- Email: [email protected]
Lymphocyte subpopulations in the skin of patients with chronic urticaria
Lymphocyte subpopulations in the skin of patients with chronic urticaria Yoseph A. Mekori, M.D., Ralph C. Giorno, Peter F. Kohler, M.D., Denver, Colo.
In order to churacterize skin of II patients with
M.D., Patricia
Anderson,
B.S., and
the nature of the mononuclear cells in the perivascular injltrutes CU, skin biopsy specimens were analyzed in situ by an uvidin-biotin
in the
immunoperoxidase technique. Serial frozen sections were stained for total T cells, helper-inducer T cells, suppressor-cytotoxic T cells, B cells, monocyteslmacrophages, und HLA-DR antigen. The injiltrates were found to consist mainly of T cells, whereus B cells und macrophages were rarely seen. Most of the T cells possessed the T4+ helper phenorypes, whereas smaller numbers of injiltrating cells were dejned as suppressor-cytotoxic cells. Most of the helper-inducer T cells coexpressed the la (HLA-DR) antigen. Several potential pathogenic mechanisms could be implicated in CU bused on these observations. (J ALLERGY CLIN IMMUNOL 72.681-684,
1983.)
The etiology and pathogenesis of CU is still obscure. ‘2 * In histopathologic examinations, the patients generally have a nonnecrotizing perivascular infiltrate in the upper layers of the dermis without evident deposition of immunoglobulins or complement ,1 The availability of adequate immunohistologic techniques and monoclonal antibodies makes it possible to characterize mononuclear cells in situ within such affected tissues.” In this study we used the avidin-biotin immunoperoxidase technique to further characterize the mononuclear infiltrate in the skin of patients with CU. MATERIAL
AND METHODS
Patient population. All patients were referred to the Allergy Clinic at the University of Colorado Health Sciences Center. These patients suffered from CU defined as from three times weekly to daily episodes of urticaria lasting 6 wk or longer. Thorough physical examination did not reveal any positive findings except the skin lesions. Three of the patients also had delayed pressure urticaria diagnosed
From the Division of Clinical Immunology, University of Colorado Health Sciences Center, Denver, Colo. Supported in part by a National Institutes of Health Allergy and Immunology training grant AI-07166 and a General Clinical Research Center grant RR-0005 1. Received for publication March 10, 1983. Accepted for publication July 12, 1983. Reprint requests: Y. Mekori, M.D., Division of Clinical Immunology (B-164), University of Colorado Health Sciences Center, Denver, CO 80262.
by a positive shoulder chal1enge.l Laboratory workup, which included erythrocyte sedimentation rate, complete blood count, complement level (CH,,), Australian antigen (HB,Ag), blood chemistry, and urinalysis, did not yield any significant abnormalities. No one had been receiving sympathomimetic or corticosteroid drugs, and in most cases, antihistamines were discontinued at least 48 hr before the biopsy was performed. Biopsy procedure. We obtained skin biopsy specimens from urticarial lesions. In most of the specimens, the lesion was less than 12 hr old at the time of the biopsy. In five patients, biopsy was also done on clinically unaffected skin. The biopsy was done (after informed consent was obtained) with a 4 mm disposable trephine punch (C. A. Baker Lab, Inc., Miami, Fla.) under local anesthesia with 1o/olidocaine without adrenalin. Only those specimens that had lymphocytic infiltrates in the dermis on hematoxylin staining were included in this study. Out of 14 consecutive patients, 11 had dermal mononuclear infiltrates. These were six women and five men, ages 25 to 60 yr. Processing of tissue. For immunoperoxidase studies, skin specimens were snap frozen in O.C.T. compound (Lab-Tek Products Division of Miles laboratories, Inc., Naperville, Ill.) and stored at -70” C. Six micron serial cryostat sections were prepared, air-dried, and fixed in acetone 10 minutes at 4” C before immunostaining. Reagents. All monoclonal antibodies were obtained from commercial sources. Monoclonal antibodies T4 (directed against helper-inducer T-lymphocyte?), T8 (directed against suppressor-cytotoxic T-lymphocytes”), I2 (directed against HLA-DR [Ia] framework antigenfi), Bl (directed against B-lymphocytes’), and MO2 (directed against monocytes/ macrophagesx) were obtained from Coulter Electronics, Hialeah, Fla. Monoclonal antibody TlOl, which reacts with 681
