RESUMO
Psoriasis is a chronic inflammatory skin condition. Repeated epicutaneous application of Aldara® (imiquimod) cream results in psoriasiform dermatitis in mice. The Aldara®-induced psoriasiform dermatitis (AIPD) mouse model has been used to examine the pathogenesis of psoriasis. Here, we used a forward genetics approach in which we compared AIPD that developed in 13 different inbred mouse strains to identify genes and pathways that modulated disease severity. Among our primary results, we found that the severity of AIPD differed substantially between different strains of inbred mice and that these variations were associated with polymorphisms in Itga11. The Itga11 gene encodes the integrin α11 subunit that heterodimerizes with the integrin ß1 subunit to form integrin α11ß1. Less information is available about the function of ITGA11 in skin inflammation; however, a role in the regulation of cutaneous wound healing, specifically the development of dermal fibrosis, has been described. Experiments performed with Itga11 gene-deleted (Itga11-/- ) mice revealed that the integrin α11 subunit contributes substantially to the clinical phenotype as well as the histopathological and molecular findings associated with skin inflammation characteristic of AIPD. Although the skin transcriptomes of Itga11-/- and WT mice do not differ from one another under physiological conditions, distinct transcriptomes emerge in these strains in response to the induction of AIPD. Most of the differentially expressed genes contributed to extracellular matrix organization, immune system, and metabolism of lipids pathways. Consistent with these findings, we detected a reduced number of fibroblasts and inflammatory cells, including macrophages, T cells, and tissue-resident memory T cells in skin samples from Itga11-/- mice in response to AIPD induction. Collectively, our results reveal that Itga11 plays a critical role in promoting skin inflammation in AIPD and thus might be targeted for the development of novel therapeutics for psoriasiform skin conditions. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Assuntos
Dermatite , Cadeias alfa de Integrinas , Psoríase , Animais , Camundongos , Dermatite/genética , Dermatite/patologia , Modelos Animais de Doenças , Imiquimode/efeitos adversos , Inflamação/patologia , Cadeias alfa de Integrinas/genética , Cadeias alfa de Integrinas/metabolismo , Psoríase/induzido quimicamente , Psoríase/genética , Pele/patologiaRESUMO
Transposons are parasitic genetic elements that frequently hijack vital cellular processes of their host. HMGXB4 is a known Wnt signaling-regulating HMG-box protein, previously identified as a host-encoded factor of Sleeping Beauty (SB) transposition. Here, we show that HMGXB4 is predominantly maternally expressed, and marks both germinal progenitor and somatic stem cells. SB piggybacks HMGXB4 to activate transposase expression and target transposition to germinal stem cells, thereby potentiating heritable transposon insertions. The HMGXB4 promoter is located within an active chromatin domain, offering multiple looping possibilities with neighboring genomic regions. HMGXB4 is activated by ERK2/MAPK1, ELK1 transcription factors, coordinating pluripotency and self-renewal pathways, but suppressed by the KRAB-ZNF/TRIM28 epigenetic repression machinery, also known to regulate transposable elements. At the post-translational level, SUMOylation regulates HMGXB4, which modulates binding affinity to its protein interaction partners and controls its transcriptional activator function via nucleolar compartmentalization. When expressed, HMGXB4 can participate in nuclear-remodeling protein complexes and transactivate target gene expression in vertebrates. Our study highlights HMGXB4 as an evolutionarily conserved host-encoded factor that assists Tc1/Mariner transposons to target the germline, which was necessary for their fixation and may explain their abundance in vertebrate genomes.
