Linda K. Green

Antielastin autoimmunity in tobacco smoking–induced emphysema

Chronic obstructive pulmonary disease and emphysema are common destructive inflammatory diseases that are leading causes of death worldwide. Here we show that emphysema is an autoimmune disease characterized by the presence of antielastin antibody and T-helper type 1 (TH1) responses, which correlate with emphysema severity. These findings link emphysema to adaptive immunity against a specific lung antigen and suggest the potential for autoimmune pathology of other elastin-rich tissues such as the arteries and skin of smokers.

An Immune Basis for Lung Parenchymal Destruction in Chronic Obstructive Pulmonary Disease and Emphysema

ABSTRACT Background Chronic obstructive pulmonary disease and emphysema are a frequent result of long-term smoking, but the exact mechanisms, specifically which types of cells are associated with the lung destruction, are unclear. Methods and Findings We studied different subsets of lymphocytes taken from portions of human lungs removed surgically to find out which lymphocytes were the most frequent, which cell-surface markers these lymphocytes expressed, and whether the lymphocytes secreted any specific factors that could be associated with disease. We found that loss of lung function in patients with chronic obstructive pulmonary disease and emphysema was associated with a high percentage of CD4+ and CD8+ T lymphocytes that expressed chemokine receptors CCR5 and CXCR3 (both markers of T helper 1 cells), but not CCR3 or CCR4 (markers of T helper 2 cells). Lung lymphocytes in patients with chronic obstructive pulmonary disease and emphysema secrete more interferon gamma—often associated with T helper 1 cells—and interferon-inducible protein 10 and monokine induced by interferon, both of which bind to CXCR3 and are involved in attracting T helper 1 cells. In response to interferon-inducible protein 10 and monokine induced by interferon, but not interferon gamma, lung macrophages secreted macrophage metalloelastase (matrix metalloproteinase-12), a potent elastin-degrading enzyme that causes tissue destruction and which has been linked to emphysema. Conclusions These data suggest that Th1 lymphoctytes in the lungs of people with smoking-related damage drive progression of emphysema through CXCR3 ligands, interferon-inducible protein 10, and monokine induced by interferon.

Lung Myeloid Dendritic Cells Coordinately Induce T H 1 and T H 17 Responses in Human Emphysema

Specialized immune cells in the lungs of patients with emphysema create an inflammatory environment that drives lung destruction in a characteristic autoimmune reaction. Dendritic Cells of Destruction Underlie Emphysema Tobacco smoke is never good for your lungs, and in some people it sets up a destructive process called emphysema. In this disease, air sacs that normally exchange carbon dioxide for oxygen become enlarged, ultimately losing their elastic recoil and physiological function. Breathing becomes labored. Even uninfected lungs with emphysema show signs of a complex immune response, with an accumulation of immune cells. To attack the difficult chicken-or-the-egg problem presented by this disease, Shan et al. sorted out which of these cells serve as the ringleaders in orchestrating this immune reaction and, in the process, found the telltale presence of T helper 17 (TH17) cells—a recently identified hallmark of autoimmune inflammation. Cigarette smoke causes irritation in the lung and activates a general defensive reaction via the innate immune system. When this system cannot restore tissue health, the more precise adaptive immune system comes into play. The authors of Shan et al. now show that specialized professional antigen-presenting cells—called dendritic cells—are recruited by a chemoattractant into the lung, where they induce naïve CD4 T cells to develop into TH1 cells. These immune agents then help cytotoxic T cells to target damaged host lung tissue for destruction. Also induced by the dendritic cells are TH17 cells. These specialized T lymphocytes normally protect the barriers between the body and the environment (the skin and the gut lining, for example), but they also congregate at sites in which the body is erroneously attacking itself, as in autoimmune diseases such as rheumatoid arthritis and colitis. The cytokine interleukin-17A secreted by the TH17 cells coordinates their contribution to destruction of the lung in emphysema by causing lung macrophages to secrete two critical molecules: CCL20, a chemoattractant for the dendritic cells, which then set up an inflammatory positive feedback loop, and matrix metalloproteinase 12 (MMP12), a potent enzyme that destroys a lung endogenous protective proteinase called α1-antitrypsin. In the industrialized world, the ultimate cause of emphysema is usually smoking, but in developing countries, smoke from cooking fires and pollution are important factors in the development of this disease, which is a leading cause of death worldwide. Even after removal of the respiratory irritant, the disease progression is only slowed and existing lung damage is irreversible. Medications can ease the shortness of breath but are not a cure. A lung transplant or partial lung removal is a last resort available only to a few fortunate individuals (see Cypel et al. in this issue). Identification of the cellular players—like the dendritic and TH17 cells described by Shan et al.—through which smoke causes lung destruction is a key to discovering drugs that effect damage control. Moreover, the injurious cellular cycles established in the emphysematous lung are likely not unique, and their elucidation will undoubtedly uncover clues to other immune-related diseases that are associated with smoking. Exposure to tobacco smoke activates innate and adaptive immune responses that in long-term smokers have been linked to diseases of the lungs, cardiovascular system, joints, and other organs. The destruction of lung tissue that underlies smoking-induced emphysema has been associated with T helper 1 cells that recognize the matrix protein elastin. Factors that result in the development of such autoreactive T cells in smokers remain unknown but are crucial for further understanding the pathogenesis of systemic inflammatory diseases in smokers. Here, we show that lung myeloid dendritic cells were sufficient to induce T helper 1 and T helper 17 responses in CD4 T cells. T helper 1 and 17 cells are invariably present in lungs from patients with emphysema but not in lungs from normal individuals. Interleukin-17A, a canonical T helper 17 cytokine, enhanced secretion of CCL20, a chemoattractant for dendritic cells, and matrix metalloproteinase 12, a potent elastolytic proteinase, from lung macrophages. Thus, although diverse lung factors potentially contribute to T helper effector differentiation in vivo, lung myeloid dendritic cells direct the generation of pathogenic T cells and support a feedback mechanism that sustains both inflammatory cell recruitment and lung destruction. This mechanism may underlie disease in other elastin-rich organs and tissues.

