Evaluation of Cyclin D1 as a Discriminatory Immunohistochemical Biomarker for Idiopathic Pulmonary Fibrosis.

BACKGROUND: Distinction of idiopathic pulmonary fibrosis (IPF) from other chronic fibrosing interstitial pneumonitides, such as hypersensitivity pneumonitis (HP) and connective tissue diseases, is critical due to varied biological and clinical outcomes. However, their histologic overlaps often pose diagnostic challenges. A recent study suggested an association of herpesvirus saimiri infection with IPF. Productive viral infection is associated with coexpression of pirated mammalian protein cyclin D1, shown to be overexpressed by immunohistochemistry (IHC) in the regenerating alveolar epithelium in IPF but not in normal lungs. We evaluated the diagnostic utility of cyclin D1 to discriminate between IPF and other fibrosing interstitial lung diseases. MATERIALS AND METHODS: A retrospective study of cyclin D1 IHC expression in 27 consecutive cases of chronic fibrosing interstitial lung diseases from 2011 to 2017: 12 usual interstitial pneumonia (UIP) pattern; 5 nonspecific interstitial pneumonia pattern; 3 HP pattern; 7 unclassifiable was performed. Five cases of normal lung obtained from lobectomy specimen for malignancy are included as control. Immunoreactivity was graded semiquantitatively on a scale of 0 to 3. RESULTS: Cyclin D1 staining was uniformly strongly positive in all cases evaluated in the study, particularly in proliferating type II pneumocytes in the region of fibrosing areas. There was no statistical difference in the extent of cyclin D1 expression between UIP and non-UIP groups (2.7 vs. 2.5) and IPF versus non-IPF groups (2.7 vs. 2.4). Cyclin D1 expression is lower in control group compared with UIP groups (1.2 vs. 2.7). CONCLUSIONS: Cyclin D1 is not a specific marker of UIP pattern/IPF. The high expression of cyclin D1 in lung tissue of fibrosing interstitial pneumonitides regardless of etiology most likely correlates with proliferation in type II pneumocytes.

Claudin-18-mediated YAP activity regulates lung stem and progenitor cell homeostasis and tumorigenesis.

Claudins, the integral tight junction (TJ) proteins that regulate paracellular permeability and cell polarity, are frequently dysregulated in cancer; however, their role in neoplastic progression is unclear. Here, we demonstrated that knockout of Cldn18, a claudin family member highly expressed in lung alveolar epithelium, leads to lung enlargement, parenchymal expansion, increased abundance and proliferation of known distal lung progenitors, the alveolar epithelial type II (AT2) cells, activation of Yes-associated protein (YAP), increased organ size, and tumorigenesis in mice. Inhibition of YAP decreased proliferation and colony-forming efficiency (CFE) of Cldn18-/- AT2 cells and prevented increased lung size, while CLDN18 overexpression decreased YAP nuclear localization, cell proliferation, CFE, and YAP transcriptional activity. CLDN18 and YAP interacted and colocalized at cell-cell contacts, while loss of CLDN18 decreased YAP interaction with Hippo kinases p-LATS1/2. Additionally, Cldn18-/- mice had increased propensity to develop lung adenocarcinomas (LuAd) with age, and human LuAd showed stage-dependent reduction of CLDN18.1. These results establish CLDN18 as a regulator of YAP activity that serves to restrict organ size, progenitor cell proliferation, and tumorigenesis, and suggest a mechanism whereby TJ disruption may promote progenitor proliferation to enhance repair following injury.

Further Studies of Unsuspected Emphysema in Nonsmoking Patients With Asthma With Persistent Expiratory Airflow Obstruction.

