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Summary of the Third International Research Workshop on Alopecia Areata
Summary of the Third International Research Workshop on Alopecia Areata Lowell A. Goldsmith
University of Rochester, School of Medicine and Dentistry, Rochester, New York, U.S.A.
is defective and tyrosinase-related protein-1 may be defective. Pigment cells self-destruct before an immunologic reaction begins. The featherless chickens have severe dif®culties with heat loss. The association of a potential structural defect in addition to the polygenic immune effects is an extremely intriguing feature of this model, which should be investigated in more detail. The ®rst major lecture by Kai W. Wucherpfennig on molecular mimicry showed the ability of isolating MHC type II molecules, crystallizing them, and testing them with presumptive immunogenic peptides, including bacterial and viral peptides. These studies were done in a model of allergic encephalitis in which the presumptive antigens are known. Such an approach in alopecia areata will be more dif®cult; it will require speci®c haplotype(s) identi®cation and then a clearer identi®cation of a causative antigen. The importance of T cell clone expansion was also stressed. Molecular mimicry is structurally driven so the triggering microorganism may not be obvious; in fact, there may be multiple exciting organisms and reactivating organisms. More detailed clinical histories may be useful in determining those activating or reactivating organisms and clinicians should be alert to this avenue of clinical research. Detailed HLA analysis shows some direct associations with some speci®c haplotypes, including some high relative risks. LOD scores with the HLA are in a range of 2.3±2.4, approaching signi®cant associations. Ralf Paus presented interesting data on the role of Langerhans cells and gamma-delta T cells in the hair follicles where they normally may function to protect the follicle against resident and exogeneous ¯ora. The lupus model of the mouse presented by Edward K. Wakeland was a powerful example of identifying speci®c genes associated with a polygenic disorder and is an important direction in which the alopecia areata mouse studies should develop. Genetic hair diseases are a fruitful area of study. The hairless gene has been found in recessive familial atrichia associated with milia. Three per cent of cases of universal alopecia may represent disorders of the hairless gene, which is a transcription factor. More detailed studies of these molecular defects should be encouraged by extramural funding to de®ne hair disease related genes. Similarly, more complex models such as those associated with the Hox c13 gene may give clues to other hair disorders and syndromes. Diseases such as trichothiodystrophy with abnormalities of a transcription factor are excellent examples that one must keep a rather broad view of what the basic defect(s) in hair disease may encompass. Hair research is underfunded and, with the increased budget of the National Institutes of Health, this is the golden opportunity for hair biology and disease researchers to submit increased grants. Strategies may involve collaborations or partnerships including those between academia and the industrial sector to put together the strongest scienti®c teams. This is an excellent time for more detailed studies of the animal models. Large enough studies to
I have been privileged to summarize the ®rst two Research Workshops on Alopecia Areata in 1990 and 1994. The Workshop of 1998 was as provocative as previous ones, but still left many unanswered questions. Unna, in 1896, characterized alopecia areata as having ``a loosening of the hair and somewhat suddenly, a breaking off 3±6 mm above the surface'', ``the characteristic form of an exclamation point,'' and ``the course is chronic with long remissions and rapid relapses.'' It is still an excellent clinical description. Unna thought that ``the microorganism of this disease is still unknown, although the disease is certainly contagious.'' Unna lived in the exciting era when the causative agents of many infectious diseases were described. Direct contagious etiologies for alopecia areata seem unlikely today, but immunologic mimicry involving infectious causative agents is predicated for several diseases. The previous Workshops led to the development of clinical subsets of alopecia areata for epidemiologic studies and therapeutic trials. At this meeting, internationally derived consensus documents on these criteria were displayed and discussed, and were an important contribution. These criteria will be tested for their usefulness. The animal models, previously described, have been studied extensively; the alopecia areata mouse simulated interest internationally and is proving to be a good, albeit not simple