Biomedical subjects

D A Steeber

Publications and source records attributed to D A Steeber.

43 records · Page 3Linked to original sources

PubMed1996

CD19 regulates B lymphocyte signaling thresholds critical for the development of B-1 lineage cells and autoimmunity.

CD19 serves as a cell surface response regulator that establishes signaling thresholds critical for B lymphocyte development and activation. B lymphocytes from CD19-deficient mice are hyporesponsive to transmembrane signals, while B lymphocytes from mice that overexpress CD19 to even a small extent (25% increase) become hyperresponsive. The B-1 subpopulation of B lymphocytes is particularly sensitive to CD19 regulation, since their development is severely decreased in CD19-deficient mice. The effect of altered CD19 expression levels on the development of B cells was therefore examined using transgenic mice that express varying levels of cell surface CD19. In this study, immature B cells within the bone marrow of wild-type mice were found to specifically up-regulate CD19 expression levels by twofold as they mature, while CD5+ B cells within the spleen and peritoneum expressed even higher levels of CD19. The development of CD5+ B cells was severely decreased in CD19-deficient mice, while there was a linear correlation between increased CD19 expression levels and the increased frequency of CD5+ B cells within the peritoneum and spleen. In fact, CD5+ B cells became a major B lymphocyte population in mice that overexpressed CD19. Increased expression of CD19 also correlated with increased levels of endogenous anti-DNA Abs and rheumatoid factor. These results indicate that up-regulated expression of CD19 is functionally important for B cell development and that CD19 establishes signaling thresholds that regulate the generation of B-1 lymphocytes as well as the development of autoantibodies.

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PubMed1996

Lyphocyte migration in L-selectin-deficient mice. Altered subset migration and aging of the immune system.

Lymphocyte trafficking across high endothelial venules (HEV) of peripheral lymph nodes (PLN) is dependent upon lymphocyte expression of L-selectin. Mice that lack this adhesion molecule provide an opportunity to determine the long-term role of L-selectin-mediated migration in the maintenance of leukocyte subpopulations. HEV in L-selectin-deficient mice were phenotypically, morphologically, and functionally comparable with wild-type mice, although there was a 70 to 90% reduction in the number of lymphocytes within PLN. These lymphocytes most likely entered PLN through the afferent lymphatics, since they did not migrate into PLN of normal mice during short-term homing experiments. The impaired trafficking of lymphocytes across PLN-HEV resulted in the accumulation of memory (CD18highCD44high) lymphocytes within PLN, and also altered the distribution of lymphocyte subpopulations within other tissues. Specifically, a 30 to 55% increase in splenic cellularity occurred due to increases in both naive and memory lymphocytes. Circulating lymphocyte numbers or subpopulations were not altered in young L-selectin-deficient mice, but circulating monocyte numbers were increased nearly threefold. In contrast, older L-selectin-deficient mice had disproportionate increases of both naive and memory CD4+ T cells present within spleen and blood. These results and the finding that memory lymphocytes in wild-type mice expressed L-selectin demonstrate a requirement for L-selectin in the regulation of memory lymphocyte migration. Therefore, L-selectin-dependent pathways of lymphocyte migration are important for the normal migration of both naive and memory lymphocytes.

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PubMed1995

The CD19 signal transduction molecule is a response regulator of B-lymphocyte differentiation.

The phenotypes of CD19-deficient (CD19-/-) mice, and human CD19-transgenic (hCD19TG) mice that overexpress CD19 indicate that CD19 is a response regulator of B-lymphocyte surface receptor signaling. To further characterize the function of CD19 during B-cell differentiation, humoral immune responses to a T-cell-independent type 1 [trinitrophenyl-lipopolysaccharide (TNP-LPS)], a T-cell-independent type 2 [dinitrophenyl (DNP)-Ficoll], and a T-cell-dependent [DNP-keyhole limpet hemocyanin (KLH)] antigen were assessed in CD19-/- and hCD19TG mice. B cells from CD19-/- mice differentiated and underwent immunoglobulin isotype switching in vitro in response to mitogens and cytokines. In vivo, CD19-/- mice generated humoral responses to TNP-LPS and DNP-KLH that were dramatically lower than those of wild-type littermates. Surprisingly, the humoral response to DNP-Ficoll was significantly greater in CD19-/- mice. In contrast, hCD19TG mice were hyperresponsive to TNP-LPS and DNP-KLH immunization but were hyporesponsive to DNP-Ficoll. These results demonstrate that CD19 is not required for B-cell differentiation and isotype switching but serves as a response regulator which modulates B-cell differentiation. Since humoral responses to both T-cell-dependent and T-cell-independent antigens were similarly affected by alterations in CD19 expression, these differences are most likely to result from intrinsic changes in B-cell function rather than from the selective disruption of B-cell interactions with T cells.

