RESUMEN
Severe SARS-CoV-2 infection1 has been associated with highly inflammatory immune activation since the earliest days of the COVID-19 pandemic2-5. More recently, these responses have been associated with the emergence of self-reactive antibodies with pathologic potential6-10, although their origins and resolution have remained unclear11. Previously, we and others have identified extrafollicular B cell activation, a pathway associated with the formation of new autoreactive antibodies in chronic autoimmunity12,13, as a dominant feature of severe and critical COVID-19 (refs. 14-18). Here, using single-cell B cell repertoire analysis of patients with mild and severe disease, we identify the expansion of a naive-derived, low-mutation IgG1 population of antibody-secreting cells (ASCs) reflecting features of low selective pressure. These features correlate with progressive, broad, clinically relevant autoreactivity, particularly directed against nuclear antigens and carbamylated proteins, emerging 10-15 days after the onset of symptoms. Detailed analysis of the low-selection compartment shows a high frequency of clonotypes specific for both SARS-CoV-2 and autoantigens, including pathogenic autoantibodies against the glomerular basement membrane. We further identify the contraction of this pathway on recovery, re-establishment of tolerance standards and concomitant loss of acute-derived ASCs irrespective of antigen specificity. However, serological autoreactivity persists in a subset of patients with postacute sequelae, raising important questions as to the contribution of emerging autoreactivity to continuing symptomology on recovery. In summary, this study demonstrates the origins, breadth and resolution of autoreactivity in severe COVID-19, with implications for early intervention and the treatment of patients with post-COVID sequelae.
Asunto(s)
Autoanticuerpos , Linfocitos B , COVID-19 , Humanos , Autoanticuerpos/inmunología , Linfocitos B/inmunología , Linfocitos B/patología , COVID-19/inmunología , COVID-19/patología , COVID-19/fisiopatología , SARS-CoV-2/inmunología , SARS-CoV-2/patogenicidad , Inmunoglobulina G/inmunología , Análisis de la Célula Individual , Autoantígenos/inmunología , Membrana Basal/inmunología , Síndrome Post Agudo de COVID-19RESUMEN
AIMS: Basement membrane-related genes (BMs) participate in regulating cell polarity, invasion, metastasis, and survival across different tumor types. Nevertheless, the specific functions of BMs in colorectal cancer (CRC) remain uncertain. METHODS: To investigate the clinical relevance of BMs in CRC, we retrieved both gene expression and clinical data from The Cancer Genome Atlas (TCGA) datasets for subsequent analysis. The Kaplan-Meier (K-M) survival curve was employed to evaluate prognosis in high- and low-risk groups. Furthermore, additional analyses, including nomogram construction, functional enrichment, examination of the tumor immune microenvironment, prediction of small-molecule drugs, and more, were conducted to delve into the significance of BM-related signatures in CRC. Single-cell data from seven CRC patients were obtained from the TISCH2 database, and expression validation and cell source exploration of BM-related signatures were performed. Lastly, the expression and function of TIMP1, a key gene in BMs that may play a role in the progression of CRC, was validated in vitro through a series of basic experiments. RESULTS: We constructed a seven BMs-based model to categorize CRC patients into high-risk and low-risk groups. K-M survival analysis indicated a poorer prognosis for high-risk CRC patients. Cox regression analysis further identified the risk score as an independent prognostic factor for CRC patients. The nomogram model exhibited superior discrimination and calibration abilities of CRC patients. Based on the results from GO/KEGG and GSEA, genes in the high-risk subgroup were implicated in immune-related pathways and exhibited a positive correlation with immune checkpoints. In single-cell data, we found that TIMP1 is highly expressed in many cells, especially in malignant tumor cells. We also observed up-regulation of TIMP1 in CRC cell lines, promoting cancer invasion and migration in vitro. CONCLUSIONS: Our study has discovered a novel prognostic index derived from BM-related genes in CRC patients. Specifically, the new model enables patient stratification, improving the selection of individuals likely to benefit from immunotherapy.
