Commentary
IMMUNE REACTIONS AGAINST WARTS SEPPO PYRHONEN, M.D.
From the Laboratory of Viral Immunopathology, Department of Virology, • tjniversity ol Helsinki, Helsinki, Finland
The great interest in warts that exist among general practitioners and dermatologists is due to the common occurrence of warts and the lack of appropriate therapy. Critical assessment of therapy must be based on a knowledge of the natural behavior and the curing of warts. Warts are benign skin tumors induced by a papova virus. The same virus or an antigenicaily related virus has also been found in association with laryngeal and venereal papillomas and epidermodysplasia verruciformis. Warts have a number of different clinical appearances depending on surface location. A single lesion or multiple satellite lesions may develop. Tbey may grow rapidly or remain at a static phase for years and their natural life-span may vary from some weeks up to many decades. Some warts regrow repeatedly in spite of various treatments and then, unexpectedly, disappear spontaneously. Sometimes scattered warts all disappear abruptly, Address for reprints: Dr. Seppo Pyrhonen, Department of Virology, University of Helsinki, Haartmaninkatu 3, 00290 Helsinki, Finland.
while in other cases warts appear and others disappear concurrently. Some of their clinical features as well as the common appearance of warts during immunosuppressioni and in defects of humoral or cellular immunity^' 3 suggest that immune mechanisms are involved in the appearance and regression of warts. Immunity is probably not the only factor responsible for their regression. In this paper 1 will evaluate the available evidence of immunity against warts. Brief comments are also made on non-immune phenomena in regression. Non-Viral Antigens and Rejection Immunity Regression of warts could be due to humoral or cellular immunity against viral or some nonviral tissue antigens. Knowledge of related viral tumors in animals suggests that some cellular viruscoded antigens may induce rejection immunity. Matthews et al.-* report an anticellular antibody in wart patients, but the function of these antibodies in rejection is not known. Pass et al.^ described two nonviral antigens in wart tissue located on the cellular or nuclear membrane, but these were not wart specific. The antigens were also found in fetal epidermis and other rapidly proliferating epithelial cells without any connection with warts. Therefore, these evidently do not induce rejection immunity.
344
No. 5
WARTS • Pyrhonen
Antibodies against Wart Virus and the Regression of Warts Most studies of immune reactions against warts have been focused on reactions against the virus itself. Wart virus antibodies have been measured with various techniques such as the direct visualization of virus antibody complexes under the electron microscope, the complement fixation test, immunodiffusion, passive hemagglutination and immunofluorescence. It has been found that wart virus IgM antibodies are detected more frequently than IgC antibodies in the sera of wart patients.*^ Reports by various authors reveal that the appearance of CF antibodies, which are of IgC type, correlate with the regression of warts'' '-5. In our follow-up research,^ it was found that CF antibodies appeared in about 20% of wart patients, in the early phase of the disease and more frequently in patients with plantar warts than in patients with warts on other sites. The warts invariably healed within 2 months if CF antibodies appeared in patients who had suffered from warts for less than a year. This suggests that wart virus CF antibodies may be responsible and may not merely be a consequence of the tumor rejection in some warts. Among the possible mechanisms, that of how antibodies may induce regression of warts are discussed elsewhere.'' In our study, about 10% of the patients had CF antibodies at admission to the clinic. These patients could evidently be left untreated and the majority of them would be cured within a few weeks. An unanswered question is whether a favorable antibody response can be induced with therapeutic agents in common use; this may be so in some cases.
