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1 Official Journal of the International Hair Research Foundation Online The melanocyte subpopulations of the human skin and hair follicle Desmond J. Tobin Protected by an extraordinary privilege Fabio Rinaldi, Piero Rosati, Elisabetta Sorbellini Possible cell mechanisms of action of minoxidil Elisabetta Sorbellini, Eduardo Reyes The hair cycle: Why is hair growth cyclical? Andrea Marliani Periodico quadrimestrale - Spedizione in abbonamento postale 45% - art. 2 comma 20/B legge 662/96 - Milano In caso di mancata consegna restituire al mittente che si impegna a pagare la relativa tassa. Eye-brow and eye-lashes transplant Marco Toscani, Cristiano Monarca, Maria Ida Rizzo, Fulvio Conte, Nicolò Scuderi A clinical case of folliculitis decalvans Antonio Torti, Raffaele Gianotti

2 ALES GROUPE ITALIA SPA tel Phyto aderisce a Impatto Zero. L impatto ambientale del pack dei prodotti Phyto è stato ridotto e compensato con la creazione di nuove foreste.

3 Editorial Fabio Rinaldi President of the International Hair Research Foundation What can the aim of a new scientific journal be? There are already so many scientific publications, and some of them have an extremely high level. The Board of Directors of the International Hair Research Foundation examined this question for three years but always got to the same answer: A new journal was not needed at that moment. However, as the Foundation started to grow and broaden its activities, as the meetings with professionals started to promote an exchange of ideas and information, we realised the possible usefulness of a publication dealing specifically with trichology. In fact, a trichological journal would gather all the latest news and innovations in such a vast field and combine all the articles which are now dishomogeneously published in different types of publications (medical, dermatological, cosmetological, biological etc.). That is how Human Trichology, the official journal of the International Hair Research Foundation, was born. Human Trichology will deal with every trichological issue concerning human hair and hairs. We want our journal to be extremely precise. Therefore, we will make use of the contributions of the most influential international researchers and experts in all trichological fields and all scientific professionals dealing with hair problems. The Editorial Board has resolved to follow some very strict rules to select the articles and issues to be dealt with. We intend to respect all of these rules in order to guarantee a reliable scientific journal of quality, where every reader can find useful information and advice for their professional activity. Do we intend to produce a journal like Nature? An example: The current issue has published a review on the immune privilege enjoyed by human hair. Up to now, this extremely complex and fascinating topic has only been dealt with by an èlite of trichological biology researchers, as if it were useless in medical practice. The review in our journal reports on the mechanisms of the immune privilege of hair follicles and tries to identify the practical aspects of this issue. This is what Human Trichology aims at. With the aid of all the professionals who will assist us in our project, we are sure we will meet all of our goals. I

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5 Human Trichology Official Journal of the International Hair Research Foundation Contents Editor Fabio Rinaldi (Italy) Editor in Chief Mauro Barbareschi (Italy) Co-Editors Francisco Jimènez Acosta (Spain) Gaetano Agostinacchio (Italy) Paola Bezzola (Italy) Daniele Campo (Italy) Vincenzo Gambino (Italy) Marcella Guarrera (Italy) Andrea Marliani (Italy) Paolo Piazza (Italy) Piero Rosati (Italy) Elisabetta Sorbellini (Italy) Piero Tesauro (Italy) Desmond Tobin (United Kingdom) Marco Toscani (Italy) Managing Editor Antonio Di Maio (Italy) IHRF Secretary Staff Alessandra Ferretti (Italy) Assunta Preite (Italy) REWIEV ARTICLES pag. 1 The melanocyte subpopulations of the human skin and hair follicle Desmond J. Tobin pag. 9 Protected by an extraordinary privilege Fabio Rinaldi, Piero Rosati, Elisabetta Sorbellini TRICHOLOGICAL BIOLOGY pag. 17 Possible cell mechanisms of action of minoxidil Elisabetta Sorbellini, Eduardo Reyes pag. 25 The hair cycle: Why is hair growth cyclical? Andrea Marliani ORIGINAL ARTICLE pag. 29 Eye-brow and eye-lashes transplant Marco Toscani, Cristiano Monarca, Maria Ida Rizzo, Fulvio Conte, Nicolò Scuderi CASE REPORT pag. 35 A clinical case of folliculitis decalvans Antonio Torti, Raffaele Gianotti International Hair Research Foundation Viale Bianca Maria, Milano Tel Scripta Manent s.n.c. Direttore Responsabile Pietro Cazzola Direttore Generale Armando Mazzù Direttore Marketing Antonio Di Maio Consulenza Grafica Piero Merlini Impaginazione Stefania Cacciaglia Via Bassini, Milano Tel Fax Registrazione Tribunale di Milano n. 42 del 01/02/2010 È vietata la riproduzione totale o parziale, con qualsiasi mezzo, di articoli, illustrazioni e fotografie pubblicati su Human Trichology senza autorizzazione scritta dell Editore. L Editore non risponde dell opinione espressa dagli Autori degli articoli. III