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Membrana Basal , Neoplasias Colorrectales , Análisis de la Célula Individual , Inhibidor Tisular de Metaloproteinasa-1 , Humanos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/mortalidad , Inhibidor Tisular de Metaloproteinasa-1/genética , Pronóstico , Membrana Basal/inmunología , Análisis de Secuencia de ARN , Microambiente Tumoral/inmunología , Regulación Neoplásica de la Expresión Génica , Línea Celular TumoralRESUMEN
Current data suggest that tissue microenvironment control immune functions. Therefore, understanding the tissue environment in which immune activation occurs will enhance our capability to interfere with abnormal immune pathology. Here, we argue that studying the constitutively abnormal functions of clinically uninvolved psoriatic skin in patients with plaque type psoriasis is very important to better understand psoriasis pathobiology, because non-lesional skin provides the tissue environment in which the psoriatic lesion develops. A key question in psoriasis is what initiates the abnormal, uncontrolled immune activation in the first place and the answer may lie in the skin. In light of this concept, we summarize abnormalities at the dermal-epidermal junction region which shows a special "non-healing-like" micro-wound phenotype in the psoriatic non-lesional skin that may act as a crucial susceptibility factor in the development of the disease.
Asunto(s)
Membrana Basal/inmunología , Membrana Basal/patología , Psoriasis/inmunología , Psoriasis/patología , Piel/inmunología , Piel/patología , Susceptibilidad a Enfermedades , HumanosRESUMEN
Islet transplantation in man is limited by multiple factors including islet availability, islet cell damage caused by collagenase during isolation, maintenance of islet function between isolation and transplantation, and allograft rejection. In this study, we describe a new approach for preparing islets that enhances islet function in vitro and reduces immunogenicity. The approach involves culture on native decellularized 3D bone marrow-derived extracellular matrix (3D-ECM), which contains many of the matrix components present in pancreas, prior to islet transplantation. Compared to islets cultured on tissue culture plastic (TCP), islets cultured on 3D-ECM exhibited greater attachment, higher survival rate, increased insulin content, and enhanced glucose-stimulated insulin secretion. In addition, culture of islets on 3D-ECM promoted recovery of vascular endothelial cells within the islets and restored basement membrane-related proteins (eg, fibronectin and collagen type VI). More interestingly, culture on 3D-ECM also selectively decontaminated islets of "passenger" cells (co-isolated with the islets) and restored basement membrane-associated type VI collagen, which were associated with an attenuation in islet immunogenicity. These results demonstrate that this novel approach has promise for overcoming two major issues in human islet transplantation: (a) poor yield of islets from donated pancreas tissue and (b) the need for life-long immunosuppression.
Asunto(s)
Membrana Basal/fisiología , Médula Ósea/fisiología , Matriz Extracelular/fisiología , Tolerancia Inmunológica/fisiología , Islotes Pancreáticos/inmunología , Islotes Pancreáticos/fisiología , Animales , Membrana Basal/inmunología , Membrana Basal/metabolismo , Médula Ósea/inmunología , Médula Ósea/metabolismo , Colágeno Tipo VI/inmunología , Colágeno Tipo VI/metabolismo , Matriz Extracelular/inmunología , Matriz Extracelular/metabolismo , Fibronectinas/inmunología , Fibronectinas/metabolismo , Glucosa/inmunología , Glucosa/metabolismo , Tolerancia Inmunológica/inmunología , Insulina/inmunología , Insulina/metabolismo , Secreción de Insulina/inmunología , Secreción de Insulina/fisiología , Islotes Pancreáticos/metabolismo , Trasplante de Islotes Pancreáticos/métodos , Masculino , Ratas , Ratas Endogámicas F344 , Ratas Endogámicas Lew , Ratas Endogámicas WFRESUMEN
Since the first clinicopathologic description by Ernest Goodpasture of a patient whom he considered to have died of influenza in 1919, substantial progress has been made in our knowledge of anti-glomerular basement membrane disease. This has led to a significant decrease in the morbidity and mortality associated with this disease. In this paper, we aim to review the literature that has enhanced our understanding of classic anti-glomerular basement membrane disease and its clinic-pathologic variants in the key areas of immunopathogenesis and histopathology. We also summarize varied clinical presentations and therapeutic strategies.