Role of nuclear grading in stage I renal cell carcinoma

Through a retrospective histologic analysis of 55 cases of Stage I renal cell carcinoma, we evaluated the usefulness of the nuclear grading system (Fuhrman, Lasky, Limas) in identifying those tumors that will eventually metastasize and kill the patient. The difference in five-year survival rates between patients with combined nuclear grade 1-3 tumors (n = 50, 91%) and grade 4 tumors (n = 5, 9%) was significant (P less than 0.0046). Other predictors of death due to renal cell carcinoma included: tumor size greater than 8 cm (P less than 0.001) and mitoses greater than one per 10 high-power field (P less than 0.01). Within Stage I tumors, therefore, nuclear grade is an important morphologic variable for predicting long-term survival. Identification of nuclear grade 4 neoplasms may become prognostically indispensable to determine the metastatic potential of early-stage tumors and thereby to institute appropriate systemic therapy.

Renal cell carcinoma metastatic to the thyroid

Metastatic renal cell carcinoma to the thyroid is an uncommon occurrence that can cause clinical and pathologic problems in diagnosis. The authors report seven cases from the files of The University of Texas M. D. Anderson Cancer Center, Houston, Texas. Each presented clinically as a palpable thyroid nodule months or years after the primary renal cell carcinoma had been resected. Although renal cell carcinoma is more common in men, we found a female predominance of 6:1 in this series. These lesions appear as solitary “cold” nodules on iodine 131 scans and may be misdiagnosed as primary thyroid neoplasms, especially if the renal primary is still unrecognized. A correct diagnosis is important because surgical management can be curative. The diagnosis is facilitated by the use of fat stains, electron microscopic study, and immunoperoxidase stains.

Intracranial metastases as the first manifestation of prostate cancer

We report on 2 patients with neurologic symptoms secondary to intracranial metastases from carcinoma of the prostate. In one of these patients, the intracranial lesion was the only clinically detectable metastasis. We have found only three other such cases reported in the English-language literature.

DNA flow cytometry as a predictor of outcome of Stage I renal cell carcinoma

The features most frequently used in predicting the outcome of renal cell carcinoma are stage at presentation and nuclear grade. Recently DNA ploidy pattern, as detected by DNA flow cytometry has also been shown to be predictive. In this study DNA flow cytometry was performed on formalin‐fixed paraffin‐embedded tissue from 50 patients with Stage I renal cell carcinoma for whom long‐term follow‐up data were available. Two were eliminated for technical reasons. Of the 48 evaluable tumors, 25 (52%) were diploid, 19 (40%) were nondiploid, and in four, (8%) the ploidy was uncertain. The ploidy pattern was statistically significantly associated with nuclear grade (P < 0.02), and primary tumor size (P < 0.05) but did not correlate with cell type, microscopic growth pattern, or the presence or absence of mitotic activity. In the group as a whole, ten patients (21%) died of renal cell carcinoma, seven of 19 (37%) with nondiploid tumor patterns, and two of 25 (8%) with a diploid pattern (P < 0.03). One of four patients (25%) with tumors of uncertain ploidy also died. However, only two factors, nuclear grade and primary tumor size, were independent predictors of outcome. For Stage I renal cell carcinoma, ploidy can significantly predict patient outcome and correlates with nuclear grade and tumor size, but is not an independent predictive variable.

