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Evolving Concepts in the Immunology of Cutaneous Diseases

Scott N. Isenhath, MD Oregon Health & Science University, Portland, Oregon Theories on the etiologies of psoriasis and rosacea are focusing upon mechanisms at the molecular level. Relatively recently, researchers discovered that psoriasis is driven by T cells and a cascade of events involving different molecular pathways. This knowledge has led to a whole new view of possible treatment strategies for this disease. Investigators recognized the importance of such antimicrobial peptides as cathelicidins and -defensins in the propagation of certain dermal conditions. The cathelicidins fight the infectious process and stimulate events leading to angiogenesis, inflammation, and changes in dermal matrix. The -defensins may cause migration of dendritic and T cells to the site of microbial invasion and may contribute to both normal and abnormal immune responses. Many new and exciting discoveries in dermatology are lending substantial insight into the immunologic basis and pathogenesis of several dermatologic diseases, including psoriasis and rosacea. The more we learn about the molecular components of skin diseases, the more we understand why some therapies work and others fail. During the 4th annual Advances in Cosmetic and Medical Dermatology meeting, held in Wailea, Maui, Hawaii, from February 25 to March 1, 2008, several experts in skin and its pathology discussed important findings about common dermatologic conditions. Andrew Blauvelt, MD, Professor, Department of Dermatology, Oregon Health and Science University, Portland, provided an overview of the etiologies of psoriasis and rosacea, the role of antimicrobial peptides in their development, and ways in which this knowledge may be used to best treat affected patients.

Pathogenesis of Psoriasis

Dr. Isenhath is Chief Resident in the Department of Dermatology, Oregon Health & Science University, Portland, Oregon.

Psoriasis is a polygenic disease, and a variety of triggering factors (eg, infection, trauma, medications) may cause its development in predisposed individuals.1 Because it primarily affects the interfollicular epidermis, psoriasis was considered for years to result from a defect within the keratinocyte. However, a major paradigm occurred when such T-cell suppressive agents as cyclosporine significantly improved psoriasis. An immunologic basis of psoriasis subsequently was established, and, for the past 20 years, psoriasis was known as a T-cell–driven disease. Until recently, psoriasis was considered to be a prototypic type 1 T-helper (Th1) cell disease.2 Patients with psoriasis exhibit increased concentrations of Th1 cytokines (interferon- and

3. IL-17F.3 IL-23 and the Th17 Pathway . IFN = interferon. IL = interleukin.interleukin [IL]-2) and decreased levels of anti-inflammatory cytokine IL-10. Adapted.4 Th17 cells produce cytokines IL-17A. and IL-22. Th17 cells are distinct from Th1 and Th2 cells (Figure 1). from Fitch et al. lesional psoriatic skin expresses increased amounts of IL-22. IL-22 levels in the serum of individuals with psoriasis correlate with disease severity. Thus. with permission. Of them. the discovery of a new helper T-cell pathway that involves an entity known as Th17 recently challenged the Th1 dogma for the pathogenesis of psoriasis. conversely. Further. IL-6. with permission. Tbet = Th1-specific T box transcription factor. Adapted. IL-22 is the major Th17 cytokine involved in psoriasis (Figure 2). targeted therapies for psoriasis have aimed to block mediators of the Th1 system. lesional psoriatic skin expresses lower levels of IL-22. following effective psoriasis therapy. IFN = interferon. TNF = tumor necrosis factor. tumor necrosis factor (TNF)-.3 When compared with normal skin.5 Figure 2 Interleukin (IL)-23 is critical for the survival and proliferation of T-helper (Th) 17 cells.4 Figure 1 T-helper (Th) 17 cells are distinct from Th1 and Th2 cells. from Blauvelt. However.