684
Mekori
et al
emphasized that unlike atopic dermatitis there is no proliferation of Langerhans cells in CU. The in situ picture found in these studies is consistent with the in vitro observation that helper-inducer T cells proliferate in response to soluble antigens.‘:’ These helper-inducer T4+ cells express surface Ia antigens after mitogenic or antigenic stimulation.” It was also previously demonstrated that soluble factors secreted from activated T cells can induce mediator release and proliferation of mast cells.‘4-26 Thus we can agree with Leung et al.“* who suggest that the presence of activated T cells in the dermis may play a role in the pathogenesis of the skin lesions in atopic dermatitis and CU. On the other hand, we cannot rule out the possibility of an “opposite” mechanism, that is, the cellular infiltrate is induced by mast cell degranulation as was documented in the past in the late phase of immediate hypersensitivity reactions.“‘, 2HIn this instance, the role of mast cells would be primary, and the presence of T-helper lymphocytes would be a secondary phenomenon that may not contribute directly to the pathogenesis of CU. This question could be answered directly by studying skin biopsy specimens after challenge with 48 : 80 compound at various time sequences. REFERENCES 1. Yecies LW. Kaplan AP: U&aria. In Parker C, editor: Clinical immunology. Philadelphia, 1980, WB Saunders Co, p 1283 2. Kohler PF: The University of Colorado chronic urticaria study. Proc N Engl Allergy Sot 2:136, 1981 3. Giorno R, Kohler PF: lmmunohistological localization of human lymphocyte subsets. Diagn Immunol 1:17, 1983 4. Sussman GL. Harvey RP, Schocket AL: Delayed pressure urticaria. J ALLERGY CLIN IMMUNOL 70:337, 1982 5. Kung PC, Goldstein G: Functional and developmental compartments of human T lymphocytes. VOX Sang 39:121, 1980 6. Nadler LM, Stashenko P, Handy R, et al: Monoclonal antibodies defining serologically distinct HLA-DR related Ia-like antigens in man. Hum Immunol 1:77, 1981 7. Bhan AK, Nadler LM, Stashenko P, et al: Stages of B cell differentiation in human lymphoid tissue. J Exp Med 154:737, 1981 8. Todd RF, Schlossman SF: Analysis of antigenic determinants on human monocytes and macrophages. Blood 59:77.5, 1982
J. ALLERGY CLIN. IMMUNOL DECEMBER 1983
9. Royston I, Majda JA, Baird SM, et al: Monoclonal antibody specific for human T lymphocytes. Blood 54(suppl): 106. 1979 10. Wamke R, Levy R: Detection of T and B cell antigens with hybridoma monoclonal antibodies: a biotin-avidin horseradish peroxidase method. J Histochem Cytochem 28:77 I. 1980 11. Giorno R, Goetz G: Immunohistologic analysis of lymphocyte surface markers. ,Lab Med 13554, 1982 12. Reinherz EL, King PC, Pesando JM, et al: la determinants on human T cell subsets defined by monoclonal antibody. J Exp Med 150:1472. 1979 13. Lampson L, Levy R: Two populations of Ia like molecules on a human B-cell line. J Immunol 125:293, 1980 14. Mathews KP: Management of urticaria and angioedema. J ALLERGY CLIN IMMUNOL 66:347, 1980 15. Kaplan AP: The pathogenic basis of urticaria and angioedema. Am J Med 70:755, 198 1 16. Phanuphak P, Schocket AL. Arroyave CM, et al: Skin histamine in chronic urticaria. J ALLERGY CLIN IMMUNOL 65:371, 1980 17. Natbony S, Philips M, Elias J, et al: Histologic studies of idiopathic chronic urticaria. J ALLERGY CLIN IMML’NOL 71:177, 1983 18. Phanuphak P, Kohler PF, Stanford RE, et al: Vasculitis in chronic u&aria. J ALLERGY CLIN IMMUNOL 65:436, 1980 19. Scheynius A, Klareskog L, Forsum U: In situ identification of T lymphocyte subsets and HLA-DR expressing cells in the human skin tuberculin reaction. Clin Exp Immunol 49:325, 1982 20. Van Voorhis WC, Kaplan G, Samo EN, et al: The cutaneous infiltrates of leprosy. N Engl J Med 307: 1593. 1982 21. Lampert IA, Janossy G, Suitters AJ, et al: Immunological analysis of the skin in graft-vs.-host disease. Clin Exp Immuno1 50:123, 1982 22. Leung DY, Bhan A, Schneeberger EE, et al: Characterization of the mononuclear cell infiltrate in atopic dermatitis using monoclonal antibodies. J ALLERGY CLIN IMMUNOL 71:47, 1983. 23. Reinherz EL, King PC, Goldstein G, et al: Separation of functional subsets of human T cells by a monoclonal antibody. Proc Nat1 Acad Sci USA 76:4061, 1979 24. Thueson DO, Speck LS, Lett-Brown MA, et al: Histamine releasing activity. I. Production of mitogen or antigen stimulated human mononuclear cells. J Immunol 123:626, 1979 25. Ida S, Hooks J, Siraganian RP, et al: Enhancement of IgEmediated histamine release from human basophils by immunespecific lymphokines. Clin Exp Immunol 41:380, 1980 26. Nabel G, Galli SJ, Dvorak AM, et al: Inducer T lymphocytes synthesize a factor that stimulates proliferation of cloned mast cells. Nature 291:332. 1981 27. Tannenbaum S, Oertel H, Henderson W, Kaliner M: The biologic activity of mast cell granules. J Immunol 125:325, 1980 28. Center DM: Identification of rat mast ceil-derived chemoatractant factors for lymphocytes. J ALLERGY CLIN IMMUNOL 71:29, 1983
Lymphocyte
VOLUME 72 NUMBER 6
FIG. 1. Dermal mononuclear stained with anti-T4 antibodies.
infiltrate
of
a urticarial
of the biotin-avidin horseradish peroxidase method. Most infiltrating cells were T-lymphocytes; most of them possessed the helper-inducer phenotypes. Only a few were suppressor-cytotoxic cells. We also postulate that most of the helper-inducer T cells coexpress Ia surface antigens. Our findings appear to be similar to those in skin affected by other immunologic processes. Scheynius et al.lg found mostly helper-inducer T4 cells in the dermis of delayed-type hypersensitivity reaction. Only a few were suppressor T8 cells. Both subsets appeared and could be seen in apposition to HLA-DRexpressing cells. The cutaneous tuberculoid infiltrates of leprosy also contain predominantly helper-inducer T cells that express the HLA-DR antigen .*OIn contrast to this distribution, lymphoid infiltrates in the skin in acute graft-versus-host disease consist of a virtually pure population of cells with the suppressor-cytotoxic phenotype.?’ It is likely that these variations in proportions of T cell subpopulations reflect differences in the pathogenesis and immune responses involved. Recently Leung et al .22 reported on the characteristics of the mononuclear cell infiltrates in atopic dermatitis. These authors found that in all biopsy specimens of involved and uninvolved skin, the infiltrating mononuclear cells were predominantly T-lymphocytes possessing the helper-inducer phenotypes. Only a small number of the cells were reactive with anti-T8 antibodies. Some of the helper-inducer T cells also ex-
lesion.
Most
rTlOl
of the
cells
T4
subpopulations
are
683
positively
Tt3
: . 0.0 . l em 0
FIG. 2. Lymphocyte
subpopulations
in urticarial
lesions.
pressed Ia surface antigens. These findings are very similar to ours, and one should wonder whether we are dealing with two clinical manifestations of the same pathogenic mechanism. However, it should be
684
Mekori
et al
emphasized that unlike atopic dermatitis there is no proliferation of Langerhans cells in CU. The in situ picture found in these studies is consistent with the in vitro observation that helper-inducer T cells proliferate in response to soluble antigens.“’ These helper-inducer T4+ cells express surface Ia antigens after mitogenic or antigenic stimulation.‘” It was also previously demonstrated that soluble factors secreted from activated T cells can induce mediator release and proliferation of mast cells.z”-2fi Thus we can agree with Leung et al.“’ who suggest that the presence of activated T cells in the dermis may play a role in the pathogenesis of the skin lesions in atopic dermatitis and CU. On the other hand, we cannot rule out the possibility of an “opposite” mechanism, that is, the cellular infiltrate is induced by mast cell degranulation as was documented in the past in the late phase of immediate hypersensitivity reactions.“7* 2xIn this instance, the role of mast cells would be primary, and the presence of T-helper lymphocytes would be a secondary phenomenon that may not contribute directly to the pathogenesis of CU. This question could be answered directly by studying skin biopsy specimens after challenge with 48 : 80 compound at various time sequences. REFERENCES I 2. 3. 4. 5. 6.
7.
8.
Yecies LW, Kaplan AP: Urticaria. In Parker C, editor: Clinical immunology. Philadelphia, 1980, WB Saunders Co, p 1283 Kohler PF: The University of Colorado chronic urticaria study. Proc N Engl Allergy Sot 2: 136, 1981 Giorno R, Kohler PF: lmmunohistological localization of human lymphocyte subsets. Diagn Immunol 1: 17, 1983 Sussman GL, Harvey RP, Schocket AL: Delayed pressure UTticaria. J ALLERGY CLIN IMMUNOL 70:337, 1982 Kung PC, Goldstein G: Functional and developmental compartments of human T lymphocytes. VOX Sang 39: 121, 1980 Nadler LM, Stashenko P, Handy R, et al: Monoclonal antibodies defining serologically distinct HLA-DR related Ia-like antigens in man. Hum Immunol 1:77, 1981 Bhan AK, Nadler LM, Stashenko P, et al: Stages of B cell differentiation in human lymphoid tissue. J Exp Med 154:737, 1981 Todd RF, Schlossman SF: Analysis of antigenic determinants on human monocytes and macrophages. Blood 59:775, 1982
J ALLERGY CLIN. IMMUNOL. DECEMBER 1983
9. Royston I, Majda JA, Baird SM. et al: Monoclonal antibody specific for human T lymphocytes. Blood 54(suppl): 106, 1979 10. Wamke R, Levy R: Detection of T and B cell antigens with hybridoma moncclonal antibodies: a biotin-avidin horseradish oeroxidase method. J Histochem Cvtochem 28:77 I. 1980 11. biorno R, Goetz G: Immunohistologic analysis of lymphocyre surface markers. ,Lab Med 13554. 1982 12. Reinherz EL, King PC, Pesando JM, et al: la determinants on human T cell subsets defined by monoclonal antibody. J Exp Med 150:1472, 1979 13. Lampson L, Levy R: Two populations of la like molecules on a human B-cell line. J Immunol 125:293. 1980 14. Mathews KP: Management of urticaria and angioedema. J ALLERGY CLIN IMMUNOL 66:347, 1980 15. Kaplan AP: The pathogenic basis of urticaria and angioedema. Am J Med 70:755, 198 1 16. Phanuphak P. Schocket AL, Arroyave CM, et al: Skin histamine in chronic u&aria. J ALLERGY CLIN IMMUNOL. 65:37 I, 1980 17. Natbony S. Philips M, Elias J. et al: Histologic studies of idiopathic chronic urticaria. J ALLERGY CLIN IMMUNOL 71:177, 1983 18. Phanuphak P. Kohler PF, Stanford RE, et al: Vasculitis in chronic urticaria. J ALLERGY CLIN IMMUNOL 65:436. 1980 19. Scheynius A, Klareskog L, Forsum U: In situ identification of T lymphocyte subsets and HLA-DR expressing cells in the human skin tuberculin reaction. Clin Exp Immunol 49:325, 1982 20. Van Voorhis WC, Kaplan G, Sarno EN, et al: The cutaneous infiltrates of leprosy. N Engl J Med 307:1593. 1982 2 1. Lampert IA, Janossy G, Suitters AJ, et al: Immunological analysis of the skin in graft-vs.-host disease. Clin Exp Immuno1 50:123, 1982 22. Leung DY, Bhan A, Schneeberger EE, et al: Characterization of the mononuclear cell infiltrate in atopic dermatitis using monoclonal antibodies. J ALLERGY CLIN IMMIJNOI. 71:47. 1983. 23. Reinherz EL, King PC, Goldstein G, et al: Separation of functional subsets of human T cells by a monoclonal antibody. Proc Nat1 Acad Sci USA 76:4061, 1979 24. Thueson DO, Speck LS, Lett-Brown MA, et al: Histamine releasing activity. I. Production of mitogen or antigen stimulated human mononuclear cells. J Immunol 123:626, 1979 25. Ida S, Hooks J. Siraganian RP, et al: Enhancement of IgEmediated histamine release from human basophils by immunespecific lymphokines. Clin Exp Immunol 41:380, 1980 26. Nabel G, Galli SJ, Dvorak AM, et al: Inducer T lymphocytes synthesize a factor that stimulates proliferation of cloned mast cells. Nature 291:332, 1981 27. Tannenbaum S, Oertel H, Henderson W, Kaliner M: The biologic activity of mast cell granules. J Immunol 125:325, 1980 28. Center DM: Identification of rat mast cell-derived chemoatractant factors for lymphocytes. J ALLERGY CLIN IMMUNOL 71:29, 1983
In order to churacterize skin of II patients with
M.D., Patricia
Anderson,
B.S., and
the nature of the mononuclear cells in the perivascular injltrutes CU, skin biopsy specimens were analyzed in situ by an uvidin-biotin
in the
immunoperoxidase technique. Serial frozen sections were stained for total T cells, helper-inducer T cells, suppressor-cytotoxic T cells, B cells, monocyteslmacrophages, und HLA-DR antigen. The injiltrates were found to consist mainly of T cells, whereus B cells und macrophages were rarely seen. Most of the T cells possessed the T4+ helper phenorypes, whereas smaller numbers of injiltrating cells were dejned as suppressor-cytotoxic cells. Most of the helper-inducer T cells coexpressed the la (HLA-DR) antigen. Several potential pathogenic mechanisms could be implicated in CU bused on these observations. (J ALLERGY CLIN IMMUNOL 72.681-684,
1983.)
The etiology and pathogenesis of CU is still obscure. ‘2 * In histopathologic examinations, the patients generally have a nonnecrotizing perivascular infiltrate in the upper layers of the dermis without evident deposition of immunoglobulins or complement ,1 The availability of adequate immunohistologic techniques and monoclonal antibodies makes it possible to characterize mononuclear cells in situ within such affected tissues.” In this study we used the avidin-biotin immunoperoxidase technique to further characterize the mononuclear infiltrate in the skin of patients with CU. MATERIAL
AND METHODS
Patient population. All patients were referred to the Allergy Clinic at the University of Colorado Health Sciences Center. These patients suffered from CU defined as from three times weekly to daily episodes of urticaria lasting 6 wk or longer. Thorough physical examination did not reveal any positive findings except the skin lesions. Three of the patients also had delayed pressure urticaria diagnosed
From the Division of Clinical Immunology, University of Colorado Health Sciences Center, Denver, Colo. Supported in part by a National Institutes of Health Allergy and Immunology training grant AI-07166 and a General Clinical Research Center grant RR-0005 1. Received for publication March 10, 1983. Accepted for publication July 12, 1983. Reprint requests: Y. Mekori, M.D., Division of Clinical Immunology (B-164), University of Colorado Health Sciences Center, Denver, CO 80262.
by a positive shoulder chal1enge.l Laboratory workup, which included erythrocyte sedimentation rate, complete blood count, complement level (CH,,), Australian antigen (HB,Ag), blood chemistry, and urinalysis, did not yield any significant abnormalities. No one had been receiving sympathomimetic or corticosteroid drugs, and in most cases, antihistamines were discontinued at least 48 hr before the biopsy was performed. Biopsy procedure. We obtained skin biopsy specimens from urticarial lesions. In most of the specimens, the lesion was less than 12 hr old at the time of the biopsy. In five patients, biopsy was also done on clinically unaffected skin. The biopsy was done (after informed consent was obtained) with a 4 mm disposable trephine punch (C. A. Baker Lab, Inc., Miami, Fla.) under local anesthesia with 1o/olidocaine without adrenalin. Only those specimens that had lymphocytic infiltrates in the dermis on hematoxylin staining were included in this study. Out of 14 consecutive patients, 11 had dermal mononuclear infiltrates. These were six women and five men, ages 25 to 60 yr. Processing of tissue. For immunoperoxidase studies, skin specimens were snap frozen in O.C.T. compound (Lab-Tek Products Division of Miles laboratories, Inc., Naperville, Ill.) and stored at -70” C. Six micron serial cryostat sections were prepared, air-dried, and fixed in acetone 10 minutes at 4” C before immunostaining. Reagents. All monoclonal antibodies were obtained from commercial sources. Monoclonal antibodies T4 (directed against helper-inducer T-lymphocyte?), T8 (directed against suppressor-cytotoxic T-lymphocytes”), I2 (directed against HLA-DR [Ia] framework antigenfi), Bl (directed against B-lymphocytes’), and MO2 (directed against monocytes/ macrophagesx) were obtained from Coulter Electronics, Hialeah, Fla. Monoclonal antibody TlOl, which reacts with 681
684
Mekori
et al
emphasized that unlike atopic dermatitis there is no proliferation of Langerhans cells in CU. The in situ picture found in these studies is consistent with the in vitro observation that helper-inducer T cells proliferate in response to soluble antigens.‘:’ These helper-inducer T4+ cells express surface Ia antigens after mitogenic or antigenic stimulation.” It was also previously demonstrated that soluble factors secreted from activated T cells can induce mediator release and proliferation of mast cells.‘4-26 Thus we can agree with Leung et al.“* who suggest that the presence of activated T cells in the dermis may play a role in the pathogenesis of the skin lesions in atopic dermatitis and CU. On the other hand, we cannot rule out the possibility of an “opposite” mechanism, that is, the cellular infiltrate is induced by mast cell degranulation as was documented in the past in the late phase of immediate hypersensitivity reactions.