BACKGROUND: Previously, we and other investigators have described reversible loss of lung elastic recoil in patients with acute and persistent, moderate-to-severe, chronic, treated asthma who never smoked, and its adverse effect on maximal expiratory airflow. In four consecutive autopsies, we reported the pathophysiologic mechanism(s) has been unsuspected mild, diffuse, middle and upper lobe centrilobular emphysema. METHODS: We performed prospective studies (5 to 22 years) in 25 patients (12 female) with chronic asthma, age 55 ± 15 years, who never smoked, with persistent moderate-to-severe expiratory obstruction. Studies included measuring blood eosinophils, IgE, total exhaled nitric oxide (NO), central airway NO flux, peripheral airway/alveolar NO concentration, impulse oscillometry, heliox curves, lung elastic recoil, and high-resolution thin-section (1 mm) lung CT imaging at full inspiration with voxel quantification. RESULTS: In 25 patients with stable asthma with varying type 2 phenotype, after 270 µg of aerosolized albuterol sulfate had been administered with a metered dose inhaler with space chamber, FVC was 3.1 ± 1.0 L (83% ± 13% predicted) (mean ± SD), FEV1 was 1.8 ± 0.6 L (59% ± 11%), the FEV1/FVC ratio was 59% ± 10%, and the ratio of single-breath diffusing capacity of the lung for carbon monoxide to alveolar volume was 4.8 ± 1.1 mL/min/mm Hg/L (120% ± 26%). All 25 patients with asthma had loss of static lung elastic recoil pressure, which contributed equally to decreased intrinsic airway conductance in limiting expiratory airflow. Lung CT scanning detected none or mild emphysema. In all four autopsied asthmatic lungs previously reported and one unreported explanted lung, microscopy revealed unsuspected mild, diffuse centrilobular emphysema in the upper and middle lung fields, and asthma-related remodeling in airways. In eight cases, during asthma remission, there were increases in measured static lung elastic recoil pressure-calculated intrinsic airway conductance, and measured maximal expiratory airflow at effort-independent lung volumes. CONCLUSIONS: As documented now in five cases, unsuspected microscopic mild centrilobular emphysema is the sentinel cause of loss of lung elastic recoil. This contributes significantly to expiratory airflow obstruction in never-smoking patients with asthma, with normal diffusing capacity and near-normal lung CT scan results. TRIAL REGISTRY: Protocol No. 20070934 and Study No. 1090472, Western Institutional Review Board, Olympia, WA; ClinicalTrials.gov; No. NCT00576069; URL: www.clinicaltrials.gov.

Handling and interpretation of the medical renal biopsy.

Renal biopsy is the gold standard for diagnosis of kidney disease; indeed, it allows for determination of the type, extent, site, and nature of renal involvement in medical diseases, and it alters the clinical diagnosis in as many as 25-50 % of cases. At the same time, it is a relatively safe procedure with life-threatening complications occurring in less than 0.1 % of biopsies. The diagnosis of renal biopsies is complex, requiring correlation of the findings in three modalities: light, immunofluorescence, and electron microscopy. For that reason, appropriate division and fixation of the renal biopsy is required, and protocols for these processes are provided.

Pulmonary nodular lymphoid hyperplasia (pulmonary pseudolymphoma): the significance of increased numbers of IgG4-positive plasma cells.

On the basis of an initial case, we hypothesized that IgG4-positive plasma cells may be increased in pulmonary nodular lymphoid hyperplasia (PNLH) compared with other lymphoid proliferations of the lung. Six cases of PNLH, 9 cases of low-grade B-cell lymphoma of the bronchus-associated lymphoid tissue (BALT), 8 cases of intraparenchymal lymph nodes, 8 cases of either primary or secondary follicular bronchiolitis, and 4 cases of lymphocytic interstitial pneumonitis were stained by immunohistochemical analysis for IgG4 and IgG. The mean number of IgG4-positive and IgG-positive plasma cells and the IgG4/IgG ratio were determined from a manual count of images from 3 separate high-power fields (hpf) of areas showing the highest numbers of stained cells, respectively. The mean number of IgG4-positive plasma cells and the IgG4/IgG ratio were significantly increased in PNLH (IgG4=78/hpf, IgG4/IgG=0.35) compared to low-grade lymphoma of BALT (IgG4=4/hpf, P=0.02; IgG4/IgG=0.03, P=0.005), intraparenchymal lymph nodes (IgG4=7/hpf, P=0.03; IgG4/IgG=0.06, P=0.007), follicular bronchiolitis (IgG4=0/hpf, P=0.02; IgG4/IgG=0, P=0.004), and lymphocytic interstitial pneumonitis (IgG4=2/hpf, P=0.02; IgG4/IgG=0.06, P=0.007). These findings support our current understanding of PNLH as a distinct form of reactive lymphoid proliferation, potentially aid in its distinction from low-grade B-cell lymphoma of BALT, and raise the possibility that PNLH may belong within the family of IgG4-related sclerosing diseases.

