Emerging functions of basophils in protective and allergic immune responses.

Basophils that were long thought to have a redundant role in mast cells in the effector response to allergens and parasites are now being recognized to have important roles in the regulation of adaptive immune responses. Recent data have revealed their role in the initiation of the T helper cell 2 (Th2)-mediated immune response. Not only do basophils guide the Th1-Th2 balance by providing an early source of crucial Th2-skewing cytokines, interleukin (IL)-4 and thymic stromal lymphopoietin, but recent findings have also illustrated their capacity to function as antigen-presenting cells. Thus, basophils activate and instruct naive CD4 T cells, and guide their development into Th2 cells. Not only do basophils directly interact with T cells, but new insights have illustrated that they may also directly guide antibody responses in both the primary and memory responses. These and other studies have illustrated the emerging role of basophils in the regulation of type 2 immunity.

Fas/Fas ligand deficiency results in altered localization of anti-double-stranded DNA B cells and dendritic cells.

Autoantibodies directed against dsDNA are found in patients with systemic lupus erythematosus as well as in mice functionally deficient in either Fas or Fas ligand (FasL) (lpr/lpr or gld/gld mice). Previously, an IgH chain transgene has been used to track anti-dsDNA B cells in both nonautoimmune BALB/c mice, in which autoreactive B cells are held in check, and MRL-lpr/lpr mice, in which autoantibodies are produced. In this study, we have isolated the Fas/FasL mutations away from the autoimmune-prone MRL background, and we show that anti-dsDNA B cells in Fas/FasL-deficient BALB/c mice are no longer follicularly excluded, and they produce autoantibodies. Strikingly, this is accompanied by alterations in the frequency and localization of dendritic cells as well as a global increase in CD4 T cell activation. Notably, as opposed to MRL-lpr/lpr mice, BALB-lpr/lpr mice show no appreciable kidney pathology. Thus, while some aspects of autoimmune pathology (e.g., nephritis) rely on the interaction of the MRL background with the lpr mutation, mutations in Fas/FasL alone are sufficient to alter the fate of anti-dsDNA B cells, dendritic cells, and T cells.

The origin of anti-nuclear antibodies in bcl-2 transgenic mice.

bcl-2 transgenic mice develop anti-double-stranded (ds) DNA antibodies similar to those present in systemic lupus erythematosus. To begin to understand where a breakdown in the regulation of autoreactive lymphocytes is occurring, we have used a bcl-2 transgene (Tg) in conjunction with an Ig Tg that allows us to identify and track anti-dsDNA B cells. Previously, we have shown that anti-dsDNA B cells are actively tolerized in BALB/c mice as manifested by their developmental arrest, follicular exclusion, increased in vivo turnover rate and lack of their antibody in the serum. The bcl-2 Tg mice increased the lifespan of anti-dsDNA B cells, but did not alter the other features of tolerance, indicating that the anergy of the anti-dsDNA B cells is independent of their reduced lifespan. Furthermore, these data suggest that the serum anti-dsDNA antibodies in bcl-2 transgenic mice are not due to a breakdown in the induction or maintenance of B cell anergy; rather they may originate from B cells that have transited through a germinal center.

MRL-lpr/lpr mice exhibit a defect in maintaining developmental arrest and follicular exclusion of anti-double-stranded DNA B cells.

A hallmark of systemic lupus erythematosus and the MRL murine model for lupus is the presence of anti-double-stranded (ds)DNA antibodies (Abs). To identify the steps leading to the production of these Abs in autoimmune mice, we have compared the phenotype and localization of anti-dsDNA B cells in autoimmune (MRL+/+ and lpr/lpr) mice with that in nonautoimmune (BALB/c) mice. Anti-dsDNA B cells are actively regulated in BALB/c mice as indicated by their developmental arrest and accumulation at the T-B interface of the splenic follicle. In the MRL genetic background, anti-dsDNA B cells are no longer developmentally arrested, suggesting an intrinsic B cell defect conferred by MRL background genes. With intact Fas, they continue to exhibit follicular exclusion; however, in the presence of the lpr/lpr mutation, anti-dsDNA B cells are now present in the follicle. Coincident with the altered localization of anti-dsDNA B cells is a follicular infiltration of CD4 T cells. Together, these data suggest that MRL mice are defective in maintaining the developmental arrest of autoreactive B cells and indicate a role for Fas in restricting entry into the follicle.

Characterization of anergic anti-DNA B cells: B cell anergy is a T cell-independent and potentially reversible process.

Anti-single stranded DNA (ssDNA) and anti-double stranded DNA (dsDNA) B cells are regulated in non-autoimmune mice. In this report we show that while both anti-ssDNA and anti-dsDNA B cells are blocked in their ability to differentiate into antibody-secreting cells, other phenotypic and functional characteristics distinguish them from one another. Splenic anti-ssDNA B cells are found distributed throughout the B cell follicle, and are phenotypically mature and long-lived. On the other hand, splenic anti-dsDNA B cells are short-lived, exhibit an immature and antigen-experienced phenotype, and localize to the T-B interface of the splenic follicle. Functionally, anti-ssDNA B cells proliferate, albeit suboptimally, in response to anti-IgM, lipopolysaccharide (LPS) and CD40L/IL-4 + anti-IgM stimulation, and tyrosine phosphorylate intracellular proteins upon mIgM cross-linking. Anti-dsDNA B cells, on the other hand, are functionally unresponsive to anti-IgM and LPS stimulation, and do not phosphorylate intracellular proteins, including Syk, upon mIg stimulation. Importantly, anti-DNA B cell anergy is maintained in the absence of T cells since both anti-ssDNA and anti-dsDNA B cells are as efficiently regulated in RAG2(-/-) mice as in their RAG2(+/+) counterparts. Interestingly, the severely anergic state of anti-dsDNA B cells is partially reversible upon stimulation with CD40 ligand and IL-4. In response to these signals, anti-dsDNA B cells remain viable, up-regulate cell surface expression of B7-2 and IgM, and restore their ability to proliferate and phosphorylate Syk upon mIg cross-linking. Collectively, these data suggest that anti-DNA B cell anergy encompasses distinct phenotypes which, even in its most severe form, may be reversible upon stimulation with T cell-derived factors.

