PubMed Health⌕ Search

Biomedical subjects

Christine Bodemer

Publications and source records attributed to Christine Bodemer.

At least 19 recordsLinked to original sources
PubMed2026

An isogenic hiPSC-derived keratinocyte model reveals CXCL10/CXCL11 inflammatory dysregulation in epidermolysis bullosa simplex.

Epidermolysis bullosa simplex (EBS) is a genetic skin disorder driven by dominant pathogenic variants in KRT5 or KRT14 genes, leading to cytoskeletal fragility in basal keratinocytes and intraepidermal blistering. No curative therapies are currently available, and the link between keratin mutations and disease mechanisms remains incompletely understood. To further investigate the inflammatory component of EBS, we used a model of hiPSC-derived keratinocytes carrying dominant KRT5 variants, alongside a genetically corrected isogenic counterpart. This approach established a direct link between the KRT5 variants and keratin aggregation, impaired proliferation, and an inflammatory phenotype. The inflammatory signature was confirmed by increased expression of IL1A and IL1B, consistent with previous observations in EBS, while CXCL10 and CXCL11 emerged as newly identified dysregulated chemokines. Their consistent increase across independent cell lines, elevated secretion, and normalization in the CRISPR-corrected isogenic cells indicate that KRT5 variants trigger a keratinocyte-intrinsic CXCL10/CXCL11 inflammatory response. Pharmacological inhibition of the IFN-γ-JAK1/2-STAT1 pathway suppressed their secretion, supporting JAK inhibition as a potential therapeutic strategy to modulate EBS-associated inflammatory dysregulation. In conclusion, this study shows that beyond structural defects, KRT5 variants establish a keratinocyte-intrinsic inflammatory phenotype in which the CXCL10 and CXCL11 axis emerges as a key disease-associated signature and a promising therapeutic target.

CXCL10/CXCL11↗
PubMed2006

Epigallocatechin gallate's protective effect against MMP7 in recessive dystrophic epidermolysis bullosa patients.

The analysis of phenotype-genotype correlations of patients suffering from recessive dystrophic epidermolysis bullosa (RDEB) evidenced intrafamilial and interfamilial phenotype variability occurring for the same mutation of COL7A1; this underscores the role of other genetics environmental factors in the expressivity of the disease. In this work, we checked whether matrilysin 1 (matrix metalloproteinase (MMP)7) could take part in the epidermal detachment in RDEB. Furthermore, we investigated epigallocatechin 3 gallate (EGCG) to determine whether it could inhibit matrilysin activities on collagen type VII and fibrillin 1 known to be associated with the dermo-epidermal junction. In this work, matrilysin 1 was detected in affected and unaffected skins of the three RDEB patients; furthermore, MMP7 was shown to degrade ex vivo on healthy normal skin collagen VII and fibrillin 1. Thus, we suspect that MMP7 could take an active part in the epidermal detachment occurring during RDEB. We evidenced that EGCG in in vitro as well as in ex vivo experiments was a good inhibitor of MMP7 and developed a good protection of collagen type VII and fibrillin 1 susceptible of being degraded by MMP7. We therefore propose that EGCG could be used beneficially in patients suffering from RDEB.

Adult↗
PubMed2006

X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production.

Germline mutations in five autosomal genes involved in interleukin (IL)-12-dependent, interferon (IFN)-gamma-mediated immunity cause Mendelian susceptibility to mycobacterial diseases (MSMD). The molecular basis of X-linked recessive (XR)-MSMD remains unknown. We report here mutations in the leucine zipper (LZ) domain of the NF-kappaB essential modulator (NEMO) gene in three unrelated kindreds with XR-MSMD. The mutant proteins were produced in normal amounts in blood and fibroblastic cells. However, the patients' monocytes presented an intrinsic defect in T cell-dependent IL-12 production, resulting in defective IFN-gamma secretion by T cells. IL-12 production was also impaired as the result of a specific defect in NEMO- and NF-kappaB/c-Rel-mediated CD40 signaling after the stimulation of monocytes and dendritic cells by CD40L-expressing T cells and fibroblasts, respectively. However, the CD40-dependent up-regulation of costimulatory molecules of dendritic cells and the proliferation and immunoglobulin class switch of B cells were normal. Moreover, the patients' blood and fibroblastic cells responded to other NF-kappaB activators, such as tumor necrosis factor-alpha, IL-1beta, and lipopolysaccharide. These two mutations in the NEMO LZ domain provide the first genetic etiology of XR-MSMD. They also demonstrate the importance of the T cell- and CD40L-triggered, CD40-, and NEMO/NF-kappaB/c-Rel-mediated induction of IL-12 by monocyte-derived cells for protective immunity to mycobacteria in humans.