Asunto(s)
Enfermedad por Anticuerpos Antimembrana Basal Glomerular/patología , Membrana Basal/inmunología , Riñón/patología , Enfermedad por Anticuerpos Antimembrana Basal Glomerular/inmunología , Autoanticuerpos , Humanos , Riñón/inmunologíaRESUMEN
INTRODUCTION: Patients with AL amyloidosis and immunoglobulin deposition diseases (IDD) are vulnerable during the COVID-19 pandemic due to the immune compromise from the plasma cell disorder and therapy-related immune defects. We describe a local experience in providing care for patients with AL amyloidosis and IDD. METHOD: Patient treatment and disease status since the beginning of the pandemic on March 11, 2020, as declared by WHO, were collected and analyzed. RESULTS: Ninety-six patients with AL amyloidosis and IDD were included. Four patients with IDD and 22 patients with systemic AL amyloidosis were receiving treatment during the pandemic. Since the pandemic, patients' treatments were discontinued if they achieved VGPR or better postinduction. Seven patients discontinued all treatment after achieving VGPR, and others required treatment modifications. 28 patients have been tested for COVID-19, and all tests have been negative. Three patients died since the pandemic, two from organ complications of systemic AL amyloidosis and one from an unrelated cause. CONCLUSION: The management of AL amyloidosis and IDD must be individualized on the clinical characteristics, centers' access to care under the pandemic restrictions, and the epidemiological aspects of the outbreak.
Asunto(s)
COVID-19 , Cadenas Ligeras de Inmunoglobulina/análisis , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/tratamiento farmacológico , Pandemias , Paraproteinemias/tratamiento farmacológico , SARS-CoV-2 , Anciano , Alberta/epidemiología , Anticuerpos Monoclonales/uso terapéutico , Membrana Basal/inmunología , Membrana Basal/patología , Bortezomib/uso terapéutico , COVID-19/diagnóstico , COVID-19/epidemiología , Prueba de COVID-19/estadística & datos numéricos , Ciclofosfamida/uso terapéutico , Dexametasona/uso terapéutico , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Quimioterapia Combinada , Femenino , Humanos , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/mortalidad , Estimación de Kaplan-Meier , Lenalidomida/uso terapéutico , Masculino , Metilprednisolona/uso terapéutico , Persona de Mediana Edad , Neoplasia Residual , Paraproteinemias/mortalidad , Medicina de Precisión , Estudios Retrospectivos , TelemedicinaRESUMEN
A 70-year-old Japanese man with diabetes mellitus was referred to our hospital for treatment of renal dysfunction. Renal biopsy revealed that the tubular basement membrane (TBM) showed extreme thickening histologically, and selective polyclonal immunoglobulin G deposition on the thickened TBM, whereas no immunoglobulin deposition was found in the glomeruli in an immunofluorescence study. In electron microscopy, a powdery type of electron dense material, which was similar to that seen in Randall-type monoclonal immunoglobulin deposition disease (MIDD), was observed on the tubular epithelial side of the TBM. However, the present case was differentiated from MIDD, because polyclonal deposition with both kappa and lambda deposition on the TBM was observed. Moreover, there was no noticeable glomerular deposition, which is usually found in cases of MIDD. Anti-TBM disease was also considered as a differential diagnosis, in which polyclonal immunoglobulin deposits selectively on the TBM. However, in the present case, prominent interstitial nephritis was not observed. A similar case with a history of diabetes mellitus has been reported, which was diagnosed as Polyclonal Immunoglobulin G Deposition Disease. No further reports of this case have emerged thereafter; we present this case as the second report supporting this article.
Asunto(s)
Membrana Basal/inmunología , Nefropatías Diabéticas/inmunología , Nefropatías Diabéticas/patología , Inmunoglobulina G/inmunología , Túbulos Renales/inmunología , Anciano , Membrana Basal/patología , Humanos , Túbulos Renales/patología , MasculinoRESUMEN
SARS-CoV-2, a new virus that appeared in Wuhan, China, in 2019 has approximately an 80% genomic match to the Severe Acute Respiratory Symptom (SARS) virus, which is known to come from a bat virus. Symptoms of Kawasaki disease in general and incomplete Kawasaki disease have been seen in a subset of pediatric patients having a current or previous infection of SARS-CoV-2. A viral infection, such as a SARS-CoV-2 virus infection, could result in extensive antigen-antibody immune complexes that cannot be quickly cleared in a subset of patients and thus create a type III hypersensitivity immune reaction and cause Kawasaki disease or Kawasaki disease symptoms (also known as multisystem inflammatory syndrome) in a subset of patients. Extensive binding of antibodies to viral antigens can create antigen-antibody immune complexes, which, if not eliminated in certain individuals having dysfunctional complement systems, can start inflammatory type III hypersensitivity symptoms, including protease releases that can disrupt epithelium, mesothelium, and endothelium basement membranes, and induce pervasive inflammation throughout the body. This could continue after SARS-CoV-2 infections end if the first wave of protease attacks on basement membranes created new secondary autoantibodies and new uncleared antigen-antibody immune complexes.
