The Experts below are selected from a list of 1464 Experts worldwide ranked by ideXlab platform
Bushra Husain - One of the best experts on this subject based on the ideXlab platform.
-
The Immunoglobulin Superfamily Receptome Defines Cancer-Relevant Networks Associated with Clinical Outcome.
Cell, 2020Co-Authors: Erik Verschueren, Bushra Husain, Kobe C. Yuen, Yi Sun, Sairupa Paduchuri, Yasin Senbabaoglu, Isabelle Lehoux, Tia A Arena, Blair Wilson, Steve LianoglouAbstract:Cell surface receptors and their interactions play a central role in physiological and pathological signaling. Despite its clinical relevance, the immunoglobulin superfamily (IgSF) remains uncharacterized and underrepresented in databases. Here, we present a systematic extracellular protein map, the IgSF interactome. Using a high-throughput technology to interrogate most single transmembrane receptors for binding to 445 IgSF proteins, we identify over 500 interactions, 82% previously undocumented, and confirm more than 60 receptor-ligand pairs using orthogonal assays. Our study reveals a map of cell-type-specific interactions and the landscape of dysregulated receptor-ligand crosstalk in cancer, including selective loss of function for tumor-associated mutations. Furthermore, investigation of the IgSF interactome in a large cohort of cancer patients identifies interacting protein signatures associated with clinical outcome. The IgSF interactome represents an important resource to fuel biological discoveries and a framework for understanding the functional organization of the surfaceome during homeostasis and disease, ultimately informing therapeutic development.
-
The Immunoglobulin Superfamily Receptome Defines Cancer-Relevant Networks Associated with Response to Immunotherapy
Annals of Oncology, 2019Co-Authors: Nadia Martinez-martin, Erik Verschueren, Bushra HusainAbstract:Abstract Background Cell surface receptors fundamentally determine physiological and pathological signaling, and as such, deciphering the ensemble of receptor-ligand interactions in the extracellular milieu is vital to understand cellular communication and identify new therapeutic targets. Despite its clinical relevance, the Immunoglobulin Superfamily (IgSF) remains remarkably uncharacterized and many proteins, including some immune checkpoints, are orphan. In this study, we present the first experimentally validated map of receptor-ligand interactions, the IgSF Interactome. Methods An automated platform for unbiased and high sensitivity receptor discovery was implemented. Using this technology, we interrogate 445 IgSF proteins for binding to most single transmembrane receptors in the human genome. Results The IgSF Interactome consists of over 500 interactions, with 85% previously unreported. Using orthogonal methodologies, we confirm loss-of-binding mutations specifically found in tumors, as well as new potential modulators for immune checkpoints such as PD-L1/PD-L2. Integration of this map of extracellular interactions with gene expression profiles in tumors and healthy tissues reveals receptor-ligand networks dysregulated in cancer. Furthermore, investigation of the IgSF Interactome in a large cohort of patients with metastatic urothelial cancer who were treated with the anti-PD-L1 agent Atezolizumab identifies interacting protein signatures associated with clinical outcome, suggesting new determinants of response to treatment. Conclusion The IgSF Interactome represents the first map of receptor-ligand interactions in humans, providing a framework for understanding the functional organization of the surfaceome during homeostasis and disease, and ultimately informing therapeutic development. Legal entity responsible for the study Genentech, Inc. Funding Genentech, Inc. Disclosure N. Martinez-Martin: Shareholder / Stockholder / Stock options: Roche. E. Verschueren: Shareholder / Stockholder / Stock options: Roche. B. Husain: Shareholder / Stockholder / Stock options: Roche.
Erik Verschueren - One of the best experts on this subject based on the ideXlab platform.
-
The Immunoglobulin Superfamily Receptome Defines Cancer-Relevant Networks Associated with Clinical Outcome.
Cell, 2020Co-Authors: Erik Verschueren, Bushra Husain, Kobe C. Yuen, Yi Sun, Sairupa Paduchuri, Yasin Senbabaoglu, Isabelle Lehoux, Tia A Arena, Blair Wilson, Steve LianoglouAbstract:Cell surface receptors and their interactions play a central role in physiological and pathological signaling. Despite its clinical relevance, the immunoglobulin superfamily (IgSF) remains uncharacterized and underrepresented in databases. Here, we present a systematic extracellular protein map, the IgSF interactome. Using a high-throughput technology to interrogate most single transmembrane receptors for binding to 445 IgSF proteins, we identify over 500 interactions, 82% previously undocumented, and confirm more than 60 receptor-ligand pairs using orthogonal assays. Our study reveals a map of cell-type-specific interactions and the landscape of dysregulated receptor-ligand crosstalk in cancer, including selective loss of function for tumor-associated mutations. Furthermore, investigation of the IgSF interactome in a large cohort of cancer patients identifies interacting protein signatures associated with clinical outcome. The IgSF interactome represents an important resource to fuel biological discoveries and a framework for understanding the functional organization of the surfaceome during homeostasis and disease, ultimately informing therapeutic development.