Adolescent↗
PubMed2006

Successful allogeneic hemopoietic stem cell transplantation in a child who had anhidrotic ectodermal dysplasia with immunodeficiency.

Anhidrotic ectodermal dysplasia with immunodeficiency is associated with multiple infections and a poor clinical outcome. Hypomorphic mutations in nuclear factor kappaB essential modulator (NEMO)/IkappaB kinase complex and a hypermorphic mutation in inhibitor alpha of nuclear factor kappaB (IkappaBalpha) both result in impaired nuclear factor kappaB activation and are associated with X-recessive and autosomal-dominant forms of anhidrotic ectodermal dysplasia with immunodeficiency, respectively. Autosomal-dominant anhidrotic ectodermal dysplasia with immunodeficiency is also associated with a severe T-cell phenotype. It is not known whether hematopoietic stem cell transplantation can cure immune deficiency in children with anhidrotic ectodermal dysplasia with immunodeficiency. A boy with autosomal-dominant anhidrotic ectodermal dysplasia with immunodeficiency and a severe T-cell immunodeficiency underwent transplantation at 1 year of age with haploidentical T-cell-depleted bone marrow after myeloablative conditioning. Engraftment occurred, with full hematopoietic chimerism. Seven years after transplantation, clinical outcome is favorable, with normal T-cell development. As expected, the developmental features of the anhidrotic ectodermal dysplasia syndrome have appeared and persisted. This is the first report of successful hematopoietic stem cell transplantation in a child with anhidrotic ectodermal dysplasia with immunodeficiency. Hematopoietic stem cell transplantation is well tolerated and efficiently cures the profound immunodeficiency associated with autosomal-dominant anhidrotic ectodermal dysplasia with immunodeficiency.

Chimerism↗
PubMed2006

Corneodesmosomal cadherins are preferential targets of stratum corneum trypsin- and chymotrypsin-like hyperactivity in Netherton syndrome.

SPINK5 (serine protease inhibitor Kazal-type 5), encoding the protease inhibitor LEKTI (lympho-epithelial Kazal-type related inhibitor), is the defective gene in Netherton syndrome (NS), a severe inherited keratinizing disorder. We have recently demonstrated epidermal protease hyperactivity in Spink5(-/-) mice resulting in desmosomal protein degradation. Herein, we investigated the molecular mechanism underlying the epidermal defect in 15 patients with NS. We demonstrated that, in a majority of patients, desmoglein 1 (Dsg1) and desmocollin 1 (Dsc1) were dramatically reduced in the upper most living layers of the epidermis. These defects were associated with premature degradation of corneodesmosomes. Stratum corneum tryptic enzyme (SCTE)-like and stratum corneum chymotryptic enzyme (SCCE)-like activities were increased, suggesting that these proteases participate in the premature degradation of corneodesmosomal cadherins. SCTE and SCCE expression was extended to the cell layers where Dsg1 and Dsc1 immunostaining was reduced. In contrast, a subset of six patients with normal epidermal protease activity or residual LEKTI expression displayed apparently normal cadherin expression and less severe disease manifestations. This suggests a degree of correlation between cadherin degradation and clinical severity. This work further supports the implication of premature corneodesmosomal cadherin degradation in the pathogenesis of NS and provides evidence for additional factors playing a role in disease expression.

Abnormalities, Multiple↗
PubMed2006

Kaposi's sarcoma in a child with Wiskott-Aldrich syndrome.

