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Anticorpos Monoclonais Humanizados , Quimioterapia Combinada , Lúpus Eritematoso Sistêmico , Rituximab , Humanos , Rituximab/administração & dosagem , Rituximab/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/complicações , Anticorpos Monoclonais Humanizados/uso terapêutico , Feminino , Quimioterapia Combinada/métodos , Resultado do Tratamento , Epidermólise Bolhosa/tratamento farmacológico , Epidermólise Bolhosa/complicações , Imunossupressores/uso terapêutico , Imunossupressores/administração & dosagem , AdultoRESUMO
Epidermolysis bullosa acquisita is a highly uncommon condition in the paediatric population. This article describes three children with this disease, different clinical presentation and management. It also reviews the most relevant articles on this topic.
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Epidermólise Bolhosa Adquirida , Epidermólise Bolhosa , Criança , Epidermólise Bolhosa Adquirida/diagnóstico , Epidermólise Bolhosa Adquirida/tratamento farmacológico , HumanosRESUMO
B cells emerge from the bone marrow as transitional (TS) B cells that differentiate through T1, T2, and T3 stages to become naive B cells. We have identified a bifurcation of human B cell maturation from the T1 stage forming IgMhi and IgMlo developmental trajectories. IgMhi T2 cells have higher expression of α4ß7 integrin and lower expression of IL-4 receptor (IL4R) compared with the IgMlo branch and are selectively recruited into gut-associated lymphoid tissue. IgMhi T2 cells also share transcriptomic features with marginal zone B cells (MZBs). Lineage progression from T1 cells to MZBs via an IgMhi trajectory is identified by pseudotime analysis of scRNA-sequencing data. Reduced frequency of IgMhi gut-homing T2 cells is observed in severe SLE and is associated with reduction of MZBs and their putative IgMhi precursors. The collapse of the gut-associated MZB maturational axis in severe SLE affirms its existence in health.
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Diferenciação Celular/imunologia , Trato Gastrointestinal/imunologia , Imunoglobulina M/metabolismo , Nefrite Lúpica/imunologia , Tecido Linfoide/imunologia , Células Precursoras de Linfócitos B/imunologia , Adulto , Idoso , Doadores de Sangue , Estudos de Casos e Controles , Linhagem da Célula/genética , Linhagem da Célula/imunologia , Células Cultivadas , Feminino , Humanos , Cadeias beta de Integrinas/metabolismo , Subunidade alfa de Receptor de Interleucina-4/metabolismo , Nefrite Lúpica/sangue , Nefrite Lúpica/patologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Transcriptoma , Adulto JovemRESUMO
PURPOSE: To assess whether a panel of serum pemphigoid autoantibody tests could be used to confirm an immunopathologic diagnosis of mucous membrane pemphigoid (MMP) in direct immunofluorescent negative (DIF-) MMP patients. DESIGN: Prospective cross-sectional study. PARTICIPANTS: Seventy-six patients with multisite MMP with 45 matched control participants. METHODS: Enzyme-linked immunosorbent assays (ELISAs) for BP180 and BP230 (MBL International), immunoglobulin A (IgA) A and immunoglobulin G indirect immunofluorescence (IIF) on human salt-split skin and the keratinocyte footprint assay for anti-laminin 332 antibodies. MAIN OUTCOME MEASURES: Sensitivity and specificity of autoantibody detection and significant differences for individual tests and test combinations for MMP involving different sites. RESULTS: All DIF- patients (24/73 [31.8%]) had either ocular-only disease or ocular involvement in multisite disease. Serum pemphigoid autoantibodies were detected in 29 of 76 MMP patients (38.2%) compared with 3 of 45 control participants (6.7%). Autoantibody reactivity detected by any 1 or more of the tests was present in 6 of 24 DIF- patients (25%) compared with 22 of 49 DIF positive (DIF+) patients (44.9%). Ocular-only MMP serum reactivity was not significantly different for any test or test combination compared with control participants, whereas DIF- multisite ocular MMP differed for 1 ELISA and 3 of 7 test combinations. By contrast, for DIF+ nonocular MMP patients, all the individual tests, apart from IgA IIF, and all test combinations were significantly different compared with those for control participants. For the entire MMP cohort, the sensitivity of all individual tests was low, having a maximum of 21.05% for BP180 reactivity but increasing to 38.16% for an optimal test combination. Disease activity was associated strongly with positive serologic findings. CONCLUSIONS: Pemphigoid serum autoantibody tests did not provide immunopathologic evidence of MMP in ocular-only MMP patients but showed limited value in DIF- multisite ocular MMP patients. The requirement for immunopathologic confirmation of MMP by autoantibody detection is inappropriate for DIF- ocular-only MMP patients, resulting in missed diagnoses, delayed therapy, and poor outcomes. Alternative diagnostic criteria for ocular-only MMP are required to exclude the other causes of scarring conjunctivitis until more sensitive and specific immunopathologic tests become available.
