Jean-Claude Bystryn

Patterns of remission in pemphigus vulgaris

BACKGROUND The incidence of remissions in pemphigus is unclear because these are usually reported at a single point in the evolution of the disease. Thus it is uncertain whether treatment simply suppresses the manifestations of the disease and consequently must be continuously administered, or induces complete and long-lasting remissions that permit therapy to be discontinued. OBJECTIVE To answer this question, we investigated the incidence of remission in a long-term longitudinal study. METHODS The induction of complete and long-lasting remissions (lesion free with no systemic therapy for at least 6 months) was studied in 40 patients with pemphigus vulgaris treated conventionally and followed up for an average of 7.7 years by the same investigator. RESULTS Five (5%) of the patients died of the disease. Complete and long-lasting remissions were induced in 25%, 50%, and 75% of patients 2, 5, and 10 years, respectively, after diagnosis. Most of the remaining patients were in partial remission or had mild disease controlled with a small dose of steroids. The course of the disease followed different patterns, with some patients rapidly entering complete and long-lasting remissions, whereas others never entered into a complete remission. The induction of complete remission was related to the initial severity and extent of disease and to early response to treatment. CONCLUSION It is possible to eventually induce complete and durable remissions in most patients with pemphigus that permit systemic therapy to be safely discontinued without a flare in disease activity. The proportion of patients in whom this can be achieved increases steadily with time, and therapy can be discontinued in approximately 75% of patients after 10 years.

Are desmoglein autoantibodies essential for the immunopathogenesis of pemphigus vulgaris, or just ‘witnesses of disease'?

Abstract:  Pemphigus vulgaris (PV) is fascinating to dermatologists, epithelial biologists and immunologists alike, as its pathogenesis has been clarified to a much greater extent than that of most other organ‐specific autoimmune diseases, and as it has provided abundant novel insights into desmoglein biology and pathology along the way. Historically, the most influential PV pathogenesis concept is that of Stanley and Amagai. This concept holds that autoantibodies against desmogleins are both essential and sufficient for epidermal blister formation (acantholysis) by impeding the normal functioning of these major adhesion proteins. However, as with most good theories, this landmark concept has left a number of intriguing and important questions open (or at least has not managed to answer these to everyones satisfaction). Moreover, selected dissenting voices in the literature have increasingly called attention to what may or may not be construed as inconsistencies in this dominant PV pathogenesis paradigm of the recent past. The present debate feature therefore bravely rises to the challenge of re‐examining the entire currently available evidence, as rationally and as undogmatically as possible, by provocatively asking a carefully selected congregation of experts (who have never before jointly published on this controversial topic!) to discuss how essential anti‐desmoglein autoantibodies really are in the immunopathogenesis of PV. Not surprisingly, some of our expert ‘witnesses’ in this animated debate propose diametrically opposed answers to this question. While doing so, incisive additional questions are raised that relate to the central one posed, and our attention is called to facts that may deserve more careful consideration than they have received so far. Together with the intriguing (often still very speculative) complementary or alternative pathogenesis scenarios proposed in the following pages, this offers welcome ‘food for thought’ as well as very specific suggestions for important future research directions – within and beyond the camp of PV aficionados. The editors trust that this attempt at a rational public debate of the full evidence that is currently at hand will constructively contribute to further dissecting the exciting – and clinically very relevant! – immunopathogenesis of PV in all its complexity.

Alopecia areata: an autoimmune disease?

Abstract: A wide range of hypotheses such as focal infection, trophoneur‐ oses, and endocrine dysfunction, have been previously proposed to explain the pathogenesis of alopecia areata (AA). Currently, the most widely held belief is that AA is an autoimmune disease with cellular and/or humoral immunity directed against anagen hair follicle antigen(s). However, until recently evidence in support of an autoimmune mechanism of AA has been largely circumstantial. More fundamental evidence has recently been amassed in support of AA as an autoimmune disease by using animal models. These data include: 1) identification of cross‐species hair follicle specific IgG autoantibodies, 2) The ability to induce AA in an animal model with transfer of skin from affected to naive individuals, and 3) the induction of disease by transfer of lymphocytes to human skin grafted to severe combined immunodeficiency mutant mice. A review of the pre‐ vious and current data related to the autoimmune basis of AA is provided to put into perspective the future studies needed to definitively determine whether AA is an autoimmune disease.