Asunto(s)
Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/virología , Síndrome Mucocutáneo Linfonodular/etiología , Síndrome Mucocutáneo Linfonodular/virología , Neumonía Viral/complicaciones , Neumonía Viral/virología , Complejo Antígeno-Anticuerpo , Membrana Basal/inmunología , Membrana Basal/patología , COVID-19 , Niño , Humanos , Enfermedades del Complejo Inmune/inmunología , Síndrome Mucocutáneo Linfonodular/diagnóstico , Pandemias , Péptido Hidrolasas/química , Piel/patología , Síndrome de Respuesta Inflamatoria Sistémica/terapiaRESUMEN
A kidney biopsy is done to determine the etiology of the glomerulonephritis (GN) and the severity of the lesion, to identify whether other lesions, related to or not related to the GN, are present on the kidney biopsy and finally to ascertain the extent of chronicity of the GN. The etiology of GN is based on the classification of GN into five groups: immune complex-mediated GN, antineutrophil cytoplasmic antibody (ANCA)-associated GN, anti-glomerular basement membrane (GBM) GN, monoclonal immunoglobulin-mediated GN and C3 glomerulopathy. Immune complex GN includes multiple specific diseases such as lupus nephritis, IgA nephropathy, infection-related GN and fibrillary GN. ANCA GN, anti-GBM GN and C3 glomerulopathy are specific diseases in themselves, while monoclonal Ig GN includes proliferative GN with monoclonal Ig deposits and monoclonal Ig deposition disease. Thus identification of the class of GN and within it the specific disease determines the etiology of GN. Ancillary studies may be required to confirm the etiology of GN. The severity of the GN is revealed by the pattern of injury, such as crescentic, necrotizing, diffuse proliferative, exudative, membranoproliferative, mesangial proliferative or a sclerosing GN. Secondary diagnosis either related or unrelated to the GN, such as diabetic glomerulosclerosis, acute tubular necrosis or thrombotic microangiopathy, may also be present. The secondary diagnosis may sometimes be the reason for the kidney biopsy. The chronicity of GN is determined by evaluating the extent of glomerulosclerosis, tubular atrophy and interstitial fibrosis and vascular sclerosis present on the biopsy. This review summarizes the approach to standardizing a kidney biopsy report that includes these components in a logical and sequential manner.
Asunto(s)
Anticuerpos Anticitoplasma de Neutrófilos/análisis , Biopsia/normas , Glomerulonefritis por IGA/clasificación , Glomerulonefritis/clasificación , Nefrología/normas , Membrana Basal/inmunología , Complemento C3/inmunología , Glomerulonefritis/diagnóstico , Glomerulonefritis/patología , Glomerulonefritis por IGA/diagnóstico , Humanos , Inmunoglobulinas/inmunología , Glomérulos Renales/fisiopatología , Nefritis Lúpica/clasificación , Nefritis Lúpica/diagnósticoRESUMEN
BACKGROUND: Tubular basement membrane immune deposits (TBMID) has rarely been observed in renal allografts. It is usually found in BK virus nephropathy and immune complex glomerulonephritis; however, its significance is not well understood. We conducted a retrospective clinicopathological study on monoclonal immunoglobulin G (IgG) TBMID. METHODS: We studied 7177 renal allograft biopsy specimens obtained from Tokyo Women's Medical University from 2007 to 2015 and performed light microscopic, electron microscopic and immunofluorescence studies. RESULTS: Tubular basement membrane (TBM) deposits of IgG were found in 73 biopsies from 61 patients and the IgG subclass was obtained in 31 biopsies. There were no cases of monoclonal IgA or IgM TBMID. In total, 13 biopsies from 10 patients showed monoclonal IgG TBMID. Of these, seven showed monoclonal IgG1κ TBMID and one each showed monoclonal IgG2κ, IgG2λ and IgG3κ TBMID. Conversely, eight patients showed polyclonal IgG TBMID. In electron microscopy, large granular electron-dense deposits (EDDs) in the TBM were detected in all patients with monoclonal IgG1κ TBMID. EDDs were absent in TBM in patients with monoclonal IgG2κ, IgG2λ or IgG3κ TBMID. Progression of interstitial fibrosis and tubular atrophy (IFTA) was significantly higher in patients with monoclonal IgG1κ TBMID than in those with polyclonal IgG TBMID (P < 0.05). There were no significant differences in the other clinical parameters between monoclonal IgG1κ and polyclonal IgG TBMID. CONCLUSIONS: This is the first study of patients with monoclonal IgG TBMID in renal allografts. We found that monoclonal IgG1κ TBMID was associated with EDD formation in TBM and IFTA progression.
Asunto(s)
Anticuerpos Monoclonales/inmunología , Membrana Basal/inmunología , Glomerulonefritis/inmunología , Inmunoglobulina G/inmunología , Trasplante de Riñón/métodos , Nefritis Intersticial/inmunología , Adolescente , Adulto , Anciano , Aloinjertos , Anticuerpos Monoclonales/metabolismo , Membrana Basal/metabolismo , Niño , Femenino , Glomerulonefritis/metabolismo , Glomerulonefritis/patología , Humanos , Inmunoglobulina G/metabolismo , Masculino , Persona de Mediana Edad , Nefritis Intersticial/metabolismo , Nefritis Intersticial/patología , Pronóstico , Estudios Retrospectivos , Adulto JovenRESUMEN
Leukocyte recruitment is a hallmark of the inflammatory response. Migrating leukocytes breach the endothelium along with the vascular basement membrane and associated pericytes. While much is known about leukocyte-endothelial cell interactions, the mechanisms and role of pericytes in extravasation are poorly understood and the classical paradigm of leukocyte recruitment in the microvasculature seldom adequately discusses the involvement of pericytes. Emerging evidence shows that pericytes are essential players in the regulation of leukocyte extravasation in addition to their functions in blood vessel formation and blood-brain barrier maintenance. Junctions between venular endothelial cells are closely aligned with extracellular matrix protein low expression regions (LERs) in the basement membrane, which in turn are aligned with gaps between pericytes. This forms preferential paths for leukocyte extravasation. Breaching of the layer formed by pericytes and the basement membrane entails remodelling of LERs, leukocyte-pericyte adhesion, crawling of leukocytes on pericyte processes, and enlargement of gaps between pericytes to form channels for migrating leukocytes. Furthermore, inflamed arteriolar and capillary pericytes induce chemotactic migration of leukocytes that exit postcapillary venules, and through direct pericyte-leukocyte contact, they induce efficient interstitial migration to enhance the immunosurveillance capacity of leukocytes. Given their role as regulators of leukocyte extravasation, proper pericyte function is imperative in inflammatory disease contexts such as diabetic retinopathy and sepsis. This review summarizes research on the molecular mechanisms by which pericytes mediate leukocyte diapedesis in inflamed tissues.
Asunto(s)
Leucocitos/metabolismo , Pericitos/metabolismo , Animales , Membrana Basal/inmunología , Membrana Basal/metabolismo , Barrera Hematoencefálica/inmunología , Barrera Hematoencefálica/metabolismo , Humanos , Inflamación/inmunología , Inflamación/metabolismo , Leucocitos/inmunología , Pericitos/inmunologíaAsunto(s)
Antibacterianos/efectos adversos , Dermatosis Bullosa IgA Lineal/inducido químicamente , Vancomicina/efectos adversos , Anciano , Membrana Basal/inmunología , Técnica del Anticuerpo Fluorescente , Humanos , Inmunoglobulina A/análisis , Dermatosis Bullosa IgA Lineal/patología , Masculino , Miositis/tratamiento farmacológico , Osteomielitis/tratamiento farmacológico , Piel/patologíaRESUMEN
Spontaneous tumour regression after high-dose therapy and autologous stem cell transplantation is associated with the aplastic anaemia-like syndrome and the presence of polyclonal autoantibodies against carbonic anhydrase I (CA I). When tumour cells were grown in vitro in the presence of patients' sera positive for anti-CA I autoantibodies, their morphological pattern was altered. These changes were accompanied by modifications in the gene expression profile. We observed downregulation of genes of the basal lamina assembly (collagen type IV alpha 4, the laminin subunit gamma 2), the extracellular matrix (collagen type I alpha 1), the cytoskeleton (keratin 14 type I), the collagen triple helix repeat containing 1 and the proto-oncogene WNT7B. On the other hand, the expression of the CA 1 gene was increased in the tumour cells. It was also noticed that the presence of anti-CA I autoantibodies did not impair tumour cell proliferation and cell viability in vitro. These findings were observed only in the presence of patients' sera positive for anti-CA I autoantibodies.
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Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Anhidrasa Carbónica I/inmunología , Proteínas de la Matriz Extracelular/metabolismo , Matriz Extracelular/metabolismo , Neoplasias/sangre , Neoplasias/inmunología , Adulto , Anciano , Especificidad de Anticuerpos/inmunología , Membrana Basal/inmunología , Membrana Basal/metabolismo , Anhidrasa Carbónica I/metabolismo , Proliferación Celular/fisiología , Supervivencia Celular/inmunología , Colágeno/inmunología , Colágeno/metabolismo , Cadena alfa 1 del Colágeno Tipo I , Citoesqueleto/inmunología , Citoesqueleto/metabolismo , Regulación hacia Abajo/inmunología , Matriz Extracelular/inmunología , Proteínas de la Matriz Extracelular/inmunología , Femenino , Expresión Génica/genética , Expresión Génica/inmunología , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/metabolismo , Proto-Oncogenes MasRESUMEN
BACKGROUND: Thickening of reticular basement membrane, increased airway smooth muscle mass and eosinophilic inflammation are found in adult fatal asthma. At the present study the histopathology of fatal paediatric and adolescent asthma is evaluated. METHODS: Post-mortem lung autopsies from 12 fatal asthma cases and 8 non-asthmatic control subjects were examined. Thickness of reticular basement membrane (RBM) and percentage of airway smooth muscle (ASM%) mass area were measured and inflammatory cells were counted. Patient records were reviewed for clinical history. RESULTS: The age range of the cases was from 0.9 to 19.5 years, eight were males and five had received inhaled corticosteroids. Thickened RBM was detected in majority of the cases without any correlation to treatment delay, age at onset of symptoms or diagnosis. In the large airways ASM was clearly increased in one third of the cases whereas the median ASM% did not differ from that in healthy controls (14.0% vs. 14.0%). In small airways no increase of ASM was found, instead mucous plugs were seen in fatal asthma. The number of eosinophils, plasmacytoid dendritic cells, macrophages, and B-cells were significantly increased in fatal asthma cases compared with controls and the two latter correlated with the length of the fatal exacerbation. CONCLUSIONS: The findings highlight the strong presence of eosinophils and mucous plugs even in small airways in children and adolescents with fatal asthma. Thickened RBM was obvious in majority of the patients. Contrary to our hypothesis, increased ASM% was detected in only one third of the patients.