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Autoanticorpos/sangue , Autoantígenos/imunologia , Doenças da Túnica Conjuntiva/diagnóstico , Penfigoide Mucomembranoso Benigno/diagnóstico , Penfigoide Bolhoso/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças da Túnica Conjuntiva/imunologia , Estudos Transversais , Ensaio de Imunoadsorção Enzimática , Feminino , Técnica Direta de Fluorescência para Anticorpo , Humanos , Masculino , Pessoa de Meia-Idade , Penfigoide Mucomembranoso Benigno/imunologia , Estudos Prospectivos , Sensibilidade e Especificidade , Adulto JovemRESUMO
The histopathologic assessment of a scalp biopsy for alopecia relies largely on the quality of the specimen provided for evaluation. There are a number of different protocols in the literature which have been proposed over the years, but no consensus has yet been reached as to the appropriate number of biopsies to be taken, or to which sectioning technique is the gold standard for achieving the best diagnostic yield. We herein review the pros and cons of the various protocols and share the experience with our St John's protocol.
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Alopecia/patologia , Patologia Clínica/métodos , Feminino , Humanos , Masculino , Patologia Clínica/normas , Patologia Clínica/tendênciasAssuntos
Esclerose Múltipla/imunologia , Penfigoide Bolhoso/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/sangue , Autoantígenos/sangue , Membrana Basal/imunologia , Proteínas de Transporte , Proteínas do Citoesqueleto , Distonina , Feminino , Humanos , Masculino , Glicoproteínas de Membrana/sangue , Pessoa de Meia-Idade , Esclerose Múltipla/complicações , Proteínas do Tecido Nervoso , Colágenos não Fibrilares/sangue , Penfigoide Bolhoso/complicações , Colágeno Tipo XVIIRESUMO
Pyoderma gangrenosum (PG) is an important disease with significant complications. The objectives of this study were to determine incidence and mortality of PG and strength of reported associations. A retrospective cohort study was completed using computerized medical records from the General Practice Research Database, a large representative UK database. Patients with PG and three groups of age-, sex-, and practice-matched controls--general population, rheumatoid arthritis (RA), and inflammatory bowel disease (IBD) controls--were included in the study. Incidence and mortality were determined and validation undertaken to inform diagnostic accuracy. In all there were 313 people with the median age of 59 (interquartile range 41-72) years, and of them 185 (59%) were female. The adjusted incidence rate standardized to European standard population was 0.63 (95% confidence interval (CI) 0.57-0.71) per 100,000 person-years. The risk of death was three times higher than that for general controls (adjusted hazard ratio=3.03, 95% CI 1.84-4.73, P<0.001), 72% higher than that for IBD controls (adjusted hazard ratio=1.72, 95% CI 1.17-2.59, P=0.013), with a borderline increase compared with RA controls (adjusted hazard ratio=1.55, 95% CI 1.01-2.37, P=0.045). Disease associations were present in 110 (33%) participants: IBD, n=67 (20.2%); RA, n=39 (11.8%); and hematological disorders, n=13 (3.9%). To our knowledge, there are no previous population-based studies of the epidemiology of PG, an important disease with significantly increased mortality.
