Pemphigus--diseases of antidesmosomal autoimmunity.
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Aged↗
Biomedical subjects
J R Stanley
Publications and source records attributed to J R Stanley.
Fetal immunization of baboons induces a fetal-specific antibody response.
Neonates face a high risk of infection because of the immaturity of their immune systems. Although the transplacental transfer of maternal antibodies to the fetus may convey improved postnatal immunity, this transfer occurs late in gestation and may fail to prevent in utero infection. Both fetal immunization and in utero exposure to antigen can result in a state of immunologic tolerance in the neonate. Tolerance induction of fetal and premature infant lymphocytes has become a paradigm for neonatal responsiveness. However, fetal IgM responses have been demonstrated to maternal immunization with tetanus toxoid and to congenital infections such as rubella, toxoplasma, cytomegalovirus and human immunodeficiency virus. Moreover, 1-week-old infants can respond to standard pediatric vaccination, and neonates immunized with polysaccharide antigens do not develop immunologic tolerance. Here, direct immunization of the baboon fetus with recombinant hepatitis B surface antigen produced a specific fetal IgG antibody response. No specific maternal antibody response was detected, eliminating the possibility of vertical antibody transmission to the fetus. Some infants also responded to later vaccinations with hepatitis B surface antigen, indicating that no immunological tolerance was induced by prior fetal immunization. These results characterize the ability of the fetal immune system to respond to in utero vaccination. We demonstrate that active fetal immunization can serve as a safe and efficient vaccination strategy for the fetus and neonate.
Animals↗
Pemphigus vulgaris and pemphigus foliaceus antibodies are pathogenic in plasminogen activator knockout mice.
Previous studies have suggested that urokinase plasminogen activator is required for blister formation in pemphigus vulgaris and pemphigus foliaceus. Other studies, however, have shown that downregulation of plasminogen activator does not inhibit blisters induced by pemphigus immunoglobulin G. To eliminate the possibility that small amounts of urokinase plasminogen activator might be sufficient for blister formation, we passively transferred pemphigus immunoglobulin G to urokinase plasminogen activator knockout neonatal mice. Pemphigus foliaceus and pemphigus vulgaris immunoglobulin G caused gross blisters and acantholysis in the superficial and suprabasal epidermis, respectively, to the same degree in knockout and control mice, demonstrating that urokinase plasminogen activator is not absolutely required for antibody-induced blisters. Some studies have shown elevated tissue-type plasminogen activator in pemphigus lesions. Tissue-type plasminogen activator, however, is not necessary for blister formation, because pemphigus foliaceus and pemphigus vulgaris immunoglobulin G caused blisters to the same degree in tissue-type plasminogen activator knockout and control mice. To rule out that one plasminogen activator might compensate for the other in the knockout mice, we bred urokinase plasminogen activator, tissue-type plasminogen activator double knockouts. After passive transfer of pemphigus foliaceus and pemphigus vulgaris immunoglobulin G these mice blistered to the same degree as the single knockout and control mice, and histology indicated blisters at the expected level of the epidermis. These data definitively demonstrate that plasminogen activator is not necessary for pemphigus immunoglobulin G to induce acantholysis in the neonatal mouse model of pemphigus.
Animals↗
Explanations for the clinical and microscopic localization of lesions in pemphigus foliaceus and vulgaris.
Patients with pemphigus foliaceus (PF) have blisters on skin, but not mucous membranes, whereas patients with pemphigus vulgaris (PV) develop blisters on mucous membranes and/or skin. PF and PV blisters are due to loss of keratinocyte cell-cell adhesion in the superficial and deep epidermis, respectively. PF autoantibodies are directed against desmoglein (Dsg) 1; PV autoantibodies bind Dsg3 or both Dsg3 and Dsg1. In this study, we test the hypothesis that coexpression of Dsg1 and Dsg3 in keratinocytes protects against pathology due to antibody-induced dysfunction of either one alone. Using passive transfer of pemphigus IgG to normal and DSG3(null) neonatal mice, we show that in the areas of epidermis and mucous membrane that coexpress Dsg1 and Dsg3, antibodies against either desmoglein alone do not cause spontaneous blisters, but antibodies against both do. In areas (such as superficial epidermis of normal mice) where Dsg1 without Dsg3 is expressed, anti-Dsg1 antibodies alone can cause blisters. Thus, the anti-desmoglein antibody profiles in pemphigus sera and the normal tissue distributions of Dsg1 and Dsg3 determine the sites of blister formation. These studies suggest that pemphigus autoantibodies inhibit the adhesive function of desmoglein proteins, and demonstrate that either Dsg1 or Dsg3 alone is sufficient to maintain keratinocyte adhesion.