Genome-scale analysis of DNA methylation in lung adenocarcinoma and integration with mRNA expression.

Lung cancer is the leading cause of cancer death worldwide, and adenocarcinoma is its most common histological subtype. Clinical and molecular evidence indicates that lung adenocarcinoma is a heterogeneous disease, which has important implications for treatment. Here we performed genome-scale DNA methylation profiling using the Illumina Infinium HumanMethylation27 platform on 59 matched lung adenocarcinoma/non-tumor lung pairs, with genome-scale verification on an independent set of tissues. We identified 766 genes showing altered DNA methylation between tumors and non-tumor lung. By integrating DNA methylation and mRNA expression data, we identified 164 hypermethylated genes showing concurrent down-regulation, and 57 hypomethylated genes showing increased expression. Integrated pathways analysis indicates that these genes are involved in cell differentiation, epithelial to mesenchymal transition, RAS and WNT signaling pathways, and cell cycle regulation, among others. Comparison of DNA methylation profiles between lung adenocarcinomas of current and never-smokers showed modest differences, identifying only LGALS4 as significantly hypermethylated and down-regulated in smokers. LGALS4, encoding a galactoside-binding protein involved in cell-cell and cell-matrix interactions, was recently shown to be a tumor suppressor in colorectal cancer. Unsupervised analysis of the DNA methylation data identified two tumor subgroups, one of which showed increased DNA methylation and was significantly associated with KRAS mutation and to a lesser extent, with smoking. Our analysis lays the groundwork for further molecular studies of lung adenocarcinoma by identifying novel epigenetically deregulated genes potentially involved in lung adenocarcinoma development/progression, and by describing an epigenetic subgroup of lung adenocarcinoma associated with characteristic molecular alterations.

Near fatal asthma: clinical and airway biopsy characteristics.

Background. Inflammation and remodeling are integral parts of asthma pathophysiology. We sought to describe the clinical and pathologic features of near fatal asthma exacerbation (NFE). Methods. Bronchial biopsies were collected prospectively from NFE I subjects. Another NFE II group and a moderate severity exacerbation control group (ME II) were retrospectively identified-no biopsies obtained. Results. All NFE II (n = 9) subjects exhibited remodeling and significant inflammation (eosinophilic, neutrophilic). NFE II group (n = 37) had a significant history of prior intubation and inhaled corticosteroids usage compared to ME II group (n = 41). They also exhibited leukocytosis, eosinophilia, and longer hospitalization days. Conclusions. Remodeling, eosinophilic, and neutrophilic inflammation were observed in NFE. NFE is associated with prior intubation and inhaled corticosteroids usage.

B Cell and BAFF dependence of IFN-α-exaggerated disease in systemic lupus erythematosus-prone NZM 2328 mice.

IFN-α is a potent activator of innate and adaptive immunity, and its administration to preautoimmune (NZB×NZW)F1 mice promotes virulent systemic lupus erythematosus (SLE) disease. Given the known contributions of B cells and BAFF to SLE, we evaluated the ability of IFN-α administration to induce disease in wild-type (WT), B cell-deficient, and BAFF-deficient NZM 2328 mice. Whereas WT mice rapidly developed proliferative glomerulonephritis, marked proteinuria, and increased mortality in response to IFN-α administration, B cell-deficient mice developed neither renal pathology nor clinical disease. Moreover, BAFF-deficient mice, despite developing limited glomerular IgG and C3 deposition, also remained free of histological glomerulonephritis and clinical disease. Strikingly, similar T cell expansion and serum IgG responses were observed in adenovirus (Adv)-IFN-treated WT and BAFF-deficient mice despite their disparate pathological and clinical responses, whereas numbers of activated B cells increased in WT mice but not in BAFF-deficient mice. Nonetheless, B cell, plasma cell, and T cell infiltration of the kidneys in Adv-IFN-treated WT mice was similar to that in WT mice treated with Adv-control. Its ability to promote SLE disease in WT mice notwithstanding, IFN-α administration failed to drive the preferential expansion of CD4(+) memory T cells that occurs during the natural course of disease, and glomerular infiltration of macrophages failed to associate with development of disease. These results collectively suggest that therapeutic targeting in SLE of BAFF and/or B cells in SLE could be successful even in states of IFN-α overexpression. Moreover, our results document important biological differences between IFN-α-driven and spontaneous natural SLE disease.