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7 REVIEW ARTICLE Desmond J. Tobin Centre for Skin Sciences, School of Life Sciences, University of Bradford, Bradford, West Yorkshire, Great Britain The melanocyte subpopulations of the human skin and hair follicle Desmond J. Tobin The melanocyte subpopulations of the human skin and hair follicle Comparative Biology of Epidermal and Hair Follicle Melanocytes: The relative independence of the epidermal and follicular melanin units can be appreciated by the co-expression of white hair and black skin in aging Africans and conversely raven hair in white-skinned Europeans. The presence of immature melanocytes (melanoblasts) in fully-developed adult anagen hair follicles has been confirmed in situ and in vitro. Although amelanotic hair follicle melanocytes lack dopa-oxidase activity, low levels of the tyrosinase protein itself may be detected in some cells, as well as KIT and Bcl-2. The role of these amelanotic melanocytes in hair pigmentation is unclear, although it has been speculated that these cells represent a pool of transient melanocytes that migrate from precursor melanocyte stores in the upper outer root sheath. The Fate of Hair Follicle Melanocytes during the Hair Growth Cycle: Active pigmentation occurs only during the hair growth phase (anagen), which in human scalp hair can be very long (up to 8 years or more). This extended anagen of human scalp hair, together with its mosaic pattern of hair growth, hinders systematic analysis of melanocyte dynamics during the human hair cycle. The relatively quiescent telogen hair germ contains all cell precursors needed to reconstitute a fully developed anagen VI hair follicle. Some DCT-positive melanocytes begin to express TRP1 at this stage, especially melanocytes located close to the forming hair bulb, while melanocytes residing in the upper outer root sheath (site of the presumptive germ cell reservoir) remain TRP1-negative. By anagen IV, when the hair pigmentary unit becomes fully functional with respect to melanin synthesis, melanocytes are distributed into discrete locations throughout the hair follicle). Only melanocytes distributing to the hair follicle melanogenic zone, i.e., the hair bulb matrix above the DP, express TRP1, DCT, tyrosinase, KIT, and also Ki67 in the majority of melanocytes. DCT protein is undetectable in melanogenic melanocytes of the human scalp anagen hair bulb, though other human hair follicles may show variable expression. Melanocyte proliferation mainly ceases by anagen VI (full anagen). A long enduring enigma of both hair follicle and pigment biology concerns the fate of the hair bulb melanocytes when they become undetectable during catagen. Where do these melanocytes go during catagen and telogen? Our current view suggests that many of the so-called re-differentiating melanocytes in early anagen correspond to newly recruited immature melanocytes derived from a melanocyte reservoir and are not re-activated from pre-existing hair bulb melanocytes that were melanogenically active during the previous anagen phase. Moreover, these hair follicle melanocyte stem cells appear to have the capacity to enter vacant niches, including (via migration to) the epidermis. In any event at least a proportion of the highly melanotic (possibly terminally differentiated melanocytes) hair bulb melanocytes do not survive catagen. Aging of the Follicle Melanocytes and Hair Graying (Canities): For every decade after 30 years of age the number of pigment-producing melanocytes in exposed/unexposed epidermis decreases by 10%-20%, accounting for much of the loss of skin tone with age. It is likely that the antioxidant systems within the hair follicle melanocyte become impaired with age, leading to uncontrolled damage to the melanocyte itself from its own melanogenesis-related oxidative stress. Recent work suggests that the follicular-melanin unit of graying hair is associated with increased melanocyte apoptosis and oxidative stress. A relatively small number of melanocytes (< 100 cells per scalp anagen hair follicle) can, in a single hair growth cycle, produce sufficient melanin to intensely pigment up to 1.5 m of hair shaft. Beard and body hair is usually affected later. Key words: Hair follicle, Melanocytes, Hair growth cycle, Hair graying 1

8 rigin of cutaneous melanocytes O Melanocytes of both the epidermal melanin unit and the follicular pigmentary unit derive from melanoblasts that migrate from the neural crest to the skin. Commitment and differentiation of cells to the melanocytic lineage in the neural crest are determined by several factors including, amongst others, microphthalmia-associated transcription factor (MITF), SOX10, Pax3, KIT, fibroblast growth factor- 2, and endothelin 3 1. Melanoblasts migrate out of the neural crest along stereotypic routes to enter the dermis of the skin. Melanogenesis occurs very early during human embryologic development and melanocytes can be detected in human skin as early as 7 weeks of gestation 2 with pigment synthesis some 5 months before birth. Some melanoblasts proliferate and differentiate into melanocytes while residing in the epidermis, while others and their progeny, so-called transit-amplifying melanocytes, leave the epidermis to distribute in the developing hair follicles as dopa (3,4-dihydroxy phenylalanine) -positive or -negative cells in the hair follicle and sebaceous gland. More than 90 loci are known to affect hair color 3 ; mutations in the receptor tyrosine kinase KIT and its cognate ligand SCF, and endothelin 3 and its receptor Ednrb are the most informative. omparative biology of epidermal C and hair follicle melanocytes The relative independence of the epidermal and follicular melanin units can be appreciated by the coexpression of white hair and black skin in aging Africans and conversely raven hair in white-skinned Europeans. This is further supported clinically, by the selective/preferential targeting of epidermal but not follicular melanocytes in most cases of vitiligo, while follicular melanocytes alone are damaged by immune-mediated pathology in acute alopecia areata 4, 5. In the fully-developed anagen human scalp, follicle melanocytes can be detected in distinct anatomic compartments with region-specific differentiation status. In the mature hair follicle, melanotic melanocytes positive for dopa oxidase are readily detectable in the basal layer of the infundibulum and around the upper dermal papilla; moderately differentiated melanocytes may also be detected in the basal layer of the sebaceous gland. However, the hair bulb is the only site of pigment production for the hair shaft, and contains both highly melanogenic melanocytes and a minor subpopulation of poorly differentiated melanocytes 6, 7. Melanogenically-active melanocytes are however restricted to the upper hair bulb matrix, just below the precortical keratinocytes, a location that facilitates the transfer of melanin to the hair shaft cortex, less so to the medulla, and very rarely the hair cuticle. The presence of immature melanocytes (melanoblasts) in fully-developed adult anagen hair follicles has been confirmed in situ and in vitro 8, 9. Dopa-negative amelanotic melanocytes appear in the mid-to-lower outer root sheath, but also in the periphery of the bulb and the most proximal matrix. All the dopa-positive cells, and also some dopanegative melanocytes of the mid outer root sheath contain (pre)melanosomes (i.e., gp100-positive) 8. Although amelanotic hair follicle melanocytes lack dopa-oxidase activity, low levels of the tyrosinase protein itself may be detected in some cells, as well as KIT and Bcl-2. These melanocytes do not express the melanogenic enzymes tyrosinase-related protein-1 (TRP1) and TRP2 (dopachrome tautomerase, DCT) 8. The role of these amelanotic melanocytes in hair pigmentation is unclear, although it has been speculated that these cells represent a pool of transient melanocytes that migrate from precursor melanocyte stores in the upper outer root sheath 10. This multi-functionality of follicular melanocyte subpopulations is attested by their complex responses to chemotherapy 10, 11. Recent immunologic data have shown that the follicularmelanin unit resides in the immune-privileged proximal anagen hair bulb (c.f. 12 ). Melanocytes of the follicularmelanin unit are larger, more dendritic, have more extensive Golgi and rough ER, and produce larger melanosomes compared to melanocytes in the epidermal-melanin unit (c.f. 13 ). While melanin produced by the latter degrades almost completely in the differentiating layers of the epidermis, eumelanin granules transferred into hair cortical keratinocytes remain minimally digested; hence, the similarly pigmented proximal and distal ends of a typical hair shaft (c.f. 13 ). By far the most striking difference between the epidermaland follicular-melanin units, and one with significant implications for the regulation of hair pigmentation, is the observation that the activity of the hair bulb melanocyte is under tight cyclical control and that melanogenesis is coupled to the hair growth cycle (c.f. 10 ). Epidermal melanogenesis, by contrast, appears to be continuous 14, though this constitutive activity can be stimulated further, e.g., after exposure to UV radiation. 2