“‘, 2HIn this instance, the role of mast cells would be primary, and the presence of T-helper lymphocytes would be a secondary phenomenon that may not contribute directly to the pathogenesis of CU. This question could be answered directly by studying skin biopsy specimens after challenge with 48 : 80 compound at various time sequences. REFERENCES 1. Yecies LW. Kaplan AP: U&aria. In Parker C, editor: Clinical immunology. Philadelphia, 1980, WB Saunders Co, p 1283 2. Kohler PF: The University of Colorado chronic urticaria study. Proc N Engl Allergy Sot 2:136, 1981 3. Giorno R, Kohler PF: lmmunohistological localization of human lymphocyte subsets. Diagn Immunol 1:17, 1983 4. Sussman GL. Harvey RP, Schocket AL: Delayed pressure urticaria. J ALLERGY CLIN IMMUNOL 70:337, 1982 5. Kung PC, Goldstein G: Functional and developmental compartments of human T lymphocytes. VOX Sang 39:121, 1980 6. Nadler LM, Stashenko P, Handy R, et al: Monoclonal antibodies defining serologically distinct HLA-DR related Ia-like antigens in man. Hum Immunol 1:77, 1981 7. Bhan AK, Nadler LM, Stashenko P, et al: Stages of B cell differentiation in human lymphoid tissue. J Exp Med 154:737, 1981 8. Todd RF, Schlossman SF: Analysis of antigenic determinants on human monocytes and macrophages. Blood 59:77.5, 1982
J. ALLERGY CLIN. IMMUNOL DECEMBER 1983
9. Royston I, Majda JA, Baird SM, et al: Monoclonal antibody specific for human T lymphocytes. Blood 54(suppl): 106. 1979 10. Wamke R, Levy R: Detection of T and B cell antigens with hybridoma monoclonal antibodies: a biotin-avidin horseradish peroxidase method. J Histochem Cytochem 28:77 I. 1980 11. Giorno R, Goetz G: Immunohistologic analysis of lymphocyte surface markers. ,Lab Med 13554, 1982 12. Reinherz EL, King PC, Pesando JM, et al: la determinants on human T cell subsets defined by monoclonal antibody. J Exp Med 150:1472. 1979 13. Lampson L, Levy R: Two populations of Ia like molecules on a human B-cell line. J Immunol 125:293, 1980 14. Mathews KP: Management of urticaria and angioedema. J ALLERGY CLIN IMMUNOL 66:347, 1980 15. Kaplan AP: The pathogenic basis of urticaria and angioedema. Am J Med 70:755, 198 1 16. Phanuphak P, Schocket AL. Arroyave CM, et al: Skin histamine in chronic urticaria. J ALLERGY CLIN IMMUNOL 65:371, 1980 17. Natbony S, Philips M, Elias J, et al: Histologic studies of idiopathic chronic urticaria. J ALLERGY CLIN IMML’NOL 71:177, 1983 18. Phanuphak P, Kohler PF, Stanford RE, et al: Vasculitis in chronic u&aria. J ALLERGY CLIN IMMUNOL 65:436, 1980 19. Scheynius A, Klareskog L, Forsum U: In situ identification of T lymphocyte subsets and HLA-DR expressing cells in the human skin tuberculin reaction. Clin Exp Immunol 49:325, 1982 20. Van Voorhis WC, Kaplan G, Samo EN, et al: The cutaneous infiltrates of leprosy. N Engl J Med 307: 1593. 1982 21. Lampert IA, Janossy G, Suitters AJ, et al: Immunological analysis of the skin in graft-vs.-host disease. Clin Exp Immuno1 50:123, 1982 22. Leung DY, Bhan A, Schneeberger EE, et al: Characterization of the mononuclear cell infiltrate in atopic dermatitis using monoclonal antibodies. J ALLERGY CLIN IMMUNOL 71:47, 1983. 23. Reinherz EL, King PC, Goldstein G, et al: Separation of functional subsets of human T cells by a monoclonal antibody. Proc Nat1 Acad Sci USA 76:4061, 1979 24. Thueson DO, Speck LS, Lett-Brown MA, et al: Histamine releasing activity. I. Production of mitogen or antigen stimulated human mononuclear cells. J Immunol 123:626, 1979 25. Ida S, Hooks J, Siraganian RP, et al: Enhancement of IgEmediated histamine release from human basophils by immunespecific lymphokines. Clin Exp Immunol 41:380, 1980 26. Nabel G, Galli SJ, Dvorak AM, et al: Inducer T lymphocytes synthesize a factor that stimulates proliferation of cloned mast cells. Nature 291:332. 1981 27. Tannenbaum S, Oertel H, Henderson W, Kaliner M: The biologic activity of mast cell granules. J Immunol 125:325, 1980 28. Center DM: Identification of rat mast ceil-derived chemoatractant factors for lymphocytes. J ALLERGY CLIN IMMUNOL 71:29, 1983
Lymphocyte
VOLUME 72 NUMBER 6
FIG. 1. Dermal mononuclear stained with anti-T4 antibodies.