model for alopecia areata. Much progress has been made on the genetically de®ned hair defects (Angela Christiano). Cytomegalovirus has not proven to be an agent of alopecia areata. This Workshop and the previous one emphasized the distinction between genetic traits associated with disease susceptibility and severity. Major questions in this conference related to the detailed nature of the genetic factors; and the nature(s) of an environmental trigger. Those favoring hypotheses of molecular mimicry would determine MHC type II haplotypes for speci®c endogenous antigens, which could then be characterized and associated with external agents. Many papers presented addressed detailed dissections of the immune response. The mouse model showed that CD4 depletion of alopecia areata mice led to restoration of hair growth and transfer of lymph node cells from affected animals led to disease in recipient animals. Alopecia areata biopsies transferred to SCID mice with the addition of lesional lymphocytes were able to recreate the disease. The work of Amos Gilhar led to detailed models of the immune response in tissue, although the molecular autoantigens have still not been identi®ed. Interestingly, cultures of lesional lymphocytes with melanoma cells led to activation of those lymphocytes in the SCID model. Whether this was a speci®c melanoma antigen effect and whether melanocytes are a nonspeci®c stimulator of the lymphocytes remains to be determined. J. Robert Smyth described the Smyth chickens with alopecia, vitiligo, and sometimes blindness. The genetics of the defects in Smyth chickens are polygenic; most interestingly, the pigment cell 1087-0024/99/$14.00
´ Copyright # 1999 by The Society for Investigative Dermatology, Inc. 200
VOL. 4, NO. 3 DECEMBER 1999
THIRD INTERNATIONAL RESEARCH WORKSHOP ON ALOPECIA AREATA
de®ne all relevant disease and protective haplotypes in alopecia areata should be performed to more precisely de®ne the HLA relationships. The examples of the defects with abnormalities of basic transcription factors are examples that should be investigated further. Signi®cant effort should be devoted to determining the autoantigens in this disease and to determine whether they are
201
primary or secondary to the underlying disease. Some antibodies to these antigens may have a role in pathogenesis and some may not. We are sure that when hair investigators meet next time at the Fourth International Research Workshop on Alopecia Areata, there will be answers to many of these scienti®c questions.
University of Rochester, School of Medicine and Dentistry, Rochester, New York, U.S.A.
is defective and tyrosinase-related protein-1 may be defective. Pigment cells self-destruct before an immunologic reaction begins. The featherless chickens have severe dif®culties with heat loss. The association of a potential structural defect in addition to the polygenic immune effects is an extremely intriguing feature of this model, which should be investigated in more detail. The ®rst major lecture by Kai W. Wucherpfennig on molecular mimicry showed the ability of isolating MHC type II molecules, crystallizing them, and testing them with presumptive immunogenic peptides, including bacterial and viral peptides. These studies were done in a model of allergic encephalitis in which the presumptive antigens are known. Such an approach in alopecia areata will be more dif®cult; it will require speci®c haplotype(s) identi®cation and then a clearer identi®cation of a causative antigen. The importance of T cell clone expansion was also stressed. Molecular mimicry is structurally driven so the triggering microorganism may not be obvious; in fact, there may be multiple exciting organisms and reactivating organisms. More detailed clinical histories may be useful in determining those activating or reactivating organisms and clinicians should be alert to this avenue of clinical research. Detailed HLA analysis shows some direct associations with some speci®c haplotypes, including some high relative risks. LOD scores with the HLA are in a range of 2.3±2.4, approaching signi®cant associations. Ralf Paus presented interesting data on the role of Langerhans cells and gamma-delta T cells in the hair follicles where they normally may function to protect the follicle against resident and exogeneous ¯ora. The lupus model of the mouse presented by Edward K. Wakeland was a powerful example of identifying speci®c genes associated with a polygenic disorder and is an important direction in which the alopecia areata mouse studies should develop. Genetic hair diseases are a fruitful area of study. The hairless gene has been found in recessive familial atrichia associated with milia. Three per cent of cases of universal alopecia may represent disorders of the hairless gene, which is a transcription factor. More detailed