IgG4-related interstitial lung disease: a new and evolving concept.

PURPOSE OF REVIEW: This review examines recent advances in our knowledge of the clinical, pathological, diagnostic, and therapeutic aspects of IgG4-related interstitial lung disease (ILD). RECENT FINDINGS: A recent case series of ILD with IgG4-positive plasma cells suggested grade 1 lymphomatoid granulomatosis. The presence of the IgG4-positive plasma cells with the lack of atypical cells favored IgG4-related ILD as a diagnosis. In another case study, four out of 30 patients with autoimmune pancreatitis developed pulmonary involvement during follow-up. Elevations of IgG4 and Krebs von den Lungen-6 levels were associated and thought to be predictive of the development of IgG4-related lung disease. A retrospective analysis investigating radiological/pathologic correlation in IgG4 lung disease identified computed tomographic features pathologically corresponding to IgG4-related sclerosing inflammation in the pulmonary interstitium. SUMMARY: IgG4-related ILD is a new and evolving entity. It can occur with or without systemic involvement. Larger studies are necessary to elucidate the exact mechanism and clinical characteristics of this disorder.

Wegener granulomatosis presenting as epididymitis.

Isolated epididymitis is a very rare presentation of Wegener granulomatosis (WG). Only 1 such case has been previously reported. We report a case of epididymitis in which WG was not suspected clinically or pathologically at orchiectomy, and the patient subsequently developed pulmonary involvement with WG. WG was ultimately diagnosed and treated after lung biopsy several months after the orchiectomy. The retrospective pathologic review of the orchiectomy specimen confirmed the presence of WG in the epididymis; the testicular tissue was not involved.

Accelerated pathological and clinical nephritis in systemic lupus erythematosus-prone New Zealand Mixed 2328 mice doubly deficient in TNF receptor 1 and TNF receptor 2 via a Th17-associated pathway.

TNF-alpha has both proinflammatory and immunoregulatory functions. Whereas a protective role for TNF administration in systemic lupus erythematosus (SLE)-prone (New Zealand Black x New Zealand White)F(1) mice has been established, it remains uncertain whether this effect segregates at the individual TNFR. We generated SLE-prone New Zealand Mixed 2328 mice genetically deficient in TNFR1, in TNFR2, or in both receptors. Doubly-deficient mice developed accelerated pathological and clinical nephritis with elevated levels of circulating IgG anti-dsDNA autoantibodies and increased numbers of CD4(+) T lymphocytes, especially activated memory (CD44(high)CD62L(low)) CD4(+) T cells. We show that these cells expressed a Th17 gene profile, were positive for IL-17 intracellular staining by FACS, and produced exogenous IL-17 in culture. In contrast, immunological, pathological, and clinical profiles of mice deficient in either TNFR alone did not differ from those in each other or from those in wild-type controls. Thus, total ablation of TNF-alpha-mediated signaling was highly deleterious to the host in the New Zealand Mixed 2328 SLE model. These observations may have profound ramifications for the use of TNF and TNFR antagonists in human SLE and related autoimmune disorders, as well as demonstrate, for the first time, the association of the Th17 pathway with an animal model of SLE.

Identification of a panel of sensitive and specific DNA methylation markers for squamous cell lung cancer.

BACKGROUND: Lung cancer is the leading cause of cancer death in men and women in the United States and Western Europe. Over 160,000 Americans die of this disease every year. The five-year survival rate is 15% - significantly lower than that of other major cancers. Early detection is a key factor in increasing lung cancer patient survival. DNA hypermethylation is recognized as an important mechanism for tumor suppressor gene inactivation in cancer and could yield powerful biomarkers for early detection of lung cancer. Here we focused on developing DNA methylation markers for squamous cell carcinoma of the lung. Using the sensitive, high-throughput DNA methylation analysis technique MethyLight, we examined the methylation profile of 42 loci in a collection of 45 squamous cell lung cancer samples and adjacent non-tumor lung tissues from the same patients. RESULTS: We identified 22 loci showing significantly higher DNA methylation levels in tumor tissue than adjacent non-tumor lung. Of these, eight showed highly significant hypermethylation in tumor tissue (p < 0.0001): GDNF, MTHFR, OPCML, TNFRSF25, TCF21, PAX8, PTPRN2 and PITX2. Used in combination on our specimen collection, this eight-locus panel showed 95.6% sensitivity and specificity. CONCLUSION: We have identified 22 DNA methylation markers for squamous cell lung cancer, several of which have not previously been reported to be methylated in any type of human cancer. The top eight markers show great promise as a sensitive and specific DNA methylation marker panel for squamous cell lung cancer.