9 he fate of hair follicle melanocytes T during the hair growth cycle Active pigmentation occurs only during the hair growth phase (anagen), which in human scalp hair can be very long (up to 8 years or more) 15. This extended anagen of human scalp hair, together with its mosaic pattern of hair growth, hinders systematic analysis of melanocyte dynamics during the human hair cycle. However, the C57BL/6 mouse strain has proven to be a very useful model for human hair pigmentation, with is short anagen (15-17d), synchronous hair growth pattern, restriction of melanogenically active truncal melanocytes to hair follicles, exclusively eumelanin production, and the similar linkage of murine melanogenesis with anagen 15. The relatively quiescent telogen hair germ contains all cell precursors needed to reconstitute a fully developed anagen VI hair follicle. Some melanocytes/melanoblasts from the telogen secondary germ are immunohistochemically positive for DCT, and, of these, a subpopulation also expresses KIT 16. During the first 1 or 2 days of anagen induction some cells begin to express tyrosinase mrna and protein becomes barely detectable. Some DCT-positive melanocytes begin to express TRP1 at this stage, especially melanocytes Figure 1. Cartoon of pigmented and canities-affected human anagen scalp hair follicle, showing loss of melanization in the hair bulb and hair shaft with graying. Some amelanotic melanocytes can be seen in the outer root sheath (ORS) and in the most proximal and peripheral hair bulb (HB). SB, sebaceous gland; Epi, epidermis. located close to the forming hair bulb, while melanocytes residing in the upper outer root sheath (site of the presumptive germ cell reservoir) remain TRP1-negative. A second subpopulation, which expresses TRP1 or DCT together with KIT, begins to show proliferative activity. Melanocytes in the DNA-synthesis or S phase of the cell cycle have been reported as early as anagen II and significant proliferation is clearly apparent in anagen III 17. Bulbar melanocytes during the transition from anagen III to anagen VI increase in number, in dendricity, develop more Golgi and rough endoplasmic reticulum, increase the size/number of their melanosomes, and begin to transfer mature melanosomes to precortical keratinocytes. By anagen IV, when the hair pigmentary unit becomes fully functional with respect to melanin synthesis, melanocytes are distributed into discrete locations throughout the hair follicle). Melanocytes localized to the murine HF bulge (site of presumptive reservoir) express only DCT, lacking TRP1, KIT, and Ki67 immunoreactivities. Melanocytes located in the elongating outer root sheath express DCT and KIT and in some cases are also positive for the proliferation marker Ki67, but express little TRP1 and no tyrosinase 16. Only melanocytes distributing to the hair follicle melanogenic zone, i.e., the hair bulb matrix above the DP, express TRP1, DCT, tyrosinase, KIT, and also Ki67 in the majority of melanocytes. DCT protein is undetectable in melanogenic melanocytes of the human scalp anagen hair bulb 18, though other human hair follicles may show variable expression. Melanocyte proliferation mainly ceases by anagen VI (full anagen). Both the activity and concentration of tyrosinase remain constant during mid to late anagen VI, and decrease rapidly during the anagen VI to catagen transition phase, to become undetectable or very low in catagen 15. The expression of other melanogenesis-related proteins follows a similar pattern. This physiologic decrease in follicular melanogenesis may reflect two possible mechanisms for termination of melanogenesis; namely, exhaustion of an active signaling system that stimulates melanogenesis, and/or the production of inhibitors of melanocyte activity 19. Even before catagen-associated structural changes are apparent in the hair bulb, the earliest signs of imminent hair follicle regression include the retraction of melanocyte dendrites and the attenuation of melanogenesis during 3