Animals↗
Successful management of myocardial infarction during pregnancy in a renal transplant recipient.
Myocardial infarction (MI) complicating pregnancy in a renal transplant recipient is described. Management challenges of MI in pregnancy and the possible predisposing roles of renal transplantation and erythropoietin (EPO) use are discussed.
Adult↗
Effectiveness of prostaglandin E2 intracervical gel (Prepidil), with immediate oxytocin, versus vaginal insert (Cervidil) for induction of labor.
OBJECTIVE: Our purpose was to compare the effectiveness of labor induction with use of prostaglandin E2 either as an intracervical gel (Prepidil), with immediate oxytocin, or as a sustained-release vaginal insert (Cervidil) with subsequent oxytocin as needed. STUDY DESIGN: Hospitalized patients at >/=37 weeks' gestation requiring labor induction and having an unfavorable cervix (Bishop score </=6) were randomly assigned to receive either Prepidil or Cervidil. Oxytocin was begun immediately after Prepidil placement or 30 minutes after removal of the Cervidil insert if needed. RESULTS: Of the 150 patients, there were no differences in demographics and eventual pregnancy outcomes between the Prepidil group (n = 77) and the Cervidil group (n = 73). Those pregnancies receiving the Prepidil-immediate oxytocin regimen were delivered sooner than those receiving the Cervidil among nulliparous (11.3 +/- 7.3 hours vs 25.2 +/- 12.5 hours, P <.001) and multiparous (8.4 +/- 7.8 hours vs 18.4 +/- 7.2 hours, P <.001) women. The mean cost savings, which favored the Prepidil-immediate oxytocin regimen, was $458 (range $204 to $630) per patient. CONCLUSION: Compared with Cervidil, the Prepidil-immediate oxytocin regimen resulted in a shorter induction-to-vaginal delivery interval and in more hospital cost savings without increasing adverse outcomes.
Administration, Intravaginal↗
The members of the plakin family of proteins recognized by paraneoplastic pemphigus antibodies include periplakin.
Sera of patients with paraneoplastic pemphigus (PNP) characteristically immunoprecipitate five proteins, observations confirmed with the sera examined in this study. The proteins characterized thus far as autoantigens in PNP all belong to the plakin family of proteins and include desmoplakin, the 230 kDa bullous pemphigoid antigen, and envoplakin. The pattern of bands precipitated from metabolically labeled human keratinocyte extracts by each PNP serum was different, suggesting varying titers of antibodies against unique epitopes in various plakin family members. To further characterize this PNP antibody response, we produced fusion proteins of the homologous tail region of five plakin family members, including the recently cloned periplakin. Immunoblotting of equal amounts of each plakin tail-glutathione S-transferase fusion protein with PNP sera revealed a strong reaction with the envoplakin tail domain. Each sera also recognized periplakin, and certain sera recognized desmoplakin and plectin, and, weakly, bullous pemphigoid antigen 1. PNP sera were affinity purified with periplakin and envoplakin tail fusion proteins. Immunoprecipitation and immunoblotting with these affinity purified antibodies revealed shared as well as unique epitopes in the tail domains of these plakins. This study indicates that a homologous region in the carboxy-terminus of plakins, including the newly characterized periplakin, serves as an antigenic site in PNP.
Amino Acid Sequence↗
Translocation of the zinc finger protein basonuclin from the mouse germ cell nucleus to the midpiece of the spermatozoon during spermiogenesis.
