This report was reviewed for medical and scientific accuracy by Babar K. Rao, MD, Clinical Assistant Professor of Medicine, Division of Dermatology, University of Medicine & Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey

Expert Commentary

Brian J. Nickoloff, MD, PhD, Professor and Associate Chair of Pathology, Loyola University of Chicago Medical Center, Maywood, Illinois

A growing body of evidence supports the fundamentally important role of professional antigen-presenting cells, such as dendritic cells, as instigators and perpetuators of inflammatory and autoimmune skin diseases. Just as the past decade introduced targeted therapies directed at T-cell subsets, it is now possible to envision targeting specific dendritic cell subsets, such as epidermal Langerhans cells, dermal dendritic cells, and plasmacytoid dendritic cells, for the treatment of chronic inflammatory skin diseases including psoriasis and systemic lupus erythematosus. This shifting paradigm portends an exciting era in investigative dermatology.

Dendritic cells serve a number of important functions in human skin. The fundamental role of dendritic cells is the initiation of a primary immune response. By using cell-surface receptors, dendritic cells recognize, bind, and engulf infectious agents,^1,2 such as gram-positive/gram-negative bacteria, Candida albicans, Mycobacterium tuberculosis, and a number of viruses (eg, dengue, human immunodeficiency/AIDS, and papilloma). Secondly, dendritic cells play an important role in maintaining skin tolerance through the elimination of apoptotic and necrotic cell debris. Thirdly, dendritic cells generate effective immunity as a result of epicutaneous or intracutaneous vaccination.

Normal skin has a confederacy of immunocyte subsets, including Langerhans cells, dermal dendritic cells, macrophages, and veil cells. During inflammatory conditions, an admixture of dendritic cells arises, beginning with lymphoid-derived dendritic cells known as plasmacytoid dendritic cells. The admixture also includes myeloid-derived cells such as highly inflammatory dendritic cells, interstitial dendritic cells, and tumor necrosis factor-α/inducible nitric oxide synthase (TNF-α/iNOS) or Tip dendritic cells.

Dendritic cells are thought to be very plastic and, depending on the stimulus and expression of various receptors, play a major role in the polarization of T-cell response characterized by TH-1 or TH-2 cytokine immune responses.^2-4 In this cascade, dendritic cells produce a variety of dendrikines (eg, interleukin [IL]-12, IL-23, IL-27, TNF-α, and interferon-α) that further influence T-cell signaling components and additional cytokine release (eg, IL-17, TNF-β, interferon-γ). Ultimately, this cascade results in CD4+ and/or CD8+ T-cell proliferation, which in turn drives chronic cutaneous inflammation of the skin. Indeed, psoriasis, systemic lupus erythematosus, and cutaneous T-cell lymphoma are characterized by increased presence of dendritic cells in lesional skin that accompany the T lymphocytic infiltrate.

This Dermatology Express Report reviews data presented at a satellite symposium held during the Society for Investigative Dermatology 66th Annual Meeting. Our understanding of the molecular basis for dendritic cell proliferation, maturation, migration, and the resulting inflammatory immune response continues to evolve. Whereas past research has focused on T-cell subsets, future efforts will be directed toward dendritic cells and their role in inflammatory and autoimmune diseases.

Life Cycle and Role of Langerhans Cells

According to Edgar G. Engleman, MD, Professor of Pathology and Medicine, Stanford University School of Medicine, Stanford, California,⁵ dendritic cells, including Langerhans cells, are present in the blood and the majority of peripheral tissues and appear to perform the same function in all of these tissues. Dendritic cells arise from an as-yet identified progenitor or progenitors in the bone marrow and migrate via the bloodstream from the bone marrow to peripheral tissues, where they can reside in an inactivated state for a prolonged period of time, perhaps for the entire life of the cell in the case of Langerhans cells, Dr. Engleman noted. Eventually, the dendritic cells come in contact with stimuli or pathogens that interact with cell-surface receptors and cause the dendritic cells to become activated. Activation leads to profound changes in morphology and metabolism in the dendritic cells whereby migration occurs (antigen processing), leading to the induction of an immune response by activation in the draining lymph node.

"The dendritic cells take up the materials [pathogens/stimuli] they come in contact with, metabolize them, and then escape their station via the afferent lymphatics," stated Dr. Engleman. "When the dendritic cells reach the lymph node, the cells are fully activated and present the metabolized materials - primarily to T cells - but they may also stimulate natural killer cells, probably natural killer T cells and B cells."

Dr. Engleman observed that Langerhans cells represent a critical immunologic barrier to the external environment, but little is known about the origin or life cycle. In order to address this, Dr. Engleman and colleagues developed a mouse model system to study the origin and life cycle of Langerhans cells. In their model, CD45.2 recipient mice receive lethal irradiation followed by congenic bone marrow transplantation from CD45.1 donor mice. The donor marrow is marked and tracked with a monoclonal antibody.

