title: Distinct innate immunity pathways to activation and tolerance in subgroups of chronic lymphocytic leukemia with distinct immunoglobulin receptors.
abstract: Subgroups of patients with chronic lymphocytic leukemia (CLL) have distinct expression profiles of Toll-like receptor (TLR) pathway-associated genes. To test the hypothesis that signaling through innate immunity receptors may influence the behavior of the malignant clone, we investigated the functional response triggered by the stimulation of TLRs and NOD2 in 67 CLL cases assigned to different subgroups on the basis of immunoglobulin heavy variable (IGHV ) gene usage, IGHV gene mutational status or B-cell receptor (BcR) stereotypy. Differences in the induction of costimulatory molecules and/or apoptosis were observed in mutated versus unmutated CLL. Different responses were also identified in subsets with stereotyped BcRs, underscoring the idea that "subset-biased" innate immunity responses may occur independently of mutational status. Additionally, differential modulation of kinase activities was induced by TLR stimulation of different CLL subgroups, revealing a TLR7-tolerant state for cases belonging to stereotyped subset #4. The distinct patterns of TLR/NOD2 functional activity in cells from CLL subgroups defined by the molecular features of the clonotypic BcRs might prove relevant for elucidating the immune mechanisms underlying CLL natural history and for defining subgroups of patients who might benefit from treatment with specific TLR ligands.
authors.affiliation: School of Biology, University of Athens, Athens, Greece.
authors.forename: Stavroula
authors.initials: S
authors.lastname: Ntoufa
authors.forename: Anna
authors.initials: A
authors.lastname: Vardi
authors.forename: Nikos
authors.initials: N
authors.lastname: Papakonstantinou
authors.forename: Achilles
authors.initials: A
authors.lastname: Anagnostopoulos
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Aleporou-Marinou
authors.forename: Chrysoula
authors.initials: C
authors.lastname: Belessi
authors.forename: Paolo
authors.initials: P
authors.lastname: Ghia
authors.forename: Federico
authors.initials: F
authors.lastname: Caligaris-Cappio
authors.forename: Marta
authors.initials: M
authors.lastname: Muzio
authors.forename: Kostas
authors.initials: K
authors.lastname: Stamatopoulos
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D002470:Cell Survival / Q000276:immunology; D002999:Clone Cells; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007113:Immunity, Innate / Q000276:immunology*; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D053473:Nod2 Signaling Adaptor Protein / Q000378:metabolism; D010766:Phosphorylation; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*; D051193:Toll-Like Receptors / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D007143:Immunoglobulin Heavy Chains; D008024:Ligands; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D011947:Receptors, Antigen, B-Cell; D051193:Toll-Like Receptors; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases