Original Article
Brief Report
Protection against Pemphigus Foliaceus by Desmoglein 3 in Neonates
N Engl J Med 2000; 343:31-35July 6, 2000
- Article
Pemphigus foliaceus is an autoantibody-mediated blistering disease in which antibodies against desmoglein 1 cause loss of adhesion among keratinocytes in the superficial epidermis.1 Desmogleins are transmembrane glycoproteins found in desmosomes, which provide physical connections between cells. The main desmogleins expressed in the epidermis are desmoglein 1 and desmoglein 3. In adults, desmoglein 1 is present throughout the epidermis, but desmoglein 3 is present only in the basal and immediate suprabasal layers.2,3 It has been proposed that in patients with pemphigus foliaceus the antibodies interfere with the adhesive function of desmoglein 1 and that blisters occur only in the superficial epidermis, which contains desmoglein 1 without coexpressed desmoglein 3. In the unaffected deep epidermis, the presence of desmoglein 3 may compensate for the loss of function of desmoglein 1.2,3
In pregnant women with pemphigus foliaceus, autoantibodies cross the placenta and bind to the fetal epidermis, but they rarely cause blisters in neonates.4-6 We hypothesized that the coexpression of desmoglein 3 in the superficial epidermis in neonates protects their skin from blistering caused by passively transferred maternal antibodies against desmoglein 1, with the presence of desmoglein 3 compensating for the antibody-induced loss of desmoglein 1. To confirm this hypothesis, we determined the distribution of desmoglein 3 in neonatal and adult skin and evaluated blistering after the injection of pemphigus foliaceus antibodies in transgenic mice with desmoglein 3 expressed in both the superficial and deep layers of the epidermis.
Methods
Antibodies
To identify desmoglein 1 in skin, we used serum from a patient with pemphigus foliaceus (Patient 1), as well as two monoclonal antibodies, 27B2 and 18D4, raised against the cytoplasmic domain of desmoglein 1. To identify desmoglein 3, we used monoclonal antibody 5G11, raised against the extracellular domain of human desmoglein 3.7,8 IgG from Patient 1 and another patient with pemphigus foliaceus (Patient 2) was passively transferred to neonatal mice. We also used a rabbit polyclonal antibody against an octapeptide epitope called the FLAG tag9 (Zymed, San Francisco), which was genetically engineered on the carboxy terminus of recombinant desmoglein 3 expressed in transgenic mice.
Immunofluorescence Staining
Trunk and leg skin from adults and trunk skin from a term fetus and a four-day-old infant were obtained from the Cooperative Human Tissue Network at the University of Pennsylvania, according to protocols approved by the institutional review board at the University of Pennsylvania.
Indirect immunofluorescence staining with mouse monoclonal antibodies was performed on formalin-fixed, paraffin-embedded skin sections with the use of a staining system (MicroProbe, Fisher, Pittsburgh) and a series of reagents (Signature Series, Research Genetics, Huntsville, Ala.), as previously described.10,11 After incubation with pepsin for eight to nine minutes, the tissue sections were incubated for one hour in blocking buffer (5 percent normal goat serum, 1 percent bovine serum albumin, and 0.1 percent Triton X-100 in phosphate-buffered saline) and were then incubated with monoclonal antibodies diluted in blocking buffer at 4°C overnight. The sections were then washed and incubated at room temperature for one hour with a 1:400 dilution of goat antimouse IgG conjugated to a red fluorescent cyanine dye (Cy-3, Jackson ImmunoResearch Laboratories, West Grove, Pa.). After they had been washed, the sections were examined with a fluorescence microscope (Olympus BX 60, Olympus Optical, Tokyo, Japan).
The same procedure was used to stain for the FLAG octapeptide, but instead of being incubated with pepsin, the tissue sections were microwaved in Tissue Unmasking Fluid (Signet Laboratories, Dedham, Mass.), washed in phosphate-buffered saline, and then incubated with 0.1 percent trypsin (T-7168, Sigma, St. Louis) at 41°C for 10 minutes.12 The rabbit anti-FLAG antibody (at a dilution of 1:50) was detected with Texas Red–conjugated goat antirabbit IgG (Molecular Probes, Eugene, Oreg.).
Double immunofluorescence staining, to detect both desmoglein 1 and desmoglein 3, was performed on sections of frozen skin fixed for 10 minutes in acetone at room temperature, as previously described.13 The following primary and secondary antibodies were used: IgG from Patient 1 that was detected by fluorescein-isothiocyanate–conjugated goat antihuman IgG (Biosource International, Camarillo, Calif.) and mouse monoclonal antibody 5G11 that was detected by Texas Red–conjugated goat antimouse IgG (Molecular Probes). Antibodies were diluted in phosphate-buffered saline containing 0.1 percent Triton X-100 and 5 percent normal goat serum.
Transgenic Mice
Mouse desmoglein 3 complementary DNA (cDNA) was cloned as follows: an 844-bp cDNA corresponding to the central region of mouse desmoglein 3, previously synthesized by polymerase-chain-reaction (PCR) amplification of mouse Balb/k cell with RNA as template,14 was used as a probe to screen a mouse keratinocyte library. We isolated a 4.3-kb cDNA clone with a 2979-bp open reading frame encoding a deduced polypeptide of 993 amino acids (GenBank accession number U86016). This cDNA clone was sequenced in both directions by automated nucleotide sequencing. Comparison of the amino acid sequences of mouse and human desmoglein 3 revealed 86 percent homology.
PCR was used to add nucleotides encoding the FLAG octapeptide to the 3' end of the cDNA, which was then cloned to the 3' end of the human involucrin promoter.15 The linearized construct was used to create transgenic mice, which were screened for the presence of the transgene by PCR. One-to-two-day-old mice from breedings of one founder with normal B6SJL/F1J mice and from the interbreeding of F1 transgenic heterozygotes from another founder were used for the passive transfer of pemphigus foliaceus IgG.16 The mice were evaluated for blistering 18 hours after one injection of IgG from Patient 1 or Patient 2. The gross and histologic features of pemphigus induced in these mice do not depend on the strain of mouse used.16-18
Results
Coexpression of Desmoglein 3 and Desmoglein 1 in Neonatal Epidermis
We hypothesized that pemphigus foliaceus does not occur in human neonates because desmoglein 3 compensates for the antibody-induced loss of function of desmoglein 1. We found that the distribution of desmoglein 1 was similar in the skin of neonates and adults (Figure 1AFigure 1
Distribution of Desmoglein 1 and Desmoglein 3 in Neonatal and Adult Skin as Detected by Immunofluorescence Staining (×100). and Figure 1D). This distribution was confirmed with the use of two monoclonal antibodies against desmoglein 1 and IgG from Patient 1 with pemphigus foliaceus. In contrast, the distribution of desmoglein 3 differed in neonatal and adult skin. In neonatal skin, desmoglein 3 was present on the surface of keratinocytes throughout the epidermis, whereas in adult skin, it was present only in the deep epidermis (Figure 1B and Figure 1E).Staining of serial tissue sections for both desmoglein 1 and desmoglein 3 (Figure 1A and Figure 1B) and dual staining for desmoglein 1 (with IgG from a patient with pemphigus foliaceus) detected with the use of fluorescein and for desmoglein 3 (with monoclonal antibody 5G11) detected with the use of Cy-3 (Figure 1C) showed overlapping yellow staining throughout the epidermis, indicating the coexpression of desmoglein 1 and desmoglein 3. The findings were similar in skin samples from the term fetus and the four-day-old infant. In contrast, in the control samples of trunk and leg skin from adults, desmoglein 1 was present throughout the epidermis, although it was more abundant in the superficial layers, but desmoglein 3 was present only in the basal and immediate suprabasal layers (Figure 1D, 1E, and 1F), a distribution similar to that reported previously in adult skin.2,3
These findings are consistent with the hypothesis that the expression of desmoglein 3 in the superficial epidermis provides protection against the formation of blisters induced by pemphigus foliaceus antibodies.
Ectopic Expression of Desmoglein 3 in the Superficial Epidermis
To validate our hypothesis about the compensatory role of desmoglein 3, we induced pemphigus foliaceus in neonatal mice by the passive transfer of IgG from a patient with pemphigus foliaceus. The distribution of desmoglein 1 and desmoglein 3 in the epidermis of neonatal mice is the same as that in the epidermis of adult humans, with desmoglein 3 present only in the deep epidermis. The injection of IgG from a patient with pemphigus foliaceus into neonatal mice causes superficial blisters with histologic features identical to those of blisters in adult humans with the disease.16 To determine whether this reaction was abrogated by the expression of desmoglein 3 in the superficial epidermis, we created transgenic mice in which desmoglein 3 was expressed on the involucrin promoter, which is active in the superficial epidermis.15 Mice descended from two independent transgenic founders were analyzed.
We injected a weakly pathogenic IgG, from Patient 2, into transgenic neonatal mice and normal littermates to determine whether the transgene provided any protection. The IgG from the patient with pemphigus foliaceus caused blisters on histologic examination in 4 of 10 normal mice but did not cause any blisters in 4 of 4 transgenic mice. These results were consistent with the hypothesis that the transgene has a protective effect.
To demonstrate the protective effect more convincingly, we injected transgenic and normal neonatal mice with a more pathogenic IgG, from Patient 1, and rated the resulting gross and histologic features of blisters on a semiquantitative scale.18 Most of the transgenic mice had no blisters, but the normal mice had extensive blisters (Figure 2Figure 2
Extent of Blistering in Transgenic and Normal Neonatal Mice Injected with IgG from a Patient with Pemphigus Foliaceus., 3A, and 3F). There was also a difference in the histologic characteristics of skin from the transgenic and normal mice after the injection of IgG from the patient with pemphigus foliaceus. The normal mice had extensive superficial blisters, many of which involved the entire epidermis (Figure 3BFigure 3
Gross and Histologic Features of Blister Formation in Neonatal Mice Injected with IgG from a Patient with Pemphigus Foliaceus. and Figure 3C), whereas most of the transgenic mice had no histologic evidence of blistering (Figure 3G and Figure 3H).We also tested for the expression of the transgene by immunofluorescence staining for the FLAG epitope that was engineered on the carboxy terminus of the transgenic desmoglein 3. We analyzed seven mice that had a resistance to blistering induced by IgG from a patient with pemphigus foliaceus. All seven were positive for the transgene by PCR analysis and had the FLAG epitope on the cell surface of keratinocytes in the superficial epidermis (Figure 3D, 3E, 3I, and 3J).
Discussion
The localization of dermatologic disease, with respect to both body sites and epidermal layers, has largely remained a mystery. However, recent studies have shown that the pattern of expression of molecules, such as keratins, that are genetic targets of disease is associated with the sites of disease.19 Similarly, the pattern of expression of desmogleins, the antigens involved in pemphigus, has been correlated with the sites of disease.17,20 We speculated that differences in the distribution of desmogleins might explain the absence of blistering in neonates of mothers with pemphigus foliaceus, even though maternal autoantibodies cross the placenta and bind to the skin.
We found that the distribution of desmoglein 3 in neonatal epidermis is unlike that in adult epidermis and is more like the distribution in mucous membranes. Neither neonatal skin nor adult mucous membranes are affected by pemphigus foliaceus, a finding consistent with the hypothesis that desmoglein 3 provides protection against the loss of desmoglein 1 function induced by pemphigus foliaceus antibodies.
Our studies in transgenic mice show that the ectopic expression of desmoglein 3 in the superficial epidermis provides protection against the formation of blisters caused by pemphigus foliaceus antibodies against desmoglein 1. Our results also show that, to some extent, different members of the desmoglein family are functionally interchangeable. Finally, these studies confirm and extend the compensation hypothesis with respect to desmogleins, which provides an explanation of the distribution of skin lesions in patients with pemphigus.
Supported by grants from the U.S. National Institutes of Health and from a Grant-in-Aid for Scientific Research and for International Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan.
We are indebted to Dr. Lorne Taichman for providing the involucrin promoter, to Dr. Jean Richa of the University of Pennsylvania Transgenic Facility for creating the transgenic mice, to Drs. Hung Tseng and Yaping Liu for helpful discussion, and to Mr. William Witmer for assistance with the preparation of the figures.
Source Information
From the Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia (H.W., Z.H.W., A.Y., S.L., S.F., J.R.S.); the University of Toledo, Toledo, Ohio (J.K.W., M.J.W.); the Department of Dermatology and Cutaneous Biology, Jefferson Medical College, Philadelphia (H.I., J.U.); and the Department of Dermatology, Keio University School of Medicine, Tokyo, Japan (M.A.).
Address reprint requests to Dr. Stanley at the Department of Dermatology, University of Pennsylvania School of Medicine, 211B Clinical Research Bldg., 415 Curie Blvd., Philadelphia, PA 19104-6142.
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