Asunto(s)
Remodelación de las Vías Aéreas (Respiratorias)/inmunología , Asma/inmunología , Asma/patología , Membrana Basal/inmunología , Membrana Basal/patología , Adolescente , Asma/mortalidad , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Músculo Liso/inmunología , Músculo Liso/patología , Distribución Aleatoria , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/patología , Adulto JovenRESUMEN
BACKGROUND: Linear IgA bullous dermatosis (LABD) is a heterogeneous disease. Different diagnostic criteria have been used in different reports. OBJECTIVES: To reappraise the characteristic features of LABD with only IgA deposition at the basement membrane zone (BMZ) with direct immunofluorescence (DIF). METHODS: We retrospectively collected data from 101 patients from our archival records from 1 January 1996 to 31 December 2014 who had: (i) blisters on the skin and/or mucous membranes; (ii) subepidermal blisters in a biopsy specimen; and (iii) linear IgA deposition along the BMZ with/without linear C3 deposition at the BMZ with DIF. Most patients were referred for serological evaluation. Patients who showed concurrent linear IgG and/or IgM deposition at the BMZ under DIF were excluded. Clinical manifestations and serological findings were analysed. RESULTS: Heterogeneity of autoantigens in LABD was confirmed. Fifty-four of 101 patients (53%) had IgG antibodies detected either by indirect immunofluorescence, immunoblotting or enzyme-linked immunosorbent assays (ELISA). No statistical difference in clinical manifestations was found between patients in the IgG antibody-possessing group and patients in the other group. CONCLUSIONS: An association of IgG anti-BMZ antibodies with LABD may increase if new IgG immunoblotting or ELISA techniques become available. Consensus for diagnostic criteria for LABD is desired for prospective data storage, although it may be arbitrary.
Asunto(s)
Membrana Basal/inmunología , Inmunoglobulina A/metabolismo , Dermatosis Bullosa IgA Lineal/inmunología , Adolescente , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Ensayo de Inmunoadsorción Enzimática , Femenino , Técnica del Anticuerpo Fluorescente Directa , Humanos , Lactante , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
Linear IgG deposits along the basement membrane of adnexa has been proposed to be useful in the diagnosis of bullous pemphigoid (BP), but no controlled studies have been performed. This study evaluated linear IgG fluorescence of the basement membrane of sweat gland ducts (SGD) and other adnexa in perilesional biopsies from patients with BP (n = 64) and controls (n = 82), using direct immunofluorescence microscopy. Fluorescence intensity was graded semi-quantitatively. Positive SGDs were found in 58 (90.6%) patients with BP and 44 (53.7%) controls, a statistically significant difference (p < 0.0001). The sensitivity of positive SGDs for BP was high (90.6%), but the specificity was low (46.3%). Only strong fluorescence intensity was associated with high specificity. In conclusion, positive SGDs in direct immunofluorescence microscopy are highly sensitive for BP; however, only strong fluorescence has acceptable specificity. Weak positivity of SGDs without linear fluorescence of the epidermal basement membrane may not be sufficiently specific for BP.
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Autoanticuerpos/análisis , Autoantígenos/inmunología , Membrana Basal/inmunología , Distonina/inmunología , Inmunoglobulina G/análisis , Microscopía Fluorescente , Colágenos no Fibrilares/inmunología , Penfigoide Ampolloso/diagnóstico , Glándulas Sudoríparas/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Membrana Basal/patología , Biomarcadores/análisis , Estudios de Casos y Controles , Niño , Femenino , Humanos , Mediciones Luminiscentes , Masculino , Persona de Mediana Edad , Penfigoide Ampolloso/inmunología , Penfigoide Ampolloso/patología , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Glándulas Sudoríparas/patología , Turquía , Adulto Joven , Colágeno Tipo XVIIRESUMEN
The mechanism underlying immune system recognition of different types of pathogens has been extensively studied over the past few decades; however, the mechanism by which healthy self-tissue evades an attack by its own immune system is less well-understood. Here, we established an autoimmune model of melanotic mass formation in Drosophila by genetically disrupting the basement membrane. We found that the basement membrane endows otherwise susceptible target tissues with self-tolerance that prevents autoimmunity, and further demonstrated that laminin is a key component for both structural maintenance and the self-tolerance checkpoint function of the basement membrane. Moreover, we found that cell integrity, as determined by cell-cell interaction and apicobasal polarity, functions as a second discrete checkpoint. Target tissues became vulnerable to blood cell encapsulation and subsequent melanization only after loss of both the basement membrane and cell integrity.