Apoptolysis: a novel mechanism of skin blistering in pemphigus vulgaris linking the apoptotic pathways to basal cell shrinkage and suprabasal acantholysis

Abstract:  Understanding the acantholytic pathways leading to blistering in pemphigus vulgaris (PV) is a key to development of novel treatments. A novel paradigm of keratinocyte damage in PV, termed apoptolysis, links the suprabasal acantholytic and cell death pathways to basal cell shrinkage rendering a ‘tombstone’ appearance to PV lesions. In contrast to apoptolysis, the classic keratinocyte apoptosis mediating toxic epidermal necrolysis causes death and subsequent sloughing of the entire epidermis. Apoptolysis includes five consecutive steps. (1) Binding of autoantibodies to PV antigens. (2) Activation of EGF receptor, Src, mTOR, p38 MAPK and other signalling elements downstream of ligated antigens, elevation of intracellular calcium and launching of the cell death cascades. (3) Basal cell shrinkage due to: (i) collapse and retraction of the tonofilaments cleaved by executioner caspases; and (ii) dissociation of interdesmosomal adhesion complexes caused by phosphorylation of adhesion molecules. (4) Massive cleavage of cellular proteins by activated cell death enzymes leading to cell collapse, and tearing off desmosomes from the cell membrane stimulating secondary autoantibody production. (5) Rounding up and death of acantholytic cells. Thus, the structural damage (acantholysis) and death (apoptosis) of keratinocytes are mediated by the same cell death enzymes. Appreciation of the unifying concept of apoptolysis have several important implications: (i) linking together a number of seemingly unrelated events surrounding acantholysis; (ii) opening new avenues of investigation into the pathomechanism of pemphigus; and (iii) creating new approaches to the treatment of pemphigus based on blocking the signalling pathways and enzymatic processes that lead to blistering.

Effect of plasmapheresis therapy on circulating levels of pemphigus antibodies

We determined the circulating levels of pemphigus antibodies in 11 patients with pemphigus treated with plasmapheresis, corticosteroids, and immunosuppressive drugs and in 11 patients treated with corticosteroids and immunosuppressive drugs alone. Three weeks after hospitalization, the average titer of pemphigus antibodies had decreased from admission levels by 83% in patients treated with plasmapheresis but by only 18% in the other group (p less than 0.05). These results suggest that plasmapheresis, in conjunction with high doses of corticosteroids and immunosuppressive drugs, reduces circulating levels of pemphigus antibodies more rapidly than conventional therapy.

Stimulation of CD8+ T cell responses to MAGE‐3 and Melan A/MART‐1 by immunization to a polyvalent melanoma vaccine

A critical requirement for cancer vaccines is that they stimulate CD8+ T cell responses. In this study, we tested the ability of a polyvalent melanoma vaccine to induce CD8+ T cell responses to the melanoma associated antigens MAGE‐3 and Melan A/MART‐1. Fifteen HLA‐A2+ patients with resected malignant melanoma were immunized with the vaccine s.c. every 2–3 weeks. CD8+ T cells in peripheral blood reacting to HLA‐A2 restricted epitopes on MAGE‐3 (FLWGPRALV) and Melan A/MART‐1/(AAGIGILTV) were quantitated using a filter spot assay at baseline and following 4 immunizations. Vaccine immunization induced CD8+ T cells reacting to one or both of these peptides in 9 of the 15 (60%) patients. These cells were CD8+ and HLA‐A2 restricted, as reactivity was abrogated by monoclonal antibodies (MAbs) to CD8 and class I HLA, but not by anti‐CD4. All responding patients remained recurrence‐free for at least 12 months (median 15 months, range 12 to >21 months), whereas melanoma recurred within 3–5 months in non‐responders. The differences in outcome were unrelated to differences in disease severity or overall immunological competence between responders and non‐responders. Our results demonstrate directly that MAGE‐3 and Melan A/MART‐1 can stimulate CD8+ T cell responses in humans, and suggest that these responses are protective and surrogate markers of vaccine efficacy. Int. J. Cancer 72:972–976, 1997.

