ABSTRACT
Atopic dermatitis is a chronic form of allergic contact dermatitis that is closely associated with a compromised epidermal barrier. Immunogenicity of a given electrophilic hapten after penetration of this barrier depends directly on biochemical reactions in the thiol-rich layer in the stratum granulosum. In response to electrophilic hapten, NF-erythroid 2-related factor 2 (NRF2) in keratinocytes efficiently induces the production of antioxidants. In this study, we show that the immunogenicity of a given hapten depends directly on the extent to which it induces antioxidant host defenses within the epidermal tissue. We found that allergic contact dermatitis did not develop in NRF2-deficient mice because of compromise of the epidermal innate immune responses that upregulate IL-1α. We also analyzed epidermal NRF2 in association with congenital disorders with features similar to atopic dermatitis in humans. Epidermal samples from patients with Netherton syndrome and peeling skin syndrome exhibited elevated levels of NRF2 and also elevated levels of its downstream target, small proline-rich protein 2. Taken together, these results suggest that the thiol-mediated biochemical responses in the stratum granulosum provide a critical link between defective epidermal barrier function and the development of atopy. Likewise, our results suggested that NRF2 may have a profound impact on the generation of cutaneous immunological memory.
Subject(s)
Antioxidants/metabolism , Dermatitis, Atopic/metabolism , Epidermis/metabolism , NF-E2-Related Factor 2/metabolism , Skin/metabolism , Animals , Cells, Cultured , Dermatitis, Atopic/immunology , Dermatitis, Exfoliative/immunology , Dermatitis, Exfoliative/metabolism , Epidermis/immunology , Humans , Immunity, Innate/immunology , Interleukin-1alpha/immunology , Interleukin-1alpha/metabolism , Keratinocytes/immunology , Keratinocytes/metabolism , Mice , Mice, Inbred BALB C , NF-E2-Related Factor 2/immunology , Netherton Syndrome/immunology , Netherton Syndrome/metabolism , Skin/immunology , Skin Diseases, Genetic/immunology , Skin Diseases, Genetic/metabolism , Up-Regulation/immunologyABSTRACT
Erythroderma can occur in cutaneous T-cell lymphoma (CTCL). Staphylococcus aureus (S. aureus) prevalence is increased in CTCL patients and contributes to CTCL disease flares. Our primary aim was to describe S. aureus infections, including resistance patterns and the antibiotic treatment regimens used, in erythrodermic CTCL patients. This was a retrospective chart review of erythrodermic CTCL patients who had S. aureus infection or colonization and were treated at the UT MD Anderson Cancer Center's Melanoma Skin Center between 2012 and 2016. Twenty-six erythrodermic CTCL patients had 50 documented S. aureus colonization or infection events. Patients had an improvement in body surface area (BSA) or modified Severity Weighted Assessment Tool (mSWAT) in 53% events treated for S. aureus. Seventeen of the 50 (34%) events were due to methicillin-resistant S. aureus (MRSA). One-third (33%) of MRSA events were initially treated with dicloxacillin. The MRSA isolates were sensitive to trimethoprim-sulfamethoxazole (92%) and doxycycline (88%). Patients treated in the outpatient setting (OR 0.073; 95% CI 0.008-0.627; p = 0.017) and patients with a previous history of topical anti-S. aureus decolonization treatments before S. aureus event as stand-alone (OR 0.125; 95% CI 0.018-0.887; p = 0.038) or in combination treatment with systemic antibiotics (OR 0.094; 95% CI 0.009-0.944; p = 0.045) were less likely to see improvement in BSA or mSWAT from S. aureus treatment. Treatment of S. aureus improved CTCL skin score in a high number of erythrodermic patients. The MRSA prevalence was high in erythrodermic CTCL patients. Clinicians should consider using empiric MRSA antibiotic coverage for these patients.
