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N Solvason

Publications and source records attributed to N Solvason.

18 recordsLinked to original sources
PubMed2000

Chemokines in autoimmune diseases.

Autoimmune diseases like multiple sclerosis (MS) and insulin-dependent diabetes (IDD) are believed to be mediated by pathogenic CD4+ autoreactive T cells which mediate selective destruction of specific host cells. Interrupting the trafficking of such T cells from host circulation to the sites of pathology, such as the central nervous system in the case of MS and the pancreas in the case of IDD, potentially offers a novel opportunity for therapeutic intervention in these diseases. The following summarizes our evolving thoughts on the role of the chemokine network in MS and IDD, and focuses on the chemokine receptor CXCR3 as a potential target for impeding T-cell-mediated destruction in these disease settings.

Autoimmune Diseases↗
PubMed2000

Cyclin D2 is essential for BCR-mediated proliferation and CD5 B cell development.

Progression into G(1) in B lymphocytes is regulated by cyclins D2 and D3, components of the cell cycle machinery currently believed to have overlapping and potentially redundant roles in cell cycle control. To study the specific role of cyclin D2 in B lymphocyte proliferation, we examined B cells from cyclin D2(-/-) mice and demonstrate a specific requirement for cyclin D2 in BCR- but not CD40- or lipopolysaccharide-induced proliferation. Furthermore, conventional B cell development proceeds normally in the mutant mice; however, the CD5 B cell compartment is dramatically reduced, suggesting that cyclin D2 is important in CD5 B cell development as well as antigen-dependent B cell clonal expansion.

Animals↗
PubMed1999

A conformationally-constrained MHC class II I-Ag7-derived peptide protects NOD mice from the development of diabetes.

Allele-specific peptide vaccination against disease-associated MHC class II molecules is a promising new strategy for modulating self-antigen presentation to autoreactive T cells in autoimmune diseases. To evaluate the potential of this approach for treatment of insulin-dependent diabetes mellitus (IDDM), we have designed a cyclic peptide vaccine, DiavaX, from the third hypervariable region of the beta-chain of the NOD mouse MHC class II I-Ag7. NOD mice were treated at 5 and 9 weeks of age with 100 microg DiavaX emulsified in alum, a control peptide in alum, or alum alone. At the end of the study, 87% of alum treated mice had developed diabetes, compared with only 28% of DiavaX-treated mice. None of the control peptides, including a linear I-Ag7, a scrambled cyclic I-Ag7, or an analogous cyclic I-Aspeptide, reduced the incidence of diabetes, demonstrating that the protective effect of DiavaX is conformationally dependent and both allele- and sequence-specific. DiavaX treatment did not cause any general immune suppression, but did induce peptide-specific antibodies and memory T cells. DiavaX-induced protection from diabetes was associated with the maintenance of a non-destructive islet-associated autoimmune response. These data indicate that a conformationally constrained peptide from the disease-associated MHC represents a potential vaccine candidate for the prevention of clinical IDDM.

Amino Acid Sequence↗
PubMed1998

Transgene expression of bcl-xL permits anti-immunoglobulin (Ig)-induced proliferation in xid B cells.

Mutations in the tyrosine kinase, Btk, result in a mild immunodeficiency in mice (xid). While B lymphocytes from xid mice do not proliferate to anti-immunoglobulin (Ig), we show here induction of the complete complement of cell cycle regulatory molecules, though the level of induction is about half that detected in normal B cells. Cell cycle analysis reveals that anti-Ig stimulated xid B cells enter S phase, but fail to complete the cell cycle, exhibiting a high rate of apoptosis. This correlated with a decreased ability to induce the anti-apoptosis regulatory protein, Bcl-xL. Ectopic expression of Bcl-xL in xid B cells permitted anti-Ig induced cell cycle progression demonstrating dual requirements for induction of anti-apoptotic proteins plus cell cycle regulatory proteins during antigen receptor mediated proliferation. Furthermore, our results link one of the immunodeficient traits caused by mutant Btk with the failure to properly regulate Bcl-xL.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed1998

CD38: a new paradigm in lymphocyte activation and signal transduction.

