Douglas M. England

Inhibition of Interleukin-17 Prevents the Development of Arthritis in Vaccinated Mice Challenged with Borrelia burgdorferi

ABSTRACT We showed that Borrelia burgdorferi-vaccinated interferon gamma-deficient (IFN-γ0) mice challenged with the Lyme spirochete developed a prominent chronic severe destructive osteoarthropathy. The immune response underlying the development of the severe destructive arthritis involves interleukin-17 (IL-17). Treatment of vaccinated IFN-γ0 mice challenged with B. burgdorferi with anti-IL-17 antibody delayed the onset of swelling of the hind paws but, more importantly, inhibited the development of arthritis. Histopathologic examination confirmed that treatment with anti-IL-17 antibody prevented the destructive arthropathy seen in vaccinated and challenged IFN-γ0 mice. Similar preventive results were obtained when vaccinated and challenged IFN-γ0 mice were treated with anti-IL-17 receptor antibody or sequentially with anti-IL-17 antibody followed by anti-IL-17 receptor antibody. By contrast, treatment of vaccinated and challenged IFN-γ0 mice with recombinant IL-17 (rIL-17) did not alter the development and progression of arthritis found in vaccinated and challenged IFN-γ0 mice without treatment with rIL-17. Therapeutic intervention may be a realistic approach to prevent arthritis, especially if IL-17 is involved in the perpetuation of chronic or intermittent arthritis.

Association of CD4+ CD25+ T Cells with Prevention of Severe Destructive Arthritis in Borrelia burgdorferi-Vaccinated and Challenged Gamma Interferon-Deficient Mice Treated with Anti-Interleukin-17 Antibody

ABSTRACT CD4+ CD25+ T cells are a population of regulatory T cells responsible for active suppression of autoimmunity. Specifically, CD4+ CD25+ T cells have been shown to prevent insulin-dependent diabetes mellitus, inflammatory bowel disease, and pancreatitis. Here, we present evidence that CD4+ CD25+ T cells also play a major role in controlling the severity of arthritis detected in Borrelia burgdorferi-vaccinated gamma interferon-deficient (IFN-γ°) C57BL/6 mice challenged with the Lyme spirochete. When B. burgdorferi-vaccinated and challenged IFN-γ° mice were treated with anti-interleukin-17 (IL-17) antibody, the number of CD4+ CD25+ T cells increased in the local lymph nodes. Furthermore, histopathologic examination showed the mice to be free of destructive arthritis. When these anti-IL-17-treated B. burgdorferi-vaccinated and challenged mice were also administered anti-CD25 antibody, the number of CD4+ CD25+ T cells in the local lymph nodes decreased. More importantly, severe destructive arthropathy was induced. In addition, delayed administration of anti-CD25 antibody decreased the severity of the arthritis. These results suggest that CD4+ CD25+ T cells are involved in regulation of a severe destructive arthritis induced with an experimental model of vaccination and challenge with B. burgdorferi.

Occurrence of Severe Destructive Lyme Arthritis in Hamsters Vaccinated with Outer Surface Protein A and Challenged with Borrelia burgdorferi

ABSTRACT Arthritis is a frequent and major complication of infection withBorrelia burgdorferi sensu stricto. The antigens responsible for the induction of arthritis are unknown. Here we provide direct evidence that a major surface protein, outer surface protein A (OspA), can induce arthritis. Hamsters were vaccinated with 30, 60, or 120 μg of recombinant OspA (rOspA) in aluminum hydroxide and challenged with B. burgdorferi sensu stricto isolate 297 or C-1-11. Swelling of the hind paws was detected in 100, 100, and 50% of hamsters vaccinated with 30, 60, or 120 μg of rOspA, respectively. In addition, arthritis developed in 57% of hamsters vaccinated with a canine rOspA vaccine after infection with B. burgdorferisensu stricto. When the canine rOspA vaccine was combined with aluminum hydroxide, all vaccinated hamsters developed arthritis after challenge with B. burgdorferi sensu stricto. Histopathologic examination confirmed the development of severe destructive arthritis in rOspA-vaccinated hamsters challenged with B. burgdorferisensu stricto. These findings suggest that rOspA vaccines should be modified to eliminate epitopes of OspA responsible for the induction of arthritis. Our results are important because an rOspA vaccine in aluminum hydroxide was approved by the Food and Drug Administration for use in humans.