10 late anagen VI 9, 10. Limited keratinocyte proliferation continues for a while, so the most proximal telogen hair shaft remains unpigmented the functional relevance of which remains enigmatic. One can detect a dramatic and rapid drop in the levels of active tyrosinase beginning during late anagen VI itself, while DCT activity exhibits moderate reductions from mid to late anagen VI and is lowest during catagen. A long enduring enigma of both hair follicle and pigment biology concerns the fate of the hair bulb melanocytes when they become undetectable during catagen. Where do these melanocytes go during catagen and telogen? Where do they originate from when follicular melanogenesis is resumed during the next anagen phase? 9, 10. Until very recently, the dominant view was that the hair bulb melanocyte system is a self-perpetuating arrangement, whereby melanocytes involved in the pigmentation of one hair generation are also involved in the pigmentation of the next 17 via multiple cycles of de-differentiation followed by re-differentiation. The level of plasticity level invoked by the self-perpetuating theory would imply a degree of plasticity not seen in most non-malignant cell systems. Moreover, fully differentiated bulbar melanocytes would also need to survive/avoid the extensive apoptosis-driven regression of the hair bulb 20 by actively suppressing apoptosis. Our current view suggests that many of the so-called re-differentiating melanocytes in early anagen correspond to newly recruited immature melanocytes derived from a melanocyte reservoir 21, 10 and are not re-activated from pre-existing hair bulb melanocytes that were melanogenically active during the previous anagen phase. These melanocyte stem cells are located at the base of the permanent part of the hair follicle and are immature, slow cycling, self-maintaining and are fully competent to regenerate progeny at early anagen 21. Moreover, these hair follicle melanocyte stem cells appear to have the capacity to enter vacant niches, including (via migration to) the epidermis. It is possible, however, that some new generation melanogenically active melanocytes derive from a population of catagen-surviving melanocytes. Indeed, low numbers of apparently dendritic melanocytes can be detectable in the retreating epithelial strand of catagen hair follicles undergoing active resorption via apoptosis 11. In any event at least a proportion of the highly melanotic (possibly terminally differentiated melanocytes) hair bulb melanocytes do not survive catagen 22. Deletion of individual melanotic melanocytes by apoptosis was confirmed using well-described ultrastructural features and TUNEL/TRP-1 co-localization. ging of the follicle melanocytes A and hair graying (canities) For every decade after 30 years of age the number of pigment-producing melanocytes in exposed/unexposed epidermis decreases by 10%-20% 24, accounting for much of the loss of skin tone with age. Nevertheless, epidermal melanocytes are relatively long-living cells, protected in part from reactive oxygen species (including those generated during melanogenesis) by their high expression of antiapoptotic cell survival factors, e.g., bcl-2. Hair color shows striking age-related changes, particularly in those of Eurasian origin. During puberty there is often a switch from fair intermediate hair to more deeply pigmented, coarser terminal hair during puberty. Furthermore, hair fiber heterochromia may become more apparent with age, most strikingly for scalp and beard 25. However, the most dramatic age-related change in hair pigment is the onset of hair graying or canities, which is the gradual age-dependent dilution of hair color to gray or white, also known as senile canities. The increasing longevity of human life inevitably means we will spend an increasing proportion of our lives sporting this sign of lost youth. Canities/graying first appears in our 30s, and so is unlikely to have exerted significant evolutionary selective pressure, occurring as it does after reproductive peak age. The examination of melanocyte aging has only recently been pursued with any particular vigor. Clinical observation suggests that the follicular- and epidermal-melanin units have a different melanogenetic clock. It has been observed that loss of melanocyte replicative potential in vitro is associated not only with increasing age of the donor but also with the melanin content of the cell. Accumulation of oxidative damage is an important determinant of the rate of cell aging, although it is unclear whether it is the primary cause of aging. It is likely that the antioxidant systems within the hair follicle melanocyte become impaired with age, leading to uncontrolled damage to the melanocyte itself from its own melanogenesis-related oxidative stress. In addition, melanin synthesis, by its very nature, produces mutagenic intermediates. Reactive oxygen species (ROS) can damage DNA (both nuclear and mitochondrial), result in the accumulation of mutations, and can induce both oxidative stress and antioxidant mechanisms. Thus, the induction of replicative senescence in melanogenic hair bulb melanocytes may be an important protective mechanism against cell transformation. The extraordinary melanogenic activity of pigmented bulbar melanocytes (up to 10 years in some scalp hair folli- 4

11 cles) is likely to generate large amounts of ROS via the oxidation of tyrosine and dopa to melanin 22, 26. If not adequately removed, an accumulation of these ROS may generate significant oxidative stress in both the melanocyte itself and in the highly proliferative anagen hair bulb epithelium. Thus, in these circumstances, melanogenic bulbar melanocytes are perhaps best suited to assume a post-mitotic, terminally differentiated (pre)senescence status to prevent cell transformation. Recent work suggests that the follicular-melanin unit of graying hair is associated with increased melanocyte apoptosis and oxidative stress 27. Moreover, this study also reported that the common deletion in mitochondrial DNA (associated with oxidative stress) occurred more prominently in graying compared to normally pigmented hair follicles. Graying hair follicles were also less well equipped to handle an exogenous oxidative stress, which is likely to be the result of impaired antioxidant mechanisms. Specifically, gray hair follicles may show loss of methionine sulfoxide reductase activity to carry out protein repair of oxidized enzymes like tyrosinase 27. A characteristic feature of bulbar melanocytes is their extremely high melanin load and phenomenal synthetic capacity for melanin production. A relatively small number of melanocytes (< 100 cells per scalp anagen hair follicle) can, in a single hair growth cycle, produce sufficient melanin to intensely pigment up to 1.5 m of hair shaft. Moreover, they do this within the context of a melaninladen cell cytoplasm. In this way, hair bulb melanocytes are very different from melanogenically active epidermal melanocytes, which retain few fully mature melanosomes in their cytoplasm at any one time. This intrinsic ability of bulbar melanocytes to pool melanin internally may make them more vulnerable than epidermal melanocytes to the toxic elements of melanogenesis. On average, an individual scalp hair follicle will experience fewer than 15 melanocyte seedings from the presumptive reservoir in the outer root sheath to the hair bulb in the average fully gray-free life span of 35 years for Caucasians 23, 28. In any event, the onset and progression of hair graying correlates closely with chronological aging and occurs to varying degrees in all individuals, regardless of gender or race. Age of onset also appears to be genetically controlled and inheritable. Thus, the average age for Caucasians is mid-30s; for Asians, late-30s; and for Africans, mid-40s. Similarly, hair is said to gray prematurely if it occurs before the age of 20 in whites, before 25 in Asians, and before 30 in Africans. A good rule of thumb is that by 50 years of age, 50% of people have 50% gray hair. Clearly, the darker the hair, the more noticeable early graying will be. However, graying can be more extensive in dark hair before total whitening is apparent; the reverse is true for blond hair. Graying first appears usually at the temples, and spreads to the vertex and then the remainder of the scalp, affecting the occiput last. Beard and body hair is usually affected later. Graying often follows a wave that spreads slowly from the crown to the occiput. R eferences 1. Dupin E, Le Douarin NM. Development of melanocyte precursors from the vertebrate neural crest. Oncogene 2003; 22: Holbrook KA, Vogel AM, Underwood RA, et al. Melanocytes in human embryonic and fetal skin: a review and new findings. Pigment Cell Res [Suppl] 1998; 1: Nakamura M, Tobin DJ, Richards-Smith B, et al. Mutant laboratory mice with abnormalities in pigmentation: annotated tables. J Dermatol Sci 2002; 28: Tobin DJ. Biology of hair pigmentation. In: Forslind B, Lindberg M (eds.) Skin, Hair and Nails. Structure and Function. Marcel Dekker, New York 2004; Tobin DJ, Bystryn JC. Immunology of alopecia areata. In: Camacho FM, Randall VA, Price V (eds.) Hair and Hair Disorders: Research, Pathology and Management. Martin Dunitz, London 2000; Tobin DJ. The ageing hair follicle pigmentary unit. In: Van Neste (ed.) Hair Science and Technology. Skinterface srl, Tournai, Belgium 2003; Tobin DJ, Kauser S. Hair melanocytes as neuro-endocrine sensors pigments for our imagination. Mol Cell Endocrinol 2005; 243: Horikawa T, Norris DA, Johnson TW, et al. DOPA-negative melanocytes in the outer root sheath of human hair follicles express premelanosomal antigens but not a melanosomal antigen or the melanosome associated glycoproteins tyrosinase, TRP-1, and TRP-2. J Invest Dermatol 1996; 106: Slominski A, Paus R, Plonka P, et al. Melanogenesis during the anagen-catagentelogen transformation of the murine hair cycle. J Invest Dermatol 1994; 102: Tobin DJ, Slominski A, Botchkarev V, et al. The fate of hair follicle melanocytes during the hair growth cycle. J Investig Dermatol Symp Proc 1999; 4: Slominski A, Paus R, Plonka P, et al. Pharmacological disruption of hair follicle pigmentation by cyclophosphamide as a model for studying the melanocyte response to and recovery from cytotoxic drug damage in situ. J Invest Dermatol 1996; 106: Stenn KS, Paus R. Controls of hair follicle cycling. Physiol Rev 2001; 81: Tobin DJ, Bystryn JC. Different populations of melanocytes are present in hair follicles and epidermis. Pigment Cell Res 1996; 9: Slominski A, Tobin DJ, Shibahara S, et al. Melanin pigmentation in mammalian skin and its hormonal regulation. Physiol Rev 2004; 84: Tobin DJ. Human hair pigmentation--biological aspects. Int J Cosmet Sci 2008; 30: Botchkareva NV, Khlgatian M, Longley BJ, et al. SCF/c-KIT signaling is required for cyclic regeneration of the hair pigmentation unit. FASEB J 2001; 15:

12 17. Sugiyama S. Mode of re-differentiation and melanogenesis of melanocytes in murine hair follicle. J Ultrastructural Res 1979; 67: Commo S, Gaillard O, Thibaut S, et al. Absence of TRP-2 in melanogenic melanocytes of human hair. Pigment Cell Res 2004; 17: Slominski A, Wortsman J, Plonka PM, et al. Hair follicle pigmentation. J Invest Dermatol 2005; 124: Lindner G, Botchkarev VA, Botchkareva NV, et al. Analysis of apoptosis during hair follicle regression (catagen). Am J Pathol 1997; 151: Nishimura EK, Jordan SA, Oshima H, et al. Dominant role of the niche in melanocyte stem-cell fate determination. Nature 2002; 416: Tobin DJ, Paus R. Graying: gerontobiology of the hair follicle pigmentary unit. Exp Gerontol 2001; 36: Commo S, Bernard BA. Melanocyte subpopulation turnover during the human hair cycle: an immunohistochemical study. Pigment Cell Res 2000; 13: Whiteman DC, Parsons PG, Green AC. Determinants of melanocyte density in adult human skin. Arch Dermatol Res 1999; 291: Lee WS, Lee IW, Ahn SK. Diffuse heterochromia of scalp hair. J Am Acad Dermatol 1996; 35: Hegedus ZL. The probable involvement of soluble and deposited melanins, their intermediates and the reactive oxygen side-products in human diseases and aging. Toxicology 2000; 145: Arck PC, Overall R, Spatz K, et al. Towards a "free radical theory of graying": melanocyte apoptosis in the aging human hair follicle is an indicator of oxidative stress induced tissue damage. FASEB J 2006; 20: Wood JM, Decker H, Hartmann H, et al. Senile hair graying: H2O2-mediated oxidative stress affects human hair color by blunting methionine sulfoxide repair. FASEB J 2009; 23: Keogh EV, Walsh RJ. Rate of graying of human hair. Nature 1965; 207:

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14 DOMANDA ALL ORIGINE DELLA CADUTA: LA MICRO-IRRITAZIONE RISPOSTA DOPPIA AZIONE ANTI-CADUTA 4 BREVETTI DEPOSITATI INNOVAZIONE KERIUM ANTI-CADUTA TRATTAMENTO ANTI-CADUTA INTENSIVO [ FORMULA BREVETTATA AL MADECASSOSIDE ] 1. MICRO-IRRITAZIONE 1. MADECASSOSIDE Sotto l influenza dello stress, appare una micro-irritazione impercettibile sotto la superficie del cuoio capelluto. Per riassorbire la micro-irritazione impercettibile che accelera il processo di caduta. 2. SOFFOCAMENTO 2. AMINEXIL In risposta, i tessuti si contraggono intorno al bulbo. Il capello diventa più fine e cade. Per impedire la rigidificazione del collagene* e ancorare più solidamente la radice del capello nel cuoio capelluto. * Test in vitro CADUTA DEI CAPELLI PERSISTENTE ADATTO A UOMINI E DONNE Frena visibilmente la caduta. Favorisce la crescita. Ridona corpo e resistenza alla fibra.