Assuntos
Cromossomos , Elementos de DNA Transponíveis , Animais , Elementos de DNA Transponíveis/genética , Células-Tronco , Proteína HMGB2/metabolismoRESUMO
BACKGROUND: Pemphigus is a group of bullous diseases characterized by acantholysis and skin blisters. As for other autoimmune diseases, the strongest genetic associations found so far for pemphigus foliaceus (PF) and vulgaris (PV) are with alleles of HLA genes. However, apart from protein-coding genes, the MHC region includes a set of poorly explored long non-coding RNA (lncRNA) genes, the HLA complex group (HCG). OBJECTIVES: To investigate if HCG lncRNA alleles are associated with pemphigus susceptibility. METHODS AND RESULTS: We analyzed SNPs in 13 HCG lncRNA genes, both in PV (Germany: 241 patients; 1,188 controls) and endemic PF (Brazil: 227 patients; 194 controls), applying multivariate logistic regression. We found 55 associations with PV (pcorr < 0.01) and nine with endemic PF (pcorr < 0.05), the majority located in TSBP1-AS1 (which includes HCG23) and HCG27 lncRNA genes, independently of HLA alleles previously associated with pemphigus. The association of TSBP1-AS1 rs3129949*A allele was further replicated in sporadic PF (p = 0.027, OR = 0.054; 75 patients and 150 controls, all from Germany). Next, we evaluated the expression levels of TSBP1-AS1, TSBP1, HCG23, and HCG27 in blood mononuclear cells of Brazilian patients and controls. HCG27 was upregulated in endemic PF (p = 0.035, log2 FC = 1.3), while TSBP1-AS1 was downregulated in PV (p = 0.029, log2 FC = -1.29). The same expression patterns were also seen in cultured keratinocytes stimulated with IgG antibodies from patients and controls from Germany. TSBP1 mRNA levels were also decreased in endemic PF blood cells (p = 0.042, log2 FC = -2.14). TSBP1-AS1 and HCG27 were also observed downregulated in CD19+ cells of endemic PF (p < 0.01, log2 FC = -0.226 and -0.46 respectively). CONCLUSIONS: HCG lncRNAs are associated with susceptibility to pemphigus, being TSBP1-AS1 and HCG27 also differentially expressed in distinct cell populations. These results suggest a role for HCG lncRNAs in pemphigus autoimmunity.
Assuntos
Antígenos HLA/genética , Pênfigo/genética , Pênfigo/imunologia , RNA Longo não Codificante/fisiologia , Humanos , Queratinócitos/imunologia , Polimorfismo Genético , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Lichen sclerosus et atrophicus (LSA) is a chronic inflammatory skin disease. It is frequently diagnosed following circumcision. Diabetes mellitus (DM) is a known risk factor in men. Malignant pathology is more common in patients with LSA. Data on LSA in men are very limited. OBJECTIVE: This study investigated the incidence of LSA in men who had undergone circumcision. Risk factors and likelihood of malignancy were captured. MATERIALS AND METHODS: Data of 215 patients were retrospectively analyzed. As potential risk factors, age, body mass index (BMI), DM, coronary heart disease (CHD) and arterial hypertension were identified. Data were analyzed and displayed graphically as spike histograms. Logistic regression was applied. Age and BMI were transformed using cubic spline function. RESULTS: Mean age of patients was 37 years (±â¯22 years). Mean BMI was 26.4. In all, 24% of the patients had a BMI >â¯30. Of the patients, 11% had DM, 5.1% had CHD, and 19% had arterial hypertension. Pathology revealed LSA in 47% of patients. Malignant disease was apparent in 3.3% of patients (2.7% without concomitant LSA, 4% with concomitant LSA). Age (55 vs 20 years, odds ratio [OR]: 3.210 [1.421, 7.251]) was a significant risk factor for LSA. BMI (30 vs 22â¯kg/m2, OR 1.059 [0.614, 1.828]) and DM (OR: 0.42 [0.148, 1.192]) elevated the risk for LSA. CONCLUSION: We saw high rates of LSA in patients had undergone circumcision. Higher age represents a significant risk factor. In 3.3%, final pathology revealed squamous cell carcinoma of the penis. Therefore, pathologic work-up of circumcision specimen is mandatory.
Assuntos
Carcinoma de Células Escamosas , Circuncisão Masculina , Líquen Escleroso e Atrófico , Neoplasias Penianas , Fimose , Humanos , Masculino , Líquen Escleroso e Atrófico/epidemiologia , Líquen Escleroso e Atrófico/patologia , Fatores de Risco , Neoplasias Penianas/epidemiologia , Neoplasias Penianas/patologia , Fimose/epidemiologia , Fimose/patologia , Fimose/etiologia , Adulto , Incidência , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/patologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem , Idoso , Comorbidade , AdolescenteRESUMO
Approximately 5% of the world-wide population is affected by autoimmune diseases. Overall, autoimmune diseases are still difficult to treat, impose a high burden on patients, and have a significant economic impact. Like other complex diseases, e.g., cancer, autoimmune diseases develop over several years. Decisive steps in the development of autoimmune diseases are (i) the development of autoantigen-specific lymphocytes and (often) autoantibodies and (ii) potentially clinical disease manifestation at a later stage. However, not all healthy individuals with autoantibodies develop disease manifestations. Identifying autoantibody-positive healthy individuals and monitoring and inhibiting their switch to inflammatory autoimmune disease conditions are currently in their infancy. The switch from harmless to inflammatory autoantigen-specific T and B-cell and autoantibody responses seems to be the hallmark for the decisive factor in inflammatory autoimmune disease conditions. Accordingly, biomarkers allowing us to predict this progression would have a significant impact. Several factors, such as genetics and the environment, especially diet, smoking, exposure to pollutants, infections, stress, and shift work, might influence the progression from harmless to inflammatory autoimmune conditions. To inspire research directed at defining and ultimately targeting autoimmune predisease, here, we review published evidence underlying the progression from health to autoimmune predisease and ultimately to clinically manifest inflammatory autoimmune disease, addressing the following 3 questions: (i) what is the current status, (ii) what is missing, (iii) and what are the future perspectives for defining and modulating autoimmune predisease.