infiltrate
of
a urticarial
of the biotin-avidin horseradish peroxidase method. Most infiltrating cells were T-lymphocytes; most of them possessed the helper-inducer phenotypes. Only a few were suppressor-cytotoxic cells. We also postulate that most of the helper-inducer T cells coexpress Ia surface antigens. Our findings appear to be similar to those in skin affected by other immunologic processes. Scheynius et al.lg found mostly helper-inducer T4 cells in the dermis of delayed-type hypersensitivity reaction. Only a few were suppressor T8 cells. Both subsets appeared and could be seen in apposition to HLA-DRexpressing cells. The cutaneous tuberculoid infiltrates of leprosy also contain predominantly helper-inducer T cells that express the HLA-DR antigen .*OIn contrast to this distribution, lymphoid infiltrates in the skin in acute graft-versus-host disease consist of a virtually pure population of cells with the suppressor-cytotoxic phenotype.?’ It is likely that these variations in proportions of T cell subpopulations reflect differences in the pathogenesis and immune responses involved. Recently Leung et al .22 reported on the characteristics of the mononuclear cell infiltrates in atopic dermatitis. These authors found that in all biopsy specimens of involved and uninvolved skin, the infiltrating mononuclear cells were predominantly T-lymphocytes possessing the helper-inducer phenotypes. Only a small number of the cells were reactive with anti-T8 antibodies. Some of the helper-inducer T cells also ex-
lesion.
Most
rTlOl
of the
cells
T4
subpopulations
are
683
positively
Tt3
: . 0.0 . l em 0
FIG. 2. Lymphocyte
subpopulations
in urticarial
lesions.
pressed Ia surface antigens. These findings are very similar to ours, and one should wonder whether we are dealing with two clinical manifestations of the same pathogenic mechanism. However, it should be
684
Mekori
et al
emphasized that unlike atopic dermatitis there is no proliferation of Langerhans cells in CU. The in situ picture found in these studies is consistent with the in vitro observation that helper-inducer T cells proliferate in response to soluble antigens.“’ These helper-inducer T4+ cells express surface Ia antigens after mitogenic or antigenic stimulation.‘” It was also previously demonstrated that soluble factors secreted from activated T cells can induce mediator release and proliferation of mast cells.z”-2fi Thus we can agree with Leung et al.“’ who suggest that the presence of activated T cells in the dermis may play a role in the pathogenesis of the skin lesions in atopic dermatitis and CU. On the other hand, we cannot rule out the possibility of an “opposite” mechanism, that is, the cellular infiltrate is induced by mast cell degranulation as was documented in the past in the late phase of immediate hypersensitivity reactions.“7* 2xIn this instance, the role of mast cells would be primary, and the presence of T-helper lymphocytes would be a secondary phenomenon that may not contribute directly to the pathogenesis of CU. This question could be answered directly by studying skin biopsy specimens after challenge with 48 : 80 compound at various time sequences. REFERENCES I 2. 3. 4. 5. 6.
7.
8.
