Susan R. Schwab, Ph.D.

Lipid phosphate phosphatase 3 enables efficient thymic egress
Breart, Beatrice; Ramos-Perez, Willy D; Mendoza, Alejandra; Salous, Abdelghaffar K; Gobert, Michael; Huang, Yong; Adams, Ralf H; Lafaille, Juan J; Escalante-Alcalde, Diana; Morris, Andrew J; Schwab, Susan R
2011 Jun 6;208(6):1267-1278, Journal of experimental medicine
The signaling lipid sphingosine-1-phosphate (S1P) stabilizes the vasculature, directs lymphocyte egress from lymphoid organs, and shapes inflammatory responses. However, little is known about how S1P distribution is controlled in vivo, and it is not clear how a ubiquitously made lipid functions as a signal that requires precise spatial and temporal control. We have found that lipid phosphate phosphatase 3 (LPP3) enables efficient export of mature T cells from the thymus into circulation, and several lines of evidence suggest that LPP3 promotes exit by destroying thymic S1P. Although five additional S1P-degrading enzymes are expressed in the thymus, they cannot compensate for the loss of LPP3. Moreover, conditional deletion of LPP3 in either epithelial cells or endothelial cells is sufficient to inhibit egress. These results suggest that S1P generation and destruction are tightly regulated and that LPP3 is essential to establish the balance
— id: 134311, year: 2011, vol: 208, page: 1267, stat: Journal Article,

Cortical sinus probing, S1P1-dependent entry and flow-based capture of egressing T cells
Grigorova, Irina L; Schwab, Susan R; Phan, Tri Giang; Pham, Trung H M; Okada, Takaharu; Cyster, Jason G
2009 Jan;10(1):58-65, Nature immunology
The cellular dynamics of the egress of lymphocytes from lymph nodes are poorly defined. Here we visualized the branched organization of lymph node cortical sinuses and found that after entry, some T cells were retained, whereas others returned to the parenchyma. T cells deficient in sphingosine 1-phosphate receptor type 1 probed the sinus surface but failed to enter the sinuses. In some sinuses, T cells became rounded and moved unidirectionally. T cells traveled from cortical sinuses into macrophage-rich sinus areas. Many T cells flowed from medullary sinuses into the subcapsular space. We propose a multistep model of lymph node egress in which cortical sinus probing is followed by entry dependent on sphingosine 1-phosphate receptor type 1, capture of cells in a sinus region with flow, and transport to medullary sinuses and the efferent lymph
— id: 94653, year: 2009, vol: 10, page: 58, stat: Journal Article,

Sympathetic cardiovascular hyperactivity precedes brain death
Intravooth, T; Marthol, H; Hilz, MJ; De Fina, P; Schwab, S
2009 OCT ;285(5):S320-S320, Journal of the neurological sciences
— id: 106961, year: 2009, vol: 285, page: S320, stat: Journal Article,

Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate
Pappu, Rajita; Schwab, Susan R; Cornelissen, Ivo; Pereira, Joao P; Regard, Jean B; Xu, Ying; Camerer, Eric; Zheng, Yao-Wu; Huang, Yong; Cyster, Jason G; Coughlin, Shaun R
2007 Apr 13;316(5822):295-298, Science
Lymphocytes require sphingosine-1-phosphate (S1P) receptor-1 to exit lymphoid organs, but the source(s) of extracellular S1P and whether S1P directly promotes egress are unknown. By using mice in which the two kinases that generate S1P were conditionally ablated, we find that plasma S1P is mainly hematopoietic in origin, with erythrocytes a major contributor, whereas lymph S1P is from a distinct radiation-resistant source. Lymphocyte egress from thymus and secondary lymphoid organs was markedly reduced in kinase-deficient mice. Restoration of S1P to plasma rescued egress to blood but not lymph, and the rescue required lymphocyte expression of S1P-receptor-1. Thus, separate sources provide S1P to plasma and lymph to help lymphocytes exit the low-S1P environment of lymphoid organs. Disruption of compartmentalized S1P signaling is a plausible mechanism by which S1P-receptor-1 agonists function as immunosuppressives
— id: 74368, year: 2007, vol: 316, page: 295, stat: Journal Article,

Finding a way out: lymphocyte egress from lymphoid organs
Schwab, Susan R; Cyster, Jason G
2007 Dec;8(12):1295-1301, Nature immunology
The egress of lymphocytes from the thymus and secondary lymphoid organs into circulatory fluids is essential for normal immune function. The discovery that a small-molecule inhibitor of lymphocyte exit, FTY720, is a ligand for sphingosine 1-phosphate (S1P) receptors led to studies demonstrating that S1P receptor type 1 (S1P1) is needed in T cells and B cells for their egress from lymphoid organs. S1P exists in higher concentrations in blood and lymph than in lymphoid organs, and this differential is also required for lymphocyte exit. Transcriptional and post-translational mechanisms regulate S1P1 and thus the egress of lymphocytes. In this review we discuss the body of evidence supporting a model in which lymphocyte egress is promoted by encounter with S1P at exit sites. We relate this model to work examining the effects of S1P receptor agonists on endothelium
— id: 94654, year: 2007, vol: 8, page: 1295, stat: Journal Article,

Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients
Schwab, Susan R; Pereira, Joao P; Matloubian, Mehrdad; Xu, Ying; Huang, Yong; Cyster, Jason G
2005 Sep 9;309(5741):1735-1739, Science
Lymphocyte egress from the thymus and from peripheral lymphoid organs depends on sphingosine 1-phosphate (S1P) receptor-1 and is thought to occur in response to circulatory S1P. However, the existence of an S1P gradient between lymphoid organs and blood or lymph has not been established. To further define egress requirements, we addressed why treatment with the food colorant 2-acetyl-4-tetrahydroxybutylimidazole (THI) induces lymphopenia. We found that S1P abundance in lymphoid tissues of mice is normally low but increases more than 100-fold after THI treatment and that this treatment inhibits the S1P-degrading enzyme S1P lyase. We conclude that lymphocyte egress is mediated by S1P gradients that are established by S1P lyase activity and that the lyase may represent a novel immunosuppressant drug target
— id: 74359, year: 2005, vol: 309, page: 1735, stat: Journal Article,

All the peptides that fit: the beginning, the middle, and the end of the MHC class I antigen-processing pathway
Shastri, Nilabh; Cardinaud, Sylvain; Schwab, Susan R; Serwold, Thomas; Kunisawa, Jun
2005 Oct;207:31-41, Immunological reviews
The end result of the antigen-processing pathway is the display of peptide-bound major histocompatibility complex I (pMHC I) molecules. The pMHC I molecules are expressed on the cell surface where they can be surveyed by CD8(+) T cells for abnormal proteins. MHC I molecules present a large repertoire of peptides that fit perfectly in their binding grooves and represent the otherwise hidden intracellular contents. Many peptides originate as defective ribosomal products in the cytoplasm. In a stepwise manner, the antigen-processing pathway generates and protects the proteolytic intermediates until they yield the final peptides that can fit the MHC I in the endoplasmic reticulum
— id: 74361, year: 2005, vol: 207, page: 31, stat: Journal Article,

Reduced competitiveness of autoantigen-engaged B cells due to increased dependence on BAFF
Lesley, Robin; Xu, Ying; Kalled, Susan L; Hess, Donna M; Schwab, Susan R; Shu, Hong-Bing; Cyster, Jason G
2004 Apr;20(4):441-453, Immunity
Peripheral autoantigen binding B cells are poorly competitive with naive B cells for survival and undergo rapid cell death. However, in monoclonal Ig-transgenic mice lacking competitor B cells, autoantigen binding B cells can survive for extended periods. The basis for competitive elimination of autoantigen binding B cells has been unknown. Here we demonstrate that autoantigen binding B cells have increased dependence on BAFF for survival. In monoclonal Ig-transgenic mice, each autoantigen binding B cell receives elevated amounts of BAFF, exhibiting increased levels of NFkappaB p52 and of the prosurvival kinase Pim2. When placed in a diverse B cell compartment, BAFF receptor engagement and signaling are reduced and the autoantigen binding cells are unable to protect themselves from Bim and possibly other death-promoting factors induced by chronic BCR signaling. These findings indicate that under conditions where BAFF levels are elevated, autoantigen-engaged cells will be rescued from rapid competitive elimination, predisposing to the development of autoimmune disease
— id: 74349, year: 2004, vol: 20, page: 441, stat: Journal Article,

Unanticipated antigens: translation initiation at CUG with leucine
Schwab, Susan R; Shugart, Jessica A; Horng, Tiffany; Malarkannan, Subramaniam; Shastri, Nilabh
2004 Nov;2(11):e366-e366, PLoS biology
Major histocompatibility class I molecules display tens of thousands of peptides on the cell surface for immune surveillance by T cells. The peptide repertoire represents virtually all cellular translation products, and can thus reveal a foreign presence inside the cell. These peptides are derived from not only conventional but also cryptic translational reading frames, including some without conventional AUG codons. To define the mechanism that generates these cryptic peptides, we used T cells as probes to analyze the peptides generated in transfected cells. We found that when CUG acts as an alternate initiation codon, it can be decoded as leucine rather than the expected methionine residue. The leucine start does not depend on an internal ribosome entry site-like mRNA structure, and its efficiency is enhanced by the Kozak nucleotide context. Furthermore, ribosomes scan 5' to 3' specifically for the CUG initiation codon in a eukaryotic translation initiation factor 2-independent manner. Because eukaryotic translation initiation factor 2 is frequently targeted to inhibit protein synthesis, this novel translation mechanism allows stressed cells to display antigenic peptides. This initiation mechanism could also be used at non-AUG initiation codons often found in viral transcripts as well as in a growing list of cellular genes
— id: 74351, year: 2004, vol: 2, page: e366, stat: Journal Article,

