Immunohistochemical studies on the class and the subclass of the anticolon antibody and the distribution of the antigen recognized by the anticolon antibody in patients with ulcerative colitis

The immunologic mechanisms mediated by anticolon antibodies have been suggested for the injury of colonic mucosa in ulcerative colitis (UC). For the understanding of pathogenetic relevance of the anticolon antibody in UC, we examined the class and the subclass of the anticolon antibody reactive to rat colonic epithelial cells in sera from 10 patients with UC immunohistochemically by an indirect immunoperoxidase method. We also examined the distribution of the antigen recognized by the anticolon antibody by immunoelectron microscopy. The antibody reactive to the rat colonic epithelial cell was detected in 2 of the 10 patients, and the class and subclass of the antibody was mainly IgG2. The antigen recognized by the anticolon antibody was located on the apical membrane of the colonic epithelial cells and mucous substances of the goblet cells. These findings suggest that the anticolon antibody detected in this study is inadequate to cause the colonic mucosal injury by activating complements or mediating antibody-dependent cellular cytotoxicity. A potential pathogenetic role of the anticolon antibody in UC remains to be established.     

Alveolar macrophage procoagulant activity is increased in acute hyperoxic lung injury.

Alveolar macrophage accumulation and interstitial fibrin deposition are prominent in adult respiratory distress syndrome and chronic interstitial lung diseases. The role of alveolar macrophages in the initiation of fibrin deposition and lung injury in these diseases is uncertain. Expression of procoagulant activity by these cells may provide evidence of macrophage activation and involvement in the initiation of lung fibrin deposition. An experimental model of hyperoxia-induced lung injury in rats was studied for assessment of the relationship of lung injury, fibrin deposition, and alveolar macrophage procoagulant activity. Lung injury was assessed histologically and functionally, and the accumulation of inflammatory cells was quantified by bronchoalveolar lavage. Pulmonary injury, manifested by increased capillary permeability, developed progressively during exposure to hyperoxia and was associated with significant augmentation of the procoagulant activity of alveolar macrophages early in the disease. This increase preceded the accumulation of polymorphonuclear leukocytes. Alveolar macrophage procoagulant activity had functional characteristics consistent with tissue factor. These studies provide evidence of early alveolar macrophage activation in acute hyperoxic lung injury in rats and suggest a role for procoagulant activity in the development of interstitial fibrin deposition.     

Pathology of hepatitis C virus infection

This paper reviews our current knowledge of hepatitis C virus, its structure, epidemiology and pathological effects in man. The histopathological features of acute and chronic hepatitis due to hepatitis C virus are detailed and illustrated. The possible pathogenetic mechanisms involved in the liver injury are outlined and the significance of genotypic subtypes of the virus and of host genetic predisposition in relation to the liver injury and the response to therapy are summarized.     

A distinctive glomerular lesion complicating placental site trophoblastic tumor: report of two cases

Renal disease with distinctive pathologic features developed in two young women who had placental site trophoblastic tumors. The renal abnormalities were manifested by proteinuria in both cases and by hematuria in one case; blood pressure was elevated in one of the patients. Pathologic examination of the kidneys showed distinctive glomerular abnormalities, characterized mainly by the presence of occlusive eosinophilic deposits in many of the glomerular capillary lumina, most of which stained for fibrinogen-related antigens and IgM by immunohistochemical techniques. Ultrastructural examination showed the deposits to consist mainly of granular material that contained packets of fibrillar material with the appearance of fibrin. The uterine tumors were composed of mononucleated and multinucleated cells with abundant cytoplasm that infiltrated between the muscle bundles of the myometrium; in both tumors there was prominent deposition of eosinophilic material that had the tinctorial properties of fibrin and that stained for fibrinogen and IgM in immunoperoxidase studies. The renal abnormalities disappeared after hysterectomy in one case; the other patient, who was receiving chemotherapy and had disseminated intravascular coagulation, died with leukopenia and sepsis. The clinical and pathologic features in these cases suggest that the renal abnormalities were related to the uterine tumors and that the production of immune complexes and/or the activation of intravascular coagulation by the tumors were pathogenetic mechanisms.     

