Não consta resumo na publicação. / Abstract not available.

Primary immune-mediated hemolytic anemia (IMHA) is an important cause of serious morbidity and mortality in dogs. Despite numerous studies examining the demographics, treatment options, and prognostic indicators of disease, the mechanisms that underlie immune dysregulation remain poorly understood. The purpose of this study was to directly identify unique erythrocyte membrane antigens in dogs diagnosed with primary IMHA. Blood samples were obtained from dogs presented to the Ontario Veterinary College Teaching Hospital with primary IMHA prior to treatment, and also from control dogs (healthy dogs and dogs with non-immunologic anemia). Antibodies bound to erythrocyte membranes were eluted using xylene. Immunoblots using patient eluates reacted against pooled canine erythrocyte lysates, and autologous patient plasma reacted against xylene eluates, were performed. These results were compared to results of similar experiments using samples from control dogs. Bands appearing in patient but not control samples were considered potential autoantigens, and were submitted for identification by liquid chromatography followed by tandem mass spectrometry. Samples from 13 dogs with primary IMHA, 4 dogs with non-immunologic anemia, and 2 healthy dogs, were analyzed. Immunoblotting confirmed the presence of immunoglobulin in eluates from all dogs. Semi-quantitatively, eluates from IMHA patients contained more immunoglobulin than those of control dogs. Mass spectrometry identified complement C3 in patient but not in control dog samples. Additional peptides identified by mass spectrometry in patient but not control dog samples included peroxiredoxin 2 and calpain. The former comprises a cytosolic hydrogen peroxide scavenger, and has been associated with erythrocyte membranes under oxidative stress conditions inducing spherocytosis. Calpain is a calcium-dependent protease that may become activated with oxidative stress and induce erythrocyte apoptosis. These findings suggest that oxidative stress and apoptosis contribute to the pathogenesis of canine IMHA. / OVC Pet Trust Fund, American Kennel Club Canine Health Foundation

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 4 uppsatser.

Não consta resumo na publicação. / Abstract not available.

Sub-acute/chronic inflammatory diseases are often associated with altered inflammatory response, leading to increased host vulnerability to secondary inflammatory challenges. In the first study, by employing streptozotocin (STZ)-induced diabetes in mice, we further investigate mechanisms leading to enhanced polymorphonuclear leukocytes (PMN) response under hyperglycemia. We show that existence of a proinflammatory state associated with broad increases of macrophages in various organs plays a dominant role in promoting PMN response in diabetic mice. Studies of PMN infiltration during zymosan-induced peritonitis reveal that hyperglycemia enhances PMN recruitment through increasing F4/80+ macrophages in the peritoneal cavity. Insulin reversal of hyperglycemia reduces peritoneal macrophage numbers and ameliorates PMN infiltration. Significantly increased macrophages are also observed in the liver, kidneys, and intestines under hyperglycemia, and are attributable to exacerbated nephropathy and colitis when respective inflammatory conditions are induced. We also find that significant monocytosis of inflammatory F4/80+Gr-1+ monocytes from the spleen and macrophage proliferation in situ synergistically contribute to the increased macrophage population under hyperglycemia. In conclusion, our results demonstrate that STZ-induced hyperglycemic/diabetic mice develop a systemic proinflammatory state mediated by broad infiltration of macrophages. In the second study, we focus on the identification of the carrier that binds to and delivers Shiga toxin 2(Stx2) to the target organ causing hemolytic uremic syndrome (HUS). By employing a murine HUS model through co-injection of LPS-Stx2, we show that, adoptive transfer of CD11b+ leukocytes, but not CD11b- leukocytes, RBC, platelets or plasma, isolated from mice with HUS induces HUS in healthy recipients. Interestingly, we find that LPS priming of mice significantly promotes CD11b+ leukocytes binding to Stx2. Compared to CD11b+ leukocytes from mice without LPS priming, CD11b+ leukocytes isolated from mice after LPS priming demonstrate higher frequencies of toxin binding and augmented potency to induce HUS. In sum, our results demonstrate peripheral CD11b+ myeloid leukocytes act as effective Stx2 carriers that deliver toxin to kidneys causing HUS and that LPS-induced inflammation enhances the carrier capacity and aggravates HUS.

Chronic Granulomatous Disease is the most commonly encountered immunodeficiency involving the phagocyte, and is characterized by repeated infections with bacterial and fungal pathogens, as well as the formation of granulomas in tissue. The disease is the result of a disorder of the NADPH oxidase system, culminating in an inability of the phagocyte to generate superoxide, leading to the defective killing of pathogenic organisms. This can lead to infections with Staphylococcus aureus, Psedomonas species, Nocardia species, and fungi (such as Aspergillus species and Candida albicans). Involvement of vital or large organs can contribute to morbidity and/or mortality in the affected patients. Major advances have occurred in the diagnosis and treatment of this disease, with the potential for gene therapy or stem cell transplantation looming on the horizon. © 2011 Song et al; licensee BioMed Central Ltd.

No description available.

Thesis (doctoral)--Lund University, 1997. / Added t.p. with thesis statement inserted. Includes bibliographical references.

Thesis (Ph. D.)--University of Virginia, 2007. / Title from title page. Includes bibliographical references. Also available online through Digital Dissertations.

One of the most effective immunological interventions for human disease prevention is the administration of anti-red blood cell (RBC) IgG, more specifically, anti-D IgG, for prevention of hemolytic disease of the fetus and newborn (HDN), a serious and potentially fatal condition caused by the maternal immune response against the Rhesus (Rh) blood group system D antigen on fetal RBC. Despite its widespread clinical use, the mechanism of the suppressive anti-RBC IgG effect is not fully understood. In a murine model of immunity to foreign RBCs, transfusion of mice with IgG-opsonized RBCs strongly attenuated the antibody response compared to transfusion of untreated RBCs. This model was used to study the anti-RBC IgG effect on the host immune response. Contrary to the predominant theories of the anti-D effect, here it is shown that IgG-mediated RBC clearance is not sufficient for the attenuation of antibody responses. IgG-opsonized RBCs internalized by the mononuclear phagocytic cells could stimulate T and B cell responses against RBC antigens. This thesis also shows that the adaptive tolerance at the T or B cell level is not the reason for the attenuation of the antibody response. Instead, IgG selectively prevented the appearance of antigen-primed RBC-specific B cells and, surprisingly, induced the host B cell response against the IgG in complex with RBCs. These results suggest that the inability of RBC-specific B cells to recognize and present RBC-specific epitopes may explain the inhibitory IgG effect.