Constitutive display of cryptic translation products by MHC class I molecules
Schwab, Susan R; Li, Katy C; Kang, Chulho; Shastri, Nilabh
2003 Sep 5;301(5638):1367-1371, Science
Major histocompatibility complex (MHC) class I molecules display tens of thousands of peptides on the cell surface, derived from virtually all endogenous proteins, for inspection by cytotoxic T cells (CTLs). We show that, in normal mouse cells, MHC I molecules present a peptide encoded in the 3' 'untranslated' region. Despite its rarity, the peptide elicits CTL responses and induces self-tolerance, establishing that immune surveillance extends well beyond conventional polypeptides. Furthermore, translation of this cryptic peptide occurs by a previously unknown mechanism that decodes the CUG initiation codon as leucine rather than the canonical methionine
— id: 74346, year: 2003, vol: 301, page: 1367, stat: Journal Article,

Producing nature's gene-chips: the generation of peptides for display by MHC class I molecules
Shastri, Nilabh; Schwab, Susan; Serwold, Thomas
2002 ;20:463-493, Annual review of immunology
Gene-chips contain thousands of nucleotide sequences that allow simultaneous analysis of the complex mixture of RNAs transcribed in cells. Like these gene-chips, major histocompatibility complex (MHC) class I molecules display a large array of peptides on the cell surface for probing by the CD8(+) T cell repertoire. The peptide mixture represents fragments of most, if not all, intracellular proteins. The antigen processing machinery accomplishes the daunting task of sampling these proteins and cleaving them into the precise set of peptides displayed by MHC I molecules. It has long been believed that antigenic peptides arose as by-products of normal protein turnover. Recent evidence, however, suggests that the primary source of peptides is newly synthesized proteins that arise from conventional as well as cryptic translational reading frames. It is increasingly clear that for many peptides the C-terminus is generated in the cytoplasm, and N-terminal trimming occurs in the endoplasmic reticulum in an MHC I-dependent manner. Nature's gene-chips are thus both parsimonious and elegant
— id: 74344, year: 2002, vol: 20, page: 463, stat: Journal Article,

No association between the dopamine D3 receptor Bal I polymorphism and schizophrenia in a family-based study of a Palestinian Arab population
Kremer, I; Rietschel, M; Dobrusin, M; Mujaheed, M; Murad, I; Blanaru, M; Bannoura, I; Muller, D J; Schulze, T G; Reshef, A; Gathas, S; Schwab, S; Wildenauer, D; Bachner-Melman, R; Belmaker, R H; Maier, W; Ebstein, R P
2000 Dec 4;96(6):778-780, American journal of medical genetics
Several recent meta-analyses appear to show a weak but significant effect of both forms of the gly/ser DRD3 polymorphism in conferring risk for schizophrenia. Since most studies have employed the artifact-prone case-control design, we thought it worthwhile to examine the role of this polymorphism using a robust family-based strategy in an ethnic group not previously systematically studied in psychiatric genetics, Palestinian Arabs. We failed to obtain any evidence in 129 Palestinian triads, using the haplotype relative risk (allele frequency: Pearson chi-square = 0.009, P > 0.1, df = 1, n = 258 alleles) or transmission disequilibrium test design (chi-square = 0.38, P > 0.1, n = 86 families) for association/linkage (or increased homozygosity) of the DRD3 Bal I polymorphism to schizophrenia in our sample. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:778-780, 2000
— id: 149617, year: 2000, vol: 96, page: 778, stat: Journal Article,

Searching for susceptibility genes in schizophrenia by genetic linkage analysis
Wildenauer, D B; Hallmayer, J; Schwab, S G; Albus, M; Eckstein, G N; Zill, P; Honig, S; Strauss, M; Borrmann, M; Lichtermann, D; Ebstein, R P; Lerer, B; Risch, N; Maier, W
1996 ;61:845-850, Cold Spring Harbor symposia on quantitative biology
— id: 149644, year: 1996, vol: 61, page: 845, stat: Journal Article,

Evaluation of a susceptibility gene for schizophrenia on chromosome 6p by multipoint affected sib-pair linkage analysis
Schwab, S G; Albus, M; Hallmayer, J; Honig, S; Borrmann, M; Lichtermann, D; Ebstein, R P; Ackenheil, M; Lerer, B; Risch, N
1995 Nov;11(3):325-327, Nature genetics
The influence of genetic factors in schizophrenia has been convincingly demonstrated by family, twin and adoption studies, but the mode of transmission remains uncertain. The reported pattern of recurrence risks suggests a set of interacting loci. Based on prior evidence for linkage on chromosome 6p (K. Kendler, pers. comm.), we have scanned the short arm of chromosome 6 in 54 families for loci predisposing to schizophrenia, using 25 microsatellite markers spanning 60 centiMorgans (cM). Allele sharing identity by descent was examined in affected sib-pairs from these families, followed by multipoint sib-pair linkage analysis. Positive lod scores were obtained over a wide region (D6S470 to D6S271), with a maximum lod score of 2.2 occurring near D6S274, located in 6p22. However, we obtained a lod score of -2 at D6S296, the locus found by others to provide the greatest linkage evidence. At D6S274, we report a positive lod score as do Straub et al. (individually non-significant). A combined total lod of 3.6-4.0 suggests the possibility of a susceptibility locus in this region. However, methodological differences between our studies makes a firm conclusion difficult
— id: 149646, year: 1995, vol: 11, page: 325, stat: Journal Article,