Erythema multiforme associated with anti-plakin antibodies: a multicentric retrospective case series.

BACKGROUND: Erythema multiforme (EM) is a muco-cutaneous inflammatory disease mainly triggered by herpes simplex virus (HSV) recurrences. Association of EM and circulating auto-antibodies against plakins (anti-PLK-Abs [EM-PLK+]) has been reported. However, little is known about this subset of EM. OBJECTIVES: We aimed to describe the clinical and immunological features and response to treatment of EM-PLK+. METHODS: We conducted a retrospective multicentric study of EM-PLK+ selected from the database of the immunological laboratory of Bichat hospital, Paris, France, from January 2009 to December 2020. Anti-PLK-Abs were detected in ≥1 immunological tests: immunofluorescence assay, immunoblotting and/or ELISA. Patients with alternative diagnoses were excluded. RESULTS: We included 29 patients (16 women, median age 25 [range 2-58] years). EM-PLK+ were mostly major (EM with ≥2 mucosal involvements; n = 24, 83%) and relapsing (≥2 flares; n = 23, 79%). Cutaneous lesions were target (n = 13, 54%) and target-like lesions (n = 9, 38%) with usual topography (acral, n = 19, 79%; limbs, n = 21, 88%). Mucosal lesions affected the mouth (n = 27, 96%) and genitalia (n = 19, 68%), with a median of 2 [range 0-5] mucous membranes. EM-PLK+ were suspected as certain or possible postherpetic (EM-HSV) in 19 cases (65.5%); no triggering factors were detected in 9 (31%) patients. Desmoplakin-I/II Abs were the most frequent anti-PLK-Abs (n = 20, 69%); envoplakin and periplakin Abs were detected in 11 and 9 cases. Relapsing EM-PLK+ (n = 23) were still active (≥1 flare within 6 months) in 13 (57%) patients despite immunosuppressive therapy (n = 8, 62%). Antiviral drugs were ineffective in preventing relapse in 15/16 (94%) EM-HSV. CONCLUSION: The rationale for anti-PLK-Ab detection in EM is not elucidated. More systematic research of anti-PLK-Abs is warranted to better understand whether this association reflects humoral immune activity in a subset of EM or is fortuitous, related to an epitope spreading process. However, EM-PLK+ seems to be associated with major and relapsing subtypes, and difficult-to-treat cases.

[In-transit metastasis in melanoma: Efficacy of topical imiquimod combined with carbon dioxide laser or with electrocautery]. / Métastases en transit du mélanome : efficacité de l'imiquimod topique combiné au laser CO2 ou à l'électrocoagulation.

BACKGROUND: In-transit metastases in cutaneous melanoma are common and difficult to manage. Therapy is mainly palliative. Use of topical imiquimod has been assessed for surface metastases. PATIENTS AND METHODS: We report on four patients with cutaneous melanoma metastases treated with topical imiquimod associated with carbon dioxide laser in the first two patients and with electrocoagulation in the two others. For two patients, we noted complete regression of the lesions after 15 and 18 months. For the two others, treatment was stopped after 9 to 10 months because of progression of subcutaneous metastasis and distant metastasis. DISCUSSION: Topical imiquimod is an alternative treatment used in superficial in-transit metastasis of melanoma. Its use as a monotherapy is sometimes ineffective. We elected to use combined pre-treatment with carbon dioxide laser or electrocoagulation in order to potentiate the action of imiquimod. This simple and inexpensive therapeutic strategy constitutes a palliative treatment that can allow prolonged local control of cutaneous metastasis.

Human papillomavirus 16-specific T cell responses in classic HPV-related vulvar intra-epithelial neoplasia. Determination of strongly immunogenic regions from E6 and E7 proteins.

Cell-mediated immunity directed against human papillomavirus 16 (HPV-16) antigens was studied in 16 patients affected with classic vulvar intra-epithelial neoplasia (VIN), also known as bowenoid papulosis (BP). Ten patients had blood lymphocyte proliferative T cell responses directed against E6/2 (14-34) and/or E6/4 (45-68) peptides, which were identified in the present study as immunodominant among HPV-16 E6 and E7 large peptides. Ex vivo enzyme-linked immunospot-interferon (IFN)-gamma assay was positive in three patients who had proliferative responses. Twelve months later, proliferative T cell responses remained detectable in only six women and the immunodominant antigens remained the E6/2 (14-34) and E6/4 (45-68) peptides. The latter large fragments of peptides contained many epitopes able to bind to at least seven human leucocyte antigen (HLA) class I molecules and were strong binders to seven HLA-DR class II molecules. In order to build a therapeutic anti-HPV-16 vaccine, E6/2 (14-34) and E6/4 (45-68) fragments thus appear to be good candidates to increase HPV-specific effector T lymphocyte responses and clear classic VIN (BP) disease lesions.