studies of these molecular defects should be encouraged by extramural funding to de®ne hair disease related genes. Similarly, more complex models such as those associated with the Hox c13 gene may give clues to other hair disorders and syndromes. Diseases such as trichothiodystrophy with abnormalities of a transcription factor are excellent examples that one must keep a rather broad view of what the basic defect(s) in hair disease may encompass. Hair research is underfunded and, with the increased budget of the National Institutes of Health, this is the golden opportunity for hair biology and disease researchers to submit increased grants. Strategies may involve collaborations or partnerships including those between academia and the industrial sector to put together the strongest scienti®c teams. This is an excellent time for more detailed studies of the animal models. Large enough studies to
I have been privileged to summarize the ®rst two Research Workshops on Alopecia Areata in 1990 and 1994. The Workshop of 1998 was as provocative as previous ones, but still left many unanswered questions. Unna, in 1896, characterized alopecia areata as having ``a loosening of the hair and somewhat suddenly, a breaking off 3±6 mm above the surface'', ``the characteristic form of an exclamation point,'' and ``the course is chronic with long remissions and rapid relapses.'' It is still an excellent clinical description. Unna thought that ``the microorganism of this disease is still unknown, although the disease is certainly contagious.'' Unna lived in the exciting era when the causative agents of many infectious diseases were described. Direct contagious etiologies for alopecia areata seem unlikely today, but immunologic mimicry involving infectious causative agents is predicated for several diseases. The previous Workshops led to the development of clinical subsets of alopecia areata for epidemiologic studies and therapeutic trials. At this meeting, internationally derived consensus documents on these criteria were displayed and discussed, and were an important contribution. These criteria will be tested for their usefulness. The animal models, previously described, have been studied extensively; the alopecia areata mouse simulated interest internationally and is proving to be a good, albeit not simple model for alopecia areata. Much progress has been made on the genetically de®ned hair defects (Angela Christiano). Cytomegalovirus has not proven to be an agent of alopecia areata. This Workshop and the previous one emphasized the distinction between genetic traits associated with disease susceptibility and severity. Major questions in this conference related to the detailed nature of the genetic factors; and the nature(s) of an environmental trigger. Those favoring hypotheses of molecular mimicry would determine MHC type II haplotypes for speci®c endogenous antigens, which could then be characterized and associated with external agents. Many papers presented addressed detailed dissections of the immune response. The mouse model showed that CD4 depletion of alopecia areata mice led to restoration of hair growth and transfer of lymph node cells from affected animals led to disease in recipient animals. Alopecia areata biopsies transferred to SCID mice with the addition of lesional lymphocytes were able to recreate the disease. The work of Amos Gilhar led to detailed models of the immune response in tissue, although the molecular autoantigens have still not been identi®ed. Interestingly, cultures of lesional lymphocytes with melanoma cells led to activation of those lymphocytes in the SCID model. Whether this was a speci®c melanoma antigen effect and whether melanocytes are a nonspeci®c stimulator of the lymphocytes remains to be determined. J. Robert Smyth described the Smyth chickens with alopecia, vitiligo, and sometimes blindness. The genetics of the defects in Smyth chickens are polygenic; most interestingly, the pigment cell 1087-0024/99/$14.00
´ Copyright # 1999 by The Society for Investigative Dermatology, Inc. 200
VOL. 4, NO. 3 DECEMBER 1999
THIRD INTERNATIONAL RESEARCH WORKSHOP ON ALOPECIA AREATA
de®ne all relevant disease and protective haplotypes in alopecia areata should be performed to more precisely de®ne the HLA relationships. The examples of the defects with abnormalities of basic transcription factors are examples that should be investigated further. Signi®cant effort should be devoted to determining the autoantigens in this disease and to determine whether they are
201
primary or secondary to the underlying disease. Some antibodies to these antigens may have a role in pathogenesis and some may not. We are sure that when hair investigators meet next time at the Fourth International Research Workshop on Alopecia Areata, there will be answers to many of these scienti®c questions.