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1.
Lupus ; 31(1): 19-27, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34911399

RESUMO

BACKGROUND: Lupus nephritis (LN) is a common manifestation and a major cause of morbidity and mortality in systemic lupus erythematosus (SLE) patients. It is characterized by glomerular and often extraglomerular immune complex deposition. PURPOSE: Given the emerging importance of the tubulointerstitial compartment, we conducted a retrospective study of 78 LN biopsies to enumerate the spectrum of extraglomerular immune complex deposition that can be observed in lupus nephritis by electron microscopy and to identify possible clinical or pathologic correlates. RESULTS: The presence of tubulointerstitial immune complex deposition often accompanied interstitial inflammation, but some discrepancies were also seen. CONCLUSIONS: As target antigens are identified, correlation with glomerular, tubulointerstitial, and vascular immune complex deposition will be of increasing interest.


Assuntos
Lúpus Eritematoso Sistêmico , Nefrite Lúpica , Complexo Antígeno-Anticorpo , Humanos , Glomérulos Renais/imunologia , Estudos Retrospectivos
2.
J Pathol Clin Res ; 7(5): 459-470, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33960723

RESUMO

Autopsies of patients who have died from COVID-19 have been crucial in delineating patterns of injury associated with SARS-CoV-2 infection. Despite their utility, comprehensive autopsy studies are somewhat lacking relative to the global burden of disease, and very few comprehensive studies contextualize the findings to other fatal viral infections. We developed a novel autopsy protocol in order to perform postmortem examinations on victims of COVID-19 and herein describe detailed clinical information, gross findings, and histologic features observed in the first 16 complete COVID-19 autopsies. We also critically evaluated the role of ancillary studies used to establish a diagnosis of COVID-19 at autopsy, including immunohistochemistry (IHC), in situ hybridization (ISH), and electron microscopy (EM). IHC and ISH targeting SARS-CoV-2 were comparable in terms of the location and number of infected cells in lung tissue; however, nonspecific staining of bacteria was seen occasionally with IHC. EM was unrevealing in blindly sampled tissues. We then compared the clinical and histologic features present in this series to six archival cases of fatal seasonal influenza and six archival cases of pandemic influenza from the fourth wave of the 'Spanish Flu' in the winter of 1920. In addition to routine histology, the inflammatory infiltrates in the lungs of COVID-19 and seasonal influenza victims were compared using quantitative IHC. Our results demonstrate that the clinical and histologic features of COVID-19 are similar to those seen in fatal cases of influenza, and the two diseases tend to overlap histologically. There was no significant difference in the composition of the inflammatory infiltrate in COVID-19 and influenza at sites of acute lung injury at the time of autopsy. Our study underscores the relatively nonspecific clinical features and pathologic changes shared between severe cases of COVID-19 and influenza, while also providing important caveats to ancillary methods of viral detection.


Assuntos
COVID-19/patologia , Influenza Humana/patologia , Pandemias , SARS-CoV-2/fisiologia , Idoso , Autopsia , COVID-19/diagnóstico , COVID-19/virologia , Feminino , Humanos , Imuno-Histoquímica , Hibridização In Situ , Influenza Humana/diagnóstico , Influenza Humana/virologia , Pulmão/patologia , Pulmão/virologia , Masculino , Estações do Ano
3.
Hum Mol Genet ; 20(2): 211-22, 2011 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-20940147

RESUMO

Cerebral cavernous malformations (CCMs) are vascular lesions of the central nervous system appearing as multicavernous, blood-filled capillaries, leading to headache, seizure and hemorrhagic stroke. CCM occurs either sporadically or as an autosomal dominant disorder caused by germline mutation of one of the three genes: CCM1/KRIT1, CCM2/MGC4607 and CCM3/PDCD10. Surgically resected human CCM lesions have provided molecular and immunohistochemical evidence for a two-hit (germline plus somatic) mutation mechanism. In contrast to the equivalent human genotype, mice heterozygous for a Ccm1- or Ccm2-null allele do not develop CCM lesions. Based on the two-hit hypothesis, we attempted to improve the penetrance of the model by crossing Ccm1 and Ccm2 heterozygotes into a mismatch repair-deficient Msh2(-/-) background. Ccm1(+/-)Msh2(-/-) mice exhibit CCM lesions with high penetrance as shown by magnetic resonance imaging and histology. Significantly, the CCM lesions range in size from early-stage, isolated caverns to large, multicavernous lesions. A subset of endothelial cells within the CCM lesions revealed somatic loss of CCM protein staining, supporting the two-hit mutation mechanism. The late-stage CCM lesions displayed many of the characteristics of human CCM lesions, including hemosiderin deposits, immune cell infiltration, increased endothelial cell proliferation and increased Rho-kinase activity. Some of these characteristics were also seen, but to a lesser extent, in early-stage lesions. Tight junctions were maintained between CCM lesion endothelial cells, but gaps were evident between endothelial cells and basement membrane was defective. In contrast, the Ccm2(+/-)Msh2(-/-) mice lacked cerebrovascular lesions. The CCM1 mouse model provides an in vivo tool to investigate CCM pathogenesis and new therapies.


Assuntos
Modelos Animais de Doenças , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Hemangioma Cavernoso do Sistema Nervoso Central/patologia , Mutação , Animais , Cruzamento , Células Endoteliais/patologia , Genótipo , Humanos , Proteína KRIT1 , Camundongos , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/deficiência , Proteínas Associadas aos Microtúbulos/genética , Proteína 2 Homóloga a MutS/deficiência , Proteína 2 Homóloga a MutS/genética , Fenótipo , Proteínas Proto-Oncogênicas/deficiência , Proteínas Proto-Oncogênicas/genética , Quinases Associadas a rho/metabolismo
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