IFN treatment regimens until side stage I melanoma IFN-α-2b–treated subjects did effects become intolerable.65 not have a significantly different disease progression However, IFN-α is one of the most effective than the untreated stage I controls at 3- and 5-year single-therapy agents for the treatment of CTCL.66 follow-up. Low-grade, non-Hodgkin’s T-cell lymphomas are Therefore, IFN-α-2b therapy appears to be more always associated with cutaneous involvement effective in patients with advanced melanoma. and include mycosis fungoides (MF) and the A recent study examined the combination of IFN- Sézary syndrome (SS).67 A literature review by Bunn α-2b and surgery in high-risk melanoma patients. et al.68 of 207 MF and SS cases treated with IFN- In this retrospective study of 150 patients, adjuvant α-2a revealed an overall response rate of 55%, high-dose IFN was an effective treatment option with 17% of cases being complete responders to for patients with high-risk melanoma (stages IIC IFN-α-2a therapy. According to this review, the and III) after definitive surgery. The 2- and 5-year optimal treatment regimen is 3 million IU of IFN- relapse-free survival were estimated at 48% and α-2a given subcutaneously three times per week to 36%, respectively.50 patients with early-stage disease. No therapeutic The effect of IFNs has also been studied in difference was observed between IFN-α-2a and patients with low-risk nodular or superficial basal -2b. Another study found that intralesional injection cell carcinoma (BCC); BCC cells have been shown of MF plaques with IFN-α-2b at a dose of 1 mil- to express CD95 ligand (FasL) and CD95 recep- lion IU given three times per week for 4 weeks tor (FasR), whereas the surrounding CD4+ T cells produces substantial localized clinical and histologic predominantly express FasR. Thus, in IFN-treated improvement, with 10 of 12 MF plaques demon- patients, BCC may regress by FasR-FasL–mediated strating complete regression localized to the IFN-α-2b apoptosis.60 Intralesional IFN-α-2b demonstrated injected sites.58 a success rate of up to 100% when used over a 3- Serendipitous findings have also supported a to 4-week period at a concentration of 1.5 million role for IFN in the pathogenesis of inflammatory 1. Cytokines and Chemokines 7 dermatoses. Patients with psoriasis have been cells in the normotrophic scars (p <.0155). These shown to have an immunologic response char- findings suggest that low TNF-α levels may pro- acterized by the production of Th1 CD4+ T-cell mote the formation of hypertrophic scars. Tumor cytokines such as IFN.69 Topical application of necrosis factor-α has also been associated with kel- imiquimod 5% cream, which upregulates the innate oid formation. Human keloid dermal fibroblasts are immune system through activation of toll-like less sensitive than normal dermal fibroblasts to the receptors, has been shown to produce aggravation inhibitory effects of TNF-α on collagen synthesis, and spread of psoriasis plaques, apparently through and peripheral blood mononuclear cell fractions the induction of IFN production by dendritic cell from patients susceptible to keloid formation have precursors.70 Also, the treatment of cancer patients increased the levels of TNF-α when compared to with IFN-α as well as the treatment of warts with controls.87–89 The bioactivity of TNF-α overlaps intralesional IFN-α have produced psoriasis flares with that of IL-1, and TNF-α can induce IL-1 pro- and the development of psoriasis, respectively, duction by several cell types.90 Like TNF-α, IL-1 in a location where psoriasis had not developed regulates collagen gene expression and protein previously.71,72 The development of new psoriasis production.13,91 lesions has also been induced by the injection of Increased serum levels of TNF-α have also IFN-γ into the skin of patients with psoriasis.73,74 been found in patients with inflammatory der- Although a Th1 CD4+ T-cell cytokine pattern matoses when compared to control92,93 (Fig. 1.3). predominates in diseases such as psoriasis and Therefore, it is not surprising that inhibition of allergic contact dermatitis, a Th2 cytokine pattern the proinflammatory cytokine TNF-α has proven is considered to be characteristic of acute skin to be an effective treatment for the inflamma- lesions in patients with atopic dermatitis (AD) and tory dermatoses. Specifically, the soluble TNF-α late-stage CTCL.4,75–77 Given that IFN-γ regulates receptor etanercept, which inactivates circulating the Th1–Th2 balance and favors the development TNF-α, has good efficacy in the management of of a Th1 response and downregulates IgE antibody psoriasis.94,95 Chimeric mouse antihuman IgG1 expression, it is not surprising that IFN-γ therapy monoclonal antibodies that bind to and inactivate has been efficacious in the treatment of AD.78–82 TNF-α (e.g., adalimumab, infliximab) have also New therapies for AD are therefore targeting the reduction of the Th2 response via anti–IL-4, soluble IL-4 receptor, anti–IL-13, as well as the inhibition of chemokine action via C-C chemokine Psoriatric skin and macrophage-lymphocyte interaction in chronic inflammation receptor-4 and cutaneous lymphocyte-associated antigen inhibition.2,77

