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Hair is a uniquely mammalian trait with important functions, most easily appreciated in furred mammals. Our skin and hair color contribute very significantly to our overall visual appearance by highlighting striking variations between human sub-groups. Although melanins, hemoglobins, and carotenoids define the color perceived at the skin surface, our hair color relies only on the presence or absence of different melanins. The hair shaft's physical aspects provide only minor color modification. Various selective evolutionary pressures have determined that within the context of our specific ethnic backgrounds a bewildering array of natural shades are seen; ranging from yellows, reds, and browns to black and that harbinger of lost youth, gray/white hair. Skin/hair follicle melanins are formed in cytoplasmic organelles called melano-somes produced by neural crest-derived pigment cells called melano-cytes and are the product of a complex, phylogenetically ancient, biochemical pathway called melanogenesis. The following provides a review of research presented at the 4th Intercontinental Meeting of Hair Research Societies 2004 and so is not intended to represent a fully comprehensive overview of the subject-for that readers are directed to key references.

The proopiomelanocortin (POMC) gene and protein are expressed principally in the pituitary and brain (e.g., hypothalamus). The POMC gene, protein, and derived peptides, however, can also be detected in the skin. It appears that POMC can also be processed in the skin, a tissue that also expresses the prohormone convertases PC1 and PC2 and 7B2 protein. All POMC peptides may be produced in the skin epidermis, dermis, and adnexa by epithelial cells, melanocytes, and mesenchymal cells (e.g., immune cells, fibroblasts, and endothelial cells), and can also be released from cutaneous sensory nerve endings (cf. Slominski et al, 2004).

Alopecia areata is a common disfiguring hair loss disorder that primarily affects the hair follicle as it enters the prolonged growth phase called anagen. The last few years have yielded an explosion of more rigorously obtained data on the etiology and pathogenesis of this disorder. While a consensus is rapidly building in support of an autoimmune pathogenesis, there are still several enigmatic issues to be resolved. These include the possibility that alopecia areata is really a multientity disorder with causes that are multifactorial. This will have important implications for the research scientist's search for the jigsaw puzzle's largest missing piece--the identification of the target autoantigen(s). There is now much evidence that autoimmune diseases with both T and B cell components have shared target autoantigens/epitopes. It is likely that alopecia areata is similar, as there is now very strong evidence for the generation of autoantibodies as well as autoreactive T cells to hair follicles in the pathogenesis of this disease. The following brief review outlines the progress we have made over the last five to ten years in the characterization of hair follicle antigens targeted by antibodies in alopecia areata. Results of these studies now show that the elicitation of antibodies to hair follicle-specific proteins is a highly conserved phenomenon in all affected species studied to date. Candidate autoantigens that have been identified include the 44/46 kDa hair-specific keratin (expressed in the precortical zone of anagen hair follicles) and trichohyalin (an important intermediate filament-associated protein) expressed in the inner root sheath of the growing hair follicle. Moreover, there is evidence that anti-hair follicle antibodies are modulated during the disease process, can occur before clinically detectable hair loss, and may be reduced in titer during successful treatment. Preliminary data from passive transfer experiments suggest that in some species these antibodies may disrupt hair cycling. We are currently applying a more molecular approach (e.g., cDNA library screening) to identify hair follicle antigens truly associated with the onset of the disorder.

Hair fiber production is the macroscopic end-point of a highly complex set of interactions between the hair follicle's epithelial and mesenchymal components. The nature of this relationship is largely set during hair follicle morphogenesis, but is dramatically revisited in the adult during the unique tissue remodeling events required for hair follicle cycling. Whereas significant attention has focused on the fate of the hair follicle epithelium during these events, associated changes in hair follicle fibroblast subpopulations remain unclear. Here, we present a speculative review that represents a critical and innovative synthesis of the current literature and summarizes a recently submitted original study by the authors, on the nature of hair cycle-dependent fibroblast dynamics and on how perturbations thereof may lead to several clinical manifestations of altered human hair growth.

The fate of the follicular pigmentary unit during the hair growth cycle has long been one of the great enigmas of both hair follicle and pigment cell biology. Although melanocytes are distributed in several different compartments of the anagen hair follicle, melanogenically active cells are located only in the hair bulb, where they are directly involved in hair shaft pigmentation. These pigment cells are readily detectable only when they become melanogenically active during anagen III of the hair growth cycle. Thus, their status during hair follicle regression (catagen), when melanogenesis is switched off, until they re-appear again as pigment-producing cells in the anagen III hair follicle, has remained poorly defined. Historically, it has been proposed that hair bulb melanocytes adopt a self-perpetuating, catagen-resistant strategy of de-differentiation during hair follicle regression and re-differentiation upon entry into a new anagen phase; however, this explanation remains problematic in the absence of evidence for de-differentiation/re-differentiation plasticity in most nonmalignant cell systems.

To date there is compelling in vitro and in vivo evidence for epidermal H2O2 accumulation in vitiligo. This paper reviews the literature and presents new data on oxidative stress in the epidermal compartment of this disorder. Elevated H2O2 levels can be demonstrated in vivo in patients compared with healthy controls by utilizing Fourier-Transform Raman spectroscopy. H2O2 accumulation is associated with low epidermal catalase levels. So far, four potential sources for epidermal H2O2 generation in vitiligo have been identified: (i) perturbed (6R)-L-erythro 5,6,7,8 tetrahydrobiopterin (6BH4) de novo synthesis/recycling/regulation; (ii) impaired catecholamine synthesis with increased monoamine oxidase A activities; (iii) low glutathione peroxidase activities; and (iv) "oxygen burst" via NADPH oxidase from a cellular infiltrate. H2O2 overproduction can cause inactivation of catalase as well as vacuolation in epidermal melanocytes and keratinocytes. Vacuolation was also observed in vitro in melanocytes established from lesional and nonlesional epidermis of patients (n = 10) but was reversible upon addition of catalase. H2O2 can directly oxidize 6BH4 to 6-biopterin, which is cytotoxic to melanocytes in vitro. Therefore, we substituted the impaired catalase with a "pseudocatalase". Pseudocatalase is a bis-manganese III-EDTA-(HCO3-)2 complex activated by UVB or natural sun. This complex has been used in a pilot study on 33 patients, showing remarkable repigmentation even in long lasting disease. Currently this approach is under worldwide clinical investigation in an open trial. In conclusion, there are several lines of evidence that the entire epidermis of patients with vitiligo is involved in the disease process and that correction of the epidermal redox status is mandatory for repigmentation.