Reduced Fas ligand-expressing splenic CD5+ B lymphocytes in severe collagen-induced arthritis

Abstract Introduction The objective was to study immune regulation in a mouse model of rheumatoid arthritis that exhibits considerable heterogeneity of disease activity. Methods T-cell receptor transgenic mice, in which nearly all CD4+ T cells recognize a single peptide of type II collagen, were immunized with collagen and observed for development of arthritis for 4 weeks. At 28 days post-immunization, splenocytes were analyzed by flow cytometry and in vitro assays for markers of immune activation and regulation. Results Disease severities ranging from 0 to 12 (on a 12-point scale) were observed. Among splenic lymphocyte populations, only the CD5+ B-cell subset displayed a decrease in relative numbers as arthritis severity increased. Splenic CD5+ B cells expressed higher levels of Fas ligand (FasL) than did CD4+ T cells or CD5- B cells in all mice, and antigen-dependent T-cell death correlated with higher levels of CD5+ B cells in cocultures. Ratios of interleukin (IL)-17 to interferon-gamma production were higher in antigen-driven cultures of splenocytes from severely arthritic mice compared to mildly or nonarthritic mice. A correlation was established between the reduced production of IL-17 in antigen-driven T-cell/B-cell cocultures and FasL, but not IL-10. Confirmation of the direct killing effect of B cells on T cells was demonstrated using an antigen-specific T hybridoma cell line. Conclusions Reduced numbers of splenic FasL+ CD5+ B cells correlated with increasing arthritis severity and decreased T-cell death in a T-cell receptor transgenic mouse model of collagen-induced arthritis. These 'killer' B cells may provide a novel mechanism for inducing T-cell death as a treatment for arthritis.http://deepblue.lib.umich.edu/bitstream/2027.42/112538/1/13075_2009_Article_2632.pd

T Helper 1 Cellular Immunity Toward Recoverin Is Enhanced in Patients With Active Autoimmune Retinopathy

Autoimmune retinopathy (AIR) causes rapidly progressive vision loss that is treatable but often is confused with other forms of retinal degeneration including retinitis pigmentosa (RP). Measurement of anti-retinal antibodies (ARA) by Western blot is a commonly used laboratory assay that supports the diagnosis yet does not reflect current disease activity. To search for better diagnostic indicators, this study was designed to compare immune biomarkers and responses toward the retinal protein, recoverin, between newly diagnosed AIR patients, slow progressing RP patients and healthy controls. All individuals had measurable anti-recoverin IgG and IgM antibodies by ELISA regardless of disease status or Western blot results. Many AIR patients had elevated anti-recoverin IgG1 levels and a strong cellular response toward recoverin dominated by IFNγ. RP patients and controls responded to recoverin with a lower IFNγ response that was balanced by IL-10 production. Both AIR and RP patients displayed lower levels of total peripheral blood mononuclear cells that were due to reductions of CD4+ TH cells. A comparison of messenger RNA (mRNA) for immune-related genes in whole blood of AIR patients versus RP patients or controls indicated lower expression of ATG5 and PTPN22 and higher expression of several genes involved in TH cell signaling/transcription and adhesion. These data indicate that an immune response toward recoverin is normal in humans, but that in AIR patients the balance shifts dramatically toward higher IFNγ production and cellular activation

Deficiency of regulatory B cells increases allergic airway inflammation

Objective: To investigate the effect of the X-linked immunodeficiency (Xid) B cell defect on the response to the cockroach allergen in mice.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45272/1/11_2005_Article_1387.pd

Sudden acquired retinal degeneration syndrome (SARDS) â a review and proposed strategies toward a better understanding of pathogenesis, early diagnosis, and therapy

Sudden acquired retinal degeneration syndrome (SARDS) is one of the leading causes of currently incurable canine vision loss diagnosed by veterinary ophthalmologists. The disease is characterized by acute onset of blindness due to loss of photoreceptor function, extinguished electroretinogram with an initially normal appearing ocular fundus, and mydriatic pupils which are slowly responsive to bright white light, unresponsive to red, but responsive to blue light stimulation. In addition to blindness, the majority of affected dogs also show systemic abnormalities suggestive of hyperadrenocorticism, such as polyphagia with resulting obesity, polyuria, polydipsia, and a subclinical hepatopathy. The pathogenesis of SARDS is unknown, but neuroendocrine and autoimmune mechanisms have been suggested. Therapies that target these disease pathways have been proposed to reverse or prevent further vision loss in SARDSâ affected dogs, but these treatments are controversial. In November 2014, the American College of Veterinary Ophthalmologists' Vision for Animals Foundation organized and funded a Think Tank to review the current knowledge and recently proposed ideas about disease mechanisms and treatment of SARDS. These panel discussions resulted in recommendations for future research strategies toward a better understanding of pathogenesis, early diagnosis, and potential therapy for this condition.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/122446/1/vop12291.pd