Asunto(s)
Membrana Basal/citología , Drosophila melanogaster/inmunología , Tolerancia Inmunológica , Animales , Animales Modificados Genéticamente , Autoinmunidad/genética , Membrana Basal/inmunología , Comunicación Celular , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/citología , Drosophila melanogaster/genética , Laminina/genética , Laminina/metabolismo , Larva/inmunología , Interferencia de ARNRESUMEN
Animal models are indispensable for the study of glomerulonephritis, a group of diseases that destroy kidneys but for which specific therapies do not yet exist. Novel interventions are urgently needed, but their rational design requires suitable in vivo platforms to identify and test new candidates. Animal models can recreate the complex immunologic microenvironments that foster human autoimmunity and nephritis and provide access to tissue compartments not readily examined in patients. Study of rat Heymann nephritis identified fundamental disease mechanisms that ultimately revolutionized our understanding of human membranous nephropathy. Significant species differences in expression of a major target antigen, however, and lack of spontaneous autoimmunity in animals remain roadblocks to full exploitation of preclinical models in this disease. For several glomerulonephritides, humanized models have been developed to circumvent cross-species barriers and to study the effects of human genetic risk variants. Herein we review humanized mouse prototypes that provide fresh insight into mediators of IgA nephropathy and origins of antiglomerular basement membrane nephritis and Goodpasture's disease, as well as a means to test novel therapies for ANCA vasculitis. Additional and refined model systems are needed to mirror the full spectrum of human disease in a genetically diverse population, to facilitate development of patient-specific interventions, to determine the origin of nephritogenic autoimmunity, and to define the role of environmental exposures in disease initiation and relapse.
Asunto(s)
Modelos Animales de Enfermedad , Glomerulonefritis/patología , Riñón/patología , Investigación Biomédica Traslacional , Animales , Autoinmunidad , Membrana Basal/inmunología , Membrana Basal/patología , Glomerulonefritis/inmunología , Humanos , Riñón/inmunología , Ratones , RatasRESUMEN
Laminins are ubiquitous constituents of the basement membranes with major architectural and functional role as supported by the fact that absence or mutations of laminins lead to either lethal or severely impairing phenotypes. Besides genetic defects, laminins are involved in a wide range of human diseases including cancer, infections, and inflammatory diseases, as well as autoimmune disorders. A growing body of evidence implicates several laminin chains as autoantigens in blistering skin diseases, collagenoses, vasculitis, or post-infectious autoimmunity. The current paper reviews the existing knowledge on autoimmunity against laminins referring to both experimental and clinical data, and on therapeutic implications of anti-laminin antibodies. Further investigation of relevant laminin epitopes in pathogenic autoimmunity would facilitate the development of appropriate diagnostic tools for thorough characterization of patients' antibody specificities and should decisively contribute to designing more specific therapeutic interventions.
Asunto(s)
Autoanticuerpos/inmunología , Autoantígenos/inmunología , Autoinmunidad/inmunología , Laminina/inmunología , Animales , Autoantígenos/genética , Autoinmunidad/genética , Membrana Basal/inmunología , Humanos , Laminina/genética , Mutación/inmunología , Neoplasias/genética , Neoplasias/inmunología , Neoplasias/patología , Enfermedades de la Piel/genética , Enfermedades de la Piel/inmunologíaRESUMEN
We have previously reviewed alterations to basement membrane laminin in psoriasis and how disruption of this layer could lead to at least some of the pathological changes observed. We here postulate that basement membrane laminin is the key antigen in driving psoriasis, inducing a T cell-mediated autoimmune response. For laminin to be considered as the key autoantigen in psoriasis, it would be reasonable to expect the following to be demonstrable: (1) that autoantigens are present in psoriatic inflammation; (2) that basement membrane laminin is perturbed in involved and uninvolved skin, and that some of the pathological changes associated with psoriasis could be predicted as a sequel to this; (3) that disruption of the basement membrane is among the earliest events in the evolution of psoriatic lesions; (4) that as streptococcal pharyngitis is the most clearly defined event to trigger or exacerbate psoriasis, then a T cell-mediated autoimmune response to laminin should be anticipated as a potential sequelae to streptococcal pharyngitis; (5) that T cells in psoriasis can be shown to react to peptides with homology to laminin; (6) that HLACw6, as the most closely related gene associated with psoriasis and which is involved in antigen expression, should be preferentially expressed within lesional psoriasis towards the basement membrane, together with other proximal associated immune activity; and (7) that there is some association between antilaminin pemphigoid, a humorally mediated autoimmune disease to skin basement membrane laminin, and psoriasis. We here review the data relevant to each of these requirements.