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Pioderma Gangrenoso/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/epidemiologia , Criança , Bases de Dados Factuais/estatística & dados numéricos , Feminino , Doenças Hematológicas/epidemiologia , Humanos , Incidência , Doenças Inflamatórias Intestinais/epidemiologia , Masculino , Pessoa de Meia-Idade , Pioderma Gangrenoso/mortalidade , Estudos Retrospectivos , Risco , Reino Unido/epidemiologia , Adulto JovemRESUMO
Previous small studies and case reports have suggested that neurological disorders may be associated with bullous pemphigoid (BP). The objective of this study was to assess BP risk in patients with neurological diseases. Computerized medical records from the Health Improvement Network, a large population-based UK general practice database, were used to conduct a matched case-control analysis. Conditional logistic regression was used to calculate odds ratios for specified neurological disorders. Comparing cases (n=868) to controls (n=3,453), stroke was seen in 8 vs. 5%, odds ratio (OR) 1.8 (1.3-2.5); dementia in 7 vs. 2%, OR 3.4 (2.4-4.8); Parkinson's disease in 3 vs. 1%, OR 3.0 (1.8-5.0); epilepsy in 2 vs. 1%, OR 1.7 (1.0-3.0); and multiple sclerosis in 1 vs 0.1% (OR 10.7 (2.8-40.2). Estimates were not altered greatly when diagnoses up to 3 years before BP were excluded, except the association with epilepsy was no longer significant. Significant associations were only observed where neurological disease was diagnosed before the onset of pemphigoid. Study findings, except the association with epilepsy, were robust to sensitivity analysis. Strong associations were observed between specific neurological diseases and the later development of BP, supporting possible causal associations. Mechanisms for disease occurrence based on these findings include immobility or age-related autoimmunity.
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Doenças do Sistema Nervoso/complicações , Penfigoide Bolhoso/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Demência/complicações , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/complicações , Fatores de Risco , Acidente Vascular Cerebral/complicações , Reino Unido/epidemiologiaRESUMO
OBJECTIVE: To investigate the relationship between bullous pemphigoid (BP) and neurologic disease. DESIGN: Case-control study. SETTING: Tertiary care center for immunobullous diseases and skin tumor clinics at a university hospital in Oxford, England. PARTICIPANTS: Ninety consecutive patients with BP and 141 controls. MAIN OUTCOME MEASURES: Age-adjusted prevalence of neurologic disease in patients and controls. Time interval between the diagnosis of neurologic disease and BP and type of associated neurologic disease. RESULTS: At least 1 neurologic diagnosis was present in 42 patients (46%) compared with 16 controls (11%). Patients had significantly increased odds for neurologic diseases regardless of age and sex (crude odds ratio [OR], 6.8; 95% confidence interval [CI], 3.5-13.3; adjusted OR, 6.2; 95% CI, 3.1-12.4). Four major neurologic diagnoses were observed (cerebrovascular disease, dementia, Parkinson disease, and epilepsy), with statistical significance for cerebrovascular disease and dementia (crude OR for cerebrovascular disease, 6.3; 95% CI, 2.8-14.2; adjusted OR, 6.0; 95% CI, 2.6-13.6; crude OR for dementia, 10.7; 95% CI, 2.3-49.0; adjusted OR, 7.9; 95% CI, 1.7-37.3). When accurate data on time of onset of neurologic disease were present (36 of 42 patients [85%]), BP followed neurologic disease in most patients (26 of 36 patients [72%]), with a median interval of 5.5 years. CONCLUSION: Bullous pemphigoid is significantly associated with cerebrovascular disease and dementia.
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Transtornos Cerebrovasculares/complicações , Demência/complicações , Penfigoide Bolhoso/complicações , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Epilepsia/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/complicaçõesRESUMO
Cutaneous collagenous vasculopathy is characterized by generalized cutaneous telangiectasia and unique microscopic and ultrastructural vascular changes, consisting of marked collagen deposition within the vascular walls of the post-capillary venules in the superficial dermis. There are only 4 previous cases described in the medical literature, all in males, mostly middle-aged. We have recently seen two female patients with clinical and histopathologic features diagnostic of cutaneous collagenous vasculopathy, indicating that it is not restricted to males. As cutaneous collagenous vasculopathy can be clinically indistinguishable from generalized essential telangiectasia, and histopathologic studies are rarely performed for this condition, it is likely that cutaneous collagenous vasculopathy frequently passes unrecognized, but it may be more common than previously thought.