[Anti human-papillomavirus vaccines: concepts, aims and trials]. / Vaccination anti-Papillomavirus Humains: principes et état d'avancement.

PURPOSE: Human Papillomaviruses (HPV) are epitheliotropic for stratified malpighian epithelia such as those of the cervix. Among them, oncogenic viruses are detectable in 99.7% of cervical cancers. A great priority is to develop a vaccine either against primary infection (preventive vaccine) allowing protection against HPV infection or therapeutic vaccine in order to kill previously infected or transformed keratinocytes. CURRENT KNOWLEDGE AND KEY POINTS: Preventive vaccines against HPV contain virus like particles (VLP) 16 and 18 and induce a high titer of blood anti-VLP antibodies. They were recently tested in humans and have shown true efficiency for the prevention of cervical cancer. The therapeutic vaccines are therefore currently being developed in order to increase anti-HPV natural CD4+ and CD8+ T-cell immunity in women infected during their sexual activity. FUTURE PROSPECTS: The perspective of the prophylactic vaccines is to decrease both genital HPV infection and cervical cancer. The impact of preventive vaccine must be carefully analyzed in order to prevent collateral side effects. The therapeutic vaccines have also a future in women already infected by HPV and might have an efficiency similar to surgery in the treatment of cervical intraepithelial neoplasia.

Epidermolysis bullosa acquisita in childhood.

BACKGROUND: Epidermolysis bullosa acquisita (EBA) is an autoimmune bullous disease characterized by the presence of antitype VII collagen antibodies, leading to the formation of bullae in the dermoepidermal junction. This disease is rare in childhood. OBSERVATIONS: We report 3 new cases of EBA in children. The 3 patients were similar; all 3 children were black, with a clinical phenotype resembling linear IgA bullous disease in children and typical histologic and immunologic features of EBA. In the 3 patients, diagnosis was proven using immune electron microscopy and Western blot analysis, where antitype VII collagen antibodies were demonstrated. Patients 1 and 2 were successfully treated with a combination of prednisone and dapsone. In patient 3, the lesions healed without specific therapy. We found 11 other pediatric cases of EBA in the literature and studied those cases in addition to the cases presented herein to describe the characteristics of EBA in childhood. CONCLUSIONS: Epidermolysis bullosa acquisita is a rare disease in childhood. Mucosal involvement is frequent and severe. Because the clinical features are misleading, the use of immune electron microscopy and Western blot analysis is essential to making a diagnosis. Treatment with a combination of prednisone and dapsone is often effective. The prognosis in children is better than it is in adult patients.

[Local corticosteroid therapy in dermatology]. / La corticothérapie locale en dermatologie.

UNLABELLED: FOUR LEVELS OF ACTION: The introduction of dermocorticosteroids (corticosteroids for topical application) has revolutionized management of many skin diseases. Depending on their antiinflammatory action, these products can be classed into four levels of action. Dermocorticosteroids have antiinflammatory, vasoconstrictor, antiproliferative, antisynthetic and immunosuppressive actions. SKIN PENETRATION: Penetration depends on the intrinsic characteristics of the drug, but also on many other factors including the nature of the excipient, additives, occlusion, localization, nature of the treated skin disease, and patient age. There is a reservoir effect, explaining why a single application is effective for dermatoses with a normal keratin layer. INDICATIONS AND CONTRAINDICATIONS: Dermocorticosteroids can be indicated in numerous inflammatory skin diseases (psoriasis, eczema ...). They are formally contraindicated in case of skin infections, diaper rash, acne and rosacea. Contact allergies have been reported. IN PRACTICE: The choice of a dermatocorticosteroid depends on the suspected sensitivity of the disease to treat, its degree of extension, and its localization as well as the patient's age and the planned duration of treatment. Cremes provide good cosmetic satisfaction. The number of tubes to be used must be strictly controlled. Occlusion is indicated in case of palmo-plantar or the scalp involvement.

[Hypersensitivity syndrome caused by dapsone. Transient circulating clone T]. / Syndrome d'hypersensibilité à la dapsone. Clone T circulant transitoire.