Yecies LW, Kaplan AP: Urticaria. In Parker C, editor: Clinical immunology. Philadelphia, 1980, WB Saunders Co, p 1283 Kohler PF: The University of Colorado chronic urticaria study. Proc N Engl Allergy Sot 2: 136, 1981 Giorno R, Kohler PF: lmmunohistological localization of human lymphocyte subsets. Diagn Immunol 1: 17, 1983 Sussman GL, Harvey RP, Schocket AL: Delayed pressure UTticaria. J ALLERGY CLIN IMMUNOL 70:337, 1982 Kung PC, Goldstein G: Functional and developmental compartments of human T lymphocytes. VOX Sang 39: 121, 1980 Nadler LM, Stashenko P, Handy R, et al: Monoclonal antibodies defining serologically distinct HLA-DR related Ia-like antigens in man. Hum Immunol 1:77, 1981 Bhan AK, Nadler LM, Stashenko P, et al: Stages of B cell differentiation in human lymphoid tissue. J Exp Med 154:737, 1981 Todd RF, Schlossman SF: Analysis of antigenic determinants on human monocytes and macrophages. Blood 59:775, 1982
J ALLERGY CLIN. IMMUNOL. DECEMBER 1983
9. Royston I, Majda JA, Baird SM. et al: Monoclonal antibody specific for human T lymphocytes. Blood 54(suppl): 106, 1979 10. Wamke R, Levy R: Detection of T and B cell antigens with hybridoma moncclonal antibodies: a biotin-avidin horseradish oeroxidase method. J Histochem Cvtochem 28:77 I. 1980 11. biorno R, Goetz G: Immunohistologic analysis of lymphocyre surface markers. ,Lab Med 13554. 1982 12. Reinherz EL, King PC, Pesando JM, et al: la determinants on human T cell subsets defined by monoclonal antibody. J Exp Med 150:1472, 1979 13. Lampson L, Levy R: Two populations of la like molecules on a human B-cell line. J Immunol 125:293. 1980 14. Mathews KP: Management of urticaria and angioedema. J ALLERGY CLIN IMMUNOL 66:347, 1980 15. Kaplan AP: The pathogenic basis of urticaria and angioedema. Am J Med 70:755, 198 1 16. Phanuphak P. Schocket AL, Arroyave CM, et al: Skin histamine in chronic u&aria. J ALLERGY CLIN IMMUNOL. 65:37 I, 1980 17. Natbony S. Philips M, Elias J. et al: Histologic studies of idiopathic chronic urticaria. J ALLERGY CLIN IMMUNOL 71:177, 1983 18. Phanuphak P. Kohler PF, Stanford RE, et al: Vasculitis in chronic urticaria. J ALLERGY CLIN IMMUNOL 65:436. 1980 19. Scheynius A, Klareskog L, Forsum U: In situ identification of T lymphocyte subsets and HLA-DR expressing cells in the human skin tuberculin reaction. Clin Exp Immunol 49:325, 1982 20. Van Voorhis WC, Kaplan G, Sarno EN, et al: The cutaneous infiltrates of leprosy. N Engl J Med 307:1593. 1982 2 1. Lampert IA, Janossy G, Suitters AJ, et al: Immunological analysis of the skin in graft-vs.-host disease. Clin Exp Immuno1 50:123, 1982 22. Leung DY, Bhan A, Schneeberger EE, et al: Characterization of the mononuclear cell infiltrate in atopic dermatitis using monoclonal antibodies. J ALLERGY CLIN IMMIJNOI. 71:47. 1983. 23. Reinherz EL, King PC, Goldstein G, et al: Separation of functional subsets of human T cells by a monoclonal antibody. Proc Nat1 Acad Sci USA 76:4061, 1979 24. Thueson DO, Speck LS, Lett-Brown MA, et al: Histamine releasing activity. I. Production of mitogen or antigen stimulated human mononuclear cells. J Immunol 123:626, 1979 25. Ida S, Hooks J. Siraganian RP, et al: Enhancement of IgEmediated histamine release from human basophils by immunespecific lymphokines. Clin Exp Immunol 41:380, 1980 26. Nabel G, Galli SJ, Dvorak AM, et al: Inducer T lymphocytes synthesize a factor that stimulates proliferation of cloned mast cells. Nature 291:332, 1981 27. Tannenbaum S, Oertel H, Henderson W, Kaliner M: The biologic activity of mast cell granules. J Immunol 125:325, 1980 28. Center DM: Identification of rat mast cell-derived chemoatractant factors for lymphocytes. J ALLERGY CLIN IMMUNOL 71:29, 1983