INTRODUCTION: Kaposi's sarcoma (KS) is rare in childhood. It may be favored by acquired immune deficiencies, but the predisposing factors to KS in other children are unclear. DISCUSSION: KS has been reported in only two children and one adult with primary immunodeficiency. We report here a Tunisian child with a Wiskott-Aldrich syndrome who developed KS at the age of 14 months. CONCLUSION: This observation expands the spectrum of primary immunodeficiencies associated with KS in childhood.

Combined Modality Therapy↗
PubMed2006

Rapamycin inhibits growth and survival of D816V-mutated c-kit mast cells.

Two classes of oncogenic mutations of the c-kit tyrosine kinase have been described: the juxtamembrane domain V560G mutation, which is preferentially found in gastrointestinal stromal tumors (GISTs), and the kinase domain D816V mutation, which is highly representative of systemic mastocytosis (SM). Here we show that both mutations constitutively activate the mammalian target of rapamycin (mTOR) signaling pathway. Surprisingly, the mTOR inhibitor rapamycin induces only apoptosis in HMC-1 cells bearing the D816V but not the V560G mutation. In support of this unexpected selectivity, rapamycin inhibits the phosphorylation of 4E-BP1, a downstream substrate of the mTOR pathway, but only in D816V HMC-1 cells. Importantly, D816V mast cells isolated from SM patients or from transgenic mice are sensitive to rapamycin whereas normal human or mouse mast cells are not. Thus, rapamycin inhibition appears specific to the D816V mutation. At present there is no effective cure for SM patients with the D816V mutation. The data presented here provide a rationale to test whether rapamycin could be a possible treatment for SM and other hematologic malignancies with the D816V mutation.

Animals↗
PubMed2006

Acne in recipients of renal transplantation treated with sirolimus: clinical, microbiologic, histologic, therapeutic, and pathogenic aspects.

We evaluated the clinical characteristics of sirolimus-induced acne in 80 recipients of renal transplantation. It developed in 36 of 48 (75%) men and 2 of 32 (6%) women. Lesion locations and clinical, bacteriologic, and histologic features differentiated sirolimus-induced acne from acne vulgaris, but therapeutic management was similar. The main limitation for this study was the absence of a control group without sirolimus. Epidermal growth factor inhibition by sirolimus is a plausible explanation for this acne.

Acne Vulgaris↗
PubMed2006

Presence of chimeric maternally derived keratinocytes in cutaneous inflammatory diseases of children: the example of pityriasis lichenoides.

During pregnancy, maternal cells may enter the fetal circulation and persist until adulthood. The fate of these cells remains unknown. As unexplained T-cell-mediated conditions such as pityriasis lichenoides (PL) may occur in children, we aimed at identifying maternal cells in lesional skin of PL and controls. Archived skin biopsy specimens from young males with PL, atopic dermatitis, or normal skin were scanned for the presence of female (presumably maternal) cells using fluorescence in situ hybridization (FISH) with X and Y chromosome-specific probes. Phenotyping of maternal cells relied on FISH combined with anti-CD45, anti-CD1a, or anti-cytokeratin labelling, identifying leukocytes, Langerhans cells, and keratinocytes, respectively. Maternal cells were found in PL (11/12) and controls (4/7), but their average frequency was higher in PL: 99 per million cells as compared to 5 per million cells in controls (P = 0.005). In the epidermis, the maternal microchimeric cells were labelled by anti-cytokeratin in all cases. We identified maternally derived keratinocytes in the skin of male children with inflammatory skin disorders. These cells may either help repair the damaged skin or home initially in the skin and trigger a host (child) versus graft (mother) disease.

Antigens, CD1↗
PubMed2006

Three severe cases of EBS Dowling-Meara caused by missense and frameshift mutations in the keratin 14 gene.

We report three unrelated patients affected at birth with an unusually severe form of epidermolysis bullosa simplex Dowling-Meara type (EBS-DM) because of mutations in KRT14 encoding keratin 14. Two patients were heterozygous for the previously described p.M119T mutation. The third patient was heterozygous for a novel c.1246delC mutation predicting the replacement of the helix termination peptide and the tail domain by a 25 amino-acid aberrant carboxyterminal sequence. At age 2 years, patients carrying the p.M119T mutation still suffered from severe EBS-DM, whereas the patient harboring the c.1246delC mutation has improved over time. These cases illustrate genotype-phenotype correlations and have implications for genetic counselling of EBS.