"We found that most dendritic cells are replaced by donor cells, except for Langerhans cells, which are not replaced," noted Dr. Engleman. "That tells us that Langerhans cells of the skin apparently are capable of self-renewal."

However, creation of an inflammatory environment in the skin changed that paradigm. Mice that received donor bone marrow were exposed to ultraviolet light, which created the equivalent of a mild sunburn. Over time, Langerhans cells were replaced and the replacement occurred in proportion to the amount of ultraviolet light exposure. This suggests that the intensity of inflammation was associated with increased replacement of host cells with donor cells. The bone marrow transplant studies were repeated, but T cells were eliminated from the donor marrow. In that situation, the host Langerhans cells were not replaced by donor-derived cells.

"The finding was consistent with the idea that an inflammatory milieu is required to replace host Langerhans cells with donor-derived cells," indicated Dr. Engleman.

Interestingly, Langerhans cell replacement did not occur if donor marrow came from an animal lacking the chemokine receptor CCR6. Such observations allow investigators to catalog the chemokines and cytokines that are critical to Langerhans cell replacement after allogeneic bone marrow transplantation.

These observations prompted Dr. Engleman to study the role of Langerhans cells in graft-versus-host disease (GVHD), which is the most common serious complication of allogeneic bone marrow transplantation. Dr. Engleman posed several facts - the skin is the organ most often affected by GVHD; GVHD does not occur in recipients of T-cell-depleted bone marrow; and Langerhans cells are potent stimulators of T cells. Dr. Engleman then asked, "Taken collectively, do host Langerhans cells induce graft-versus-host disease?"

Dr. Engleman recounted his mouse model. "In studies involving mice, host Langerhans cells induced severe graft-versus-host disease in animals injected with allogeneic T cells. However, exposure to ultraviolet light resulted in attenuation of graft-versus-host disease in mice injected with allogeneic T cells. These experiments led us to conclude that Langerhans cells of the skin are probably the primary stimulus of graft-versus-host disease," concluded Dr. Engleman. A complete summary of the Langerhans cells data can be found in 2 recent publications from Dr. Engelman's laboratory.^6,7

Delineation of Dendritic Cell Subsets in Allergic Contact Dermatitis

Investigation of differentiation and activation markers associated with dendritic cells has provided important clues to the involvement of dendritic cells in allergic contact dermatitis, observed Georg Stingl, MD, Chairman, Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Vienna, Austria.⁸ Allergic contact dermatitis is a T-cell mediated cutaneous immune response. The elicitation of allergic contact dermatitis presumably requires interaction between infiltrating T cells and antigen-presenting cells. Evidence exists that depletion of resident Langerhans cells after sensitization results in an increased, and not a decreased, contact hypersensitivity response.⁹ Dr. Stingl has researched the distribution of Langerhans cells, dermal dendritic cells, and plasmacytoid dendritic cells in the immunopathology of allergic contact dermatitis.¹⁰

Dr. Stingl observed that in normal human skin, large numbers of Langerin/CD207 and CD1a+ dendritic cells appear in the epidermis and less so in the dermis, while the opposite is true for CD1c+ dendritic cells. In allergic contact dermatitis, Langerin/CD207 and CD1a+ dendritic cells reverse their prominence, suggesting migration of the cells. The population of CD1c+ cells increases in the epidermis, but a much larger increase occurs in the dermis.

According to Dr. Stingl, evaluation of the activation marker CD83 has provided additional insight into the involvement of dendritic cells in allergic contact dermatitis. An increase in CD1c+ cells was associated with an absence of CD83 in both normal and inflamed skin. In contrast, the proportion of CD83+ Langerhans cells increased substantially in allergic contact dermatitis.

"In allergic contact dermatitis, Langerhans cells express activation markers and therefore are good candidates for initiating and perhaps propagating allergic response," advised Dr. Stingl. "With respect to dermal dendritic cells, the phenotype really does not change in allergic contact dermatitis, and we do not find activation markers. These observations suggest dermal dendritic cells might be involved in downregulation and ultimately resolution of the allergic response," added Dr. Stingl. Further studies are indicated to determine if this hypothesis is correct.

Plasmacytoid dendritic cells are almost absent in normal skin, but a substantial subpopulation of CD83+ and CD86+ cells appears rapidly in allergic contact dermatitis, suggesting activation of the cells, Dr. Stingl noted. Moreover, plasmacytoid dendritic cells appear in proximity to natural killer cells and receive molecular signals from natural killer cells, indicating that plasmacytoid dendritic cells might be responsible for the TH-1 bias of the allergic contact dermatitis immune response, according to Dr. Stingl.