345
Cell-Mediated Immunity against Warts Along with other human tumors, there may be cell-mediated immunity against warts. However, the absence of lymphocyte infiltration in regressing warts as reported by Brodersen et al.^" and Matthews et al.^ may suggest that cellular immunity plays only a minor part in rejection. In contrast, there is one report^' that an intense mononuclear cell infiltrate of dermis and epidermal spongiosis was associated with the regression of plane warts. Studies with a leukocyte migration inhibition testi2 also show that there may be some cell-mediated immune reaction against warts, but it is doubtful whether any in vivo immunity can be measured with such tests. Contact sensitization by topical application of 1-nitro -2,4 -dichlorobenzene (DNCB) has been reported to induce rejection of warts.^^-is it has been suggested that this may be due to cellmediated immunity against warts. Some disagreement in the reports mentioned suggests that more studies will be needed to define the role of cell-mediated immunity in the rejection of warts. Immune or Non-immune Mechanisms We do not know if mechanisms other than immune mechanisms are involved in the rejection of warts. It is not known whether interferon or transfer factor have any function. It has been suggested that some metabolic changes of skin may change the growth of tumor cells and thus induce the regression of warts. In our follow-up studies, we found many patients who had antibodies measurable only by immunodiffusion, not by complement fixation. They had a fairly constant cure rate, about 9% per month over an observation period of 6 months. The mean duration of warts in these pa-
346
INTERNATIONAL JOURNAL OF DERMATOLOGY
tients was about 2 years. Such figures have also been found in studies in which warfs have been observed for longer periods."5 This might suggest that warfs virus genome has some limited capacity fo maintain "a fransformed state" of the epidermal cell. It has been reported that warts of less than a year's duration contain numerous virus particles, but fhaf few or no such particles are detectable in older warfs.''' It may happen that during fhe loss of fhe cells from the upper layers of warts, new cells no longer become infected and the growth of warts consequenfly ceases. Immune reactions againsf wart virus, discussed earlier in fhis article, may restrict the spread of infection and thus assist non-immune regulatory mechanisms. Of course, fhis type of consideration is highly hypofhetical; but some experimenfal data and clinical features do support this view, as discussed elsewhere.'- ''' Immunotherapy of Warts A vaccine prepared from autogenous wart tissue was used many decades ago.'^ Such treatment later was reported to be useful for genital warts."- ^o Nothing is known so far of the reason for the favorable effect of these vaccines. It is not known whether an immune reaction against the virus or against some nonviral antigens was induced in these vaccinations. Recently, some authors have shown^i- 22 that a propagation of wart virus in vitro may be possible. The production of wart virus vaccines may consequently be possible in the future. Because the virus may be oncogenic, it would be necessary to get rid of the genetic material of the virus when preparing such vaccines.
June 1976
Vol. 15
Conclusions
It is clear from the foregoing that fhe function of immune mechanisms in the regression of warts is still only partly understood. Immune mechanisms are active in some cases but probably not in all. Evidently, immune reactions also have an important role in preventing reinfection or in restricting wart infection to a subclinical type. However, the available data still do not allow precise conclusions on various aspects of immunity in warts. The trials of immunotherapy will be interesting in the future. References 1. Spencer, E. S., and Andersson, FH. K., Clinically evident, non-terminal infections with Herpes virus and the wart virus in immunosuppressed renal allograft recipients. Br. Med. J. 3:251, 1970. 2. Perry, T. L., Warts in diseases with immune defects. Cutis 13:359, 1974. 3. Morison, W. L., Survey of viral warts, herpes zoster and herpes simplex in patients with secondary immune deficiencies and neoplasms. Br. J. Dermatol. 92:18, 1975. 4. Matthews, R. S., and Shirodaria, P. V., Study of regressing warts by immunofluorescence. Lancet 1:689, 1973. 5. Pass, F., and Marcus, D. M., Wart-associated antigens. I. Isolation of tissue antigens using antibody Immunoadsorbents. J. Invest. Dermatol. 60:301, 1973. 6. Coffe, A. P., Almeida, J. D., and Brown, F., Further information on the antibody response to wart virus. Lancet 2:607, 1970. 7. Ogilvie, M. M., Serologlcal studies with buman papova (wart) virus. J. Hyg. 68:479, 1970. 8. Pyrhonen, S., and Penttinen, K., Wart virus antibodies and the prognosis of wart disease. Lancet 2:1330, 1972. 9. Pyrbonen, S., and Johansson, E., Regression of warts. An Immunological study. Lancet 1:592, 1975. 10. Brodersen, I., and Genner, J., Histological and Immunological observations on common warts in regression. Acta Derm. Venereol. 53:461,1973.