Child, Preschool↗
PubMed2006

Non-penetrating deep sclerectomy for glaucoma associated with Sturge-Weber syndrome.

PURPOSE: To report the results of non-penetrating deep sclerectomy (NPDS) in the treatment of glaucoma associated with Sturge-Weber syndrome (SWS). METHODS: We carried out a retrospective case series analysis of patients who underwent NPDS for glaucoma associated with SWS between 1998 and 2003. The control of glaucoma after NPDS, the results of surgery on intraocular pressure, the need for additional medical treatment and surgical complications were studied. RESULTS: Twelve eyes of nine patients, aged 11 days to 24 years, underwent filtering surgery: nine NPDS procedures were performed and three surgical procedures had to be converted to trabeculectomy because NPDS was not technically achievable. The mean follow-up after surgery was 26.3 months (range 6-48 months). Two trabeculectomies were complicated by choroidal effusion, which resolved in both cases. Good control of glaucoma was obtained during follow-up. CONCLUSIONS: Non-penetrating deep sclerectomy is transiently efficient in the treatment of SWS-associated glaucoma. Further studies of NPDS for the treatment of glaucoma associated with SWS are warranted.

Adolescent↗
PubMed2005

NEMO mutations in 2 unrelated boys with severe infections and conical teeth.

X-linked recessive anhidrotic ectodermal dysplasia with immunodeficiency is a developmental and immunologic disorder caused by mutations in nuclear factor-kappaB essential modulator (NEMO), which is essential for nuclear factor-kappaB activation. Early in life, affected boys present a typical appearance, with hypotrichosis or atrichosis, hypohidrosis or anhidrosis, and hypodontia or anodontia with conical incisors. They are also susceptible to various microorganisms, mostly pyogenic bacteria and mycobacteria. Here we report 2 unrelated boys, aged 6 and 11 years, who have novel mutations in NEMO and present conical incisors and hypodontia as their sole and long-unrecognized developmental anomaly. One child had isolated recurrent pneumococcal disease, whereas the other had multiple infections. Our observations indicate that conical incisors should prompt the search for NEMO mutations in boys with unusual infectious diseases.

Anodontia↗
PubMed2005

Cutaneous adverse events in renal transplant recipients receiving sirolimus-based therapy.

BACKGROUND: Sirolimus is an immunosuppressive drug recently developed for organ transplantation. Its mechanism of action, independent of calcineurin, is different from that of cyclosporine and tacrolimus, two calcineurin inhibitors (CIs). Because the toxicity of CIs is partly the result of calcineurin blockade, sirolimus exhibits a different toxicity profile. In this study, we evaluated the profile, frequency, and severity of cutaneous adverse events in renal transplant recipients receiving sirolimus-based therapy. PATIENTS AND METHODS: A systematic and in-depth evaluation of skin, mucous membranes, nails, and hair was performed in 80 renal transplant recipients receiving sirolimus-based therapy. The mean duration of the graft was 6 years and of sirolimus treatment was 18 months. Mycophenolate mofetil and steroids were combined with sirolimus for 74 patients. Sirolimus was used as first immunosuppressive therapy for 36 patients, and 44 patients were switched from CIs to sirolimus. RESULTS: Seventy-nine patients (99%) experienced cutaneous adverse events. Twenty patients (25%) demonstrated serious adverse events, and six patients (7%) stopped sirolimus during the 3 months after the study because of cutaneous events. The most frequent of these were pilosebaceous apparatus involvement, including acne-like eruptions (46%), scalp folliculitis (26%), and hidradenitis suppurativa (12%); edematous complaints, including chronic edemas (55%) and angioedema (15%); mucous membrane disorders, including aphthous ulceration (60%), epistaxis (60%), chronic gingivitis (20%), and chronic fissure of the lips (11%); and last, nail disorders including chronic onychopathy (74%) and periungual infections (16%). CONCLUSIONS: Skin disorders are frequent in renal transplant recipients receiving sirolimus as a long-term therapy. Despite the usually mild nature of skin events, they are often the reason for stopping sirolimus.