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PubMed1995

L-selectin-deficient mice have impaired leukocyte recruitment into inflammatory sites.

L-selectin, a cell surface adhesion molecule that is expressed by most leukocytes, mediates leukocyte rolling along vascular endothelium at sites of inflammation. The contribution of L-selectin to leukocyte migration in models of chronic inflammation was assessed by using mice that lack cell surface L-selectin expression. Significant inhibition of neutrophil (56-62%), lymphocyte (70-75%), and monocyte (72-78%) migration into an inflamed peritoneum was observed 24 and 48 h after administration of thioglycollate, an inflammatory stimulus. L-selectin-deficient mice were also significantly impaired in delayed-type hypersensitivity reactions. Footpad swelling in response to sheep red blood cell challenge was reduced 75% in L-selectin-deficient mice compared with wild-type mice. Ear swelling in a model of contact hypersensitivity induced by oxazolone challenge was also reduced by 69% compared to wild-type mice. Consistent with L-selectin-mediating leukocyte migration into diverse vascular beds during inflammation, L-selectin-deficient mice were significantly resistant to death resulting from lipopolysaccharide (LPS)-induced toxic shock. LPS administration resulted in a 90% mortality rate in control mice after 24 h, while there was a 90% survival rate in L-selectin-deficient mice. These results demonstrate that L-selectin plays a prominent role in leukocyte homing to nonlymphoid tissues during inflammation and that blocking this process can be beneficial during pathological inflammatory responses.

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PubMed1995

The selectins: vascular adhesion molecules.

The selectin family of adhesion molecules mediates the initial attachment of leukocytes to venular endothelial cells before their firm adhesion and diapedesis at sites of tissue injury and inflammation. The selectin family consists of three closely related cell-surface molecules with differential expression by leukocytes (L-selectin), platelets (P-selectin), and vascular endothelium (E- and P-selectin). The selectins have characteristic extracellular regions composed of an amino-terminal lectin domain that binds a carbohydrate ligand, an epidermal growth factor-like domain, and two to nine short repeat units homologous to domains found in complement binding proteins. In contrast to most other adhesion molecules, selectin function is restricted to leukocyte interactions with vascular endothelium. Multiple studies indicate that the selectins mediate neutrophil, monocyte, and lymphocyte rolling along the venular wall. The generation of selectin-deficient mice has confirmed these findings and provided further insight into how the overlapping functions of these receptors regulate inflammatory processes. Selectin-directed therapeutic agents are now proven to be effective in blocking many of the pathological effects resulting from leukocyte entry into sites of inflammation. Future studies are focused on how the selectins interact with the increasing array of other adhesion molecules and inflammatory mediators.

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PubMed1990

Advances in corrosion casting methods.

This paper briefly discusses the concept of corrosion cast preparation (primarily of blood vessels), the use of the scanning electron microscope (SEM) to study these casts and the observations which can be made, together with the merits and the limitations in various applications. A number of reviews and surveys are quoted in which the different injection media, injection methods, animal preparations and corrosion procedures are described. A new procedure of cleaning the corrosion casts with sodium hydroxide and Triton X-100 is described. The observations which can be made are listed and illustrated both on the cellular level as well as in organ systems as a whole. The discussion centers around some common misconceptions, the feasibility in various applications and the limitations of the method. The conclusion is that the method has proven to be useful especially in conjunction with other methods. Moreover, while the concept of the method may be very straight-forward the approach and the interpretation often need careful consideration and might not be as straight-forward as one tends to expect from the simple sounding principle.

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PubMed1987

Vascular changes in popliteal lymph nodes due to antigen challenge in normal and lethally irradiated mice.

The microvascular system of the murine popliteal lymph node was investigated using scanning electron microscopy of microcorrosion casts. Time-dependent changes in the microvasculature following regional antigen challenge in normal and lymphocyte-depleted mice were studied. Normal lymph node microvasculature exhibited a significant increase in both the vascular bed and post-capillary venules containing high-endothelium in response to antigen challenge. Lymph nodes of lymphocyte-depleted mice showed no microvascular size increase following antigen challenge and a reduction in the amount of high-endothelium was observed.

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