Subject(s)
Anti-Bacterial Agents/pharmacology , Dermatitis, Exfoliative/microbiology , Lymphoma, T-Cell, Cutaneous/complications , Methicillin-Resistant Staphylococcus aureus/isolation & purification , Staphylococcal Skin Infections/microbiology , Adult , Aged , Aged, 80 and over , Anti-Bacterial Agents/therapeutic use , Dermatitis, Exfoliative/diagnosis , Dermatitis, Exfoliative/drug therapy , Dermatitis, Exfoliative/immunology , Female , Humans , Lymphoma, T-Cell, Cutaneous/immunology , Male , Methicillin Resistance , Methicillin-Resistant Staphylococcus aureus/drug effects , Middle Aged , Retrospective Studies , Staphylococcal Skin Infections/diagnosis , Staphylococcal Skin Infections/drug therapy , Staphylococcal Skin Infections/immunologySubject(s)
Cytomegalovirus/immunology , Dermatitis, Exfoliative/diagnosis , Drug Hypersensitivity Syndrome/diagnosis , Herpesvirus 6, Human/immunology , Administration, Oral , Aged , Cytomegalovirus/isolation & purification , Dermatitis, Exfoliative/drug therapy , Dermatitis, Exfoliative/immunology , Dermatitis, Exfoliative/virology , Diagnosis, Differential , Drug Hypersensitivity Syndrome/drug therapy , Drug Hypersensitivity Syndrome/immunology , Drug Hypersensitivity Syndrome/virology , Female , Herpesvirus 6, Human/isolation & purification , Humans , Lymphocyte Activation/drug effects , Lymphocyte Activation/immunology , Prednisolone/administration & dosage , Viral Load , Virus Activation/immunologySubject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Dermatitis, Exfoliative/drug therapy , Interleukin-17/antagonists & inhibitors , Keratoderma, Palmoplantar/drug therapy , T-Lymphocytes, Helper-Inducer/physiology , Dermatitis, Exfoliative/immunology , Failure to Thrive/drug therapy , Female , Humans , Hypotrichosis/drug therapy , Infant , Interleukin-17/immunology , Keratoderma, Palmoplantar/immunology , Lymphocyte Count , Nails, Malformed/drug therapy , SyndromeSubject(s)
Autoimmunity , Dermatitis, Exfoliative/immunology , Skin/immunology , Thymoma/complications , Thymus Neoplasms/complications , Dermatitis, Exfoliative/pathology , Disease Progression , Female , Humans , Middle Aged , Skin/pathology , Thymectomy , Thymoma/immunology , Thymoma/pathology , Thymoma/surgery , Thymus Neoplasms/immunology , Thymus Neoplasms/pathology , Thymus Neoplasms/surgery , Treatment Outcome , Tumor BurdenSubject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Dermatitis, Exfoliative/drug therapy , Dermatologic Agents/therapeutic use , Psoriasis/drug therapy , Adult , Antibodies, Monoclonal, Humanized/pharmacology , Dermatitis, Exfoliative/diagnosis , Dermatitis, Exfoliative/immunology , Dermatologic Agents/pharmacology , Drug Resistance , Drug Substitution , Female , Humans , Male , Middle Aged , Psoriasis/diagnosis , Psoriasis/immunology , Retrospective Studies , Severity of Illness Index , Treatment OutcomeSubject(s)
Dermatitis, Exfoliative/drug therapy , Immunoglobulins, Intravenous/administration & dosage , Neoplasm Recurrence, Local/therapy , Thymoma/therapy , Thymus Neoplasms/therapy , Dermatitis, Exfoliative/immunology , Dose-Response Relationship, Drug , Fatal Outcome , Female , Humans , Middle Aged , Neoplasm Recurrence, Local/complications , Neoplasm Recurrence, Local/immunology , Skin/drug effects , Skin/immunology , Skin/pathology , Thymectomy , Thymoma/complications , Thymoma/immunology , Thymus Neoplasms/complications , Thymus Neoplasms/immunology , Treatment OutcomeABSTRACT
We report herein a case of a 72-year-old man with pityriasis rubra pilaris (PRP) that was refractory to conventional therapies. His skin lesions progressed to generalized erythroderma despite anti-interleukin (IL)-17A antibody therapy. Topical corticosteroids, emollients, systemic retinoid, methotrexate, cyclosporin and phototherapy yielded no therapeutic response. However, blockade of IL-12/23 p40 dramatically improved his cutaneous lesions. Complete remission was achieved 4 weeks after the first injection of ustekinumab and maintained for more than 48 weeks. Our data indicate that IL-12 was associated with the onset of PRP in this patient, rather than IL-23. IL-12 is critical for the differentiation of T-helper (Th)1 cells. Thus, the Th1 pathway may be associated with the onset of PRP.