CD38 is a type II transmembrane glycoprotein that is extensively expressed on cells of hematopoietic and non-hematopoietic lineage. Although the intracellular domain of CD38 is not homologous to any known proteins, the extracellular domain of CD38 is structurally related to enzymes in the ADP-ribosyl cyclase family. The structural homology between CD38 and the cyclase family members extends to functional homology, as the extracellular domain of CD38 can mediate the catalysis of beta-NAD+ into nicotinamide, ADP-ribose (ADPR) and, to a lesser extent, into cyclic ADPR-ribose (cADPR). Extensive investigation in other systems has shown that cADPR is an important regulator of intracellular Ca2+ release. Since engagement of CD38 on hematopoietic cells with anti-CD38 Abs has been shown to have potent effects on a number of in vitro cellular responses, we have speculated that cADPR might control CD38-mediated signal transduction. However, it has been difficult to understand how a mediator which is typically an intracellular signaling molecule could potentiate its effects from an extracellular location, thus posing a dilemma which pertains to all ecto-enzymes and the mechanisms by which they regulate signal transduction and cellular processes. This review describes the biologic properties of murine CD38, its role in humoral immunity, and its signal transduction properties in B lymphocytes. We suggest that signaling through CD38 represents a new paradigm in lymphocyte signal transduction and is predicated upon extracellular, rather than intracellular, crosstalk.

ADP-ribosyl Cyclase↗
PubMed1997

The earliest T lineage-committed cells depend on IL-7 for Bcl-2 expression and normal cell cycle progression.

Interleukin-7 (IL-7)-deficient mice exhibit an early defect in lymphopoiesis. We examined Bcl-2 expression and the cell cycle status of immature thymocyte subsets in these mice. In IL-7-deficient mice, developmental transition to a T cell-committed fate was accompanied by a striking loss of Bcl-2 protein expression and an increased relative proportion of cells in the G0/G1 stage of the cell cycle. Short-term culture of immature thymocytes with rIL-7 caused up-regulation of Bcl-2 protein and cell survival. These data specify a T cell lineage developmental transition point, prior to T cell antigen receptor rearrangement, where IL-7 signal transduction is linked to an anti-apoptosis mechanism and the cell cycle.

Animals↗
PubMed1996

Induction of cell cycle regulatory proteins in anti-immunoglobulin-stimulated mature B lymphocytes.

Progression through the cell cycle is a tightly controlled process that integrates signals generated at the plasma membrane with the proteins that form the cell cycle machinery. The current study chronicles the induction of cyclins, cyclin-dependent kinases (cdk), and cdk inhibitors in low density primary mouse B lymphocytes after anti-immunoglobulin plus interleukin 4 (IgM + IL-4) stimulation. In this system, > 85% of cells remain in the G0/G1 phase of cell cycle for an initial 24-h period, followed by entry of up to 50% of the cells into S phase, commencing around 30 h and peaking at 48 h. Extensive time course analyses of these anti-IgM + IL-4-stimulated B cells revealed that the G1-associated D-type cyclins D2 and D3 were induced by 3 h after stimulation, and that cyclins E, A, and B were subsequently induced sequentially, beginning at mid-G1, G1/S transition, and S phase, respectively. The G1-associated cyclin D1 was not expressed at any stage of the anti-Ig + IL-4-induced B cell cycle. cdk2, cdk4, and cdk6 were induced during G1, whereas cell division cycle-2 (cdc2) was induced concomitantly with S phase. Irrespective of their expression, the kinases cdk2 and cdc2 were only active from S phase onwards, suggesting that productive cyclin/kinase complex formation did not occur until that time. Cell cycle inhibitors p21 and p19 were induced by anti-Ig + IL-4, peaking in expression at mid-G1 and S phase, respectively. Stimulation of low density B cells with anti-Ig + IL-4 caused rapid down regulation of the p27 inhibitor, however this protein was reexpressed at 54-96 h after stimulation. In contrast, B cells stimulated with anti-CD40, a stimulus which induces long-term B cell proliferation, permanently down regulated p27. These findings are consistent with the concept that p27 reexpression contributes to the G1 arrest that follows antigen receptor crosslinking. Low density B cells cultured in the viability-enhancing cytokine IL-4 alone also showed induction of D2 and D3 cyclin expression. However, the D2 expression was transient, and the D3 expression was substantially lower than that observed in B cells induced to proliferate by anti-Ig + IL-4. This partial induction of D2 and D3 expression may explain IL-4's ability to promote B cell entry into G1 but not S phase of cell cycle, and furthermore, its ability to truncate G1 progression when B cells are subsequently stimulated with anti-Ig.

Animals↗
PubMed1996

Association between Alzheimer's disease and bound autochthonous IgM on T cells.