Role of Dendritic Cells in Systemic Lupus Erythematosus

Dendritic cells also play a prominent role in autoimmune conditions, such as systemic lupus erythematosus. Dendritic cells have a fundamental role in the immune response; immature dendritic cells allow peripheral tolerance, while mature dendritic cells allow immunity, commented Jacques Banchereau, PhD, Director, Baylor Institute for Immunology Research, Baylor University, Dallas, Texas.¹¹ Dendritic cells capture dying keratinocytes and fibroblasts and migrate to the afferent lymphatics, but are not activated. When dendritic cells are stimulated by a pathogen, they undergo maturation and are transformed into cytotoxic humoral effectors.

"In autoimmune diseases, there would be permanent activation of dendritic cells," indicated Dr. Banchereau. "Rather than having elimination of T cells, there would be activation, hence, autoimmunity."

Dr. Banchereau hypothesized that if dendritic cells must be activated to induce autoimmunity, then the blood of patients with systemic lupus erythematosus should contain cells that are characteristic of dendritic cells. To test this hypothesis, Dr. Banchereau and colleagues evaluated blood monocytes exposed to normal or systemic lupus erythematosus serum.¹² In the systemic lupus erythematosus serum, the monocytes started to aggregate within 6 to 8 hours and had differentiated into dendritic cells within 24 to 48 hours.

"There is something in systemic lupus erythematosus serum that transforms monocytes into dendritic cells," observed Dr. Banchereau. "The catalyst for this transformation is interferon-alpha. Clearly, the induction of systemic lupus erythematosus dendritic cells correlates with serum levels of interferon-alpha. If we counteract interferon-alpha in the serum, we entirely block the allostimulatory capacity to produce dendritic cells. It is clear in my mind that blocking interferon-alpha will be essential to treating systemic lupus erythematosus. We are now humanizing an antibody to interferon-alpha," advised Dr. Banchereau.

Expounding on the role of interferon-α in disease states, Dr. Banchereau noted up to one-third of patients with rheumatoid arthritis, juvenile chronic arthritis, or Crohn's disease treated with TNF-α antagonists develop anti-dsDNA antibodies, mimicking a lupus-like condition. Data suggests that neutralizing autocrine TNF sustains interferon release by the plasmacytoid dendritic cells.¹³ Moreover, high serum levels of soluble TNF receptors correlate with systemic lupus erythematosus disease activity.¹⁴ Dr. Banchereau concluded his presentation by noting that much work remains to be done to fully elucidate the relationships between dendritic cells and autoimmune diseases.

Targeting Dendritic Cell-produced Cytokines in Psoriasis

Targeting dendritic cell-produced cytokines such as TNF-α and interferon-γ has proven to be an effective therapeutic strategy for the treatment of psoriasis, advised Frank O. Nestle, MD, Senior Physician and University Lecturer, Department of Dermatology, University of Zürich Medical School, Zürich, Switzerland.¹⁵

"If a patient has fully developed autoimmune-type inflammatory lesions and you block tumor necrosis factor-alpha, it can lead to clearance of the disease," advised Dr. Nestle.

Using a xenotransplantation mouse model of psoriasis, Dr. Nestle and colleagues have demonstrated that transplantation of symptomless pre-psoriatic human skin grafted onto immunosuppressed AGR 129 mice leads to the development of psoriasis.¹⁶ In that model, resident human T cells underwent local proliferation that was crucial for the development of a psoriatic phenotype because blocking of T cells led to the inhibition of psoriasis development. Dr. Nestle emphasized that TNF-α is an important dendritic cell-derived mediator whose antagonism blocks local T-cell expansion and development of psoriasis.

Dr. Nestle elaborated on the potential targets for the treatment of psoriasis. The IL-12 family of cytokines, particularly IL-23, has emerged as a potentially important contributor to the pathogenesis of psoriasis. The p19 and p40 subunits of IL-23 have been shown to be increased in psoriasis lesions compared with normal skin.¹⁷ Interferon-α, a dendritic cell-derived cytokine, might also offer a potential therapeutic target for psoriasis. Plasmacytoid dendritic cells are important early inducers of interferon-α, whereby interferon-α may impact on the maturation of dendritic cells, activation of T cells, and cytokine production, eventually leading to the development of psoriasis.

"We have at least one established cytokine target in psoriasis. Certainly, there are other cytokine targets that might contribute to our understanding of psoriasis. Importantly, our investigative efforts should fortify our future therapeutic armamentarium for patients who suffer from psoriasis," concluded Dr. Nestle.