Subject(s)
Dermatitis, Exfoliative/drug therapy , Dermatologic Agents/therapeutic use , Interleukin-12 Subunit p40/antagonists & inhibitors , Interleukin-17/antagonists & inhibitors , Pityriasis Rubra Pilaris/drug therapy , Aged , Dermatitis, Exfoliative/immunology , Dermatitis, Exfoliative/pathology , Dermatologic Agents/pharmacology , Disease Progression , Humans , Male , Pityriasis Rubra Pilaris/immunology , Pityriasis Rubra Pilaris/pathology , Skin/immunology , Skin/pathology , Treatment OutcomeSubject(s)
Anti-Inflammatory Agents/therapeutic use , Antibodies, Monoclonal/therapeutic use , Dermatitis, Exfoliative/drug therapy , Dermatologic Agents/therapeutic use , Psoriasis/drug therapy , Skin/drug effects , Adult , Antibodies, Monoclonal, Humanized , Dermatitis, Exfoliative/diagnosis , Dermatitis, Exfoliative/immunology , Humans , Male , Middle Aged , Psoriasis/diagnosis , Psoriasis/immunology , Skin/immunology , Skin/pathology , Treatment OutcomeSubject(s)
Adalimumab/administration & dosage , Dermatitis, Exfoliative/drug therapy , Dermatologic Agents/administration & dosage , Psoriasis/drug therapy , Skin/drug effects , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Adult , Dermatitis, Exfoliative/diagnosis , Dermatitis, Exfoliative/immunology , Female , Humans , Injections, Subcutaneous , Psoriasis/diagnosis , Psoriasis/immunology , Skin/immunology , Skin/pathology , Treatment Failure , Tumor Necrosis Factor-alpha/immunologyABSTRACT
Thymoma-associated multi-organ autoimmunity disease (TAMA) is a rare paraneoplastic disorder, clinicopathologically similar to graft-versus-host disease (GVHD). Many reported cases follow a difficult course; half of them die from serious infectious diseases subsequent to immunosuppression induced by chemotherapy for unresectable thymoma, or intensive therapies including systemic steroids for complicating autoimmune diseases and GVHD-like symptoms. We report a patient whose skin symptoms were improved subsequently to total thymectomy. The patient also presented with hypogammaglobulinemia, which led to the diagnosis of complicated Good syndrome. Taking account of her immunodeficient condition, antibiotics and i.v. immunoglobulin were administrated promptly on onset of bacterial pneumonia, which was successfully treated. According to a review of the published work, treatments with systemic steroids for skin symptoms have limited effects and may contribute to serious infection. Our case indicates that successful treatment of thymoma itself may lead to the amelioration of the disease. The management priority should be given to the treatment of thymoma and the control of subsequent immune abnormality other than GVHD-like erythroderma.