No, 5
WARTS • Pyrhonen
11, Tagami, FH,, Ogino, A,, Takigava, M,, Imamura, S,, and Ofuji, S,, Regression of plane warts following spontaneous inflammation, A histopatbological study, Br, J, Dermatol, 90:147, 1974, 12, Morison, W, L,, In vitro assay of cell-mediated immunity to human wart antigen, Br, J, Dermatol, 90:531, 1974, 13, Greenberg, M, ), H., Smith, M, T, L, and Katz, R, M,, Verruca vulgaris rejection, A preliminary study of contact dermatitis and cellular immunity response. Arch, Dermatol, 107:580, 1973, 14, Lewis, H. M,, Topical immunotberapy of refractory warts, Cutis 12:863, 1973, 15, Russo, L,, Russo, A,, and Russo, V,, Immunotherapy of warts. Lancet 1:921, 1975, 16, Massing, A, M,, and Epstein, W, L,, Natural history of warts. Arch, Dermatol, 87:306, 1963,
347
17, Barrela-Oro, J, G,, Smitb, K, O,, and Melnick, J, L,, Quantitation of papova virus particles in buman warts, J, Nat, Cancer Inst, 29:583, 1962, 18, Biberstein, H,, Immunization therapy of warts. Arch, Dermatol, Syphilol, 50:12, 1944, 19, Powell, L, C, Pollard, M,, and Jurkins, J. L., Treatment of condyloma accuminata by autogenous vaccine. South, Med, J, 63:202, 1970, 20, Curtis, W. W,, and Ablin, R, J,, Immunotherapy of condyloma accuminata, JAMA 255:994, 1974. 21, Cubie, FH, A., Experiments with human papilloma virus in cell culture, Br, J. Dermatol. 91:569, 1974. 22, Eisinger, M,, Kucarova, O,, Sarkar, N, H,, and Good, R, A,, Propagation of human wart virus in tissue culture. Nature 256:432, 1975,
Early Scabies Observation "Having frequently observed that the Poor Women when their Children are troubled with the Itcb, do with the point of a Pin pull out the Scabby Skin little Bladders of Water, and crack them like Fleas upon their Nails, and the Scabby Slaves in the Bagno at Legborne do often practice this Mutual Kindness upon one another; it came into my Mind to examine what these Bladders might really be. I quickly found an Itcby person, and asking him where he felt the greatest and most acute Itcbing, he pointed to a great many little Pustules not yet Scabb'd over, of which picking out one with a very fine Needle, and squeezing from it a thin Water, took out a very small white Globule scarcely discernible. Observing this with a Microscope, found it to be a very minute Living Creature, in shape resembling a Tortoise, of whitish colour, a little dark upon the Back with some thin and long Hairs, of nimble motion, with six Feet, a sharp Head, with two little Horns at the end of the Snout." —Mead, R.: Pbilosophical Transactions, London, 23:1295, 1702-03.
IMMUNE REACTIONS AGAINST WARTS SEPPO PYRHONEN, M.D.
From the Laboratory of Viral Immunopathology, Department of Virology, • tjniversity ol Helsinki, Helsinki, Finland
The great interest in warts that exist among general practitioners and dermatologists is due to the common occurrence of warts and the lack of appropriate therapy. Critical assessment of therapy must be based on a knowledge of the natural behavior and the curing of warts. Warts are benign skin tumors induced by a papova virus. The same virus or an antigenicaily related virus has also been found in association with laryngeal and venereal papillomas and epidermodysplasia verruciformis. Warts have a number of different clinical appearances depending on surface location. A single lesion or multiple satellite lesions may develop. Tbey may grow rapidly or remain at a static phase for years and their natural life-span may vary from some weeks up to many decades. Some warts regrow repeatedly in spite of various treatments and then, unexpectedly, disappear spontaneously. Sometimes scattered warts all disappear abruptly, Address for reprints: Dr. Seppo Pyrhonen, Department of Virology, University of Helsinki, Haartmaninkatu 3, 00290 Helsinki, Finland.
while in other cases warts appear and others disappear concurrently. Some of their clinical features as well as the common appearance of warts during immunosuppressioni and in defects of humoral or cellular immunity^' 3 suggest that immune mechanisms are involved in the appearance and regression of warts. Immunity is probably not the only factor responsible for their regression. In this paper 1 will evaluate the available evidence of immunity against warts. Brief comments are also made on non-immune phenomena in regression. Non-Viral Antigens and Rejection Immunity Regression of warts could be due to humoral or cellular immunity against viral or some nonviral tissue antigens. Knowledge of related viral tumors in animals suggests that some cellular viruscoded antigens may induce rejection immunity. Matthews et al.-* report an anticellular antibody in wart patients, but the function of these antibodies in rejection is not known. Pass et al.^ described two nonviral antigens in wart tissue located on the cellular or nuclear membrane, but these were not wart specific. The antigens were also found in fetal epidermis and other rapidly proliferating epithelial cells without any connection with warts. Therefore, these evidently do not induce rejection immunity.