Pathology and pathogenesis of severe acute respiratory syndrome

Severe acute respiratory syndrome (SARS) is an emerging infectious viral disease characterized by severe clinical manifestations of the lower respiratory tract. The pathogenesis of SARS is highly complex, with multiple factors leading to severe injury in the lungs and dissemination of the virus to several other organs. The SARS coronavirus targets the epithelial cells of the respiratory tract, resulting in diffuse alveolar damage. Several organs/cell types may be infected in the course of the illness, including mucosal cells of the intestines, tubular epithelial cells of the kidneys, neurons of the brain, and several types of immune cells, and certain organs may suffer from indirect injury. Extensive studies have provided a basic understanding of the pathogenesis of this disease. In this review we describe the most significant pathological features of SARS, explore the etiological factors causing these pathological changes, and discuss the major pathogenetic mechanisms. The latter include dysregulation of cytokines/chemokines, deficiencies in the innate immune response, direct infection of immune cells, direct viral cytopathic effects, down-regulation of lung protective angiotensin converting enzyme 2, autoimmunity, and genetic factors. It seems that both abnormal immune responses and injury to immune cells may be key factors in the pathogenesis of this new disease.     

Capillary apposition and density in the diagnosis of alveolar capillary dysplasia

Aim: Alveolar capillary dysplasia (ACD) is a rare disorder, typically presenting with persistent pulmonary hypertension of the newborn. The aim was to characterise further the histological features of patients suspected of having ACD and to correlate histopathological features with outcome. Methods and results: Three pathologists retrospectively reviewed 21 surgical lung biopsy specimens (SLBx) where ACD entered the differential diagnosis. Semi‐quantitative assessment showed that there was a spectrum of muscular arterial hypertrophy, capillary apposition to epithelium and capillary density within the interstitium, with the latter being more disordered in ACD. Misalignment of pulmonary vessels was also frequently seen. Four of 19 patients survived beyond the neonatal period, these having higher degrees of capillary apposition and density. Associated extrapulmonary abnormalities were common, most frequently with ACD. Conclusion: Poor capillary apposition and density, allied with medial arterial hypertrophy and misalignment of pulmonary vessels are the strongest diagnostic features of ACD. Of the four patients alive, all had high capillary apposition and density, suggesting that these features may be of prognostic value. SLBx remains useful in such cases as it may help predict patients who survive the neonatal period and also identify patients with disorders that are not primarily vascular anomalies.     

Type II pneumocyte-CD8+ T-cell interactions. Relationship between target cell cytotoxicity and activation

CD8+ T-cell responses play an important role in the clearance of respiratory virus infection, but may also contribute to lung injury in the process. The effector mechanisms involved in viral clearance and associated lung injury include both cytolytic and noncytolytic effector functions. Previously we have shown that CD8+ T-cell recognition of alveolar epithelial cells triggers chemokine expression by the epithelial cell and that this plays an important role in the inflammatory infiltration that ensues in the context of T cell-mediated injury (Zhao and colleagues, J. Clin. Invest. 2000;106:R49-R58). In the present study we sought to understand the relationship between alveolar cell cytotoxicity and chemokine expression, both of which occur as a result of CD8+ T-cell antigen recognition. Alveolar epithelial cells efficiently process and present overlapping viral epitopes, and CD8+ T-cell recognition of these class I major histocompatibility complex-restricted epitopes resulted in cytotoxicity of the alveolar cells by both wild-type and perforin-deficient T cells. However, the contribution of perforin-mediated lysis to the total cytotoxicity of alveolar cells by CD8+ T cells was minimal, and the majority of the lysis was attributable to tumor necrosis factor-alpha expressed by the T cell. CD8+ T-cell recognition also led to activation of nuclear factor-kappaB in the alveolar epithelial target cells, at levels inversely proportional to the effector/target (E:T) ratio. Finally, at varying E:T ratios, we demonstrated an inverse relationship between alveolar cell cytotoxicity and monocyte chemotactic protein-1 expression, both of which occur as a result of T-cell recognition. These findings may have important ramifications in understanding the relationship between viral clearance and lung injury.     

A Study of Human Interstitial Lung Diseases with Special Reference to Immune Complexes and Hyaline Membrane

To evaluate the pathogenetic roles of immune complexes and alveolar hyaline membrane in idiopathic interstitial pneumonia (IIP), immunohistological and ultrastructural studies of the kidney and lung were performed in 23 cases of IIP, 19 cases of autoimmune diseases, 17 cases of interstitial pneumonia other than IIP, and 11 cases of bronchopneumonia as a control group. None of the cases of IIP or interstitial pneumonia other than IIP showed immune complexes in the alveolar and glomerular capillary walls. On the other hand, one case of SLE was positive for IgG and components of complement along the alveolar and glomerular capillary walls. The alveolar hyaline membrane in the present cases revealed immunoglobulins as well as components of complement, which were poorly soluble in chaotropic solution or acidic buffer. These results indicate that circulating immune complexes play a minor role in the pathogenesis of IIP and other types of interstitial pneumonia, and that there is no relationship between immune complex deposition in alveoli and the alveolar hyaline membrane. It is necessary to further investigate factors other than immune complexes involved in alveolar tissue damage and to clarify the significance of the hyaline membrane in the processes occurring from acute changes to pulmonary fibrosis in IIP.     