References

1. Taylor PR, Martinez-Pomares L, Stacey M, Lin HH, Brown GD, Gordon S. Macrophage receptors and immune recognition. Annu Rev Immunol. 2005;23:901-944.
2. Kapsenberg ML. Dendritic-cell control of pathogen-driven T-cell polarization. Nat Rev Immunol. 2003;3:984-993.
3. Grunig G, Banz A, de Waal Malefyt R. Molecular regulation of Th2 immunity by dendritic cells. Pharmacol Ther. 2005;106:75-96.
4. Eisenbarth SC, Piggott DA, Bottomly K. The naster regulators of allergic inflammation: dendritic cells in Th2 sensitization. Curr Opin Immunol. 2003;15:620-626.
5. Engleman EG. Langerhans Cells (LCs): Life Cycle and Role in GVHD. Presented as part of the satellite symposium "Shifting Paradigms II - From T Cell to DC Subsets in the Immunobiology of Human Skin" held during the Society for Investigative Dermatology 66th Annual Meeting, May 4, 2005, St. Louis, Missouri.
6. Merad M, Manz MG, Karsunky H, et al. Langerhans cells renew in the skin throughout life under steady-state conditions. Nat Immunol. 2002;3:1135-1141.
7. Merad M, Hoffmann P, Ranheim E, et al. Depletion of host Langerhans cells before transplantation of donor alloreactive T cells prevents skin graft-versus-host disease. Nat Med. 2004;10:510-517.
8. Stingl G. Delineation of DC Subsets in Normal Skin and Allergic Contact Dermatitis. Presented as part of the satellite symposium "Shifting Paradigms II - From T Cell to DC Subsets in the Immunobiology of Human Skin" held during the Society for Investigative Dermatology 66th Annual Meeting, May 4, 2005, St. Louis, Missouri.
9. Grabbe S, Steinbrink K, Steinert M, Luger TA, Schwarz T. Removal of the majority of epidermal Langerhans cells by topical or systemic steroid application enhances the effector phase of murine contact hypersensitivity. J Immunol. 1995;155:4207-4217.
10. Bangert C, Friedl J, Stary G, Stingl G, Kopp T. Immunopathologic features of allergic contact dermatitis in humans: participation of plasmacytoid dendritic cells in the pathogenesis of the disease? J Invest Dermatol. 2003;121:1409-1418.
11. Banchereau J. Role of Plasmacytoid DCs in SLE. Presented as part of the satellite symposium "Shifting Paradigms II - From T Cell to DC Subsets in the Immunobiology of Human Skin" held during the Society for Investigative Dermatology 66th Annual Meeting, May 4, 2005, St. Louis, Missouri.
12. Blanco P, Palucka AK, Gill M, Pascual V, Banchereau J. Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus. Science. 2001;294:1540-1543.
13. Palucka AK, Blanck JP, Bennett L, Pascual V, Banchereau J. Cross-regulation of TNF and IFN-alpha in autoimmune diseases. Proc Natl Acad Sci USA. 2005;102:3372-3377.
14. Gill MA, Blanco P, Arce E, Pascual V, Banchereau J, Palucka AK. Blood dendritic cells and DC-poietins in systemic lupus erythematosus. Hum Immunol. 2002;63:1172-1180.
15. Nestle FO. Targeting DC-produced Cytokines and Clinical Results in Psoriasis. Presented as part of the satellite symposium "Shifting Paradigms II - From T Cell to DC Subsets in the Immunobiology of Human Skin" held during the Society for Investigative Dermatology 66th Annual Meeting, May 4, 2005, St. Louis, Missouri.
16. Boyman O, Hefti HP, Conrad C, Nickoloff BJ, Suter M, Nestle FO. Spontaneous development of psoriasis in a new animal model shows an essential role for resident T cells and tumor necrosis factor-alpha. J Exp Med. 2004;199:731-736.
17. Lee E, Trepicchio WL, Oestreicher JL, et al. Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. J Exp Med. 2004;199:125-130.

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Disclosure

Brian J. Nickoloff, MD, PhD:
No significant relationships to disclose

Babar K. Rao, MD:
No significant relationships to disclose

This report does not contain information on commercial products that are unlabeled for use or investigational uses of products not yet approved.

The opinions expressed in this publication are those of the participating faculty and do not necessarily reflect the opinions or the recommendations of their affiliated institutions; University of Medicine & Dentistry of New Jersey; Millennium CME Institute, Inc.; or any other persons. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this publication should not be used by clinicians without evaluation of their patients' conditions, assessment of possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with the recommendation of other authorities. This Dermatology Express Report^TM was made possible through an educational grant from Centocor, Inc.

© 2005 Millennium CME Institute, Inc. and UMDNJ-Center for Continuing and Outreach Education

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