Basonuclin was first described as a human keratinocyte zinc finger protein present in the nuclei of proliferative basal keratinocytes in the epidermis. It disappears from keratinocytes that have lost their proliferative ability and have entered terminal differentiation. We now report that basonuclin is present also in the germ cells of the mouse testis and ovary. Immunocytochemical staining detected basonuclin in the nuclei of spermatogonia and spermatocytes at various developmental stages. During spermiogenesis, it relocated from the nucleus to the midpiece of the flagellum of the spermatozoa. In the ovary, basonuclin was found mainly in the nuclei of developing oocytes. The dual presence of basonuclin in differentiated spermatozoa and oocytes suggests that it may play a role in their differentiation and the early development of an embryo.
Animals↗
Desmoglein 3 anchors telogen hair in the follicle.
Little is known about the function of desmosomes in the normal structure and function of hair. Therefore, it was surprising that mice without desmoglein 3 (the autoantigen in pemphigus vulgaris) not only developed mucous membrane and skin lesions like pemphigus patients, but also developed hair loss. Analysis of this phenotype indicated that hair was normal through the first growth phase ('follicular neogenesis'). Around day 20, however, when the hair follicles entered the resting phase of the hair growth cycle (telogen), mice with a targeted disruption of the desmoglein 3 gene (DSG3-/-) lost hair in a wave-like pattern from the head to the tail. Hair then regrew and was lost again in the same pattern with the next synchronous hair cycle. In adults, hair was lost in patches. Gentle hair pulls with adhesive tape showed that anagen (growing) hairs were firmly anchored in DSG3-/- mice, but telogen hairs came out in clumps compared to that of DSG3+/- and +/+ littermates in which telogen hairs were firmly anchored. Histology of bald skin areas in DSG3-/- mice showed cystic telogen hair follicles without hair shafts. Histology of hair follicles in early telogen, just before clinical hair loss occurred, showed loss of cell adhesion (acantholysis) between the cells surrounding the telogen club and the basal layer of the outer root sheath epithelium. Electron microscopy revealed 'half-desmosomes' at the plasma membranes of acantholytic cells. Similar acantholytic histology and ultrastructural findings have been previously reported in skin and mucous membrane lesions of DSG3-/- mice and pemphigus vulgaris patients. Immunoperoxidase staining with an antibody raised against mouse desmoglein 3 showed intense staining on the cell surface of keratinocytes surrounding the telogen hair club in normal mice. Similar staining was seen in human telogen hair with an anti-human desmoglein 3 antibody. Finally, a scalp biopsy from a pemphigus vulgaris patient showed empty telogen hair follicles. These data demonstrate that desmoglein 3 is not only critical for cell adhesion in the deep stratified squamous epithelium, but also for anchoring the telogen hair to the outer root sheath of the follicle and underscore the importance of desmosomes in maintaining the normal structure and function of hair.
Acantholysis↗
Targeted disruption of the pemphigus vulgaris antigen (desmoglein 3) gene in mice causes loss of keratinocyte cell adhesion with a phenotype similar to pemphigus vulgaris.
In patients with pemphigus vulgaris (PV), autoantibodies against desmoglein 3 (Dsg3) cause loss of cell-cell adhesion of keratinocytes in the basal and immediate suprabasal layers of stratified squamous epithelia. The pathology, at least partially, may depend on protease release from keratinocytes, but might also result from antibodies interfering with an adhesion function of Dsg3. However, a direct role of desmogleins in cell adhesion has not been shown. To test whether Dsg3 mediates adhesion, we genetically engineered mice with a targeted disruption of the DSG3 gene. DSG3 -/- mice had no DSG3 mRNA by RNase protection assay and no Dsg3 protein by immunofluorescence (IF) and immunoblots. These mice were normal at birth, but by 8-10 d weighed less than DSG3 +/- or +/+ littermates, and at around day 18 were grossly runted. We speculated that oral lesions (typical in PV patients) might be inhibiting food intake, causing this runting. Indeed, oropharyngeal biopsies showed erosions with histology typical of PV, including suprabasilar acantholysis and "tombstoning" of basal cells. EM showed separation of desmosomes. Traumatized skin also had crusting and suprabasilar acantholysis. Runted mice showed hair loss at weaning. The runting and hair loss phenotype of DSG3 -/- mice is identical to that of a previously reported mouse mutant, balding (bal). Breeding indicated that bal is coallelic with the targeted mutation. We also showed that bal mice lack Dsg3 by IF, have typical PV oral lesions, and have a DSG3 gene mutation. These results demonstrate the critical importance of Dsg3 for adhesion in deep stratified squamous epithelia and suggest that pemphigus autoantibodies might interfere directly with such a function.