adalimumab. malignancy. a known mediator of inflammation in various immune-mediated diseases.The cytokine IL-23 is critical for the survival and proliferation of Th17 cells.4 Figure 3 Interleukin (IL)-23 and IL-12 share the p40 subunit. . and infliximab) all target TNF-. although IL-12 and IL-23 have distinctly different functions. ankylosing spondylitis. p19 and p40. selection of TNFas a target involved concern about its immunologic properties in relation to clinical disease (ie. psoriatic arthritis. they share a p40 subunit (Figure 3). these new agents are promising in treating psoriasis. and Crohn’s disease. yet each has its own unique subunit. Thus. IL-23 is composed of two subunits. Originally. Adapted. IL-17 and IL-22 that may provide even more specific Th17 pathway targeting is ongoing. Early studies are encouraging—both biologics showed excellent efficacy and an excellent safety profile in early clinical trials. recently developed monoclonal antibodies that target the shared p40 subunit of IL-12 and IL-23. and neurologic disorders. Development of molecules that work against p19. In light of current understanding of the biology of the Th17 pathway and the key players of inflammation. TNF- appears to be involved in more than just inflammation. However. rheumatoid arthritis. currently are being tested in clinical trials. Anti-IL-12/23 Biologics Ustekinumab (CNTO1275) and ABT-874. The design of a more specific biologic ideally will lead to increased efficacy and reduced adverse effects.4 Further insight and understanding of the T cell and its role in psoriasis led to the creation of bioengineered molecules that target these critical pathways. inflammation). from Blauvelt. and its blockade may increase the risk for infection. including psoriasis. etanercept. with permission. Commonly used biologic agents (eg. IL-12 is a cytokine produced by dendritic cells that is composed of the p40 subunit (shared with IL-23) and a subunit called p35. These two biologic agents are the first to specifically target the Th17 and Th1 pathways.

the ancient molecules that are responsible for innate immunity. yet increased LL-37 levels were found in psoriatic lesions but not in those other three diseases (Figure 4). antimicrobial peptides generated great interest as investigators seek to understand their role in both health and disease. and prurigo nodularis.12 Thus. The first antimicrobial peptide discovered from human skin was human -defensin-2 (HBD-2). atopic dermatitis.6 Thereafter. cathelicidin peptides apparently are involved in immunomodulation and may provide a link between innate epithelial defense and adaptive immunity. LL-37 upregulation may provide further insight into the multifactorial causes and pathogenesis of psoriasis.10 Lande et al11 compared LL-37 levels in patients with several chronic skin diseases. In addition to their broad-spectrum antimicrobial activity. and patients with atopic dermatitis are prone to bacterial and viral infections. fungi. They are rapidly released upon injury to and/or infection of the skin and disrupt the microbial cell membrane. . The major antimicrobial-peptide families in the skin are -defensins (HBD-1. They found that there were clinical similarities between the four diseases. together. remain the first line of antimicrobial defense in both the plant and animal kingdoms. HBD-2. and HBD-4) and cathelicidins (LL-37). First described nearly 25 years ago. HBD-3. and certain viruses. These dendritic cells subsequently produce interferon-. these LL-37/DNA complexes are taken up by plasmacytoid dendritic cells. including psoriasis. psoriatic patients are relatively immune to many common skin infections. several other antimicrobial peptides were isolated.11 They noted that LL-37 forms specific complexes with DNA.8 Psoriasis and Immunity from Skin Infections Levels of the antimicrobial peptides HBD-2 and LL-37 are lower in atopic dermatitis skin lesions than in psoriatic skin lesions. lupus erythematosus.9 Interestingly. This lack of infections may result from the specific upregulation of HBD-2 and LL-37 in psoriatic lesions. and psoriatic lesions then form. which was isolated from psoriatic plaques.Antimicrobial Peptides: Cathelicidins and BETA-Defensins Antimicrobial peptides.7 The -defensins exhibit broad activity against bacteria.

but it most likely is multifactorial. the gene that encodes LL-37. but also harbor proteolytically processed LL-37 peptides that are different from those of persons with normal skin. they verified their findings by deleting CAMP.Figure 4 Increased LL-37 in psoriasis but not in other skin diseases. Individuals with rosacea not only express abnormally high levels of LL-37 in their facial skin. mRNA = messenger ribonucleic acid.13 The LL-37 peptides result from a posttranslational processing abnormality associated with an increase in the serine protease enzyme known as stratum corneum tryptic enzyme (SCTE). Adapted. chronic. . and found that the presence of SCTE alone did not result in increased skin inflammation. with permission. papules. and pustules. drying. and irritation. The pathogenesis of this condition remains relatively unknown. inflammatory condition characterized by erythema. from Lande et al. telangiectasias. Bevins and Liu14 found that increased skin inflammation occurred in the presence of SCTE. including eye redness. BDCA2 = blood dendritic cell antigen 2. After injecting LL-37 peptides into mouse skin. Thereafter.11 Pathogenesis of Rosacea Rosacea is a relatively common. Some patients may experience ocular symptoms.