Global T cell dysregulation in non-autoimmune-prone mice promotes rapid development of BAFF-independent, systemic lupus erythematosus-like autoimmunity.

In otherwise non-autoimmune-prone C57BL/6 (B6) mice rendered genetically deficient in CD152 (CTLA-4), polyclonal hypergammaglobulinemia with increased levels of systemic lupus erythematosus (SLE)-associated IgG autoantibodies, glomerular IgG and C3 deposition, and interstitial nephritis all developed by 3-5 wk of age. Remarkably, superimposing genetic deficiency of BAFF (B cell-activating factor belonging to the TNF family) onto CD152 deficiency did not substantially attenuate humoral autoimmunity and immunopathology in these mice, despite the resulting marked reduction in B-lineage cells. Although superimposing a BAFF transgene (resulting in constitutive BAFF overexpression) onto CD152-deficient mice did lead to increases in B-lineage cells and serum levels of certain SLE-associated IgG autoantibodies, renal immunopathology remained largely unaffected. Taken together, these results demonstrate that global T cell dysregulation, even in an otherwise non-autoimmune-prone host, can promote systemic humoral autoimmunity and immunopathology in a BAFF-independent manner. Moreover, supraphysiologic expression of BAFF in the setting of ongoing autoimmunity does not necessarily lead to greater immunopathology. These findings may help explain the limited clinical efficacy appreciated to date of BAFF antagonists in human SLE.

Identification of a panel of sensitive and specific DNA methylation markers for lung adenocarcinoma.

BACKGROUND: Lung cancer is the number one cancer killer of both men and women in the United States. Three quarters of lung cancer patients are diagnosed with regionally or distantly disseminated disease; their 5-year survival is only 15%. DNA hypermethylation at promoter CpG islands shows great promise as a cancer-specific marker that would complement visual lung cancer screening tools such as spiral CT, improving early detection. In lung cancer patients, such hypermethylation is detectable in a variety of samples ranging from tumor material to blood and sputum. To date the penetrance of DNA methylation at any single locus has been too low to provide great clinical sensitivity. We used the real-time PCR-based method MethyLight to examine DNA methylation quantitatively at twenty-eight loci in 51 primary human lung adenocarcinomas, 38 adjacent non-tumor lung samples, and 11 lung samples from non-lung cancer patients. RESULTS: We identified thirteen loci showing significant differential DNA methylation levels between tumor and non-tumor lung; eight of these show highly significant hypermethylation in adenocarcinoma: CDH13, CDKN2A EX2, CDX2, HOXA1, OPCML, RASSF1, SFPR1, and TWIST1 (p-value << 0.0001). Using the current tissue collection and 5-fold cross validation, the four most significant loci (CDKN2A EX2, CDX2, HOXA1 and OPCML) individually distinguish lung adenocarcinoma from non-cancer lung with a sensitivity of 67-86% and specificity of 74-82%. DNA methylation of these loci did not differ significantly based on gender, race, age or tumor stage, indicating their wide applicability as potential lung adenocarcinoma markers. We applied random forests to determine a good classifier based on a subset of our loci and determined that combined use of the same four top markers allows identification of lung cancer tissue from non-lung cancer tissue with 94% sensitivity and 90% specificity. CONCLUSION: The identification of eight CpG island loci showing highly significant hypermethylation in lung adenocarcinoma provides strong candidates for evaluation in patient remote media such as plasma and sputum. The four most highly ranked loci, CDKN2A EX2, CDX2, HOXA1 and OPCML, which show significant DNA methylation even in stage IA tumor samples, merit further investigation as some of the most promising lung adenocarcinoma markers identified to date.

The pathology of pulmonary sarcoidosis: update.