Assuntos
Doenças Autoimunes , Autoimunidade , Humanos , Doenças Autoimunes/etiologia , Autoanticorpos , Autoantígenos , LinfócitosRESUMO
A crucial factor for the development of inflammatory autoimmune diseases is the occurrence of antibodies directed against self-tissues and structures, which leads to damage and inflammation. While little is known about the cause of the development of mis-directed, disease-specific T and B cells and resulting IgG autoantibody responses, there is increasing evidence that their induction can occur years before disease symptoms appear. However, a certain proportion of healthy individuals express specific IgG autoantibodies without disease symptoms and not all subjects who generate autoantibodies may develop disease symptoms. Thus, the development of inflammatory autoimmune diseases seems to involve two steps. Increasing evidence suggests that harmless self-directed T and B cell and resulting IgG autoantibody responses in the pre-autoimmune disease stage might switch to more inflammatory T and B cell and IgG autoantibody responses that trigger the inflammatory autoimmune disease stage. Here, we summarize findings on the transition from the pre-disease to the disease stage and vice versa, e.g. by pregnancy and treatment, with a focus on low-/anti-inflammatory versus pro-inflammatory IgG autoantibody responses, including IgG subclass and Fc glycosylation features. Characterization of biomarkers that identify the transition from the pre-disease to the disease stage might facilitate recognition of the ideal time point of treatment initiation and the development of therapeutic strategies for re-directing inflammatory autoimmune conditions.
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Doenças Autoimunes , Imunoglobulina G , Humanos , Gravidez , Feminino , Glicosilação , Autoanticorpos , Linfócitos B/metabolismoRESUMO
IMPORTANCE: Immunoglobulin A (IgA) epidermolysis bullosa acquisita (EBA) is an autoimmune skin blistering disease with IgA autoantibodies directed against type VII collagen. There is debate whether it should be considered part of the clinical spectrum of linear IgA bullous dermatosis (LABD) or a separate disease entity. OBJECTIVE: This cohort study aimed to define the clinical features and treatment responses of IgA EBA and anti-BP180-driven LABD, and to compare the prevalences of IgA EBA anti-BP180 LABD and classic IgG-mediated EBA in an autoimmune diagnostic laboratory database. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study and case series study included demographic, immunopathologic, and serologic data from 300 patients diagnosed with IgA EBA, IgG EBA, or LABD. Furthermore, clinical features and treatment responses of IgA EBA were analyzed in a case series including 4 patients with IgA EBA. All patients from the database of the autoimmune diagnostic laboratory at the Department of Dermatology, University of Lübeck, Germany, who were diagnosed with IgA EBA, LABD, or IgG EBA between October 2010 and July 2019 were included. Four patients diagnosed with IgA EBA between October 2015 and January 2018 are described in detail. MAIN OUTCOMES AND MEASURES: The clinical course of IgA EBA was observed before and during different treatments. RESULTS: The database search yielded 21 cases of IgA EBA (12 females [57%]/9 males [43%]), 222 cases of LABD (111 females [51%]/106 males [49]), and 57 cases of IgG EBA (29 females [50%]/28 males [48%]). The median (range) age of each cohort was 64 (4-81) years for IgA EBA, 56 (3-92) years for IgG EBA, and significantly older compared with IgG EBA (P = .002) for those with LAPD (median [range], 70 [1-94] years). The patients with IgA EBA exhibited heterogeneous clinical presentations that significantly differed from those of anti-BP180 LABD. All 4 patients with IgA EBA described in detail were first treated with dapsone, but only 1 responded to this treatment. The others required treatment with high-dose dexamethasone, rituximab, and/or intravenous immunoglobulins to achieve partial clinical remission. CONCLUSIONS AND RELEVANCE: Overall, the findings of this cohort study and small case series suggest that IgA EBA may be more common than expected and may require more intensive systemic treatment than LABD, suggesting it should be considered a separate disease entity.