Animals↗
Purification and characterization of secretory IgA from baboon colostrum.
In this report, we describe a method for purifying secretory immunoglobulin A (sIgA) from baboon (Papio anubis) colostrum. The colostrum was first clarified by centrifugation and then analyzed with various anti-human Ig-specific immunologic reagents. Cross-reactive IgA in the baboon colostrum was identified by ELISA. Western blot analysis also demonstrated cross-reactive epitopes associated with human IgA1, IgA2, secretory component (SC), and joining (J) chain. To purify the sIgA, colostrum was separated into 4 distinct fractions by gel filtration chromatography. Analysis of the individual fractions by ELISA indicated that the IgA elutes over one peak. The IgA fraction was compared with purified human sIgA on SDS-PAGE, and exhibited heavy (H) chains, light (L) chains, SC, and J chain. The baboon colostrum was also analyzed by ELISA for specific IgG H and L chain epitopes utilizing monoclonal antibodies (MAbs). No significant quantity of IgG was detected in the baboon colostrum or in the individual 4 fractions, while L chain reactivity was observed in the sIgA fraction. The sIgA fraction was pooled, concentrated, and was found to contain approximately 7 mg/ml sIgA. To determine if the baboon sIgA was dimeric like human sIgA, the purified sIgA was sized by molecular sieve chromatography. The molecular size of the sIgA preparation (350 kDa) was determined empirically by comparison to known molecular species used to calibrate the column. In addition, native SDS-PAGE indicated that baboon sIgA, like human sIgA, migrates between IgG and IgM, suggesting it has a dimeric form. The purified baboon sIgA preparation should prove useful in the future study of mucosal immune responses induced in non-human primate species and for the generation of sIgA-specific immunological reagents.
Animals↗
Effects of chronic infusion of angiotensin II on renin and blood pressure in the late-gestation fetal sheep.
OBJECTIVES: Our purpose was to determine whether chronic physiologic elevations in plasma angiotensin II levels decrease plasma renin concentration, alter the relationship between active renin and prorenin in fetal plasma and kidney, and depress the expression of renal renin messenger ribonucleic acid in the fetus. STUDY DESIGN: Seventeen chronically catheterized ovine fetuses at approximately 130 days' gestation were infused with either angiotensin II (48.9 +/- 3.5 ng/kg x min) or vehicle (5% glucose in water) for 72 hours. RESULTS: Mean arterial pressure increased significantly by 1 hour of infusion and continued to increase throughout the infusion. The plasma active renin concentration was significantly decreased by 1 hour of the infusion, whereas the prorenin concentration was not decreased until 24 hours of the infusion. After 72 hours of angiotensin II infusion the renal tissue prorenin content decreased (21.5 +/- 5.1 ng/mg x hr angiotensin I vs 46.4 +/- 6.6 ng/mg - hr angiotensin I in the control animals, p = 0.01), whereas the active renin concentration did not change (26.6 +/- 5.1 ng/mg x hr angiotensin I vs 35.1 +/- 5.4 ng/mg x hr angiotensin I in the control animals, p = 0.28). The renal renin messenger ribonucleic acid expression tended to be lower in the angiotensin II-treated fetuses (p = 0.10). CONCLUSION: Chronic physiologic increases in fetal plasma angiotensin II suppress the secretion of active and prorenin and alter the relationship between processing and secretion of renin in the fetal kidney.