Tumor Necrosis Factor In contrast to the IFNs, the effects of TNF-α on Lymphocyte wound healing appear to be dose dependent. Low IL-1 TNF levels of TNF-α have a profibrotic effect and may Presents be synergistic with other growth factors, such as antigen 83 to T-cell platelet-derived growth factor (PDGF). However, Other inflammatory high concentrations of TNF-α stimulate the pro- mediators Activated Activated duction of collagenase by fibroblasts and induce lymphocyte macrophage 53,84,85 the breakdown of the ECM. Castagnoli IFN4 Other et al.86 immunostained and compared hypertrophic inflammatory mediators scar biopsies with normotrophic scar biopsies from Macrophage 13 patients undergoing reconstructive plastic sur- gery for extensive hypertrophic scars after thermal Fig. 1.3. Macrophage-lymphocyte interaction in the injury. Eight percent of cells in hypertrophic scars chronic inflammatory response of psoriatic skin. TNF, demonstrated TNF-α immunostaining vs. 35.4% of tumor necrosis factor 8 O.A. Perez and B. Berman been demonstrated to be effective in the treatment scleroderma and pulmonary interstitial fibrosis.114–117 of patients with psoriasis and marginally effec- Interleukin-6 and IL-8 levels are diminished in tive in the treatment of patients with moderate to fetal wounds, which heal without scarring, and the severe AD.96–98 The effectiveness of TNF-α inhi- addition of IL-6 to fetal wounds has been shown bition in patients with psoriasis and AD has led to induce early scarring. However, IL-10 has been to investigating its effectiveness in other inflam- shown to decrease the production of IL-6 and IL-8 matory dermatoses. TNF-α may be efficacious and to induce scarless healing when overexpressed in the treatment of bullous pemphigoid, subacute in adult mouse wounds.118 cutaneous lupus erythematosus, erythema annulare Renovo Pharmaceuticals has therefore developed centrifugum, Hailey-Hailey disease, hidradenitis Prevascar, or rhu IL-10. Preclinical experiments suppurativa, pyoderma gangrenosum, dermatomyositis, have demonstrated that application of Prevascar to and Sweet’s syndrome.2,99–109 The effectiveness the margins of acute incisional wounds by intra- of TNF-α inhibition across a wide variety of dermal injection decreases subsequent scarring. clinical entities not only provides important infor- Renovo Pharmaceuticals is currently involved in mation about the pathogenesis of these diseases, but a phase II, single-center, double-blind, placebo- also provides new directions for future research controlled, randomized, clinical trial that is evalu- (Table 1.3). ating the antiscarring efficacy of varying doses of Prevascar in 175 subjects (1400 wounds). This trial Interleukins is expected to report this year whether Prevascar is effective in preventing or reducing scarring of the An international nomenclature has been devised to skin.33 standardize the names of cytokines with dominant Interleukins have also been studied in patients immunoregulatory properties. These cytokines with metastatic melanoma.119 However, dose- have been designated as interleukins (ILs), and related serious toxicities have limited IL-2 studies newly discovered cytokines (or interleukins) are in melanoma patients, and low-dose IL-2 ther- sequentially numbered. The number of interleukins apy has produced disappointing clinical response is continuously growing, and it is currently up rates.120 When high-dose, 100,000 units/kg, intra- to IL-33110 (Table 1.2). However, cytokines with venous recombinant IL-2 was examined in 47 immunoregulatory properties such as GM-CSF patients with metastatic malignant melanoma, up have been omitted from this nomenclature system.5 to 20% achieved objective responses; however, Given the immunologic potency of interleukins and three patients developed myocardial infarction and the role they play in the metabolism of the ECM, one patient died during therapy.121 Interleukin-2– malignancy, and dermatologic inflammatory disor- based biochemotherapy (IL-2, IFN-α-2b, cisplatin, ders, they have been targeted for the development dacarbazine, and vinblastine) has shown a response of therapeutic applications.4 rate of 48%. It appears that this combination is sta- Interleukins not only regulate the metabolism tistically superior to either IL-2 or chemotherapy of the ECM but also regulate fibroblast differen- alone.122 Results of ongoing trials may clarify the tiation and proliferation.111 The interleukin profiles true value of IL-2 in combination chemotherapy. observed in hypertrophic and keloid scars are the Although IL-4, IL-6, and IL-7 have been evaluated result of polarized specific immune responses for use in immunotherapy of melanoma, they have mediated by CD4+ T-helper lymphocytes (Table not had a significant clinical impact. However, 1.1). Hypertrophic and keloid scars have a pre- GM-CSF has been shown to prolong both overall dominating Th2 cytokine profile. Hypertrophic (37.5 months in treated patients vs. 12.2 months in scars generally demonstrate increased numbers matched controls) and disease-free survival when of CD4+ Th2 cells and a low presence of CD4+ used as adjuvant therapy in patients with stage III Th1 cells.112,113 Decreased levels of IL-2 and sig- and IV malignant melanoma (p <.001).123,124 nificantly increased levels of IL-6 (p <.0001) have Given that psoriasis is characterized by an over- been found in peripheral blood mononuclear cell expression of Th1 cytokines (Table 1.1) and TNF- fractions from patients susceptible to keloids when α, the effect of rhu IL-4, a Th2 cytokine of decisive compared to controls.88,89 Interleukin-6 has also significance in regulating the Th1/Th2 balance, been implicated in other fibrotic diseases such as has been studied in an open-label trial composed 1. Cytokines and Chemokines 9

Table 1.3. Cytokines and their dermatologic therapeutic applications Cytokine Function (derived therapeutic agent) Dermatologic application(s) TGF TGF-β1,2 Stimulate fibroblast collagen gene expression and protein production TGF-β3 Reduces fibronectin and collagen types I and III deposition in the Scarring27,32,33 early stages of wound healing (rhu TGF-β3; Justiva) IFNs IFN-α T-lymphocyte and NK function enhancement, antifibrotic properties Hypertrophic scars44,46 Keloids138 Malignant melanoma50,59 Superficial BCC61,62 AK/SCC64 KS/AIDS65 CTCL58,66,68 IFN-β Inhibits endothelial cell migration/ neoangiogenesis KS/AIDS139 IFN-γ Promotes Th1 response AD78–82 TNF-α Promotes Th1 response, proapoptotic (chimeric TNF-α AD98 antibodies - adalimumab, infliximab) Hidradenitis suppurativa99–101 PG140–142 Psoriasis94,95 Sarcoidosis (lupus pernio)143,144 (soluble TNF-α receptor fusion protein—etanercept) BP109 Cicatricial pemphigoid145 EAC105 Hailey-Hailey disease104 PV146 PG106 Psoriasis96,97,103 Dermatomyositis104 SCLE104 Sweet’s syndrome108 ILs IL-2 Stimulates T-cell activation and proliferation (rhu IL-2) Stage IV malignant melanoma119–122 IL-4 Promotes Th2 response (rhu IL-4) Psoriasis147,148 IL-10 Promotes Th2 response, suppresses cellular immunity and Psoriasis149–152 TNF-α expression, antifibrotic properties (rhu IL-10 - Prevascar) Scarring33,118 IL-12 Promotes Th1 response, proinflammatory (rhu IL-12; rhu IL-12 CTCL126 p40 antibody) Psoriasis127 IL-15 Stimulates T-cell activation and proliferation, upregulates Psoriasis153 angiogenesis and TNF-α expression (rhu anti-IL-15 Ab) GM-CSF Activates macrophages and stimulates peripheral blood Stage III and IV malignant melanoma123 monocytes to become cytotoxic for human melanoma cells124 CD2 fusion Inhibits T-cell activation and proliferation (alefacept) Psoriasis154,155 protein Anti-CD11a Inhibits T-cell activation (efalizumab) Psoriasis156,157 mAb AD, atopic dermatitis; AIDS, acquired immune deficiency syndrome; AK, actinic keratosis; BCC, basal cell carcinoma; BP, bullous pemphigoid; CTCL, cutaneous T-cell lymphoma; EAC, erythema annulare centrifugum; GM-CSF, granulocyte-macrophage colony- stimulating factor; IFNs, interferons; ILs, interleukins; KS, Kaposi sarcoma; NK, natural killer; PG, pyoderma gangrenosum; PV, pemphigoid vulgaris; rhu, recombinant human; SCC, squamous cell carcinoma; SCLE, subacute cutaneous lupus erythematosus; TGF, transforming growth factor; TNF, tumor necrosis factor. of 22 subjects receiving various doses of rhu IL-4 Cutaneous T-cell lymphoma presents with for 6 weeks. Of the 20 subjects who completed the marked defects in IL-12 production, and progres- study, 18 had a reduction in the psoriasis area and sion of CTCL has been associated with profound severity index (PASI) score by 60% to 80%.125 defects in