A study of human interstitial lung diseases with special reference to immune complexes and hyaline membrane

To evaluate the pathogenetic roles of immune complexes and alveolar hyaline membrane in idiopathic interstitial pneumonia (IIP), immunohistological and ultrastructural studies of the kidney and lung were performed in 23 cases of IIP, 19 cases of autoimmune diseases, 17 cases of interstitial pneumonia other than IIP, and 11 cases of bronchopneumonia as a control group. None of the cases of IIP or interstitial pneumonia other than IIP showed immune complexes in the alveolar and glomerular capillary walls. On the other hand, one case of SLE was positive for IgG and components of complement along the alveolar and glomerular capillary walls. The alveolar hyaline membrane in the present cases revealed immunoglobulins as well as components of complement, which were poorly soluble in chaotropic solution or acidic buffer. These results indicate that circulating immune complexes play a minor role in the pathogenesis of IIP and other types of interstitial pneumonia, and that there is no relationship between immune complex deposition in alveoli and the alveolar hyaline membrane. It is necessary to further investigate factors other than immune complexes involved in alveolar tissue damage and to clarify the significance of the hyaline membrane in the processes occurring from acute changes to pulmonary fibrosis in IIP.     

Mucosal capillary thrombi in rectal biopsies

We studied the initial rectal biopsy from 46 patients in whom subsequent follow-up established the diagnosis of either self-limited colitis or inflammatory bowel disease. An additional 12 non-inflamed rectal biopsies were also studied. There was between 2 and 8 years of follow-up in each of these cases. Staining for fibrin (MSB, fibrinogen), platelets (factor XIIIA, Y2/51), and capillary basement membrane (reticulin, collagen 4) was performed to identify thrombotic material within capillaries. Mucosal capillary thrombi were best identified by staining for factor XIIIA; thrombi were observed in 8/13 cases of ulcerative colitis, 4/10 cases of Crohn's disease, 1/3 cases of unspecified inflammatory bowel disease and 5/20 cases of self-limited colitis. The presence of capillary thrombi was not related to the severity of inflammation, but none of the control biopsies showed capillary thrombi. Their presence seems of little diagnostic value in distinguishing inflammatory bowel disease from self-limited colitis. The pathogenetic significance of these mucosal capillary thrombi is uncertain.     

Familial neurofibromatosis type 1 associated with an overgrowth syndrome resembling Weaver syndrome.

The simultaneous occurrence of familial neurofibromatosis type 1 (NF1) and an overgrowth syndrome resembling Weaver syndrome was observed in two related cases (a mother and her son). NF1 was confirmed by molecular genetic analysis showing a large deletion at 17q11.2, encompassing the entire NF1 gene. The other symptoms in the two cases were similar to the features reported in Weaver syndrome. Although the combination of NF1 and an overgrowth syndrome resembling Weaver syndrome in this family may be fortuitous, we favour the hypothesis that the deletion of the entire gene has caused this combined phenotype. Possible pathogenetic mechanisms are discussed. The observation suggests a relation between NF1 with an extraordinarily large gene deletion and a Weaver(-like) syndrome. This warrants investigation for deletions in the 17q11.2 region in Weaver(-like) syndrome patients.     

Claudin-4 levels are associated with intact alveolar fluid clearance in human lungs

The removal of edema from the air spaces is a critical function of the alveolar barrier requiring intact tight junctions. Alveolar fluid clearance contributes to graft function after transplantation and is associated with survival in patients with acute lung injury. Claudin-4 concentrations are known to increase during lung injury and the loss of claudin-4 decreases alveolar fluid clearance in mice. This study was therefore undertaken to evaluate whether differences in lung expression of the tight junction protein claudin-4 are associated with alveolar fluid clearance or clinical measures of lung function. Alveolar fluid clearance rates were measured in ex vivo perfused human lungs not used for transplantation and were compared with histological lung injury and clinical measures of lung injury in the donors. Claudin-4 staining demonstrated a positive correlation with alveolar fluid clearance (Spearman rank correlation [r(s)] = 0.71; P < 0.003); however, claudin-4 staining was not strongly associated with histological measures of lung injury. The expression of other tight junction proteins (including ZO-1) was not associated with alveolar fluid clearance or claudin-4 levels. Claudin-4 staining was lower in lungs from donors with greater impairment in respiratory physiology. These data suggest that claudin-4 may promote alveolar fluid clearance and demonstrate that the amount of claudin-4 expressed may provide specific information regarding alveolar epithelial barrier function that strengthens the link between histological changes and physiological impairment.     

