Zusammenfassung
Das Pemphigoid gestationis (PG), früher als Herpes gestationis bezeichnet, ist eine Autoimmundermatose der Schwangerschaft, die typischerweise durch vesikulo-bullöse Hautveränderungen gekennzeichnet ist. Die Blasenbildung kann jedoch häufig fehlen; in diesen Fällen äußert sich die Erkrankung in Form juckender makulo-papulöser, urtikarieller oder ekzematöser Veränderungen. In der direkten immunfluoreszenzmikroskopischen Untersuchung der Haut der Patientinnen finden sich lineare Ablagerungen des Komplementfaktors C3 an der dermo-epidermalen Junktionszone. Proteinchemische und molekularbiologische Untersuchungen führten in den letzten Jahren zu einer Reihe neuer Erkenntnisse zur Pathogenese des PG. So konnte gezeigt werden, dass die Autoantikörper dieser Erkrankung gegen das 180 kDa schwere bullöse Pemphigoid Antigen (BP180) gerichtet sind. BP180 wird auch als Kollagen Typ XVII bezeichnet und stellt einen wichtigen Bestandteil epidermaler Hemidesmosomen dar, die für die Verankerung basaler Keratinozyten auf der kutanen Basalmembran von Bedeutung sind. Die Reaktivität gegen BP180 wird vor allem durch Antikörper der IgG1- und IgG3-Subklasse vermittelt. Deren Bindung führt zur Komplementaktivierung, zur Einwanderung von Entzündungszellen und schließlich zur subepidermalen Blasenbildung. Unter Verwendung rekombinanter Formen des BP180-Autoantigens können die zirkulierenden Autoantikörper im Serum der PG-Patienten mittels Immunoblot oder ELISA nachgewiesen werden. Beide Verfahren haben eine hohe Sensitivität und Spezifität und ermöglichen in den meisten Fällen die Abgrenzung des PG von anderen Schwangerschaftsdermatosen auch ohne Entnahme einer Hautbiopsie.
Summary
Pemphigoid gestationis (PG) is an autoimmune subepidermal blistering disease associated with pregnancy. Patients can present with blisters or with itchy macular, papular, urticarial or eczematous lesions. Direct immunofluorescence microscopy of perilesional skin biopsies shows linear deposits of C3 along the basement membrane. Recent biochemical and molecular biologic studies have shed light on the pathogenesis of PG. Antibodies are directed against the 180-kDa bullous pemphigoid antigen (BP180), also referred to as type XVII collagen. BP180 is an important component of epidermal hemidesmosomes, epithelial structures essential for adhesion of basal keratinocytes to the cutaneous basement membrane. Circulating anti-BP180 autoantibodies predominantly belong to the IgG1 and IgG3 subclasses. Binding of the antibodies leads to complement activation, infiltration of inflammatory cells into the skin, and, finally, to subepidermal blister formation. These autoantibodies can be demonstrated by immunoblotting and ELISA techniques using recombinant BP180 as the target antigen. Both tests are sensitive and specific and in most cases make it easier to distinguish between PG and other pregnancy-associated skin diseases without resorting to skin biopsy.
Literatur
-
1
Alcalay J, Ingber A, Hazaz B, David M, Sandbank M.
Linear IgM dermatosis of pregnancy.
J Am Acad Dermatol.
1988;
18
412-415
-
2
Borradori L, Saurat J H.
Specific dermatoses of pregnancy. Toward a comprehensive view?.
Arch Dermatol.
1994;
130
778-780
-
3
Borradori L, Didierjean L, Bernard P, Tamm K, Gaucherand M, Zurn A, Saurat J H.
IgM autoantibodies to 180- and 230- to 240-kd human epidermal proteins in pregnancy.
Arch Dermatol.
1995;
131
43-47
-
4
Borthwick G M, Holmes R C, Stirrat G M.
Abnormal expression of class II MHC antigens in placentae from patients with pemphigoid gestationis.
Placenta.
1988;
9
81-94
-
5
Chimanovitch I, Schmidt E, Messer G, Döpp R, Partscht K, Bröcker E B, Zillikens D.
IgG1 and IgG3 are the major immunoglobulin subclasses targeting epitopes within BP180 NC16 A in pemphigoid gestationis.
J Invest Dermatol.
1999;
113
140-142
-
6
Chimanovitch I, Skrobek C, Rose C, Nie Z, Hashimoto T, Bröcker E B, Zillikens D.
Pemphigoid gestationis with predominant involvement of oral mucous membranes and IgA autoantibodies targeting the C-terminus of BP180.
J Am Acad Dermatol.
2001, im Druck;
-
7
Diaz L A, Ratrie I H, Saunders W S, Futamura S, Squiquira H L, Anhalt G J, Giudice G J.
Isolation of a human epidermal cDNA corresponding to the 180 kD autoantigen recognized by bullous pemphigoid and herpes gestationis sera. Immunolocalization of this protein to the hemidesmosome.
J Clin Invest.
1990;
86
1088-1094
-
8
Döpp R, Schmidt E, Chimanovitch I, Bröcker E B, Zillikens D.
IgG4 and IgE are the major immunoglobulins targeting the NC16 A domain of BP180 in bullous pemphigoid: Serum levels of these immunoglobulins reflect disease activity.
J Am Acad Dermatol.
2000;
42
577-583
-
9
Giudice G J, Squiquira H L, Elias P M, Diaz L A.
Identification of two collagen domains within the bullous pemphigoid autoantigen, BP180.
J Clin Invest.
1991;
87
734-738
-
10
Giudice G J, Emery D J, Zelickson B D, Anhalt G J, Liu Z, Diaz L A.
Cloning and primary structural analysis of the bullous pemphigoid antigen, BP180.
J Invest Dermatol.
1992;
99
243-250
-
11
Giudice G J, Emery D J, Zelickson B D, Anhalt G J, Liu Z, Diaz L A.
Bullous pemphigoid and herpes gestationis autoantibodies recognize a common non-collageneous site on the BP180 ectodomain.
J Immunol.
1993;
151
5742-5750
-
12
Giudice G J, Wilske K, Taylor A F, Emery D J, Diaz L A.
Development of an ELISA to detect anti-BP180 autoantibodies in bullous pemphigoid and herpes gestationis.
J Invest Dermatol.
1994;
102
878-881
-
13
Haase C, Büdinger L, Borradori L, Yee C, Merck H F, Yancey K B, Hertl M.
Detection of IgG autoantibodies in the sera of patients with bullous and gestational pemphigoid: ELISA studies utilizing a baculovirus-encoded form of bullous pemphigoid antigen 2.
J Invest Dermatol.
1998;
110
282-286
-
14
Holmes R C, Black M M, Dann J, James D C, Bhogal B.
A comparative study of toxic erythema of pregnancy and herpes gestationis.
Br J Dermatol.
1982;
106
499-510
-
15
Holmes R C, Black M M, Jurecka W, Dann J, James D CO, Timlin D, Bhogal B.
Clues to the aetiology and pathogenesis of herpes gestationis.
Br J Dermatol.
1983;
109
131-139
-
16
Holmes R C, Black M M.
Fetal prognosis in pemphigoid gestationis (herpes gestationis).
Br J Dermatol.
1984;
110
67-72
-
17 Holmes R C, Black M M. Herpes gestationis. Wojnarowska F, Briggaman RA Management of Blistering Diseases. London; Chapman & Hall Medica 1990: 93-101
-
18
Hopkinson S B, Ridelle K S, Jones J CR.
Cytoplasmic domain of the BP180 kDa bullous pemphigoid antigen, a hemidesmosomal component: molecular and cell biological characterization.
J Invest Dermatol.
1992;
99
264-270
-
19
Ibbotson S H, Lawrence C M.
An uninvolved pregnancy in a patient after a previous episode of herpes gestationis.
Arch Dermatol.
1995;
131
1091
-
20
Jordon R E, Heine K G, Tappeiner G, Bushkell L L, Provost T T.
Immunofluorescence studies and characterization of the HG factor.
J Clin Invest.
1976;
57
1426-1433
-
21
Katz S I, Hertz K C, Yaoita H.
Immunopathology and characterization of the HG factor.
J Clin Invest.
1976;
57
1434-1441
-
22 Katz S I. Herpes gestationis (Pemphigoid gestationis). Freedberg IM et al Dermatology in General Medicine. New York; McGraw-Hill 1999: 686-689
-
23
Kelly S E, Bhogal B S, Wojnarowska F, Black M M.
Expression of a pemphigoid gestationis-related antigen by human placenta.
Br J Dermatol.
1988;
118
605-611
-
24
Kelly S E, Cerio R, Bhogal B S, Black M M.
The distribution of IgG subclasses in pemphigoid gestationis: PG factor is an IgG1 antibody.
J Invest Dermatol.
1989;
92
695-698
-
25
Kelly S E, Black M M, Fleming S.
Pemphigoid gestationis: A unique mechanism of initiation of an autoimmune response by MHC II molecules?.
J Pathol.
1989;
158
81-82
-
26
Kelly S E, Black M M, Fleming S.
Antigen-presenting cells in the skin and placenta in pemphigoid gestationis.
Br J Dermatol.
1990;
122
593-599
-
27
Kippes W, Schmidt E, Roth A, Rzany B, Bröcker E B, Zillikens D.
Immunpathologische Veränderungen bei 115 Patienten mit bullösem Pemphigoid.
Hautarzt.
1999;
50
866-872
-
28
Laatikainen T J.
Post-prandial serum bile acids in cholestasis of pregnancy.
Ann Clin Res.
1978;
10
307-312
-
29
Laatikainen T J, Tulenheimo A.
Maternal serum bile acid levels and fetal distress in cholestasis of pregnancy.
Int J Gynaec Obstet.
1984;
22
91-94
-
30
Labib R S, Anhalt G J, Patel H P, Mutasim D F, Diaz L A.
Molecular heterogeneity of the bullous pemphigoid antigens as detected by immunoblotting.
J Immunol.
1986;
136
1231-1235
-
31
Lawley T J, Stingl G, Katz S I.
Fetal and maternal risk factors in herpes gestationis.
Arch Dermatol.
1978;
114
552-555
-
32
Li K, Tamai K, Tan E ML, Uitto J.
Cloning of type XVII collagen.
J Biol Chem.
1993;
268
8825-8834
-
33
Liu Z, Diaz L A, Troy J L, Taylor A F, Emery D J, Fairley J A, Giudice G J.
A passive transfer model of the organ-specific autoimmune disease, bullous pemphigoid, using antibodies generated against the hemidesmosomal antigen, BP180.
J Clin Invest.
1993;
92
2480-2488
-
34
Mascaro J M, Lecha M, Mascaro J M.
Fetal morbidity in herpes gestationis.
Arch Dermatol.
1995;
131
1209-1210
-
35
Morrison L H, Labib R S, Zone J J, Anhalt G J.
Herpes gestationis antibodies recognize a 180-kD human epidermal antigen.
J Clin Invest.
1988;
81
2023-2026
-
36 Morrison L H. Vesiculo-bullous disorders of pregnancy: Herpes gestationis and pruritic papules and plaques of pregnancy. Fine JD Bullous Diseases. New York, Tokyo; Igaku-Shoin 1993: 121-132
-
37
Ogilvie P, Trautmann A, Dummer W, Rose C, Bröcker E B, Zillikens D.
Pemphigoid gestationis ohne Blasenbildung.
Hautarzt.
2000;
51
25-30
-
38
Ortonne J P, Hsi B L, Verrando P, Bernerd F, Pautrat G, Pisani A, Yeh C JG.
Herpes gestationis factor reacts with the amniotic epithelial basement membrane.
Br J Dermatol.
1987;
117
147-154
-
39
Roger D, Vailant L, Fignon A, Piere F, Bacq Y, Brechot J F, Grangepont M C, Lorette G.
Specific pruritic diseases of pregnancy. A prospective study of 3192 women.
Arch Dermatol.
1994;
130
734-739
-
40
Schmidt E, Obe K, Bröcker E B, Zillikens D.
Serum levels of antibodies to BP180 correlate with disease activity in patients with bullous pemphigoid.
Arch Dermatol.
2000;
136
174-178
-
41
Schmidt E, Bröcker E B, Zillikens D.
Neue Aspekte zur Pathogenese des bullösen Pemphigoids.
Hautarzt.
2000;
51
637-645
-
42
Schmidt E, Zillikens D.
Autoimmune and inherited subepidermal blistering diseases: advances in the clinic and the laboratory.
Adv Dermatol.
2000;
16
113-157
-
43
Shornick J K, Stastny P, Gilliam J N.
High frequency of histocompatibility antigens DR3 and DR4 in herpes gestationis.
J Clin Invest.
1981;
68
553-555
-
44
Shornick J K, Bangert J L, Freeman R G, Gilliam J N.
Herpes gestationis: clinical and histological features of twenty-eight cases.
J Am Acad Dermatol.
1983;
8
214-224
-
45
Shornick J K, Stastny P, Gilliam J N.
Paternal histocompatibility (HLA) antigens and maternal anti-HLA antibodies in herpes gestationis.
J Invest Dermatol.
1983 b;
81
407-409
-
46
Shornick J K.
Herpes gestationis.
J Am Acad Dermatol.
1987;
17
539-556
-
47
Shornick J K, Black M M.
Fetal risks in herpes gestationis.
J Am Acad Dermatol.
1992;
26
63-68
-
48
Shornick J K, Jenkins R E, Briggs D C, Welsh K I, Kelly S E, Garvey M P, Black M M.
Anti-HLA antibodies in pemphigoid gestationis (herpes gestationis).
Br J Dermatol.
1993;
129
257-259
-
49
Stanley J R, Hawley-Nelson P, Yuspa E, Shevach E, Katz S I.
Characterization of bullous pemphigoid antigen: a unique basement membrane protein of stratified squamous epithelia.
Cell.
1981;
24
897-903
-
50
Stanley J R, Woodley D T, Katz S I.
Identification and partial characterization of pemphigoid antigen extracted from normal human skin.
J Invest Dermatol.
1984;
82
108-111
-
51 Yancey K B, Lawley T J. Herpes gestationis. Jordon RE Immunologic diseases of the skin. Norwalk, Connecticut/San Mateo; Appleton & Lang 1991: 315-320
-
52
Zillikens D, Rose P A, Balding S D, Liu Z, Olague-Marchan M, Diaz L A, Giudice G J.
Tight clustering of extracellular BP180 epitopes recognized by bullous pemphigoid antibodies.
J Invest Dermatol.
1997;
109
573-579
-
53
Zillikens D, Mascaro J M, Rose P A, Liu Z, Ewing S M, Caux F, Hoffman R G, Diaz L A.
A highly sensitive enzyme-linked immunosorbernt assay for the detection of circulating anti-BP180 autoantibodies in patients with bullous pemphigoid.
J Invest Dermatol.
1997;
109
679-683
-
54
Zillikens D, Herzele K, Georgi M, Schmidt E, Chimanovitch I, Schumann H, Mascaro J M, Diaz L A, Bruckner-Tuderman L, Bröcker E B, Giudice G J.
Autoantibodies in a subgroup of patients with linear IgA disease react with the NC16 A domain of BP180.
J Invest Dermatol.
1999;
113
497-503
-
55
Zillikens D, Caux F, Mascaro J M, Wesselmann U, Schmidt E, Prost C, Callen J P, Bröcker E B, Diaz L A, Giudice G J.
Autoantibodies in lichen planus pemphigoides react with a novel epitope within the C-terminal NC16 A domain of BP180.
J Invest Dermatol.
1999;
113
117-121
-
56
Zillikens D.
Acquired skin disease of hemidesmosomes.
J Dermatol Sci.
1999;
20
134-154
-
57
Zillikens D, Giudice G J.
BP180/type XVII collagen: Its role in acquired and inherited disorders of the dermal-epidermal junction.
Arch Dermatol Res.
1999;
291
187-194
-
58
Zurn A, Celebi C R, Bernard P, Didierjean L, Saurat J H.
A prospective immunofluorescence study of 111 cases of pruritic dermatoses of pregnancy: IgM anti-basement membrane zone antibodies as a novel finding.
Br J Dermatol.
1992;
126
474-478
Prof. Dr. Detlef Zillikens
Universitäts-Hautklinik Würzburg
Josef-Schneider-Straße 2
97080 Würzburg
Email: zillikens-d.derma@mail.uni-wuerzburg.de