15 REVIEW ARTICLE Fabio Rinaldi Piero Rosati Elisabetta Sorbellini Protected by an extraordinary privilege IHRF, Milano, Italy Fabio Rinaldi Protected by an extraordinary privilege If a polar bear shed all its fur, it would not survive the extreme climate conditions: Fur is extremely important for the survival of bears and many other animals. On the contrary, humans have undergone a series of adaptive genetic changes, which have resulted in a scarce amount of hair and body hair, which have lost their original functions. However, hair and body hair still enjoy an extraordinary privilege nature granted them. Only extremely important vital organs enjoy such a great privilege. Hair bulbs are protected by an extremely complex, albeit fundamental, mechanism, immune privilege. Other immunologically privileged sites are the anterior chamber of the eye, the adrenergic cortex, some segments of the central nervous system behind the blood-brain barrier and some liver, ovary and testis areas. In hair bulbs, the collapse of the immunogenic protection system can result in alopecia areata and cicatricial alopecia. Therefore, it is extremely important to investigate this process. Investigating the defence mechanisms of antibodies and autoantibodies is fundamental to define these dermatological diseases. This also contributes to the progress in the diagnosis and therapy of other autoimmune diseases and to the control of the rejection of transplanted organs. Key words: Immune privilege, Alopecia areata, Cicatricial alopecia, Natural immune soppressors, IGF-1, MHC I In mammals and in humans only a few sites can suppress an antibody attack on cells and their own allo- and autoantigens. Immune privilege (IP) refers to the mechanism which allows the alloantigens of an organ, or of part of the organ, not to elicit an immune response and therefore not to attack on transplanted alloantigens. Research in organ transplantation has come to a clear definition of the immune privilege mechanism, in order to find the best therapies to prevent rejection. Hair bulbs are an extremely important biological model to investigate these matters. In 1948 Medawar 1 demonstrated that, if implanted in the anterior chamber of the eye or in the brain of rabbits, a skin fragment was not rejected by the immune system. In addition, several studies have shown that allotransplantated tissues in which the IP is active do not undergo rejection for a long time, even if tranplanted to immunocompetent organs which reject other grafted tissues. In fact, the Tabella 1. Human tissues having an immune privilege Anterior chamber of the eye Adrenergic cortex Segments of the central nervous system Fetoplacental unit Hair bulbs 9

16 tissues with the IP can suppress the immune response resulting in rejection. In human skin, the IP is found only in hair bulbs and in some limited areas of the nail apparatus (especially in the matrix) 2. The control system of the IP is extremely complex, as it triggers several reactions, which are not always to be found in the same tissue. This may lead to an uncontrolled immune response, with a collapse of the immune privilege resulting in several and serious autoimmune diseases, such as multiple sclerosis, autoimmune uveitis, orchitis parotidea, foetus rejection and active autoimmune chronic epatitis. When hair bulbs lose their IP, their collapse can result in alopecia areata and cicatricial alopecia. he mechanisms of the immune privilege T The IP is controlled by some special systems regulating the immune response 3. Of most importance are: 1) Absence or down-regulation of the expression of the MHC, the major histocompatibility complex, so that antigens (alloantigens and autoantigens) are not presented to CD8+ Tcells 2) Non-classical expression of MHC-I molecules, which can inhibit the activity of natural killer lymphocytes. 3) Function alteration of the cells presenting the antigene 4) Creation of barriers by the extracellular matrix to prevent the activity of immunologic cells 5) Absence of direct lymphatic vessels 6) In situ production of some potent natural immunosuppressants, such as l IGF-1, il TGF-β1, TGF-β2, Interleukin 10 and α-msh (α-melanocyte Stimulating Hormone), macrophage migration inhibitory factors. Other known regulation mechanisms intervene. Some systems of evasion of immune control very similar to the ones triggered by some viruses and malignant cells may also intervene. Hair bulbs are protected against immune aggression mainly during the anagen phase. Hair bulges also enjoy an effective IP, which is maybe even more potent than the one enjoyed by anagen bulbs. In bulges, the gene expression of CD200 immunoreactivity is really intense. CD200 is a surface glycoprotein able to minimize the inflammatory response, which acts as a potent bulge stem cell immunosuppressant 4. The activity of this protein prevents the immune destruction of follicular stem cells and regulates the cycle of the bulb. The absence or low expression of CD200 is the main aetiological factor for autoimmune cicatricial alopecia, due to the reduced perifollicular defense against inflammatory attacks (that is the histological characteristic of cicatricial alopecia). hich function does the hair bulb immune W privilege have? Why is it dermatologically relevant? It is important to consider the question again. The IP is extremely important to prevent foetus rejection during pregnancy. In addition, some parts of the eye and brain also need protection against inflammatory reactions which can induce autoimmune responses. Although hair and body hair do not help guarantee the survival of humans any more, hair follicles still play an important role in the body. The first hypothesis to explain follicular IP was the need to protect the body against autoimmune reactions against autoantigens developed in apoptosis processes during the catagen phase 5. Obviously, this is not the most convincing hypothesis, and many other hypotheses have been developed in the last years. The perifollicular region is particularly exposed to the risk of inflammation and microinflammation. The infiltration of inflammatory cells is extremely intense in this region, even in physiological conditions 6, 7, in case of chronic psychoemotional stress 8 and dermis microinflammation associated with a sensitive scalp due to the external environment 9 (Figure 1). The immune-mediated perifollicular tissue damage results in the development of alopecia areata. A further autoimmune aggression can cause an irreversible damage of bulge stem cells, with a subsequent development of cicatricial alopecia. The modification of the gene expression of certain immune regulation mechanisms contributes to the development of these conditions. he role of Interferon γ (IFN-γ) in alopecia T areata: The pulling of the trigger It is demonstrated that some genetically determined modifications of the immunologic expression (increased tendency to develop inflammatory damage subsequent to the collapse of the IP, reduced expression of nat- 10