INTRODUCTION: Hypersensitivity is a rare side-effect of dapsone. The most complete clinical presentation associates papulous exanthema, lymph node enlargement, liver cell failure and an increase in mononuclear and eosinophil counts. CASE REPORT: A 45-year-old woman developed hypersensitivity to dapsone when this drug was used to treat corticoid-dependent asthma. A transient circulating clone T was demonstrated by Southern blot during the acute phase. The clinical manifestations and laboratory findings returned to normal under systemic corticosteroid treatment. When corticoids were tapered off, hypersensitivity reactions began to progress again. DISCUSSION: Transient circulating clone T, as observed here, emphasizes the importance of close surveillance and long-term follow-up in drug-induced hypersensitivity syndromes.

Diagnosis and treatment of pulmonary arteriovenous malformations in hereditary hemorrhagic telangiectasia: An overview.

Hereditary hemorrhagic telangiectasia (HHT) or Rendu-Osler-Weber disease is an autosomic dominant disorder, which is characterized by the development of multiple arteriovenous malformations in either the skin, mucous membranes, and/or visceral organs. Pulmonary arteriovenous malformations (PAVMs) may either rupture, and lead to life-threatening hemoptysis/hemothorax or be responsible for a right-to-left shunting leading to paradoxical embolism, causing stroke or cerebral abscess. PAVMs patients should systematically be screened as the spontaneous complication rate is high, by reaching almost 50%. Neurological complications rate is considerably higher in patients presenting with diffuse pulmonary involvement. PAVM diagnosis is mainly based upon transthoracic contrast echocardiography and CT scanner examination. The latter also allows the planification of treatments to adopt, which consists of percutaneous embolization, having replaced surgery in most of the cases. The anchor technique consists of percutaneous coil embolization of the afferent pulmonary arteries of the PAVM, by firstly placing a coil into a small afferent arterial branch closely upstream the PAVM. Enhanced contrast CT scanner is the key follow-up examination that depicts the PAVM enlargement, indicating the various mechanisms of PAVM reperfusion. When performed by experienced operators as the prime treatment, percutaneous embolization of PAVMs, is a safe, efficient and sustained therapy in the great majority of HHT patients.

Blister fluid T lymphocytes during toxic epidermal necrolysis are functional cytotoxic cells which express human natural killer (NK) inhibitory receptors.

Toxic epidermal necrolysis (TEN) is a rare life-threatening adverse drug reaction characterized by a massive destruction of the epidermis. Immunohistological studies of skin biopsies of TEN showed infiltrates of predominantly CD8+ T lymphocytes even though other authors reported a prominent involvement of cells of the monocyte-macrophage lineage. The aim of this study was to characterize phenotypically and functionally the cells present in the cutaneous blister fluid of four patients with TEN. We first determined that lymphocytes were predominant in blister fluid obtained early, while monocytes/macrophages later became the most important population. We then showed that this lymphocyte population, mainly CD3+CD8+, corresponded to a peculiar cell subset as they expressed cutaneous leucocyte antigen, killer inhibitory receptors KIR/KAR and failed to express CD28 molecule. Functionally, we determined that blister T lymphocytes had a cytotoxic T lymphocyte (CTL)- and NK-like cytotoxicity. The role of this cytotoxic lymphocyte population present at the site of lesions during TEN remains to be understood.

Temporal loss of Nef-epitope CTL recognition following macaque lipopeptide immunization and SIV challenge.

To address the subtle interactions between antiviral cytotoxic T-cell (CTL) immune responses and the evolution of viral quasispecies variants in vivo, we performed a longitudinal study in a simian immunodeficiency virus (SIV)-infected rhesus macaque that had a long experimental SIV infection before developing simian AIDS. Before being infected with SIV, this animal was immunized with a mixture of seven lipopeptides derived from SIV Nef and Gag proteins and showed a bispecific antiviral CTL response directed toward Nef 169-178 and 211-225 peptides. After SIV infection, CTL activity against the Nef 169-178 epitope was no longer detectable, as assessed from peripheral blood mononuclear cells stimulated by autologous SIV. CTL activity against the 211-225 epitope was lost after 3 months, and an additional CTL response to the amino acids 112-119 Nef epitope emerged. Analysis of the Nef proviral sequence revealed the presence of immune escape variants first in the 211-225 epitope and much later in the 112-119 epitope. In contrast, epitope 169-178 showed only two mutations among all viral sequencing performed. We conclude that in this macaque, bispecific CTL exerted a strong selective pressure and escape virus mutants finally emerged. We identified CTL recognizing a conserved Nef epitope 112-119 (SYKLAIDM), essential for viral replication, which could be associated with a prolonged AIDS-free period. These results stress the importance of the induction of broader multispecific CTLs directed against highly conserved and functional T-cell epitopes by vaccination, with the aim of keeping HIV infection in check.