Ultrastructural Characteristics of Nucleated Cells in Bone Marrow of Patients with Acquired Aplastic Anemia

The objective of this study was to investigate the ultrastructural characteristics of nucleated cells in the bone marrow of patients with aplastic anemia (AA). This was done by observing the morphology of nucleated cells in bone marrow aspirates from 20 patients with AA by transmission electron microscopy. Erythroblasts were decreased in all cases and not observed in 6 cases. Nuclear abnormalities, such as pyknosis, karyolysis, karyorrhexis, apoptosis, and “Swiss cheese”-like changes, were found in 10 cases. Focal cytoplasmic necrotic changes and cytolysis were found in 3 cases. There were more megaloblasts in 4 cases. Abnormalities of granulocytes were found in 12 out of 18 cases. Megakaryocytes showed focal cytoplasmic necrotic changes. Most monocytes had dendritic features, including excessive cytoplasm, processes, and large round nuclei in all cases. Other monocytes illustrated typical monocytic features with twisted nuclei, plentiful RER, vacuoles, lysosomes, and prominent Golgi apparatus. Macrophages and hemophagocytes occurred in all cases. The incidence of lymphocytes was high in 17 out of 20 cases and occasionally lymphocytes were enlarged in 8 cases. More plasmacytes and plasmacytoid lymphocytes were found in 5 and 3 cases, respectively. The observations suggest that (1) the universal nuclear injury of erythroblasts may be related to the pathogenetic pathway of AA development; (2) the dendritic cells and hemophagocytes from the mononuclear phagocyte system may play a more critical role in hematopoietic failure of AA, directly and/or indirectly; and (3) besides T lymphocytes, increasing numbers of plasmacytes or plasmacytoid lymphocytes are associated with AA in some cases.     

血小板激活因子在小肠缺血再灌注损伤中的意义及山莨菪碱的保护作用

在大鼠小肠原位灌注模型上,发现小肠缺血—再灌注(I-R)损伤时,肠道产生的PAF显著增加;山莨菪碱灌流明显抑制其PAF的产生,并有与PAF受体拮抗剂Kadsurenone相似的抗I-R损伤效应。但山莨菪碱对外源PAF灌流引起的小肠组织损伤无显著防治效果。提示PAF在小肠I-R损伤中具有发病学意义,山莨菪碱可能是通过抑制肠道PAF的产生,而主要不是通过拮抗PAF,以改善小肠的I-R损伤。     

Ultrastructural characteristics of nucleated cells in bone marrow of patients with acquired aplastic anemia

The objective of this study was to investigate the ultrastructural characteristics of nucleated cells in the bone marrow of patients with aplastic anemia (AA). This was done by observing the morphology of nucleated cells in bone marrow aspirates from 20 patients with AA by transmission electron microscopy. Erythroblasts were decreased in all cases and not observed in 6 cases. Nuclear abnormalities, such as pyknosis, karyolysis, karyorrhexis, apoptosis, and "Swiss cheese"-like changes, were found in 10 cases. Focal cytoplasmic necrotic changes and cytolysis were found in 3 cases. There were more megaloblasts in 4 cases. Abnormalities of granulocytes were found in 12 out of 18 cases. Megakaryocytes showed focal cytoplasmic necrotic changes. Most monocytes had dendritic features, including excessive cytoplasm, processes, and large round nuclei in all cases. Other monocytes illustrated typical monocytic features with twisted nuclei, plentiful RER, vacuoles, lysosomes, and prominent Golgi apparatus. Macrophages and hemophagocytes occurred in all cases. The incidence of lymphocytes was high in 17 out of 20 cases and occasionally lymphocytes were enlarged in 8 cases. More plasmacytes and plasmacytoid lymphocytes were found in 5 and 3 cases, respectively. The observations suggest that (1) the universal nuclear injury of erythroblasts may be related to the pathogenetic pathway of AA development; (2) the dendritic cells and hemophagocytes from the mononuclear phagocyte system may play a more critical role in hematopoietic failure of AA, directly and/or indirectly; and (3) besides T lymphocytes, increasing numbers of plasmacytes or plasmacytoid lymphocytes are associated with AA in some cases.     