OBJECTIVE: To determine whether there is an association between the number of peripheral T cells binding IgM per total T cell population (%IgM+ T cells) and dementia. DESIGN: Cross-sectional study. SETTING: Two inpatient and two outpatient sites at a university medical center. PARTICIPANTS: Fifty-three adults. MEASUREMENTS: Peripheral blood was collected from each individual, and the %IgM+ T cells was determined by flow cytometry. The data obtained by medical record chart review were analyzed to determine whether the %IgM+ T cells correlated with cognitive diagnoses, demographic variables, medical diagnoses, or prescribed medications. RESULTS: The %IgM+ T cells was negatively correlated with MMSE scores (r = -.33, P = .016). There was a significant difference in the mean %IgM+ T cells between Alzheimer's disease (AD) and non-AD patients (35.6% +/- 30.2% vs 14.6% +/- 23.9%, P < .001) but no statistically significant association between the mean %IgM+ T cells and age, sex, race, prescribed medications (except gastrointestinal (GI) medications), or medical diagnoses (except stroke). After statistically controlling for GI medications and stroke, AD remained independently associated with the %IgM+ T cells (P = .008). CONCLUSIONS: Patients with AD had significantly more of their T cells coated with IgM than did non-AD patients.

Aged↗
PubMed1995

Murine CD38: an immunoregulatory ectoenzyme.

CD38 is an ectoenzyme that utilizes NAD+ and is expressed by many cells of hematopoietic origin. Antibodies to CD38 potentiate many biological activities on lymphocytes, including induction of murine B-cell proliferation. In this article, Frances Lund and colleagues summarize information concerning the expression, enzymatic activity and signal transduction pathway utilized by murine CD38.

ADP-ribosyl Cyclase↗
PubMed1995

CD38 unresponsiveness of xid B cells implicates Bruton's tyrosine kinase (btk) as a regular of CD38 induced signal transduction.

CD38 is a 42 kDa membrane-associated ectoenzyme expressed by a large proportion of human and mouse lymphocytes. Agonistic antibodies to CD38 induce a strong proliferative response in lymphocytes additionally co-stimulated with other growth co-factors such as IL-4, IL-2 plus accessory cells or sub-mitogenic doses of endotoxin. We show here that B lymphocytes from unstimulated X-linked immunodeficient (xid) mice are unresponsive to CD38 stimulation, both in terms of proliferative response and surface antigen modulation. This CD38 unresponsiveness is evident in the presence of excess quantities of, and normal responses to, the accessory growth co-stimulants required for this response. CD38 molecules expressed on xid B cells are normal in terms of expression levels, size and enzymatic activity, suggesting that CD38 unresponsiveness reflects a down-stream signaling defect. In light of the recent proposal that the xid gene encodes a tyrosine kinase called Bruton's tyrosine kinase (btk), these data suggest that btk is either an integral component or an indirect regulator of the CD38-induced signal transduction pathway.

ADP-ribosyl Cyclase↗
PubMed1992

The fetal omentum in mice and humans. A site enriched for precursors of CD5 B cells early in development.

From these studies the fetal omentum appears to be an important site of B-cell generation in humans and a source of CD5 B cells in mice. We have analyzed the fetal omentum in other species and have found that B-cell development as determined by the presence of cytoplasmic IgM+ pre-B cells is also detected in the fetal rabbit omentum. We do not know if there is bias towards the production of CD5 B cells in this species; however, these preliminary results demonstrate that this site may be conserved throughout evolution in mammals as a site of B-cell generation. Because the fetal liver is also a source of precursors that can reconstitute this B-cell subset, what is the relationship between omentum and liver during the development of Ly-1 B cells? The most obvious relationship between these two sites is that cells simply migrate from one location to the other; that is, precursor cells may migrate from the fetal liver into the fetal omentum and in this milieu give rise to exclusively Ly-1+ B cells or the sister population. Alternatively, precursors of Ly-1 B cells may arise in the omentum and migrate to the liver. This is demonstrated graphically in the diagram (Fig. 6a) of a transverse section through an 8-week human fetus. In this paper, however, we suggest a model for the development of Ly-1+ B cells from the omentum and liver in which Ly-1 B cells arise from distinct precursors located in situ in the mesodermally derived omentum and mesothelial-derived liver capsule. The omentum primordia forms as the back to back fusion of the mesodermally derived lining of the peritoneal cavity, and this lining surrounds the developing gut when the liver begins to develop as an outgrowth of the intestinal primordia at approximately 3.5 weeks gestation; the outer covering or capsule of the liver is derived from the same tissue of origin as the omentum. Figure 6B is a diagram of a section through the same plane as Figure 6A but the body wall has been omitted. We propose that the Ly-1+ B cells arise in situ in the omentum and lining of the liver as indicated in Figure 6B. That Ly-1+ B cells arise from distinct precursors has been suggested by others, but ours is the first evidence for a developmental site that apparently contains B-cell progenitors for this B-cell subset.