Sarcoidosis is a multi-system disease of unknown etiology, usually affecting the respiratory tract and other organs, and is characterized by the formation of nonnecrotizing epithelioid granulomas. The diagnosis depends on a combination of a typical clinicoradiological presentation, the finding of nonnecrotizing epithelioid granulomas in a tissue biopsy, and exclusion of other possible diseases, especially those of infectious etiology. The granulomas contain epithelioid cells, giant cells, CD4+ T cells in their center, and CD8 + T lymphocytes and B lymphocytes at their periphery. The granulomas are present in a lymphatic pattern around bronchovascular structures and, because of this, may show angioinvasion. The bronchial involvement produces a high diagnostic yield for transbronchial and endobronchial biopsies in this disease. Finally, small amounts of fibrinoid necrosis may occur within granulomas of sarcoidosis and do not exclude the diagnosis. Larger amounts suggest either infection or the rare disease necrotizing sarcoid granulomatosis (NSG). A number of cytoplasmic structures/inclusions can be identified within the granulomas of sarcoidosis, including asteroid bodies, Schaumann's bodies, calcium oxalate crystals, and Hamazaki-Wesenberg bodies; the last two of these can cause difficulties in differential diagnosis. Extra-pulmonary sarcoid can be an important factor in prognosis. Involved sites include (in decreasing frequency): skin, endocrine organs, extra-thoracic lymph nodes, neurologic sites, eyes, liver, spleen, bone marrow, cardiac, ear/nose/throat, parotid/ salivary, muscles, bones/joint, and kidney. NSG is a controversial variant of sarcoidosis consisting of granulomatous pneumonitis with sarcoid-like granulomas, variable amounts of necrosis, and granulomatous vasculitis. The lesions are most often confined to lung, and they usually appear as multiple nodules or nodular infiltrates, but occasionally as solitary or unilateral nodules ranging up to 5 cm in diameter. Nodular sarcoidosis is rare, varying from 1.6% to 4% of patients with sarcoidosis, and, as the name suggests, it shows radiographic nodules measuring 1 to 5 cm in diameter that typically consist of coalescent granulomas. Lung transplantation can be used in selected patients with fibrotic late-stage sarcoidosis. There is a high reported frequency of recurrence of disease in the pulmonary allograft, ranging from 47% to 67%, but recurrence is usually not clinically significant. Studies of the pathogenesis of sarcoidosis suggest that it is a chronic immunological response produced by a genetic susceptibility and exposure to specific environmental factors.

DNA methylation profile of 28 potential marker loci in malignant mesothelioma.

Patients with malignant mesothelioma (MM), an aggressive cancer associated with asbestos exposure, usually present clinically with advanced disease and this greatly reduces the likelihood of curative treatment. MM is difficult to diagnose without invasive techniques; the development of non-invasively detectable molecular markers would therefore be highly beneficial. DNA methylation changes in cancer cells provide powerful markers that are potentially detectable non-invasively in DNA shed into bodily fluids. Here we examined the methylation status of 28 loci in 52 MM tumors to investigate their potential as molecular markers for MM. To exclude candidate MM markers that might be positive in biopsies/pleural fluid due to contaminating surrounding non-tumor lung tissue/DNA, we also examined the methylation of these markers in lung samples (age- or environmentally induced hypermethylation is frequently observed in non-cancerous lung). Statistically significantly increased methylation in MM versus non-tumor lung samples was found for estrogen receptor 1 (ESR1; p = 0.0002), solute carrier family 6 member 20 (SLC6A20; p = 0.0022) and spleen tyrosine kinase (SYK; p=0.0003). Examination of associations between methylation levels of the 28 loci and clinical parameters suggest associations of the methylation status of metallothionein genes with gender, histology, asbestos exposure, and lymph node involvement, and the methylation status of leucine zipper tumor suppressor 1 (LZTS1) and SLC6A20 with survival.

Pulmonary sarcoidosis.

Sarcoidosis, a granulomatous disorder of unknown etiology, characteristically involves multiple organs. However, pulmonary manifestations typically dominate. Chest radiographs are abnormal in 85 to 95% of patients. Abnormalities in pulmonary function tests are common and may be associated with cough, dyspnea, and exercise limitation. However, one third or more of patients are asymptomatic, with incidental abnormalities on chest radiographs. The clinical course and expression of pulmonary sarcoidosis are variable. Spontaneous remissions occur in nearly two thirds of patients. The course is chronic in up to 30% of patients. Chronic pulmonary sarcoidosis may result in progressive (sometimes life-threatening) loss of lung function. Fatalities ascribed to sarcoidosis occur in 1 to 4% of patients. Although the impact of treatment is controversial, corticosteroids may be highly effective in some patients. Immunosuppressive, cytotoxic, or immunomodulatory agents are reserved for patients failing or experiencing adverse effects from corticosteroids. Lung transplantation is a viable option for patients with life-threatening disease failing medical therapy.