Adult↗
PubMed2004

Renal-transplant recipients and sun protection.

BACKGROUND: The incidence of skin carcinomas in organ-transplant recipients is high. The main factors implicated in carcinogenesis are immune suppression and ultraviolet radiation. Only the second is avoidable. We have evaluated knowledge of and compliance with sun protection measures among renal-transplant recipients (RTR). METHODS: A survey by means of a questionnaire including questions about clinical data, knowledge of, and compliance with sun protection was given. The questionnaire was given to 520 consecutive RTR followed up in a single center, and 445 (86%) answered. RESULTS: Of the responders, 91% have been informed of the need for sun protection, in 80% of cases by dermatologists. Sixty-eight percent used more protective measures abroad than at home, 63% avoided going outside during the hottest midday hours, 63% used sunscreen regularly, but 46% used one or less tube of sunscreen a year. A hat was always worn in the sun by 35% and long sleeves by 36%. Women and fair-skinned individuals complied better with protective measures. A minority of patients knew that ultraviolet radiation carries a risk of skin cancer. CONCLUSIONS: This survey shows that most RTR are aware of the need for sun protection, but only a minority take adequate protection measures. The better results observed in this study than in previous published investigations may be caused by the great involvement of dermatologists in the care of RTR in our institution. The results of this survey underline the need to inform RTR better about sun-protection measures and the importance of cooperation between transplant physicians and dermatologists.

Clothing↗
PubMed2004

Severe cutaneous papillomavirus disease after haemopoietic stem-cell transplantation in patients with severe combined immune deficiency caused by common gammac cytokine receptor subunit or JAK-3 deficiency.

Haemopoietic stem-cell transplantation is a life-saving treatment for severe combined immune deficiency. However, there has been little long-term follow-up of this treatment. There is evidence for the persistance of partial immunodeficiency associated with significant infections, including severe human papillomavirus (HPV) disease. We did a retrospective analysis of severe HPV disease in a group of 41 patients with severe combined immune deficiency from one centre who were alive 10 years or longer after haemopoietic stem-cell transplantation. Nine of the 41 patients had extensive chronic HPV disease limited to the skin, with a median onset at 8 years after transplantation. Four had lesions typical of epidermodysplasia verruciformis, a rare genodermatosis. Transplant characteristics, immune status, and chimerism of these nine patients did not differ significantly from those of the other patients. The nine patients with HPV disease had severe combined immune deficiency associated with either common gammac receptor cytokine subunit or Janus kinase-3 (JAK-3) deficiency. By contrast, patients with other forms of severe combined immune deficiency did not have any signs of HPV disease. That genetic causes are the only predisposing factor to be identified for severe combined immune deficiency, suggests that natural-killer cells or gammac/JAK-3-dependent signalling in keratinocytes could have a role in anti-HPV immunity.

Child↗
PubMed2004

Skin markers of occult spinal dysraphism in children: a review of 54 cases.

OBJECTIVES: To verify the diagnostic value of lumbosacral midline cutaneous lesions in asymptomatic children to detect occult spinal dysraphism (OSD) and to propose a practical approach for clinical investigations with respect to the type of cutaneous lesions observed. DESIGN: Retrospective study of 54 children referred to the Department of Pediatric Dermatology between 1990 and 1999 for congenital midline lumbosacral cutaneous lesions. SETTING: The private or institutional practices of participating dermatologists and pediatricians. MAIN OUTCOME MEASURES: Evaluation of the diagnostic value of midline cutaneous lesions for the detec-tion of OSD. Association of skin examination findings with spinal anomalies detected by magnetic resonance imaging or ultrasound. RESULTS: Occult spinal dysraphism was detected in 3 of 36 patients with an isolated congenital midline lesion and 11 of 18 patients with a combination of 2 or more different skin lesions. CONCLUSIONS: A combination of 2 or more congenital midline skin lesions is the strongest marker of OSD. Careful dermatologic examination is needed to detect suggestive markers and request a spinal magnetic resonance image, which is the most sensitive radiologic approach to detect an OSD.

Adolescent↗