Porphyromonas gingivalis oral infection exacerbates the development and severity of collagen-induced arthritis

Abstract Introduction Clinical studies suggest a direct influence of periodontal disease (PD) on serum inflammatory markers and disease assessment of patients with established rheumatoid arthritis (RA). However, the influence of PD on arthritis development remains unclear. This investigation was undertaken to determine the contribution of chronic PD to immune activation and development of joint inflammation using the collagen-induced arthritis (CIA) model. Methods DBA1/J mice orally infected with Porphyromonas gingivalis were administered with collagen II (CII) emulsified in complete Freund’s adjuvant (CFA) or incomplete Freund’s adjuvant (IFA) to induce arthritis. Arthritis development was assessed by visual scoring of paw swelling, caliper measurement of the paws, mRNA expression, paw micro-computed tomography (micro-CT) analysis, histology, and tartrate resistant acid phosphatase for osteoclast detection (TRAP)-positive immunohistochemistry. Serum and reactivated splenocytes were evaluated for cytokine expression. Results Mice induced for PD and/or arthritis developed periodontal disease, shown by decreased alveolar bone and alteration of mRNA expression in gingival tissues and submandibular lymph nodes compared to vehicle. P. gingivalis oral infection increased paw swelling and osteoclast numbers in mice immunized with CFA/CII. Arthritis incidence and severity were increased by P. gingivalis in mice that received IFA/CII immunizations. Increased synovitis, bone erosions, and osteoclast numbers in the paws were observed following IFA/CII immunizations in mice infected with P gingivalis. Furthermore, cytokine analysis showed a trend toward increased serum Th17/Th1 ratios when P. gingivalis infection was present in mice receiving either CFA/CII or IFA/CII immunizations. Significant cytokine increases induced by P. gingivalis oral infection were mostly associated to Th17-related cytokines of reactivated splenic cells, including IL-1β, IL-6, and IL-22 in the CFA/CII group and IL-1β, tumor necrosis factor-α, transforming growth factor-β, IL-6 and IL-23 in the IFA/CII group. Conclusions Chronic P. gingivalis oral infection prior to arthritis induction increases the immune system activation favoring Th17 cell responses, and ultimately accelerating arthritis development. These results suggest that chronic oral infection may influence RA development mainly through activation of Th17-related pathways.http://deepblue.lib.umich.edu/bitstream/2027.42/112639/1/13075_2013_Article_4062.pd

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Chronic Schistosome Infection Leads to Modulation of Granuloma Formation and Systemic Immune Suppression

Schistosome worms have been infecting humans for millennia, but it is only in the last half century that we have begun to understand the complexities of this inter-relationship. As our sophistication about the inner workings of every aspect of the immune system has increased, it has also become obvious that schistosome infections have broad ranging effects on nearly all of the innate and adaptive immune response mechanisms. Selective pressures on both the worms and their hosts, has no doubt led to co-evolution of protective mechanisms, particularly those that favor granuloma formation around schistosome eggs and immune suppression during chronic infection. The immune modulatory effects that chronic schistosome infection and egg deposition elicit have been intensely studied, not only because of their major implications to public health issues, but also due to the emerging evidence that schistosome infection may protect humans from severe allergies and autoimmunity. Mouse models of schistosome infection have been extremely valuable for studying immune modulation and regulation, and in the discovery of novel aspects of immunity. A progression of immune reactions occurs during granuloma formation ranging from innate inflammation, to activation of each branch of adaptive immune response, and culminating in systemic immune suppression and granuloma fibrosis. Although molecular factors from schistosome eggs have been identified as mediators of immune modulation and suppressive functions of T and B cells, much work is still needed to define the mechanisms of the immune alteration and determine whether therapies for asthma or autoimmunity could be developed from these pathways