Subject(s)
Autoimmunity , Dermatitis, Exfoliative/immunology , Immunologic Deficiency Syndromes/immunology , Thymoma/immunology , Thymus Neoplasms/immunology , Administration, Intravenous , Aged , Anti-Bacterial Agents/therapeutic use , Biopsy , Dermatitis, Exfoliative/blood , Dermatitis, Exfoliative/pathology , Dermatitis, Exfoliative/therapy , Female , Graft vs Host Disease/immunology , Humans , Hypoproteinemia/blood , Immunoglobulins/therapeutic use , Parakeratosis/pathology , Pneumonia, Bacterial/blood , Pneumonia, Bacterial/drug therapy , Pneumonia, Bacterial/microbiology , Remission, Spontaneous , Retinoids/therapeutic use , Skin/immunology , Skin/pathology , Thymectomy , Thymoma/blood , Thymoma/complications , Thymoma/surgery , Thymus Neoplasms/blood , Thymus Neoplasms/complications , Thymus Neoplasms/surgery , Ultraviolet TherapySubject(s)
Antifungal Agents/adverse effects , Dermatitis, Exfoliative/chemically induced , Drug Eruptions/etiology , Interleukin-23/immunology , Naphthalenes/adverse effects , Psoriasis/chemically induced , Skin/drug effects , Aged, 80 and over , Betamethasone/administration & dosage , Betamethasone/analogs & derivatives , Biopsy , Cells, Cultured , Dermatitis, Exfoliative/diagnosis , Dermatitis, Exfoliative/drug therapy , Dermatitis, Exfoliative/immunology , Drug Eruptions/diagnosis , Drug Eruptions/drug therapy , Drug Eruptions/immunology , Female , Glucocorticoids/administration & dosage , Humans , Lymphocyte Activation/drug effects , Methylprednisolone/administration & dosage , Psoriasis/diagnosis , Psoriasis/drug therapy , Psoriasis/immunology , Skin/immunology , Skin/pathology , T-Lymphocytes, Helper-Inducer/drug effects , T-Lymphocytes, Helper-Inducer/immunology , Terbinafine , Treatment OutcomeSubject(s)
Dermatitis, Exfoliative/diagnosis , Exome Sequencing/methods , Immunity, Cellular , Interleukin-7 Receptor alpha Subunit/genetics , Mutation , Neonatal Screening/methods , Severe Combined Immunodeficiency/diagnosis , DNA/genetics , DNA Mutational Analysis , Dermatitis, Exfoliative/etiology , Dermatitis, Exfoliative/immunology , Female , Humans , Infant , Infant, Newborn , Interleukin-7 Receptor alpha Subunit/metabolism , Pedigree , Phenotype , Severe Combined Immunodeficiency/complications , Severe Combined Immunodeficiency/geneticsSubject(s)
Dermatitis, Exfoliative/immunology , Inflammation Mediators/metabolism , Interleukin-17/metabolism , Mitochondria/metabolism , Psoriasis/immunology , Skin/metabolism , Chronic Disease , Humans , Oxidative Phosphorylation , Paraffin Embedding , Receptors, Glucocorticoid/metabolism , Signal Transduction , Skin/pathology , TOR Serine-Threonine Kinases/metabolism , Tissue Array Analysis , UbiquitinationSubject(s)
Basophils/immunology , Dermatitis, Exfoliative/immunology , Skin Diseases, Vesiculobullous/immunology , Skin/immunology , Administration, Cutaneous , Adrenal Cortex Hormones/administration & dosage , Aged , Basophils/drug effects , Basophils/pathology , Basophils/radiation effects , Biomarkers/analysis , Biopsy , Combined Modality Therapy , Dermatitis, Exfoliative/pathology , Dermatitis, Exfoliative/therapy , Humans , Immunohistochemistry , Male , Pruritus/immunology , Pruritus/therapy , Skin/drug effects , Skin/pathology , Skin/radiation effects , Skin Diseases, Vesiculobullous/pathology , Skin Diseases, Vesiculobullous/therapy , Treatment Outcome , Ultraviolet Therapy , Up-RegulationSubject(s)
Dermatitis, Exfoliative/immunology , Epidermis/immunology , Interleukin-1/analysis , Psoriasis/immunology , Biomarkers/analysis , Biopsy , Dermatitis, Exfoliative/diagnosis , Epidermis/pathology , Humans , Immunohistochemistry , Predictive Value of Tests , Psoriasis/diagnosis , Retrospective Studies , Up-RegulationABSTRACT