Squamous cell carcinoma of the pancreas

Squamous cell carcinoma of the pancreas is a controversial entity. Although some reports show that it is metastatic from another source, others demonstrate that it is a primary tumor. Between 1988 and 1997, fourteen cases of pancreatic squamous cell carcinoma were identified in the records of our pathology department. In seven instances the features were consistent with squamous cell carcinoma with no adenomatous component. The records of six of these patients were available for review and constitute the basis for this report. Five patients were diagnosed by means of percutaneous CT-guided fine-needle aspiration, whereas the sixth patient was diagnosed using a transduodenal core needle biopsy. At the time of diagnosis four patients had lung lesions, three patients had liver lesions, and two patients had lyric bone lesions. One patient had a 6 cm esophageal lesion. Surgical intervention had no impact on treatment or palliation in one of the patients. Chemotherapy and radiation therapy, alone or in combination, were ineffective in all patients. Median survival from the time of diagnosis was 2 months. We conclude that in cases of squamous cell carcinoma of the pancreas, every effort should be made to exclude adenomatous components histologically within the tumor and to exclude another primary source of squamous cell carcinoma. This will allow a better understanding of this entity and a refinement of therapy.

Histopathologic findings in ectopic tubal pregnancy.

In 141 consecutive cases of tubed ectopic pregnancy at Hermann Hospital in Houston, Texas, the histologic appearance of 129 surgically removed fallopian tubes containing ectopic pregnancies was reviewed and compared with an age- and race-matched control population. There was a higher incidence of chronic salpingitis (88 versus 2%) and salpingitis isthmica nodosa (SIN) (43 versus 5%). The ectopic pregnancy patients had a higher incidence of pelvic inflammatory disease, gonorrhea, previous abortions, bitubal ligation, intrauterine device use, and previous abdominal surgery. In our population, chronic salpingitis was the most commonly associated finding. The increase in SIN was associated with postinflammatory changes (89%). We also found that ectopic tubal pregnancies may grow either intratubally or extratubally by vil-lous invasion into the wall and blood vessels; therefore, surgical salvage of the fallopian tube by extracting the products of conception will not always be curative.

Assessment of Liver Histology in Chronic Alcoholics with and Without Hepatitis C Virus Infection

Patients with alcoholic liver disease have a high prevalence of hepatitis C virus (HCV) infection. The histological appearances of the liver in patients with alcoholic liver disease and HCV infection are well described. However, liver histology in individuals with dual pathology, both chronic alcohol abuse and HCV infection, is less well understood. The purpose of the present study was to examine this issue and to determine if there is any correlation between specific histological features and the serum biochemical abnormalities seen in these patients. Eighty-six chronic alcoholics, 65 with HCV infection and 21 uninfected subjects, were included in the study. All patients had history of heavy alcohol abuse (consuming 80 g or more of ethanol a day for at least 10 years). The following data were collected on each patient: demographic information (age, gender, race), the amount and duration of alcohol intake, biochemical results, and liver biopsy abnormalities including the histological activity index (HAI) score. HCV-infected alcoholics were younger (P = 0.05) and were more often African American than Caucasian (P < 0.01). Alcohol consumption was significantly greater in uninfected alcoholics compared to those with HCV infection (P < 0.05). Liver histology in subjects with HCV infection showed higher HAI scores for intralobular necrosis (P = 0.008) and periportal inflammation (P = 0.004). Features of “chronic hepatitis” and focal lymphoid aggregates were more frequent in HCV-infected alcoholics (P = 0.001 for each). By contrast, cirrhosis was present in a higher proportion of uninfected alcoholics compared to those with HCV infection (P = 0.05). Histological findings of hepatic fibrosis and total HAI score showed a significant correlation with serum albumin and platelet count in HCV-infected alcoholics. Chronic alcoholics with HCV infection have specific histological appearances that can usually help distinguish these patients from uninfected alcoholics. Correlation analysis indicates that of the various laboratory tests, serum albumin and platelet counts are the best predictors of the severity of liver damage at histology. In chronic alcoholics, the development of cirrhosis is related more to the amount of alcohol consumed than to the presence of HCV infection.