17 Figur3 1. Confocal microscopy of a scalp affected by AGA, 120 μm deep: Increase of collagen fibers in thin bundles around the pilosebaceous duct, vasodilatation and macrophage infiltration (we would like to thank Dr P. Bezzola). ural immunosuppressants) and the alteration of the Th1 cytokine are involved in the etiopathogenesis of alopecia areata. In follicles, the expression of HLA-DR has been shown to be indirect evidence of the production of some IFN-γ affected by alopecia areata. Therefore, it can be concluded that IFN-γ can induce an over expression of the MHC I and II in the lower part of the follicular epithelium 10. In fact, some studies have shown that rats with a deficiency in IFN-γ do not develop alopecia areata 11. Moreover, high doses of IFN-γ have been demonstrated to act as potent inducers of the catagen phase 12. Therefore, Th1 cytokine can be considered to trigger the development of hair diseases. The follicular IP controls the immune response subsequent to the inflammation caused by IFN-γ and leading to collapse. Hair follicles are affected by the damage caused by inflammation. The bulge region is even more resistant (a tenfold dose of Th1 cytokine is required to get an inflammatory response from stem cells!). Neuroendocrine factors and an increase in the P substance (due to psychoemotional stress) can induce the catagen phase 13 and lead to the collapse of the immune privilege (Figure 2). It is of note to underline the role of scalp perifollicular inflammation and microinflammation in the etiopathogenesis of cicatricial alopecia and alopecia areata, androgenetic alopecia and telogen effluvium 14. linical implications C In anagen hair follicles and in the stem cell region, the immune privilege helps prevent immune cells from Unknown autoantigens linked to anagen NATURAL IMMUNOSUPPRESSANTS controlling the PI IGF-1. αmsh, TGFβ 1, NK suppressants Collapse of the IP mediated by IFN-γ P substance Neuropeptides MHC I and II over expression Natural immunosuppresant ineffectiveness CD8+, CD4+ Induction of catagen Likely pathogenesis of alopecia areata Figura 2. Possible etiopathogenesis of alopecia areata. The collapse of the immune privilege is triggered by the inflammatory reaction induced by pro-inflammatory substances, which cause an over expression of MHC I and II. This over expression allows the presentation of follicular autoantigens to T lymphocytes. Some other secondary mechanisms of autoimmune amplification are involved in the development of AA. 11

18 attacking antigenes (allo- or autoantigenes). Several inflammatory factors can over express the secretion of Interferon γ and other mediators (neurohormones, P protein, etc.), thus leading the IP to collapse (up-regulation of the complex MHC I and II and other factors), causing the presentation of antigenes to T lymphocytes and the induction of the catagen phase. Table 2 shows the clinical implications of the immune privilege collapse. Alopecia areata 15 is an autoimmune disease affecting anagen hair follicles in their full melanogenic activity. It is now demonstrated that the autoantigenes involved have also a melanocytary origin. The association of AA with autoimmune thyroiditis and vitiligo, and the evidence of the gene expression modification of the HLA response (chromosome 2, 6) detected in several autoimmune diseases 16, 17, are well established. It is demonstrated that dermal papilla melanocytes and the "reserve" of the external epithelial sheath are involved in alopecia areata. In alopecia areata, the IP collapse is induced by the classical scheme 18 with a high expression of the MHC I complex, a reduced suppression of the activity of T NK lymphocytes, and a scarce activity or a lack of activity of the perifollicular natural immunosuppressants IGF-1, TGF-β1, TGF-β2, Interleukina 10, α- MSH- In the bulge region, the IP collapse results in the destruction of follicular stem cells and subsequently the interruption of the regular follicular cycle (anagen catagen telogen anagen). In the bulge region, the immune privilege is much more resistant than the one enjoyed by anagen follicles. The expression of the IFN-γ needs to be much stronger to cause an inflammatory damage. This condition triggers the immune response leading to the development of a primary cicatricial alopecia 19 associated with an inflammatory process having several origins. Moreover, although this has no practical implications yet, another interesting aspect is the possibility of using the mechanism of the IP of anagen bulbs and of the bulge region to perform heterologous hair microtransplantations. A study by P. Rosati 20 has demonstrated the possibility of grafting heterologous hair bulbs in a woman with acute leukemia and who had already received bone-marrow transplant. After leukemia was established to have resolved, Tabella 2. Alopecia areata Primary cicatricial alopecia Possibility of heterologous hair transplantation Rosati transplanted some hair of the woman's younger sister, who had already donated her her marrow bone. Up to now, the bulbs have not been rejected and have undergone a normal growth. The same patient also underwent two successful hair filling interventions. Piero Rosati performed another four surgical operations on patients with leukemia and got the same positive results (the patients had been addressed to him by a hematology centre of an Italian university). Due to the lack of sufficient scientific data, it is not possible to assume that heterologous transplantation can always be performed in cases of cicatricial and androgenetic alopecia. Heterologous transplantation is an interesting possibility, as it is based on the mechanism of the immune privilege. In some selected clinical cases, it may turn out to be a new therapeutic possibility. atural immunosuppressants N Several Authors 21 have underlined the capability of the main natural immunosuppressants, locally secreted by the follicular cell receptors, of reducing the inflammatory action of IFN-γ in vitro, thus reducing or neutralizing the expression of the MHC I in the bulb matrix region. In particular, IGF-1, il TGF-β and α-msh act against immune aggression in the organs endowed with the IP. This mechanism is extremely important in autoimmune alopecia areata and cicatricial alopecia, as the autoimmune attack is above all directed against follicular mesenchymal cells (especially in dermal papilla). Among these peptides, it seems that IGF- 1 plays the most important role. In 2004 T. Ito et al. 22 demonstrated that the two growth factors and the neuropeptide originating from proopiomelanocortin are able to modulate the response of MHC I and other perifollicular pro-inflammatory tracts. Moreover, their activity is one of the main signals of the regulation of the hair bulb cycle (and therefore of fibroblasts and keratinocytes) and of its melanocytes. In fact, M. Philpott et al. 23 demonstrated that physiological concentrations of IGF-1 stimulate the growth of hair follicles and suppress the catagen phase. he over expression of growth factors: T Is this a real therapeutic possibility? If the collapse of the immune privilege is one of the aetiological factors resulting in autoimmune diseases, in 12