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Derme/irrigação sanguínea , Derme/patologia , Dermatopatias Vasculares/patologia , Telangiectasia/patologia , Idoso , Biópsia , Feminino , Humanos , Pessoa de Meia-Idade , Fatores SexuaisRESUMO
Epidermolysis bullosa (EB) is a group of autosomal dominant and recessive blistering skin diseases in which pathogenic mutations have been reported in 13 different genes encoding structural proteins involved in keratinocyte integrity, as well as cell-matrix or cell-cell adhesion. We now report an inherited skin fragility disorder with a homozygous nonsense mutation in the dystonin gene (DST) that encodes the coiled-coil domain of the epithelial isoform of bullous pemphigoid antigen 1, BPAG1-e (also known as BP230). The mutation, p.Gln1124X, leads to the loss of hemidesmosomal inner plaques and a complete absence of skin immunostaining for BPAG1-e, as well as reduced labeling for plectin, the beta4 integrin subunit, and for type XVII collagen. The 38-year-old affected individual has lifelong generalized trauma-induced spontaneous blisters and erosions, particularly around the ankles. In addition, he experiences episodic numbness in his limbs, which started at the age of 37 years. These neurological symptoms may also be due to DST gene mutation, although he has a concomitant diagnosis of CADASIL (cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy), a cerebral small-vessel arteriopathy, which thus complicates the genotype-phenotype interpretation. With regard to skin blistering, the clinicopathological findings expand the molecular basis of EB by identifying BPAG1-e pathology in a new form of autosomal recessive EB simplex.
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Proteínas de Transporte/genética , Códon sem Sentido/genética , Proteínas do Citoesqueleto/genética , Epidermólise Bolhosa Simples/diagnóstico , Epidermólise Bolhosa Simples/genética , Homozigoto , Proteínas do Tecido Nervoso/genética , Adulto , Vesícula/metabolismo , Proteínas de Transporte/metabolismo , Colágeno Tipo VII/metabolismo , Proteínas do Citoesqueleto/metabolismo , Distonina , Epidermólise Bolhosa Simples/metabolismo , Hemidesmossomos/metabolismo , Humanos , Integrina beta4/metabolismo , Masculino , Proteínas do Tecido Nervoso/metabolismo , Plectina/metabolismo , Isoformas de Proteínas , Pele/metabolismoRESUMO
Rash has been reported in up to 76% of patients with lung cancer who have received the epidermal growth factor receptor inhibitor (EGFRI) erlotinib. It has also been observed in patients treated with other agents that have a similar mode of action. Erlotinib-associated skin toxicity typically presents as a papulopustular, follicular, acneiform rash. In most cases, it is mild, transient, and well tolerated, but in 8%-12% of patients, it may be sufficiently severe and persistent to necessitate intervention. Increasingly strong data suggest that the incidence and severity of skin toxicity may be predictive of response and survival in patients treated with erlotinib. This has prompted some clinicians to consider "treatment to rash" (i.e., increasing the dosage until a rash appears) as a rational management strategy. In 2007, an international consensus was developed for the management of EGFRI-associated skin toxicity. Subsequently, a multidisciplinary group (the U.K. Erlotinib Skin Toxicity Management Consensus Group) met to validate and modify the international recommendations for U.K. use, with specific reference to erlotinib. Although many aspects of the international consensus were approved by the group as being relevant for the U.K., certain parts were modified. The resulting expert opinion is a practical and workable version of the international proposal that considers all applicable national issues regarding the management of erlotinib-associated skin toxicity.
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Toxidermias/terapia , Inibidores de Proteínas Quinases/efeitos adversos , Quinazolinas/efeitos adversos , Toxidermias/etiologia , Cloridrato de Erlotinib , Humanos , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/uso terapêutico , Taxa de Sobrevida , Reino UnidoRESUMO
Langerhans cells (LC) are the dendritic APC population of the epidermis, where they reside for long periods and are self-replicating. The molecular signals underlying these characteristics are unknown. The TNF superfamily member receptor activator of NF-kappaB ligand (RANKL, TNFSF11) has been shown to sustain viability of blood dendritic cells in addition to its role in promoting proliferation and differentiation of several cell types, notably osteoclasts. In this study, we have studied expression of the RANKL system in skin and have defined a key role for this molecule in LC homeostasis. In vitro and in vivo, human KC expressed RANKL and epidermal LC expressed cell surface RANK. In vitro, RANKL sustained CD34(+) progenitor-derived LC viability following 72-h cultures in cytokine-free medium (79.5 +/- 1% vs 55.2 +/- 5.7% live cells, respectively; n = 4; p < 0.05). In vivo, RANKL-deficient mice displayed a marked reduction in epidermal LC density (507.1 +/- 77.2 vs 873.6 +/- 41.6 LC per mm(2); n = 9; p < 0.05) and their proliferation was impaired without a detectable effect on apoptosis. These data indicate a key role for the RANKL system in the regulation of LC survival within the skin and suggest a regulatory role for KC in the maintenance of epidermal LC homeostasis.