Destructive Arthritis in Vaccinated Interferon Gamma-Deficient Mice Challenged with Borrelia burgdorferi: Modulation by Tumor Necrosis Factor Alpha

ABSTRACT We found that Borrelia burgdorferi-vaccinated gamma interferon-deficient (IFN-γ0) mice challenged with B. burgdorferi developed prominent chronic destructive osteoarthropathy. When these mice were treated with anti-tumor necrosis factor alpha (TNF-α) antibody, the severity of the destructive osteoarthritis was enhanced and affected the mobility of the animals. In addition, extensive swelling of the hind paws occurred. In contrast, treatment of B. burgdorferi-vaccinated, challenged IFN-γ0 mice with recombinant TNF-α (rTNF-α) inhibited the development of arthritis, including swelling of the hind paws. Moreover, treatment of vaccinated, challenged IFN-γ0 mice with anti-TNF-α inhibited fourfold the production of an antibody that kills B. burgdorferi, while treatment of vaccinated, challenged IFN-γ0 mice with rTNF-α slightly elevated the level of the borreliacidal antibody. These results suggest that the level of TNF-α directly or indirectly regulates the production of borreliacidal antibody and the development of vaccine-induced destructive Lyme osteoarthritis. Studies are in progress to determine the mechanism by which TNF-α-dependent cytokines generate the destructive arthritis.

Urodynamic and histological correlates of benign prostatic hyperplasia.

The tissue obtained from transurethral prostatectomies was evaluated histologically and correlated to the clinical findings in 81 patients with benign prostatic hyperplasia. A median of 9 hematoxylin and eosin-stained tissue slides per patient were examined, each containing from 1 to 15 curettings. The patients were divided into 3 groups according to the following histology: predominantly stromal hyperplasia (39 patients), predominantly glandular hyperplasia (29 patients), and equal proportions of stromal and glandular hyperplasia (mixed group, 19 patients). There was no significant difference among the groups in patient age and duration of symptoms. The weight of resected tissue was significantly lower in the stromal group (median 16 mg.), compared to the glandular group (median 20 gm.) and the mixed group (median 25 gm.). Additionally, 29 of the 81 patients had chronic inflammation characterized by multifocal infiltrates of lymphocytes. These patients had significantly larger prostates (median 25 gm.) compared to those without lymphocytic infiltration (median 15 gm.). Sixty-five patients had a 3-month followup examination. Preoperatively there was no difference among the groups in maximum flow at uroflowmetry but at 3-month followup the stromal group had a median maximum flow of 13 ml. per second compared to 16.8 ml. per second in the glandular group and 21.5 ml. per second in the mixed group. These findings document histologically what has been reported from a clinical perspective: the clinical prostatism/benign prostatic hyperplasia complex is a spectrum of histological entities, and the small prostate with predominantly stromal hyperplasia responds less favorably to transurethral resection as determined by urodynamic evaluation.

Interstitial emphysema in adults: recognition and prognostic implications.

Interstitial pulmonary emphysema (IPE) is the initial manifestation of ventilator-induced barotrauma and, if unrecognized, may eventuate in life-threatening complications. It can be diagnosed by certain radiographic criteria that reflect the pathophysiology. These include parenchymal stippling, lucent mottling and streaking, perivascular halos, subpleural cysts, lucent bands, and parenchymal cysts or bullae. In the presence of continuing airway pressure elevation and/or significant underlying lung pathology, certain complications of IPE can be anticipated. These include air leak, air block, secondary infection, and extensive pulmonary fibrosis. In the patient who is already in a state of respiratory compromise, pneumothorax or alteration in cardiovascular dynamics can constitute a terminal event. We believe, therefore, that the earliest possible recognition of the radiographic changes of IPE is critical in the management of the patient who requires ventilatory assistance.