Assuntos
Epidermólise Bolhosa Adquirida , Dermatose Linear Bolhosa por IgA , Idoso , Autoanticorpos , Estudos de Coortes , Epidermólise Bolhosa Adquirida/diagnóstico , Epidermólise Bolhosa Adquirida/tratamento farmacológico , Feminino , Humanos , Imunoglobulina A , Imunoglobulinas Intravenosas/uso terapêutico , Dermatose Linear Bolhosa por IgA/diagnóstico , Dermatose Linear Bolhosa por IgA/tratamento farmacológico , Masculino , Estudos RetrospectivosRESUMO
Epidermolysis bullosa acquisita and mucous membrane pemphigoid are autoimmune blistering diseases characterized by mucocutaneous blisters elicited by an autoantibody-mediated immune response against specific proteins of the epidermal basement membrane. The antibiotic dapsone is frequently used to treat both diseases, but its therapeutic effectiveness is uncertain, and its mode of action in these diseases is largely unknown. We evaluated the effect of dapsone in antibody transfer mouse models of epidermolysis bullosa acquisita and mucous membrane pemphigoid, which do not allow the drawing of conclusions on clinical treatment regimens but can be instrumental to partially uncover the mode(s) of action of dapsone in these diseases. Dapsone significantly mitigated inflammation in both models, reducing the recruitment of neutrophils into the skin and disrupting their release of leukotriene B4 (LTB4) and ROS in response to immune complexes. LTB4 has been implicated in numerous diseases, but effective LTB4 inhibitors for clinical use are not available. Our findings indicate that the mode of action of dapsone in these models may be based on the inhibition of LTB4 and ROS release from neutrophils. Moreover, they encourage testing the use of dapsone as an effective, albeit nonspecific, inhibitor of LTB4 biosynthesis in other LTB4-driven diseases.
Assuntos
Dapsona/uso terapêutico , Penfigoide Bolhoso/tratamento farmacológico , Animais , Moléculas de Adesão Celular/imunologia , Dapsona/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Leucotrieno B4/biossíntese , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Penfigoide Bolhoso/imunologia , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo , CalininaRESUMO
Data on molecular characterization of coagulase-negative staphylococci causing neonatal sepsis in low-income countries are highly limited. This report highlights the isolation of three Staphylococcus epidermidis non-genome assembly strains (NGASs) from blood samples from neonates with unknown transmission sources. Pathogenic factors and sources of transmission of these strains warrant further investigation.
RESUMO
Epidermolysis bullosa acquisita is an autoimmune skin disease characterized by subepidermal blisters. The pathogenesis is mediated by deposits of autoantibodies directed against type VII collagen in the skin, but the sequence of events regulating the localization of skin blisters is not fully understood. In this study, using the immunization-induced mouse model of epidermolysis bullosa acquisita, we demonstrate that epidermal disruption induces not only an infiltration of CD4+ T cells but also a T helper type 1 phenotype as it has been described for delayed-type hypersensitivity reactions. This T helper type 1 reaction was not found when different antigens were applied. Deep T-cell receptor ß profiling revealed shifts in the V/J gene usage only in epidermolysis bullosa acquisita, suggesting an infiltration of autoantigen-specific T cells. To target these autoantigen-specific T cells, we established an approach with which skin inflammation could be prevented without impairing the functionality of autoantibodies. We conclude that T-cell involvement in skin blistering diseases such as epidermolysis bullosa acquisita relates not only to T-cell help for B cells that produce pathogenic autoantibodies but also to autoreactive T helper type 1 effector cells that migrate into injured skin sites, exacerbate inflammation through production of inflammatory cytokines such as IFNγ, and prevent wound healing.
Assuntos
Autoanticorpos/imunologia , Epiderme/patologia , Epidermólise Bolhosa Adquirida/imunologia , Células Th1/imunologia , Animais , Autoanticorpos/sangue , Autoanticorpos/metabolismo , Movimento Celular/imunologia , Colágeno Tipo VII/administração & dosagem , Colágeno Tipo VII/imunologia , Modelos Animais de Doenças , Epiderme/imunologia , Epidermólise Bolhosa Adquirida/sangue , Epidermólise Bolhosa Adquirida/patologia , Feminino , Humanos , Interferon gama/metabolismo , Camundongos , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/imunologia , Células Th1/metabolismo , Cicatrização/imunologiaRESUMO
BACKGROUND: In contrast to psychological interventions the usefulness of acupuncture as an adjuvant therapy in rheumatoid arthritis (RA) has not yet been demonstrated. OBJECTIVE: The efficacy of auricular electroacupuncture (EA) was directly compared with autogenic training (AT). METHODS: Patients with RA (n = 44) were randomized into EA or AT groups. EA and lessons in AT were performed once weekly for 6 weeks. Primary outcome measures were the mean weekly pain intensity and the disease activity score 28 (DAS 28); secondary outcome measures were the use of pain medication, the pain disability index (PDI), the clinical global impression (CGI) and pro-inflammatory cytokine levels, which were assessed during the study period and 3 months after the end of treatment. RESULTS: At the end of the treatment and at 3-month follow-up a clinically meaningful and statistically significant improvement (p < 0.05) could be observed in all outcome parameters and both groups. In contrast to the AT group, the onset of these effects in the EA group could already be observed after the 2nd treatment week. In the 4th treatment week the EA group reported significantly less pain than the AT group (p = 0.040). After the end of treatment (7th week) the EA group assessed their outcome as significantly more improved than the AT group (p = 0.035). The erythrocyte sedimentation rate in the EA group was significantly reduced (p = 0.010), and the serum concentration of tumor necrosis factor-alpha was significantly increased compared to the AT group (p = 0.020). CONCLUSIONS: The adjuvant use of both EA and AT in the treatment of RA resulted in significant short- and long-term treatment effects. The treatment effects of auricular EA were more pronounced.