Paucity of clinical disease despite serological autoimmunity and kidney pathology in lupus-prone New Zealand mixed 2328 mice deficient in BAFF.

Constitutive overexpression of B cell-activating factor belonging to the TNF family (BAFF) promotes development of systemic lupus erythematosus (SLE), and treatment of SLE mice with BAFF antagonists ameliorates disease. To determine whether SLE can develop de novo in BAFF-deficient hosts, BAFF-deficient New Zealand Mixed (NZM) 2328 (NZM.Baff(-/-)) mice were generated. In NZM.Baff(-/-) mice, spleen B cells (including CD5(+) B1a and CD5(-) B1b B cells), germinal centers, Ig-secreting cells, and T cells were reduced in comparison to NZM.Baff(+/+) mice. Serum total Ig and autoantibody levels were reduced at 4-6 mo but approached wild-type levels with increasing age, indicating that autoreactive B cells can survive and secrete autoantibodies despite the complete absence of BAFF. At least some of these autoantibodies are nephrophilic in that glomerular deposition of total IgG and IgG1 (but not of IgG2a, IgG2b, or C3) was substantial in NZM.Baff(-/-) mice by 12-13 mo of age. Despite proliferative glomerulonephritis, highlighted by widespread glomerular hyaline thrombi, being common among NZM.Baff(-/-) mice by 6-7 mo of age, severe proteinuria and mortality were greatly attenuated. These results demonstrate that the lifelong absence of BAFF does not protect NZM 2328 mice from serological autoimmunity and renal pathology. Nevertheless, the character of the renal pathology is altered, and the mice are largely spared from clinically overt disease (severe proteinuria and premature death). These observations may have profound ramifications for the use of BAFF antagonists in human SLE and related diseases.

The organizing pneumonias : a critical review of current concepts and treatment.

In this comprehensive review, two very closely related interstitial pneumonias are discussed: the cryptogenic form of organizing pneumonia (COP); and secondary forms of organizing pneumonia (OP), which occur in association with identifiable medical conditions. Some newer and lesser known of these associated conditions are described, most importantly post-radiation OP.Rapidly progressive, corticosteroid-resistant and poor prognostic forms of OP have been described. These types purportedly occur more frequently in secondary OP. However, OPs frequently coexist with other interstitial pneumonias, especially when associated with connective tissue diseases. Therefore, tissue sampling error or an incorrect morphologic diagnosis can be the basis for the occurrence of clinically aggressive OPs. By using the 2002 American Thoracic Society/European Respiratory Society diagnostic criteria, some pre-2002 cases reported as OP would be re-classified today.Although COP is considered to have a good prognosis and to be corticosteroid responsive, approximately 70% of patients, treated with corticosteroids, relapse even during initial treatment. Multiple and late relapses occur in about one-third of the patients. We performed a meta-analysis of second-line treatment options for corticosteroid-refractory forms of OP. Three alternative nonsteroid agents - cyclophosphamide, azathioprine, and cyclosporin - have been used in combination with corticosteroids. On careful review, in a number of cases reported as secondary OP, other histologic interstitial patterns besides OP were described. The need for second-line therapy in these patients might have been dictated by the non-organizing pneumonic component. Most of the scant number of reports come from outside the US. World experience with these is limited, but good clinical outcomes have been noted, even in patients with interstitial patterns in addition to OP.The initiation of the OP tissue response in the bronchiolar and sub-bronchiolar location may be due to the presence of bronchiolar-associated lymphoid tissue found at the bifurcations of the bronchioles. Inhaled antigens stimulate granulocyte colony stimulating factor-mediated airway inflammation, followed later by CD44-mediated clearance. Repair requires intrabronchiolar formation of granulation tissue and a favorable ratio of matrix metalloproteinase to tissue inhibitors of metalloproteinase (MMP : TIMP) within the stroma. This reparative milieu allows extracellular matrix degradation and re-synthesis to occur. MMP-expressing fibroblasts then phagocytose the collagen fibrils and microfibrils produced earlier in repair, reversing the initial fibrosis.