Animals↗
PubMed1992

The human fetal omentum: a site of B cell generation.

The fetal mouse omentum has been shown to be a source of precursors that exclusively reconstitutes Ly1+ B cells and the closely related Ly1- sister population, but not conventional B cells or T cells. We have extended these studies to compare B cell development in the human fetal omentum, liver, and spleen, and to demonstrate that the pro/pre-B cell compartment (CD24+, sIgM-) is detected in the omentum and liver but not spleen as early as 8 wk of gestation. From 8 to 12 wk of gestation, the proportions of IgM+ cells that were pre-B cells (cIgM+/sIgM-) in the omentum and liver were 53 +/- 15% and 45 +/- 13%, respectively, and IgM+ cells were not detectable in the spleen. After 12 wk, the percentage of pre-B cells was unchanged in the fetal liver (41 +/- 10%) but decreased significantly in the omentum (25 +/- 14%); pre-B cells were now detected in the spleen but at much lower percentages (2 +/- 3%) than either the omentum or liver. The nuclear enzyme, Tdt, was detected in approximately 25% of the CD24+ cells in the omentum and liver during the 8-12-wk time period, however, Tdt+ cells were not detected in the spleen. Approximately 40% of the mature B cells found in the omentum and spleen were CD5+ compared with only 20% in the liver. These results demonstrate that the fetal omentum, like the fetal liver and bone marrow, is a primary site of B cell development.

Antibodies, Monoclonal↗
PubMed1992

Development and function of the early B cell repertoire.

The early B cell repertoire is characterized by extensive interconnectivity, autoreactivity and multispecificity. Our preliminary sequence analysis of some of the idiotype specific antibodies is beginning to provide molecular clues to explain the observed multireactivity and the expression of shared idiotypic determinants on immunoglobulins of early B cells. The VH gene rearrangements analyzed are typical of the early pre-B cell and CD5 B cell repertoire. Some of these include shared or identical CDR3 regions resulting from the use of germline VH, D and JH gene segments in the absence of N region addition. As previously described, the most D proximal VH genes are also used most frequently. Collectively these genetic restrictions, together with the lack of somatic mutation, suggest that the characteristic self reactivity of the early B cell repertoire is related to the expression of germline gene segments and limited use of diversification mechanisms. It has also been possible for the first time to isolate hybridomas secreting functional IgM molecules which use the most D proximal VH gene, VH81X. These antibodies and another example from the VH7183 family have a broad multireactivity pattern possibly because of the presence of an unusually high number of charged amino acid groups present in the VH region. These findings are preliminary and more extensive studies are needed to establish if these groups are responsible for the highly cross-reactive nature of these antibodies. Nevertheless, these unusual characteristics signify a unique role for antibodies expressing this VH gene during B cell development. It is also clear that the observed anti-lymphocyte reactivity, another feature of the newborn repertoire, is the result of the prevalence of B cells using similar if not identical VHDJH genes and DJH joins. The development of these B cells appears to occur consistently in early ontogeny and, again, are not found in conventional splenic B cells obtained from the normal adult. Understanding the functional significance of the early appearance of these antibodies may help to clarify and understand their role during development as well as in autoimmunity. We propose that the unique self reactive nature of the early repertoire provides a pattern within which self-assertiveness develops and results in the establishment of the adult repertoire. In doing so, dominant clones are established which may or may not be within, but whose selection and differentiation is directed by the CD5 B cell subset.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

An embryonic source of Ly1 but not conventional B cells.

Ly1+ B cells differ from conventional B cells with respect to their anatomical localization, cell surface marker expression, and antibody repertoire suggesting that they may constitute a functionally distinct subset of B cells. To determine whether Ly1+ B cells also have a developmentally distinct site of origin we grafted various fetal primordia into adult severe combined immunodeficient (scid) mice and analyzed their potential to give rise to T and B cells. We demonstrated that fetal omentum, but not spleen or thymus grafts, reconstituted exclusively Ly1 B cells (including the Ly1 sister population) as well as a population of IgM and IgA producing plasma cells in the spleen and gut, respectively. Although thymus grafts regularly reconstituted T cells, thymus plus fetal omentum cografts gave rise to a population of Ly1+ B cells as well as T cells which were also derived from omentum. However, in neither omentum nor omentum plus thymus cografts were conventional B cells detected. These results provide the first evidence that Ly1 B cells but not conventional B cells are generated from the fetal omentum.

Animals↗