Assuntos
Acupuntura Auricular/métodos , Artrite Reumatoide/terapia , Treinamento Autógeno , Eletroacupuntura/métodos , Acupuntura Auricular/efeitos adversos , Adolescente , Adulto , Idoso , Artrite Reumatoide/complicações , Análise Química do Sangue , Eletroacupuntura/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dor/classificação , Dor/etiologia , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
Life and death of peripheral lymphocytes is strictly controlled to maintain physiologic levels of T and B cells. Activation-induced cell death (AICD) is one mechanism to delete superfluous lymphocytes by restimulation of their immunoreceptors and it depends partially on the CD95/CD95L system. Recently, we have shown that hematopoietic progenitor kinase 1 (HPK1) determines T-cell fate. While full-length HPK1 is essential for NF-kappaB activation in T cells, the C-terminal fragment of HPK1, HPK1-C, suppresses NF-kappaB and sensitizes toward AICD by a yet undefined cell death pathway. Here we show that upon IL-2-driven expansion of primary T cells, HPK1 is converted to HPK1-C by a caspase-3 activity below the threshold of apoptosis induction. HPK1-C selectively blocks induction of NF-kappaB-dependent antiapoptotic Bcl-2 family members but not of the proapoptotic Bcl-2 family member Bim. Interestingly, T and B lymphocytes from HPK1-C transgenic mice undergo AICD independently of the CD95/CD95L system but involving caspase-9. Knock down of HPK1/HPK1-C or Bim by small interfering RNA shows that CD95L-dependent and HPK1/HPK1-C-dependent cell death pathways complement each other in AICD of primary T cells. Our results define HPK1-C as a suppressor of antiapoptotic Bcl-2 proteins and provide a molecular basis for our understanding of CD95L-independent AICD of lymphocytes.
Assuntos
Apoptose/fisiologia , Linfócitos B/enzimologia , Caspase 3/metabolismo , Caspase 9/metabolismo , Proteína Ligante Fas/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Linfócitos T/enzimologia , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Proteína 11 Semelhante a Bcl-2 , Humanos , Interleucina-2/metabolismo , Ativação Linfocitária/fisiologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , NF-kappa B/metabolismo , Proteínas Serina-Treonina Quinases/genética , Estrutura Terciária de Proteína/genética , Proteínas Proto-Oncogênicas/metabolismo , Linfócitos T/citologia , Receptor fas/metabolismoRESUMO
While insufficient cell death of activated T cells can result in autoimmune disorders, elimination of too many T cells can lead to immunodeficiency. Therefore, T lymphocyte fate is highly regulated and requires that cells can switch from an apoptosis-resistant towards an apoptosis-sensitive state. This switch is tightly controlled by various effector molecules. Basically, two separate pathways control the fate of antigen-activated T cells: activation-induced cell death (AICD) and activated T cell autonomous death (ACAD). Autoreactive T lymphocytes are eliminated by restimulation via their T cell receptor (TCR) and undergo AICD involving death receptors (extrinsic pathway). In contrast, ACAD can lead to T cell deletion without TCR restimulation, and is determined by the ratio between anti- and pro-apoptotic Bcl-2 family members at the mitochondria (intrinsic pathway). While the extrinsic and the intrinsic pathway lead to caspase activation, non-caspase proteases (e.g., cathepsins) can be released by the lysosomes and might contribute to AICD as well as to ACAD. Activated T cells poses cell death escape mechanisms which are needed for survival of (memory) T cells, but are deleterious for autoimmune disorders or progression of T cell lymphomas.