-
The Immunoglobulin Superfamily Receptome Defines Cancer-Relevant Networks Associated with Response to Immunotherapy
Annals of Oncology, 2019Co-Authors: Nadia Martinez-martin, Erik Verschueren, Bushra HusainAbstract:Abstract Background Cell surface receptors fundamentally determine physiological and pathological signaling, and as such, deciphering the ensemble of receptor-ligand interactions in the extracellular milieu is vital to understand cellular communication and identify new therapeutic targets. Despite its clinical relevance, the Immunoglobulin Superfamily (IgSF) remains remarkably uncharacterized and many proteins, including some immune checkpoints, are orphan. In this study, we present the first experimentally validated map of receptor-ligand interactions, the IgSF Interactome. Methods An automated platform for unbiased and high sensitivity receptor discovery was implemented. Using this technology, we interrogate 445 IgSF proteins for binding to most single transmembrane receptors in the human genome. Results The IgSF Interactome consists of over 500 interactions, with 85% previously unreported. Using orthogonal methodologies, we confirm loss-of-binding mutations specifically found in tumors, as well as new potential modulators for immune checkpoints such as PD-L1/PD-L2. Integration of this map of extracellular interactions with gene expression profiles in tumors and healthy tissues reveals receptor-ligand networks dysregulated in cancer. Furthermore, investigation of the IgSF Interactome in a large cohort of patients with metastatic urothelial cancer who were treated with the anti-PD-L1 agent Atezolizumab identifies interacting protein signatures associated with clinical outcome, suggesting new determinants of response to treatment. Conclusion The IgSF Interactome represents the first map of receptor-ligand interactions in humans, providing a framework for understanding the functional organization of the surfaceome during homeostasis and disease, and ultimately informing therapeutic development. Legal entity responsible for the study Genentech, Inc. Funding Genentech, Inc. Disclosure N. Martinez-Martin: Shareholder / Stockholder / Stock options: Roche. E. Verschueren: Shareholder / Stockholder / Stock options: Roche. B. Husain: Shareholder / Stockholder / Stock options: Roche.
Coen M. Adema - One of the best experts on this subject based on the ideXlab platform.
-
Genomic and transcriptional analysis of genes containing fibrinogen and IgSF domains in the schistosome vector Biomphalaria glabrata, with emphasis on the differential responses of snails susceptible or resistant to Schistosoma mansoni.
PLoS neglected tropical diseases, 2020Co-Authors: Eric S. Loker, Coen M. Adema, Si-ming ZhangAbstract:Achieving a deeper understanding of the factors controlling the defense responses of invertebrate vectors to the human-infecting pathogens they transmit will provide needed new leads to pursue for control. Consequently, we provide new genomic and transcriptomic insights regarding FReDs (containing a fibrinogen domain) and FREPs (fibrinogen domain and one or two IgSF domains) from the planorbid snail Biomphalaria glabrata, a Neotropical vector of Schistosoma mansoni, causative agent of human intestinal schistosomiasis. Using new bioinformatics approaches to improve annotation applied to both genome and RNA-Seq data, we identify 73 FReD genes, 39 of which are FREPs. We provide details of domain structure and consider relationships and homologies of B. glabrata FBG and IgSF domains. We note that schistosome-resistant (BS-90) snails mount complex FREP responses following exposure to S. mansoni infection whereas schistosome-susceptible (M line) snails do not. We also identify several coding differences between BS-90 and M line snails in three FREPs (2, 3.1 and 3.2) repeatedly implicated in other studies of anti-schistosome responses. In combination with other results, our study provides a strong impetus to pursue particular FREPs (2, 3.1, 3.2 and 4) as candidate resistance factors to be considered more broadly with respect to schistosome control efforts, including involving other Biomphalaria species vectoring S. mansoni in endemic areas in Africa.