IMPORTANCE: Psoriasis and atopic dermatitis (AD) are inflammatory diseases thought to be mediated by helper T-cell subtypes 1 and 2 (TH1 and TH2), respectively. Although psoriasis and AD show histopathologic differences during chronic disease, they are difficult to distinguish histologically during erythrodermic exacerbations. OBJECTIVE: To determine whether the immune phenotype of helper T cells can differentiate erythrodermic psoriasis and erythrodermic AD by studying skin biopsy specimens of patients with psoriasis and AD during erythrodermic and chronic disease phases. DESIGN, SETTING, AND PARTICIPANTS: We conducted a retrospective study using biopsy samples of psoriasis, AD, and erythroderma belonging to the surgical pathology files of the James Homer Wright Pathology Laboratories, Massachusetts General Hospital, and collected from January 1, 2004, through December 31, 2011. Samples were obtained from patients with chronic psoriasis (n = 20), chronic AD (n = 20), erythroderma subsequently diagnosed as psoriasis (n = 7), and erythroderma subsequently diagnosed as AD (n = 5). We evaluated immunohistochemical stains for CD3 and dual stains for CD4 and T-bet, GATA binding protein 3 (GATA3), signal transducer and activator of transcription 3 (STAT3), or basonuclin 2 (BNC2), which are transcription factors reported to be specific and mutually exclusive for TH1, TH2, TH17, and TH22 cells, respectively. Two investigators independently counted CD3+ cells and dual-labeled CD4+/T-bet+, CD4+/GATA3+, CD4+/STAT3+, and CD4+/BNC2+ cells in 5 consecutive high-power fields. MAIN OUTCOMES AND MEASURES: We evaluated the percentage of TH1, TH2, TH17, and TH22 cells in CD3+ T cells and the TH1:TH2 ratio in chronic psoriasis, chronic AD, erythrodermic psoriasis, and erythrodermic AD. RESULTS: We found a significant difference in the TH1:TH2 ratio between chronic psoriasis and chronic AD (0.26 and 0.09, respectively; P = .005). However, we detected no significant difference in the percentage of TH1 (6.5% and 4.8%), TH2 (55.2% and 64.6%), TH17 (14.7% and 30.4%), and TH22 (3.8% and 3.3%) cells of CD3+ T cells or in the TH1:TH2 ratio (0.16 and 0.07) within biopsy specimens from patients with erythrodermic psoriasis and AD, respectively. CONCLUSIONS AND RELEVANCE: This study confirms the TH1- and TH2-skewed phenotype of chronic psoriasis and chronic AD, respectively. However, the immune phenotype, as determined by immunohistochemical analysis, cannot discriminate between these inflammatory diseases in the erythrodermic phase. These findings advance our understanding of the pathophysiological characteristics of erythroderma, psoriasis, and AD and may influence therapeutic decisions.
Subject(s)
Dermatitis, Atopic/immunology , Dermatitis, Exfoliative/immunology , Psoriasis/immunology , T-Lymphocytes, Helper-Inducer/immunology , Adolescent , Adult , Aged , Aged, 80 and over , CD3 Complex/analysis , CD4 Antigens/analysis , DNA-Binding Proteins/analysis , Dermatitis, Atopic/pathology , Dermatitis, Exfoliative/pathology , Female , GATA3 Transcription Factor/analysis , Humans , Immunohistochemistry , Lymphocyte Count , Male , Middle Aged , Phenotype , Psoriasis/pathology , Retrospective Studies , STAT3 Transcription Factor/analysis , T-Box Domain Proteins/analysis , Th1 Cells/immunology , Th1 Cells/pathology , Th17 Cells/immunology , Th17 Cells/pathology , Th2 Cells/immunology , Th2 Cells/pathology , Young AdultABSTRACT
BACKGROUND: Some cases of senile erythroderma tend to be diagnosed as senile atopic dermatitis (AD) based on elevated levels of immunoglobulin E (IgE) and thymus and activation-regulated chemokine (TARC). However, there are few studies that describe the detailed characteristics of senile erythroderma and senile AD. OBJECTIVE: We examined the association of erythroderma with AD. METHODS: In this retrospective observational study, 68 patients over 65 years of age who presented with erythroderma at Osaka University Hospital were enrolled. Patient data were collected through medical records and descriptive statistics. RESULTS: 47% of the patients were classified as having idiopathic erythroderma and 53% as having secondary erythroderma. In both idiopathic and secondary senile erythroderma patients, serum IgE and TARC levels were elevated. 84% of idiopathic erythroderma patients fulfilled the Japanese Dermatological Associations criteria for AD; however, only 4 patients were finally definitely diagnosed with senile AD. CONCLUSION: Many senile erythroderma patients showed AD-like symptoms due to T helper 2 polarization.