Angiotensin II↗
Update: structure and function of pemphigus vulgaris antigen.
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Autoantigens↗
The baboon as a nonhuman primate model for assessing the effects of maternal immunization with Haemophilus influenzae type b polysaccharide vaccines.
These studies were performed to assess the utility of the baboon as a nonhuman primate model to evaluate vaccines for use in humans. Specifically, we examined the antibody response of baboons immunized during the third trimester of pregnancy with Haemophilus influenzae type b (Hib) polyribosylribitol phosphate (PRP) conjugate and unconjugated polysaccharide vaccines. Some of the vaccinated mothers failed to respond to a single immunization with unconjugated Hib PRP. Specific Hib PRP immunoglobulin G (IgG) but not IgM antibodies cross the baboon placenta and are detected in the offspring. Higher-titer baboon anti-Hib PRP did not express two previously defined cross-reactive human anti-Hib PRP idiotypes and was biased towards lambda light-chain expression. Spectrotype analysis indicated that baboon anti-Hib PRP was restricted in heterogeneity and oligoclonal.
Animals↗
Periconceptional folate intake and neural tube defects.
Approximately 50% of neural tube defects may be folate-preventable and perhaps even more in other countries where prevalence is high. The Public Health Service has issued the recommendation that all women of childbearing age in the United States who are capable of becoming pregnant should consume 400 micrograms of folic acid/day for the purpose of reducing this risk. Ways in which a reproductive age woman could achieve this goal include: 1) fortifying a food sample with folic acid, 2) consuming supplements containing at least 400 mcg of folic acid, or 3) increasing nutrient intake by eating foods rich in folate. Advantages of consuming foods high in folate content are that it is a natural behavior and consistent with other dietary recommendations. However, this method is dependent upon a proper diet, and equivalencies of conjugated (dietary form) vs. unconjugated (in supplements) folate are unknown. The benefit of a supplementation policy is that the appropriate group can be targeted as pregnancies are planned, whereas primary limitations to taking a supplement would be compliance and most cases in need would not be reached. The advantage of fortification is that it is likely to reach everyone before conception, while the major disadvantage is that nontargeted populations will also receive more folic acid. Adequate consumption of folic acid should begin before and continue during at least the first 4 weeks after conception when the fetal neural tube is being formed. Standard methods of screening for neural tube defects should continue during pregnancy. The risk of a recurrent neural tube defect is 2-3%, and a higher periconception daily intake of folic acid (4 mg per day) is recommended.
Adolescent↗
Pemphigus vulgaris antigen (desmoglein 3) is localized in the lower epidermis, the site of blister formation in patients.
In Patients with pemphigus vulgaris, autoantibodies against the desmosomal glycoprotein desmoglein 3 (Dsg3) cause blisters due to loss of keratinocyte cell-cell adhesion in the basal and immediate suprabasal layer of the deeper epidermis, leaving the superficial epidermis intact. Autoantibodies from these patients, however, usually bind to the cell surface of keratinocytes throughout the entire epidermis, as determined by indirect immunofluorescence. To explain this apparent paradox, we immunoadsorbed pemphigus vulgaris sera with the extracellular domains of Dsg3 and desmoglein 1 (Dsg1) produced by insect cells infected with recombinant baculovirus. When adsorbed with extracellular domains of both Dsg3 and Dsg1, these sera no longer stained epidermis, demonstrating that most, if not all, of their cell surface reactivity can be attributed to antibodies against the extracellular domains of these desmogleins. Adsorption with only the Dsg1 extracellular domain left antibodies that stained only the basal and immediate suprabasal layers of the epidermis and immunoprecipitated only Dsg3, not Dsg1, from extracts of cultured cells synthesizing these molecules. In contrast, adsorption with only the Dsg3 extracellular domain left antibodies that stained only the more superficial epidermis and immunoprecipitated only Dsg1. These data localize Dsg3 exactly to the area in the epidermis where blisters occur in pemphigus vulgaris.
Autoantibodies↗
Autoantibodies against adhesion molecules and structures in blistering skin diseases.
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Autoantibodies↗