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Epiderme/imunologia , Queratinócitos/imunologia , Células de Langerhans/imunologia , NF-kappa B/metabolismo , Ligante RANK/metabolismo , Contagem de Células , Proliferação de Células , Sobrevivência Celular , Epiderme/metabolismo , Humanos , Queratinócitos/metabolismo , Células de Langerhans/citologia , Células de Langerhans/metabolismo , NF-kappa B/imunologia , Ligante RANK/imunologia , Receptor Ativador de Fator Nuclear kappa-B/imunologia , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Transdução de SinaisRESUMO
Langerhans cells (LC) migrate rapidly from epidermis to lymph node following epicutaneous application of antigen. In this study, we have explored the role of IL-18, a cytokine with structural similarities to IL-1 beta, in murine LC migration and contact hypersensitivity (CHS), which to oxazolone (OX) and 2-4,dinitrofluorobenzene (DNFB) was suppressed significantly in IL-18 knockout (IL-18-/-) mice and could be rescued by local intradermal administration of IL-18 prior to sensitization, suggesting that the defect in these mice was in the afferent phase of CHS. To determine the effect of IL-18 on LC migration, mice were treated topically with OX or DNFB, and remaining LC numbers were assessed. A significant decline in remaining epidermal LC occurred in wild-type (WT) mice but did not occur in IL-18-/- mice. Sodium lauryl sulfate, a nonantigenic LC migratory stimulus, induced equivalent LC migration in IL-18-/- and WT mice. In IL-18-/- mice, IL-1 beta and TNF-alpha were equally able to mobilize LC from epidermis, indicating that migration in response to these cytokines is not dependent on IL-18 and suggesting that IL-18 acts upstream of these cytokines in the initiation of antigen-induced LC migration. Moreover, IL-1 beta but not IL-18 was able to rescue the defective CHS response observed in caspase-1-/- mice, which have no functional IL-1 beta or IL-18. These data indicate that IL-18 is a key proximal mediator of LC migration and CHS, acting upstream of IL-1 beta and TNF-alpha, and may play a central role in regulation of cutaneous immune responses.
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Dermatite Alérgica de Contato/fisiopatologia , Epiderme/patologia , Interleucina-18/fisiologia , Células de Langerhans/fisiologia , Animais , Caspase 1/deficiência , Caspase 1/genética , Caspase 1/fisiologia , Contagem de Células , Movimento Celular/fisiologia , Dermatite Alérgica de Contato/imunologia , Dinitrofluorbenzeno/toxicidade , Epiderme/imunologia , Interleucina-18/deficiência , Interleucina-18/genética , Interleucina-1beta/fisiologia , Camundongos , Camundongos Knockout , Oxazolona/toxicidade , Proteínas Recombinantes/farmacologia , Dodecilsulfato de Sódio/farmacologia , Fator de Necrose Tumoral alfa/fisiologiaRESUMO
Psoriasis has been considered an autoimmune, T cell-mediated disorder in which adaptive immune responses predominate over those of non-antigen-specific innate immunity. To test this hypothesis, we profiled the transcriptome of psoriatic tissue and compared the data with that from cultured human keratinocytes exposed to the proinflammatory cytokine interleukin (IL)-1alpha and the Th1 cytokine interferon-gamma. When compared with patient-matched, nonlesional skin biopsies, psoriatic samples exhibited regulation of 90 transcripts including several members of the epidermal differentiation complex, molecules with antimicrobial activity, and hyperproliferation-associated keratins. Stimulation of keratinocytes with interferon-gamma resulted in regulation of 252 transcripts, with particularly strong expression of the CXCR3-binding ligands CXCL9, -10, and -11 and class II major histocompatibility complex genes, primarily those of the HLA-DR and -DP families. In contrast, the transcriptome resulting from exposure of keratinocytes to IL-1alpha elicited differences in just 19 transcripts, particularly genes within the epidermal differentiation complex and antimicrobial molecules, including PI3 and DEFB4. Major differences between the two keratinocyte transcriptomes were exhibited with only five induced IL-1alpha transcripts also regulated in the interferon-gamma set. Unexpectedly, there was a high correlation between psoriatic lesional tissue and the IL-1alpha transcriptome. These findings suggest that the inflammatory milieu in the epidermal microenvironment in psoriasis is more likely dependent on evolutionarily ancient cytokines such as IL-1, rather than those of the adaptive immune response.