Selection of virus variants and emergence of virus escape mutants after immunization with an epitope vaccine.

In this report, we assessed the evolution of the cytotoxic T-lymphocyte (CTL) response induced by an epitope vaccine. In two macaques immunized with a mixture of lipopeptides derived from simian immunodeficiency virus (SIV) Nef and Gag proteins, CTL responses were directed against the same, single epitope of the Nef protein (amino acids 128 to 137) presenting an alanine at position 136 (Nef 128-137/136A). However, after 5 months of SIV infection, peripheral blood mononuclear cells from both macaques lost their ability to be stimulated by autologous SIV-infected cells while still retaining their capacity to generate cytotoxic responses after specific Nef 128-137/136A peptide stimulation. The sequences of the pathogenic viral isolate used for the challenge showed a mixture of several variants. Within the Nef epitopic sequence from amino acids 128 to 137, 82% of viral variants expressed the epitopic peptide Nef 128-137/136A; the remaining variants presented a threonine at position 136 (Nef 128-137/136T). In contrast, sequence analysis of cloned proviral DNA obtained from both macaques 5 months after SIV challenge showed a different pattern of quasi-species variants; 100% of clones presented a threonine at position 136 (Nef 128-137/136T), suggesting the disappearance of viral variants with an alanine at this position under antiviral pressure exerted by Nef 128-137/136A-specific CTLs. In addition, 12 months after SIV challenge, six of eight clones from one macaque presented a glutamic acid at position 131 (Nef 128-137/131E+136T), which was not found in the infecting isolate. Furthermore, CTLs generated very early after SIV challenge were able to lyse cells sensitized with the Nef 128-137/136A epitope. In contrast, lysis was significantly less effective or even did not occur when either the selected peptide Nef 128-137/136T or the escape variant peptide Nef 128-137/131E+136T was used in a target cell sensitization assay. Dose analysis of peptides used to sensitize target cells as well as a major histocompatibility complex (MHC)-peptide stability assay suggested that the selected peptide Nef 128-137/136T has an altered capacity to bind to the MHC. These data suggest that CTL pressure leads to the selection of viral variants and to the emergence of escape mutants and supports the fact that immunization should elicit broad CTL responses.

Type 1 CD4(+) T-cell help is required for induction of antipeptide multispecific cytotoxic T lymphocytes by a lipopeptidic vaccine in rhesus macaques.

We have optimized the induction of antiviral cytotoxic T lymphocytes (CTL) in rhesus macaques by a lipopeptide vaccine containing seven peptides from simian immunodeficiency virus (SIV) Nef and Gag proteins and a strong T-helper peptide from tetanus toxoid (TT) that is promiscuous in humans (peptide TT 830-846). Two of the eight immunized macaques showed T-helper (Th) cell proliferation and a specific synthesis of gamma interferon in response to TT 830-846 peptide. They also showed multispecific cytotoxic activity against three to five of the immunizing SIV peptides. These results show the importance of a strong specific type 1 Th response for inducing a multispecific CTL response in vivo, which is essential for the development of an anti-human immunodeficiency virus vaccine.

Identification in humans of HPV-16 E6 and E7 protein epitopes recognized by cytolytic T lymphocytes in association with HLA-B18 and determination of the HLA-B18-specific binding motif.

Human papilloma virus type 16 (HPV-16) is the HPV most frequently associated with cervical carcinoma in humans. For the prevention or treatment of cervical carcinoma, the E6 and E7 oncoproteins appear to be good targets for vaccine-induced cytotoxic T lymphocytes (CTL). Lipopeptide vaccination is an efficient way of stimulating cellular responses. However, to synthesize effective lipopeptides, it is necessary to define which epitopes are immunogenic. In this study we first determined that peptide 80 - 88 of the E6 protein was recognized by CTL from a healthy donor in association with the HLA-B18 molecule. We then defined the HLA-B18 anchoring peptide motif by testing the binding of various short peptides with the HLA-B18 molecule and showed that it was related to the HLA-A1-specific peptide motif. Furthermore, in analyzing the potential E7 epitopes susceptible to associating with HLA-B18, we demonstrated that peptide E7 44 - 52 gave the strongest binding. It could also be recognized by CTL from peripheral blood mononuclear cells (PBMC) of the same healthy donor. Finally, with PBMC from a patient with a cervical intraepithelial neoplasia grade 3, we found CTL which recognized the E6 80 - 88 epitope. We have hence identified two peptides encoded by the E6 and E7 proteins which are presented by the HLA-B18 molecule and could be included in a vaccine against HPV-16.