-
A family of variable immunoglobulin and lectin domain containing molecules in the snail Biomphalaria glabrata
Developmental and Comparative Immunology, 2015Co-Authors: Nolwenn M Dheilly, Louis Pasquier, David Duval, Gabriel Mouahid, Rémi Emans, Jean-françois Allienne, Richard Galinier, Clémence Genthon, Emeric Dubois, Coen M. AdemaAbstract:Technical limitations have hindered comprehensive studies of highly variable immune response molecules that are thought to have evolved due to pathogen-mediated selection such as fibrinogen-related proteins (FREPs) from Biomphalaria glabrata. FREPs combine upstream immunoglobulin superfamily (IgSF) domains with a C-terminal fibrinogen-related domain (FreD) and participate in reactions against trematode parasites. From RNAseq data we assembled a de novo reference transcriptome of B. glabrata to investigate the diversity of FREP transcripts. This study increased over two fold the number of bonafide FREP subfamilies and revealed important sequence diversity within FREP12 subfamily. We also report the discovery of related molecules that feature one or two IgSF domains associated with different C-terminal lectin domains, named C-type lectin-related proteins (CREPs) and Galectin-related protein (GREP). Together, the highly similar FREPs, CREPs and GREP were designated VIgL (Variable Immunoglobulin and Lectin domain containing molecules).
-
Parasite-responsive IgSF members in the snail Biomphalaria glabrata : characterization of novel genes with tandemly arranged IgSF domains and a fibrinogen domain
Immunogenetics, 2001Co-Authors: Si-ming Zhang, Pascale M. Léonard, Coen M. Adema, Eric S. LokerAbstract:Two novel genes of the immunoglobulin superfamily (IgSF), FREP3 and FREP7, are reported from the snail Biomphalaria glabrata, a prominent intermediate host of the human parasite Schistosoma mansoni. They resemble other B. glabrata genes that encode fibrinogen-related proteins (FREPs), but differ in that they encode proteins with two tandemly arranged IgSF domains followed by a C-terminal fibrinogen domain. FREPs are hemolymph proteins that increase in abundance following exposure to a digenetic trematode, Echinostoma paraensei, and that bind to and precipitate parasite antigens. Within each gene, the two IgSF-coding regions are dissimilar from one another: the N-terminal IgSF1 domain is encoded by a single exon whereas the downstream IgSF2 domain is encoded by three exons. For both FREPs 3 and 7, the IgSF2 domain belongs to the variable (V) type, whereas the IgSF1 domain is not easily classified with respect to IgSF type. The fibrinogen-encoding region in both genes is relatively conserved and lacks introns. FREP3 exhibits extensive variation in the IgSF1 region. A ratio of nonsynonymous versus synonymous substitutions of 2.56 suggests that this region is under positive selection. A genomic fragment identifiable as FREP7 but lacking an exon was also found, further suggestive of variability within FREP IgSF-encoding regions. Insofar as FREPs are hypothesized to function in nonself recognition, the identification of additional novel FREP genes as part of a growing gene family in B. glabrata is of interest. Such genes, particularly given their variable nature, serve as a model to study the complexity of invertebrate defense responses.
Si-ming Zhang - One of the best experts on this subject based on the ideXlab platform.
-
Genomic and transcriptional analysis of genes containing fibrinogen and IgSF domains in the schistosome vector Biomphalaria glabrata, with emphasis on the differential responses of snails susceptible or resistant to Schistosoma mansoni.
PLoS neglected tropical diseases, 2020Co-Authors: Eric S. Loker, Coen M. Adema, Si-ming ZhangAbstract:Achieving a deeper understanding of the factors controlling the defense responses of invertebrate vectors to the human-infecting pathogens they transmit will provide needed new leads to pursue for control. Consequently, we provide new genomic and transcriptomic insights regarding FReDs (containing a fibrinogen domain) and FREPs (fibrinogen domain and one or two IgSF domains) from the planorbid snail Biomphalaria glabrata, a Neotropical vector of Schistosoma mansoni, causative agent of human intestinal schistosomiasis. Using new bioinformatics approaches to improve annotation applied to both genome and RNA-Seq data, we identify 73 FReD genes, 39 of which are FREPs. We provide details of domain structure and consider relationships and homologies of B. glabrata FBG and IgSF domains. We note that schistosome-resistant (BS-90) snails mount complex FREP responses following exposure to S. mansoni infection whereas schistosome-susceptible (M line) snails do not. We also identify several coding differences between BS-90 and M line snails in three FREPs (2, 3.1 and 3.2) repeatedly implicated in other studies of anti-schistosome responses. In combination with other results, our study provides a strong impetus to pursue particular FREPs (2, 3.1, 3.2 and 4) as candidate resistance factors to be considered more broadly with respect to schistosome control efforts, including involving other Biomphalaria species vectoring S. mansoni in endemic areas in Africa.