cell-mediated immunity and cytokine 10 O.A. Perez and B. Berman production. A phase I dose-escalation trial exam- CXC chemokine is IL-8 (CXCL8), which func- ined the effect of rhu IL-12 at a concentration tions to attract polymorphonuclear cells to sites of of 50, 100, or 300 ng/kg, given 2 times per week acute inflammation. The third and fourth families of subcutaneously for up to 24 weeks in 10 subjects chemokines only have one member each. The CX3C with CTCL. A complete clinical response (CR) is composed of fractalkine (CX3CL1), which func- was defined as complete disappearance of all tions as a cell-adhesion receptor and a soluble che- measurable CTCL lesions for at least 1 month. A moattractant when cleaved by TNF-α–converting partial response (PR) was defined as at least 50% enzyme.130 Lymphotactin (XCL1), the only member disappearance of all CTCL skin lesions for at least of the fourth chemokine family, attracts T cells and 1 month. Only subjects with plaque stage disease natural killer cells to sites of inflammation.131,132 (n = 2) presented a CR. Two plaque stage subjects It has been a growing interest to understand and one Sézary syndrome subject had a PR. None chemokines and their receptor interactions in order of the T3-stage subjects responded to the rhu IL-12 to develop new methods to treat inflammation. treatment. The authors announced the development However, chemokine receptors have proven dif- of future phase II/III clinical trials based on the ficult to antagonize. It has been hypothesized high response rate of plaque stage CTCL subjects that this may be secondary to the large surface of to rhu IL-12.126 interaction that a chemokine has with its recep- Not only has the administration of rhu IL-12 been tor. Recent studies have shown that patients with successful in the treatment of subjects with plaque psoriasis have an increased percentage of T cells stage CTCL, but the administration of rhu IL-12 p40 expressing CC receptor 4 (CCR4), and the CCR4 antibody has also been successful in the treatment of ligands CCL17 and CCL22 may be involved in the subjects with moderate-to-severe psoriasis. A phase pathogenesis of this disease.133 The CXC recep- I, nonrandomized, open-label study evaluated the tor 3 (CXCR3)-activating chemokines CXCL9, short-term safety, pharmacokinetics, and clinical CXCL10, and CXCL11 have also been shown to response of single, ascending, intravenous doses of function to attract activated T-cells to areas of skin rhu IL-12 p40 antibody in subjects with moderate- inflammation.134 Amgen-Tularik, Inc. (Thousand to-severe psoriasis. Eighteen subjects with at least Oaks, CA) has been involved in a phase 2 rand- 3% body surface area were enrolled in an escalating omized, double-blind, placebo-controlled study to dose regimen (0.1, 0.3, 1.0, and 5.0 mg/kg). The determine the safety and efficacy of T487, an oral results of this study demonstrated a significant and agent that inhibits CXCR3, in subjects with moderate sustained concentration-dependent improvement in to severe psoriasis.135 The results of this study will psoriatic lesions in most of the subjects studied.127 be released in the near future. Future clinical trials on immunomodulators will continue to change the approach, management, Chemokines and follow-up of patients with hypertrophic scars, keloids, skin cancer, and inflammatory dermatoses. There are approximately 50 human chemokines that These therapies will continue to be based on prin- are classified into four families based on differences ciples governing the immune system. As our cur- in their structure and function.128,129 The largest is rent knowledge of the immune system continues the CC chemokine family. These chemokines have to grow, the application of safe and efficacious the first two of the four cysteine residues adjacent immunomodulators to treat these common skin to each other; hence their name. These chemokines conditions will continue to change and shape the attract mononuclear cells to sites of chronic inflam- field of dermatology. mation. The most widely studied CC chemokine is monocyte chemoattractant protein (MCP)-1, which is an important stimulator of monocytes, dendritic Conclusion cells, and T cells. The second family of chemokines has been termed CXC, given that a single amino acid Cytokines and chemokines are critical messengers is interposed between first two of the four cysteine of the immune system, as well as the homeostasis residues in each molecule. The most recognized of peripheral tissues such as the skin. This class of 1. 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