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Imunidade Inata/genética , Interferon gama/farmacologia , Interleucina-1/farmacologia , Queratinócitos/imunologia , Psoríase/imunologia , Transcrição Gênica , Células Cultivadas , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Queratinócitos/efeitos dos fármacos , Hibridização de Ácido Nucleico , Análise de Sequência com Séries de OligonucleotídeosRESUMO
The pro-inflammatory cytokine interleukin-1 (IL-1) is constitutively expressed by keratinocytes in vivo and has been shown to be expressed in psoriatic lesional skin. To determine what role the IL-1 system might contribute to the inflammatory process in psoriasis, semi-quantitative RT-PCR and cRNA microarray studies were performed on biopsies excised from lesional and non-lesional skin. Whilst IL-1alpha mRNA levels showed a reduction in lesional skin in a subset of patients, steady state IL-1beta mRNA was increased markedly. Neither of the two IL-1 receptor transcripts nor total IL-1 receptor antagonist exhibited major changes within the lesion. Expression of the IL-1-induced chemokine IL-8 was only observed in lesional epidermis. Functional genomic experiments comparing transcriptome profiles derived from psoriatic lesional skin and IL-1 stimulated keratinocytes demonstrated a striking level of overlap. Taken together, these data suggest that IL-1 is likely to be an important mediator in the initiation and maintenance of psoriatic plaques and may represent an attractive therapeutic target.
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Mediadores da Inflamação/metabolismo , Interleucina-1/metabolismo , Psoríase/metabolismo , Psoríase/patologia , Pele/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Células Cultivadas , Células Epidérmicas , Feminino , Humanos , Técnicas Imunoenzimáticas , Mediadores da Inflamação/imunologia , Interleucina-1/genética , Interleucina-1/imunologia , Interleucina-8/genética , Interleucina-8/metabolismo , Masculino , Pessoa de Meia-Idade , Psoríase/imunologia , RNA Mensageiro , Pele/metabolismoRESUMO
Interleukin-1alpha (IL-1alpha) is a potent proinflammatory cytokine constitutively expressed by keratinocytes, which also synthesize a specific inhibitor of IL-1 activity, intracellular IL-1 receptor antagonist (IL-1ra). Although homeostatic regulation of the IL-1 system in keratinocytes has long been suspected, there is currently little evidence for this. To explore this issue, the PAM212 murine keratinocyte cell line was exposed to increasing concentrations of either IL-1alpha or IL-1ra and the opposing ligand was assessed by ELISA. Release of IL-1ra was induced following stimulation by murine IL-1alpha in a concentration-dependent manner and, conversely, IL-1ra stimulation increased IL-1alpha release. To determine whether a similar homeostatic circuit operates in vivo, epidermis from transgenic mice in which overexpression of IL-1alpha or IL-1ra was targeted to keratinocytes was analyzed. Epidermal sheets derived from IL-1alpha transgenic mice released eight times more IL-1ra than those from wild-type mice following ex vivo culture and similarly, IL-1alpha release was increased 3-4-fold in epidermal sheets derived from IL-1ra transgenic epidermis, Use of specific neutralizing antibodies against type I and type II IL-1 receptors indicated that the counter-regulation mechanism is mediated extracellularly through the type I IL-1 receptor alone. Taken together, these observations provide the first demonstration of mutual counter-regulation of IL-1 receptor ligands in keratinocytes.