Implementing preventive health measures: a pilot study.

OBJECTIVE: Implementation of preventive services guidelines is performed inconsistently. In an attempt to reduce variation in guideline implementation, we developed a patient questionnaire based on the US Preventive Services Task Force Guide and the Health Plan Employer Data and Information Set 3.0 performance measures of the National Committee on Quality Assurance. SUBJECTS: 100 hospitalized patients of five primary-care physicians. METHODS: In a pilot study, 100 hospitalized patients of five primary-care physicians were questioned about their compliance with evidence-based, preventive healthcare recommendations. Information was requested on blood pressure measurement, cholesterol screening, fecal occult blood testing, smoking-cessation counseling, Pap testing, mammography, postmenopausal hormonal replacement therapy counseling, prostate examination and prostate-specific antigen (PSA) testing, use of aspirin and beta-blockers following an acute myocardial infarction, testing of diabetics for hemoglobin A1c and retinal eye examinations, questioning of the elderly for auditory and visual problems, and receipt of influenza and pneumococcal vaccines. Information on variations from the recommended preventive service was fed back to their physicians. Six months after the initial survey, the patients were requestioned to determine if compliance had improved with the recommendations. RESULTS: We found significant improvement in fecal occult blood testing, smoking cessation, Pap smear testing, mammography use, prostate examinations and PSA testing, hemoglobin A1c testing, seeing or hearing loss follow-up, and the administration of influenza and pneumococcal vaccines. CONCLUSIONS: Improving implementation of preventive services recommendations is a challenge. This pilot study suggests that involving the patient more in the process and informing the physician of the results may improve the process.

Immunolocalization of basic fibroblast growth factor in porcine epiphyseal growth plate.

Recent evidence clearly indicates that basic fibroblast growth factor (bFGF) signal transduction is essential for normal skeletal development. Here, we report that bFGF and its receptor are specifically localized in the terminal hypertrophic chondrocytes of the porcine epiphyseal growth plate, the tissue responsible for longitudinal bone growth. Similar observations were obtained with the chondrocytes immediately adjacent to resorbing blood vessels in the secondary center of ossification of the epiphysis. These results are consistent with a recent proposal that bFGF functions in coupling osteogenesis with chondrogenesis by attracting the vascular invasion of cartilage from adjacent trabecular bone.

Effect of lesion size on the metabolic activity of tibial dyschondroplastic chondrocytes.

Experiments were conducted to determine the influence of lesion size and method of producing tibial dyschondroplasia on metabolic activity of cultured chondrocytes. Genetic selection was one method used to produce a high incidence of tibial dyschondroplasia. Chondrocytes obtained from severe lesions exhibited reduced mitogenic activity (3H-thymidine incorporation) and ability to synthesize matrix proteoglycans (35SO4 incorporation) when compared with normal growth plate and smaller lesions. When a commercial broiler strain was used, all chondrocytes isolated from lesions induced by feeding thiram had reduced metabolic activity. Similar results were observed with severe lesions obtained from copper-deficient chicks. It is concluded that lesion size is an important factor in determining subsequent metabolic activity of chondrocytes isolated from tibial dyschondroplastic lesions.

Cambio de actitud a través de la [quot ]odontología afectiva[quot ]. La entrevista inicial / [Change in attitude toward the [quot ]affective dentist[quot ]. The initial interview]

The role of initial patient assessment as part of a total program designed to change negative attitudes towards the dental visit is discussed. The strategy endorsed is one which takes into account the affective component of a patient’s attitude and allows for its expression trough an empathic client-centered itake. Two case studies area presented as illustrations of this approach.

[Change in attitude toward the "affective dentist". The initial interview]. / Cambio de actitud a través de la "odontología afectiva". La entrevista inicial.

The role of initial patient assessment as part of a total program designed to change negative attitudes towards the dental visit is discussed. The strategy endorsed is one which takes into account the affective component of a patient's attitude and allows for its expression trough an empathic client-centered itake. Two case studies area presented as illustrations of this approach.

Cambio de actitud a través de la [quot ]odontología afectiva[quot ]. La entrevista inicial. / [Change in attitude toward the [quot ]affective dentist[quot ]. The initial interview]

The role of initial patient assessment as part of a total program designed to change negative attitudes towards the dental visit is discussed. The strategy endorsed is one which takes into account the affective component of a patients attitude and allows for its expression trough an empathic client-centered itake. Two case studies area presented as illustrations of this approach.

A biopsychosocial approach to the management of anxious and phobic patients.

In this article, it is suggested that anxious and phobic dental patients represent an important and typically underserved population. A number of practical techniques for their management is offered, taking into account marketplace considerations as well as possible etiologic factors of their avoidance behavior. It is concluded that these patients are indeed tractable and that their incorporation into a dental practice can be highly rewarding for both patient and clinician.