19 particular alopecia areata and cicatricial alopecia, and if the role of the natural immunosuppressants locally secreted by follicles is fundamental to maintain the IP (through a MHC I down-regulation), it is reasonable to suppose that an over expression of the detected peptides can be a therapeutic possibility to treat the two autoimmune trichological diseases. F. Rinaldi et al. 24 have demonstrated the capability of IGF- 1 of prolonging the anagen phase of hair follicles in vitro. A double blind study has shown that the topical application of a nanosomial solution containg polipeptides mimicking the action of IGF-1 and FGF (Mimicking Growth Factors) can stimulate hair growth in 38% of subjects with alopecia areata 25. Some studies 26 have also shown that tacrolimus has a modulating effect on the MHC in controlling the IP collapse. Therefore, this molecule (largely administered to treat liver transplant) has been identified as a useful substance to treat alopecia areata. C onclusions The knowledge of how the hair follicle immune privilege works is extremely important to understand the etiopathology of some very frequent autoimmune diseases such as alopecia areata and cicatricial alopecia. These studies have shown the role played by inflammation and microinflammation in several trichological diseases. In particular, interferon γ (and also INF-κ) has been shown to stimulate pro-inflammation. These studies offer some new therapeutic possibilities (the suppression of the MHC I) to treat alopecia areata and even all the other dermatological and non dermatological diseases where the down-regulation of the major histocompatibility complex could be significantly effective. B ibliography 1. Medawar P. Immunity to homologous grafted skin III. The fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye. Br J Exp Pathol 1948; 129: Ito T, Ito N, Paus R. Immunology of the Human Nail Apparatus: The Nail Matrix is a site of relative immune privilege The Journal of Investigative Dermatology 2005; 125 dec Head Jr, Billingham Re. Immunologically privileged sites in transplantation immunology and oncology. Perspect Biol Med 1985; 29: Streilein Jw. Immune privilege as the result of local tissue barriers and immunosuppressive microenvironments. Curr Opin Immunol 1993; 5: Niederkorn Jy. Immunology and immunomodulation of corneal transplantation. Int Rev Immunol 2002; 21: Mellor Al, Munn DH. Immunology at the maternal-fetal interface: lessons for T cell tolerance and suppression. Annu Rev Immunol 2000; 18: Erlebacher A. Why isn t the fetus rejected? Curr Opin Immunol 2001; 13: Fuzzi B, Rizzo R. HLA- G expression in early embryos is a fundamental prerequisite for the obtainment of pregnancy. Eur J Immunol 2002; 32: Meyer Kc, Klatte Je. Evidence that the bulge region is a site of relative immune privilege in human hair follicles. British Journal of Dermatology 2008; 159: Norris D. How close are we to solving the puzzle? Rewiev of the alopecia areata workshop. J Investigative Dermatol Symp Proc 2003; 8: Paus R, Christoph T: Immunology of the hair follicle: a short journey into terra incognita. J. Investigative Dermatol Symp Proc 1999; 4: Eichmuller S. Clusters of perifollicular macrophages in normal murine skin:physiological degeneration of selected hair follicles by programmed organ deletion. J Histochem Cytochem 1998; 46: Arck Pc. Stress inhibits hair growth in mice by induction of premature catagen development and deleterious perifollicular infiammatory events via neuropeptide substance P-dependent oathways. Am J Pathol 2003; 162: Arck Pc. Indications for a brain-hair follicle axis (BHA) : inhibition of keratinocyte proliferation and upregulation of keratinocyte apoptosis in telogen hair follicles by stress and substance P. Faseb J 2001; 15: Bezzola P, Sorbellini E. The role of microinflammation and apoptosis in androgenetic alopecia: new terapeutical strategies Journal of Plastic Dermatology January-March 2009 Vol 5 n Gilhar A, Paus R. Lymphocytes, neuropeptides, and genes involved in alopecia areata The Journal of Clinical Investigation Aug 2007; 117: Freyschmidt-Paul P. Interferon-gamma deficient mice are resistant to the development of alopecia areata British Journal of Dermatology 2006; 155: Ito T. Interferon-gamma is a potent inducer of catagen-like changes in cultured human anagen hair follicles British Journal of Dermatology 2005; 152: Peters EM. Hair growth inhibition by psychoemotional stress: a mouse model for neural mechanisms in hair growth control. Exp Dermatol 2006; 15:1-13. Peters EM. Neurogenic inflammation in stress-induced termination of murine hair growth is promoted by nerve growth factor. Am J Pathol 2004; 165: Mahè YF, Michelet JF, et al. Androgenetic alopecia and microinflammation Int J Dermatol 2000; 39: Gilhar A, Paus R biblio 17. Paus R, et al. Is alopecia areata an autoimmuneresponse against melanogenesis-related proteins, exposed by abnormal MHC class I expression in the anagen hair bulb? Yale Journal of biology and medicine 1994; 66: Sonderstrup G, McDevitt HO. DR, QR, and you: MHC alleles and autoimmunity. J Clin Invest 2001; 107: Rinaldi F. La genetic dell alopecia androgenetica e dell alopecia areata Human Trichology 2009; 12 suppl 1: Gilhar A, Paus R. Lymphocytes, neuropeptides, and genes involved in alopecia areata The Journal of Clinical Investigation 2007; 117(8): Meyer Kc, Klatte Je. Evidence that the bulge region is a site of relative immune privilege in human hair follicles. British Journal of Dermatology 2008; 159:

20 20. Rosati P, Bergamo A. Allogenic Hair Transplant in a bone marrow transplant recipient. The American Society for Dermatologic Surgery 1999; 25: Christoph T, et al. The human hair follicle immune system: cellular composition and immune privilege. ecc 22. Ito T, Ito N. Collapse and Restoration of MHC Class-I-Dependent Immune Privilege Exploiting the human hair follicle as a model American Journal of Pathology 2004; 164: Philptt MP, et al. Effect of insulin an insulin-like growth factor on cultured human hair follicles: IGF-I at physiologic concentration is an important regulator of hair follicle growth in vitro 24. Rinaldi F, et al. Composizione topica a base di biopeptidi e suo utilizzo in campo cosmetico e/o tricologico Brevetto Dragotti & Associati 25. Rinaldi F, Bezzola P, Sorbellini E. Trattamento dell alopecia areata con mimicking growth factors: una nuova prospettiva terapeutica? In Press, Human Trichology McElwee KJ, et al. Topical FK506: a potent immunotherapy for alopecia areata? Studies using the Dundee experimental bald rat model. Br J Dermatol 1997; 137:

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