International Journal of Dermatology 2005, 44, 340–342 © 2004 The International Society of Dermatology 340 Blackwell Publishing, Ltd. Oxford, UK IJD International Journal of Dermatology 1365-4632 Blackwell Publishing Ltd, 2004 45 Commentary The mole theory Burkhart and Burkhart Commentary The mole theory: primary function of melanocytes and melanin may be antimicrobial defense and immunomodulation (not solar protection) Craig G. Burkhart, MPH, MD, and Craig N. Burkhart, MSBS, MD From the University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, and Medical College of Ohio, Sylvania, Ohio Correspondence Craig G. Burkhart, MPH, MD Medical College of Ohio 5600 Monroe Street Suite 106B Sylvania, OH 43560 E-mail: cgbakb@aol.com Patient: “Doctor, why do we get moles in the first place?” Physician: “No one has the foggiest notion why God gave us moles on our skin … and that’s the honest truth.” Melanocytes are derived from melanoblasts that arise from the neural crest. Melanocyte numbers vary little between human populations, although they differ in size, number, and the structure of melanosomes. 1 In the human epidermis, they have a close association with keratinocytes via dendrites. Although well known for their role in skin pigmentation, this is probably not the only function of these cells. Indeed, melanocytes have numerous enzymes with capabilities in antimicrobial defense, as well as genetic, biochemical, and functional links to the immune system. 2 Melanin, endog- enously produced by melanocytes, is able to interact with enzymes and modulate their behavior, is a powerful cation chelator, and can bind and neutralize oxidants, microbicidal peptides, and antimicrobial drugs. 3–6 A better appreciation of the biological effects of melanocytes may assist in all aspects of the evaluation, understanding, and treatment of diseases associated with this cell line, such as vitiligo and melanoma. There are definite flaws in the media dogma that melanin’s main role is in protection against ultraviolet light. To begin with, it fails to explain the increase in the prevalence of mela- nin and melanocytes in skin not normally exposed to the sun, such as the genitalia, 1 and other body tissues, such as the epithelium of the inner ear, uveal tract of the eye, brain tissue, and the peritoneum. 7 Moreover, many nocturnal animals, such as bats, are highly melanized on their exterior surface. In addition, African albinos, despite the absence of melanin’s sun protection, do not have an increased incidence of melanoma. 2 Melanins are enigmatic pigments which have evolved over 500 million years and are present in all animals, microorgan- isms, and plants. 8–10 Melanin is important in microbial patho- genesis, as it has been associated with virulence by reducing the susceptibility of melanized microbes to host defense mechanisms. 11,12 Specifically, melanin interferes with protect- ive T-cell responses, antibody-mediated phagocytosis, and antifungal toxic effects of oxidants. 12 Considerable research has been performed on melanin’s immunomodulatory functions in insects. Although much of their immune system is quite similar to ours, antibodies are lacking in insects. Thus, the detection of pathogens by pattern recognition receptors is a critical first step in their immune response. 13 Chemical patterns derived from microorganisms and parasites, such as the lipopolysaccharides on the outer cell envelope of Gram-negative bacteria and the peptidoglycan of bacterial cell walls, initiate the reaction of melanocytes. 14,15 In invertebrates, the enzyme cascade, in which melanin is the end product and tyrosinase is the initial activating enzyme, is called the prophenoloxidase activating system or the Raper– Mason pathway of melanogenesis, and is the central antimi- crobial defense system against parasites and pathogens. 14 The prophenoloxidase activation system involves a serine pro- teinase cascade with similarities to the complement system of vertebrates. 13