Thrombotic microangiopathy in cocaine abuse-associated malignant hypertension: report of 2 cases with review of the literature

Cocaine is one of the most commonly used illicit drugs. Acute renal failure is an emergent complication in patients with acute cocaine intoxication. It is well known that rhabdomyolysis and vasoconstriction can be important pathogenetic mechanisms resulting in acute renal failure in these patients. Clinically, although cocaine abuse is associated with elevated blood pressure, persistent accelerated hypertension reaching levels diagnostic of malignant hypertension is uncommon. Cocaine-induced malignant hypertension associated with morphologic features of thrombotic macroangiopathy has been rarely mentioned in the literature. We report 2 cases of cocaine abuse-associated malignant hypertension with renal failure. Kidney biopsies revealed thrombotic microangiopathy with fibrinoid necrosis of arterioles and glomerular tufts. Cocaine-mediated endothelial injury and platelet activation may play important pathogenetic roles in cocaine abusers who develop acute renal failure and malignant hypertension.     

Toxicity of pneumolysin to pulmonary alveolar epithelial cells.

Mortality during the first several days of pneumococcal pneumonia has not decreased appreciably over the past 30 years, despite the widespread use of antibiotics. Disruption of the alveolar epithelial barrier is likely an initial step in the pathogenesis of pneumococcal pneumonia. We report that soluble factors from Streptococcus pneumoniae can directly injure isolated rat alveolar epithelial cells. Using biochemical and immunological techniques, we identified pneumolysin as a major soluble S. pneumoniae toxin for alveolar epithelial cells. Alveolar epithelial cells at 24 or 72 h after isolation were equally sensitive to injury by purified pneumolysin. Purified pneumolysin substantially increased alveolar permeability in an isolated perfused rat lung model. Electron microscopy revealed that instilled pneumolysin caused widespread lung injury, primarily to type I alveolar epithelial cells. Pneumolysin toxicity to alveolar epithelial cells may be important in the pathogenesis of acute lung injury during pneumococcal pneumonia and may facilitate pneumococcal bacteremia.     

Disseminated Tubuloreticular Inclusions in Acquired Immunodeficiency Syndrome (AIDS)

Tissue biopsies and peripheral blood samples from 10 patients with the characteristic clinical features of acquired immunodeficiency syndrome (AIDS) were examined by electron microscopy and ultracytochemical myeloperoxidase technique. Abundant tubuloreticular inclusions (TRI) were detected within the endoplasmic reticulum of capillary endothelial cells, histiocytes, and lymphocytes in kidneys, small bowel, and lymph nodes, and lymphocytes and monocytes from peripheral blood. In general, TRI were found in the same type of cells and with conspicuous high frequency in our cases of AIDS as had been previously described in systemic lupus erythematosus (SLE). These findings indicate a morphologic link between these immunological disorders and the presence of TRI, raising the possibility of similar pathogenetic mechanisms.     

Disseminated tubuloreticular inclusions in acquired immunodeficiency syndrome (AIDS)

Tissue biopsies and peripheral blood samples from 10 patients with the characteristic clinical features of acquired immunodeficiency syndrome (AIDS) were examined by electron microscopy and ultracytochemical myeloperoxidase technique. Abundant tubuloreticular inclusions (TRI) were detected within the endoplasmic reticulum of capillary endothelial cells, histiocytes, and lymphocytes in kidneys, small bowel, and lymph nodes, and lymphocytes and monocytes from peripheral blood. In general, TRI were found in the same type of cells and with conspicuous high frequency in our cases of AIDS as had been previously described in systemic lupus erythematosus (SLE). These findings indicate a morphologic link between these immunological disorders and the presence of TRI, raising the possibility of similar pathogenetic mechanisms.     

Alveolar adenoma of the lung. Immunohistochemical and flow cytometric characteristics of two new cases and a review of the literature

Alveolar adenoma is a rare and benign tumour of the lung that usually presents in asymptomatic patients as a coin lesion on chest radiography. Only 25 cases have been reported in the English medical literature. Alveolar adenoma has a characteristic multicystic histology and often resembles the normal lung parenchyma. Ultrastructural studies indicate that the epithelial cells lining the cysts are type-II pneumocytes. Immunohistochemical analysis may aid in the characterization of alveolar adenoma and discriminate this condition from other types of benign lesions of the lung. An indolent clinical progression and absence of recurrence and metastasis after complete resection are the most important characteristics indicative of the benign nature of alveolar adenoma. Few studies have been conducted at the molecular level, such as by flow cytometry, with the objective of characterizing the biological nature of alveolar adenoma. Differential diagnoses include sclerosing hemangioma, papillary adenoma, lymphangioma, atypical adenomatous hyperplasia and bronchioloalveolar carcinoma. In this article we describe the immunohistochemical and flow cytometric features of this neoplasm in two male patients. Both the tumours showed a diploid DNA pattern with a low proliferation index. p53 test was found to be negative, and post-operative follow-up examinations at 22 and 32 months proved uneventful.