344
No. 5
WARTS • Pyrhonen
Antibodies against Wart Virus and the Regression of Warts Most studies of immune reactions against warts have been focused on reactions against the virus itself. Wart virus antibodies have been measured with various techniques such as the direct visualization of virus antibody complexes under the electron microscope, the complement fixation test, immunodiffusion, passive hemagglutination and immunofluorescence. It has been found that wart virus IgM antibodies are detected more frequently than IgC antibodies in the sera of wart patients.*^ Reports by various authors reveal that the appearance of CF antibodies, which are of IgC type, correlate with the regression of warts'' '-5. In our follow-up research,^ it was found that CF antibodies appeared in about 20% of wart patients, in the early phase of the disease and more frequently in patients with plantar warts than in patients with warts on other sites. The warts invariably healed within 2 months if CF antibodies appeared in patients who had suffered from warts for less than a year. This suggests that wart virus CF antibodies may be responsible and may not merely be a consequence of the tumor rejection in some warts. Among the possible mechanisms, that of how antibodies may induce regression of warts are discussed elsewhere.'' In our study, about 10% of the patients had CF antibodies at admission to the clinic. These patients could evidently be left untreated and the majority of them would be cured within a few weeks. An unanswered question is whether a favorable antibody response can be induced with therapeutic agents in common use; this may be so in some cases.
345
Cell-Mediated Immunity against Warts Along with other human tumors, there may be cell-mediated immunity against warts. However, the absence of lymphocyte infiltration in regressing warts as reported by Brodersen et al.^" and Matthews et al.^ may suggest that cellular immunity plays only a minor part in rejection. In contrast, there is one report^' that an intense mononuclear cell infiltrate of dermis and epidermal spongiosis was associated with the regression of plane warts. Studies with a leukocyte migration inhibition testi2 also show that there may be some cell-mediated immune reaction against warts, but it is doubtful whether any in vivo immunity can be measured with such tests. Contact sensitization by topical application of 1-nitro -2,4 -dichlorobenzene (DNCB) has been reported to induce rejection of warts.^^-is it has been suggested that this may be due to cellmediated immunity against warts. Some disagreement in the reports mentioned suggests that more studies will be needed to define the role of cell-mediated immunity in the rejection of warts. Immune or Non-immune Mechanisms We do not know if mechanisms other than immune mechanisms are involved in the rejection of warts. It is not known whether interferon or transfer factor have any function. It has been suggested that some metabolic changes of skin may change the growth of tumor cells and thus induce the regression of warts. In our follow-up studies, we found many patients who had antibodies measurable only by immunodiffusion, not by complement fixation. They had a fairly constant cure rate, about 9% per month over an observation period of 6 months. The mean duration of warts in these pa-
346
INTERNATIONAL JOURNAL OF DERMATOLOGY
tients was about 2 years. Such figures have also been found in studies in which warfs have been observed for longer periods."5 This might suggest that warfs virus genome has some limited capacity fo maintain "a fransformed state" of the epidermal cell. It has been reported that warts of less than a year's duration contain numerous virus particles, but fhaf few or no such particles are detectable in older warfs.''' It may happen that during fhe loss of fhe cells from the upper layers of warts, new cells no longer become infected and the growth of warts consequenfly ceases. Immune reactions againsf wart virus, discussed earlier in fhis article, may restrict the spread of infection and thus assist non-immune regulatory mechanisms. Of course, fhis type of consideration is highly hypofhetical; but some experimenfal data and clinical features do support this view, as discussed elsewhere.'- ''' Immunotherapy of Warts A vaccine prepared from autogenous wart tissue was used many decades ago.'^ Such treatment later was reported to be useful for genital warts."- ^o Nothing is known so far of the reason for the favorable effect of these vaccines. It is not known whether an immune reaction against the virus or against some nonviral antigens was induced in these vaccinations. Recently, some authors have shown^i- 22 that a propagation of wart virus in vitro may be possible. The production of wart virus vaccines may consequently be possible in the future. Because the virus may be oncogenic, it would be necessary to get rid of the genetic material of the virus when preparing such vaccines.