-
Parasite-responsive IgSF members in the snail Biomphalaria glabrata : characterization of novel genes with tandemly arranged IgSF domains and a fibrinogen domain
Immunogenetics, 2001Co-Authors: Si-ming Zhang, Pascale M. Léonard, Coen M. Adema, Eric S. LokerAbstract:Two novel genes of the immunoglobulin superfamily (IgSF), FREP3 and FREP7, are reported from the snail Biomphalaria glabrata, a prominent intermediate host of the human parasite Schistosoma mansoni. They resemble other B. glabrata genes that encode fibrinogen-related proteins (FREPs), but differ in that they encode proteins with two tandemly arranged IgSF domains followed by a C-terminal fibrinogen domain. FREPs are hemolymph proteins that increase in abundance following exposure to a digenetic trematode, Echinostoma paraensei, and that bind to and precipitate parasite antigens. Within each gene, the two IgSF-coding regions are dissimilar from one another: the N-terminal IgSF1 domain is encoded by a single exon whereas the downstream IgSF2 domain is encoded by three exons. For both FREPs 3 and 7, the IgSF2 domain belongs to the variable (V) type, whereas the IgSF1 domain is not easily classified with respect to IgSF type. The fibrinogen-encoding region in both genes is relatively conserved and lacks introns. FREP3 exhibits extensive variation in the IgSF1 region. A ratio of nonsynonymous versus synonymous substitutions of 2.56 suggests that this region is under positive selection. A genomic fragment identifiable as FREP7 but lacking an exon was also found, further suggestive of variability within FREP IgSF-encoding regions. Insofar as FREPs are hypothesized to function in nonself recognition, the identification of additional novel FREP genes as part of a growing gene family in B. glabrata is of interest. Such genes, particularly given their variable nature, serve as a model to study the complexity of invertebrate defense responses.
Gary W. Litman - One of the best experts on this subject based on the ideXlab platform.
-
Ancient divergence of a complex family of immune-type receptor genes
Immunogenetics, 2006Co-Authors: John P. Cannon, Robert N. Haire, M. Gail Mueller, Ronda T. Litman, Donna D. Eason, Deborah Tinnemore, Chris T. Amemiya, Tatsuya Ota, Gary W. LitmanAbstract:Multigene families of activating/inhibitory receptors belonging to the immunoglobulin superfamily (IgSF) regulate immunological and other cell–cell interactions. A new family of such genes, termed modular domain immune-type receptors (MDIRs), has been identified in the clearnose skate ( Raja eglanteria ), a phylogenetically ancient vertebrate. At least five different major forms of predicted MDIR proteins are comprised of four different subfamilies of IgSF ectodomains of the intermediate (I)- or C2-set. The predicted number of individual IgSF ectodomains in MDIRs varies from one to six. MDIR1 contains a positively charged transmembrane residue and MDIR2 and MDIR3 each possesses at least one immunoreceptor tyrosine-based inhibitory motif in their cytoplasmic regions. MDIR4 and MDIR5 lack characteristic activating/inhibitory signalling motifs. MDIRs are encoded in a particularly large and complex multigene family. MDIR domains exhibit distant sequence similarity to mammalian CMRF-35-like molecules, polymeric immunoglobulin receptors, triggering receptors expressed on myeloid cells (TREMs), TREM-like transcripts, NKp44 and FcR homologs, as well as to sequences identified in several different vertebrate genomes. Phylogenetic analyses suggest that MDIRs are representative members of an extended family of IgSF genes that diverged before or very early in evolution of the vertebrates and subsequently came to occupy multiple, fully independent distributions in the present day.
-
Expanding our understanding of immunoglobulin, T-cell antigen receptor, and novel immune-type receptor genes: a subset of the immunoglobulin gene superfamily.
Immunogenetics, 1999Co-Authors: Noel A. Hawke, Jeffrey A. Yoder, Gary W. LitmanAbstract:The immunoglobulin superfamily (IgSF) is an extensively diversified multigene family whose members share a common structural feature, the Ig fold. Members of the Ig/T-cell antigen receptor (TCR) subset of the IgSF mediate antigen-specific recognition in adaptive immune responses. Antigen-binding receptors belonging to this subset are present in all species of jawed vertebrates. To explore whether there are additional structurally related but otherwise distinct members of this subset, we have developed a technique termed the short-primer polymerase chain reaction (PCR) that targets structurally conserved short motifs in the Ig fold. Large-scale sequencing efforts and recent advances in information biotechnology, including "electronic PCR," provide additional computational means to implement similarly directed searches within databases. The use of these approaches has led to the discoveries of Ig/TCR homologues in a variety of phylogenetically diverse organisms, a diversified family of novel immune-type receptor genes, as well as a novel human IgSF member. The potential of random sequencing efforts and virtual screening of databases is described in the context of two novel genes in bony fish. The various methodologies that are discussed and the examples shown provide means for further investigating, and/or elucidating novel, IgSF receptors as well as components of pathways that are involved in immune responses in both traditional and nontraditional model systems.