Macrophages interact with enriched populations of distinct T lymphocyte subsets for the induction of severe destructive Lyme arthritis.

Severe destructive Lyme arthritis was detected in the hind paws of hamsters infused with enriched populations of either CD4+ or CD4‐ T lymphocytes along with macrophages exposed in vitro to formalin‐inactivated Borrelia burgdorferi and then infected with the Lyme spirochete. Swelling was detected 4 days after infection, increased rapidly, peaked on day 8 of infection, and gradually decreased. Similarly, severe destructive arthritis was induced in hamsters infused with enriched populations of unfractionated T lymphocytes and macrophages exposed to spirochetes after infection with B. burgdorferi. Histopathological examination affirmed that hamsters infused with CD4+, CD4‐, or unfractionated T lymphocytes and macrophages exposed to B. burgdorferi‐induced arthritis. In addition, macrophages exposed in vitro to B. burgdorferi demonstrated both conventional and coiling phagocytosis, suggesting a mechanism by which CD4+ and CD4‐ T lymphocytes induce arthritis, respectively. These findings demonstrate that both CD4+ and CD4‐ subpopulations of T lymphocytes are capable of interacting with macrophages for the induction of severe destructive Lyme arthritis. J. Leukoc. Biol. 65: 162–170; 1999.

Neutralization of Gamma Interferon Augments Borreliacidal Antibody Production and Severe Destructive Lyme Arthritis in C3H/HeJ Mice

ABSTRACT Development of a high level of sustained borreliacidal antibody is paramount for maintaining protection against infection with Borrelia burgdorferi. We show that production of borreliacidal antibody can be enhanced by preventing the effects of gamma interferon (IFN-γ). When lymph node cells capable of producing borreliacidal antibody were cultured with anti-murine IFN-γ, an eightfold increase in borreliacidal antibody production was obtained. However, anti-IFN-γ treatment of these cells also enhanced their ability to adaptively induce arthritis. When anti-IFN-γ-treated lymph node cells producing borreliacidal antibody were infused into C3H/HeJ mice and the mice were then challenged with B. burgdorferi, the mice developed severe destructive Lyme arthritis. Additional studies are needed to delineate the immune response responsible for the induction of arthritis and production of borreliacidal antibody. These studies are needed to ensure an effective and safe vaccine against infection with B. burgdorferi.

Limitations of the Usefulness of Microvillous Ultrastructure in Distinguishing between Carcinoma Primary in and Metastatic to the Lung

We performed ultrastructural analysis on 70 consecutive patients with solitary cancers in lung with the following histologic classifications: adenocarcinoma (42 cases), bronchioloalveolar carcinoma (13), large cell carcinoma (4), and adenosquamous carcinoma (11). Of these 70 cases, nineteen (13 adenocarcinomas, 4 bronchioloalveolar carcinomas, and 2 adenosquamous carcinomas) contained cell surface microvilli with microvillous core rootlets and/or glycocalyceal bodies. Subsequent clinical followup revealed that three of these 19 cases were actually metastatic colon carcinoma. The remaining 16 patients are currently free of extrathoracic primary disease and are therefore, presumably, primary carcinoma of the lung. Since both primary and metastatic tumors showed cell surfaces with microvilli having core rootlets and glycocalyceal bodies, we conclude that the presence of these ultrastructural features does not always permit the distinction between primary and metastatic adenocarcinoma in lung.

Solitary pulmonary nodule due to cryptococcus neoformans and mycobacterium tuberculosis

This report describes a rare combined infection of Cryptococcus neoformans and Mycobacterium tuberculosis that manifested as a solitary pulmonary nodule in a nonimmunocompromised patient. Transthoracic needle aspiration biopsy was initially nondiagnostic, and histopathologic and culture confirmation of the diagnosis was eventually attained after wedge resection of the nodule. An extensive review of the English literature failed to reveal any reported cases of such a combined infection with a similar clinical presentation. The variable morphologic features of C. neoformans in tissue sections and the protean histologic features of pulmonary cryptococcosis can lead to diagnostic difficulties, as illustrated by this case.