Comparison of Alopecia areata in Human and Nonhuman Mammalian Species

Alopecia areata (AA) is a nonscarring form of inflammatory hair loss in humans. AA-like hair loss has also been observed in other species. In recent years the Dundee experimental bald rat and the C3H/HeJ mouse have been put forward as models for human AA. AA in all species presents with a wide range of clinical features from focal, locally extensive, diffuse hair loss, to near universal alopecia. Histologically, all species have dystrophic anagen stage hair follicles associated with a peri- and intrafollicular inflammatory cell infiltrate. Autoantibodies directed against anagen stage hair follicle structures are a consistent finding. Observations on AA pathogenesis suggest nonhuman species can provide excellent models for the human disease. Ultimately, animal models will be used to determine the genetic basis of AA, potential endogenous and/or environmental trigger(s), mechanism(s) of disease initiation and progression, and allow rapid evaluation of new and improved disease treatments.

A Model for the Regulation of Antibody Synthesis by Serum Antibody

Publisher Summary This chapter discusses a model for the regulation of antibody synthesis by serum antibody. The immune response (ImR) after removal of specific antibody was studied. In these experiments, antibody was removed specifically in two ways: (1) by successive exposure of aliquots of plasma of immunized animals to solid phase immunoadsorbents followed by return of the adsorbed plasma to them; (2) by exchange transfusion of animals immunized to two antigens with blood containing antibody of one specificity only, thereby depleting the other antibody specifically. Following the removal, there was a marked rise in serum levels of specific antibody, which frequently reached peak titers exceeding those prior to removal. The assay used in these studies was phage neutralization which is affected by the binding affinity of antibody. These experiments were repeated using an antibody assay that would allow estimation in molar terms. The results obtained support a model in which the level of serum antibody regulates the ImR by means of equilibrium with antibody in an immunogen-containing compartment.

Immunogenicity of a polyvalent melanoma antigen vaccine in humans.

Fifty‐five patients with Stage II (36 patients) or Stage III (19 patients) malignant melanoma confirmed histologically received adjuvant immunotherapy with a polyvalent melanoma antigen vaccine to evaluate toxicity and immunogenicity. There was no toxicity. Antibody and/or cellular immune responses to melanoma were induced more frequently in Stage II (36 patients [69%]) than Stage III (19 patients [53%]) disease. The ability of different immunization schedules, alum, or pretreatment with low‐dose cyclophosphamide to potentiate immunogenicity was compared after 2 months of immunization. Immunization biweekly with a fixed intermediate dose of vaccine was more immunogenic than immunization weekly with escalating vaccine doses. Alum increased the intensity of cellular responses slightly, whereas pretreatment with cyclophosphamide augmented both the incidence and intensity of cellular immune responses slightly. However, these changes did not reach statistical significance. There was a reciprocal relationship between the induction of humoral and cellular immune responses. These results show that (1) active immunotherapy with a polyvalent melanoma vaccine is safe in patients with minimal disease, (2) the vaccine augments immunity to melanoma in many, but not all, patients, and (3) several immunization strategies failed to potentiate immunogenicity significantly.

Serum antibodies in vitiligo patients

Abstract Vitiligo is an acquired depigmentary disease of the skin that is caused by a selective destruction of melanocytes in discrete, usually symmetric, patches on the skin. This results in sharply outlined areas of complete depigmentation, which are particularly prominent in individuals with dark skin. Vitiligo is common, involving approximately 1% of the worlds population. Although it is asymptomatic and does not adversely affect survival, the disease can be disfiguring and cause severe psychologic stresses and difficulties with employment. The cause of vitiligo is not known; however, a striking aspect of the disease, which may be providing a clue to its pathogenesis, is that the damage it causes is highly selective, being almost entirely restricted to melanocytes.