June 1976
Vol. 15
Conclusions
It is clear from the foregoing that fhe function of immune mechanisms in the regression of warts is still only partly understood. Immune mechanisms are active in some cases but probably not in all. Evidently, immune reactions also have an important role in preventing reinfection or in restricting wart infection to a subclinical type. However, the available data still do not allow precise conclusions on various aspects of immunity in warts. The trials of immunotherapy will be interesting in the future. References 1. Spencer, E. S., and Andersson, FH. K., Clinically evident, non-terminal infections with Herpes virus and the wart virus in immunosuppressed renal allograft recipients. Br. Med. J. 3:251, 1970. 2. Perry, T. L., Warts in diseases with immune defects. Cutis 13:359, 1974. 3. Morison, W. L., Survey of viral warts, herpes zoster and herpes simplex in patients with secondary immune deficiencies and neoplasms. Br. J. Dermatol. 92:18, 1975. 4. Matthews, R. S., and Shirodaria, P. V., Study of regressing warts by immunofluorescence. Lancet 1:689, 1973. 5. Pass, F., and Marcus, D. M., Wart-associated antigens. I. Isolation of tissue antigens using antibody Immunoadsorbents. J. Invest. Dermatol. 60:301, 1973. 6. Coffe, A. P., Almeida, J. D., and Brown, F., Further information on the antibody response to wart virus. Lancet 2:607, 1970. 7. Ogilvie, M. M., Serologlcal studies with buman papova (wart) virus. J. Hyg. 68:479, 1970. 8. Pyrhonen, S., and Penttinen, K., Wart virus antibodies and the prognosis of wart disease. Lancet 2:1330, 1972. 9. Pyrbonen, S., and Johansson, E., Regression of warts. An Immunological study. Lancet 1:592, 1975. 10. Brodersen, I., and Genner, J., Histological and Immunological observations on common warts in regression. Acta Derm. Venereol. 53:461,1973.
No, 5
WARTS • Pyrhonen
11, Tagami, FH,, Ogino, A,, Takigava, M,, Imamura, S,, and Ofuji, S,, Regression of plane warts following spontaneous inflammation, A histopatbological study, Br, J, Dermatol, 90:147, 1974, 12, Morison, W, L,, In vitro assay of cell-mediated immunity to human wart antigen, Br, J, Dermatol, 90:531, 1974, 13, Greenberg, M, ), H., Smith, M, T, L, and Katz, R, M,, Verruca vulgaris rejection, A preliminary study of contact dermatitis and cellular immunity response. Arch, Dermatol, 107:580, 1973, 14, Lewis, H. M,, Topical immunotberapy of refractory warts, Cutis 12:863, 1973, 15, Russo, L,, Russo, A,, and Russo, V,, Immunotherapy of warts. Lancet 1:921, 1975, 16, Massing, A, M,, and Epstein, W, L,, Natural history of warts. Arch, Dermatol, 87:306, 1963,
347
17, Barrela-Oro, J, G,, Smitb, K, O,, and Melnick, J, L,, Quantitation of papova virus particles in buman warts, J, Nat, Cancer Inst, 29:583, 1962, 18, Biberstein, H,, Immunization therapy of warts. Arch, Dermatol, Syphilol, 50:12, 1944, 19, Powell, L, C, Pollard, M,, and Jurkins, J. L., Treatment of condyloma accuminata by autogenous vaccine. South, Med, J, 63:202, 1970, 20, Curtis, W. W,, and Ablin, R, J,, Immunotherapy of condyloma accuminata, JAMA 255:994, 1974. 21, Cubie, FH, A., Experiments with human papilloma virus in cell culture, Br, J. Dermatol. 91:569, 1974. 22, Eisinger, M,, Kucarova, O,, Sarkar, N, H,, and Good, R, A,, Propagation of human wart virus in tissue culture. Nature 256:432, 1975,
Early Scabies Observation "Having frequently observed that the Poor Women when their Children are troubled with the Itcb, do with the point of a Pin pull out the Scabby Skin little Bladders of Water, and crack them like Fleas upon their Nails, and the Scabby Slaves in the Bagno at Legborne do often practice this Mutual Kindness upon one another; it came into my Mind to examine what these Bladders might really be. I quickly found an Itcby person, and asking him where he felt the greatest and most acute Itcbing, he pointed to a great many little Pustules not yet Scabb'd over, of which picking out one with a very fine Needle, and squeezing from it a thin Water, took out a very small white Globule scarcely discernible. Observing this with a Microscope, found it to be a very minute Living Creature, in shape resembling a Tortoise, of whitish colour, a little dark upon the Back with some thin and long Hairs, of nimble motion, with six Feet, a sharp Head, with two little Horns at the end of the Snout." —Mead, R.: Pbilosophical Transactions, London, 23:1295, 1702-03.