Bowcock A. Psoriasis pathophysiology: current concepts of pathogenesis. Harper E. Skorcheva I. 2nd ed. Dermatology. Eur J Immunol. IL-17A and TGR-β1. Bolognia JL. Jorizzo JL. 5. Rapini RP. Obviously. Th17 cells are distinct from Th1 and Th2 cells.64(suppl 2):ii30–ii36. Kurtz SE. Mo: Mosby Elsevier. Furthermore. and the discovery of the Th17 pathway has shed new light on its pathogenesis. and mobility in keratinocytes: a potential role in psoriasis.9:461–467.36:1309–1323. Conclusion Important new discoveries in the pathogenesis of common inflammatory conditions such as psoriasis and rosacea have developed within the past year. Pathophysiology of psoriasis: recent advances on IL-23 and Th17 cytokines. 4. 2006. LL-37 complexes with DNA and serves as a possible autoantigen in psoriasis by stimulating interferon-. Future research results certainly will build upon our present knowledge base and lead to the development of better dermatologic therapies. Knowledge about this pathway led to the development of the novel anti–IL-12/IL-23 therapeutic agents ustekinumab and ABT-874. References 1.Collectively. eds. Blauvelt A. 2008. Fitch E. 2. Ann Rheum Dis. Ongoing clinical trials are testing this promising new class of biologic agents that target the Th17 and Th1 pathways. New concepts in the pathogenesis and treatment of psoriasis: key roles for IL-23. 2005. these findings confirmed the role of LL-37 in skin inflammatory responses and suggested that elevated levels of both LL-37 and SCTE are needed to produce the inflammation seen in rosacea. Krueger. we are just starting to understand the importance of antimicrobial proteins to cutaneous disease and the role of these proteins in innate epithelial defense and adaptive immunity. Psoriasis is a polygenic disease related to various triggering factors. it also is cleaved to novel pro-inflammatory peptides in the setting of increased SCTE to produce the erythema seen in rosacea. Blauvelt A. St. IL-23. Wolf K. 2007. et al. Curr Rheumatol Rep. Antimicrobial peptides also may be important in understanding and treating such inflammatory conditions as psoriasis and rosacea. survival of Th17 cells depends upon its key regulator. JG. IL-22 regulates the expression of genes responsible for antimicrobial defense. 3.2:69–78. cellular differentiation. Witte E. 2007. Expert Rev Dermatol. Wallace E. and IL-22 is the major Th17 cytokine in psoriasis. . Louis.

Ushio H. J Invest Dermatol. 2002. Endogenous antimicrobial peptides and skin infections in atopic dermatitis. Nakano N. 2007. Antimicrobial peptides human beta-defensins stimulate epidermal keratinocyte migration. Nat Med.449:564–569. Ong PY.13:904–906 . et al. Zheng Y. Baumgarth M. Antimicrobial peptides in human skin disease. Nature. et al. Di Nardo A. Gregorio J.347:1151–1160. 14.157:1124–1131. Bevins CL. et al. Yamasaki K. Rosacea: skin innate immunity gone awry? Nat Med. Liu FT. Yamasaki K. Christophers E. N Engl J Med. Gallo RL. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. 2007. Nature. 1997. Cathelicidin LL-37 induces the generation of reactive oxygen species and release of human alpha-defensins from neutrophils. 2007.387:861. 10. Bevins CL.6. Autoimmune disease: skin deep but complex. Facchinetti V. Lande R.449:551–553. et al. Schröder JM. Ohtake T.18:11–21. et al. Bartels J. Ushio H. 8. Br J Dermatol. 2007. Niyonsaba F. Bardan A. 11. 2008.127:594–604. 13. Brandt C. 12. 2007. 2007. Niyonsaba F.13:975–980. Eur J Dermatol. 7. Harder J. 9. A peptide antibiotic from human skin. Nature. Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. proliferation and production of proinflammatory cytokines and chemokines.