title: Rituximab therapy leads to reduced imprints of receptor revision in immunoglobulin κ and λ light chains.
abstract: OBJECTIVE
  Transient B cell depletion by rituximab (RTX) has become a specific treatment of rheumatoid arthritis (RA). Although phenotypic repopulation kinetics of B cell subsets are well documented, precise molecular analyses of the reconstituting immunoglobulin (Ig) genes encoding the B cell receptor in RA are sparse.
  
  
  METHODS
  A total of 708 individual CD19+CD27+ (memory) and CD19+CD27- (naive) B cells from 2 patients with RA were analyzed at baseline and 7 months after RTX at B cell repopulation. Ig light chain variable kappa (Vκ) and lambda (Vλ) light chain gene rearrangements were amplified, sequenced, and analyzed with a focus on receptor revision.
  
  
  RESULTS
  The naive as well as the memory repertoire repopulated polyclonally with diverse use of variable light chain gene families and minigenes. During the reconstitution phase, B cells used significantly fewer Jκ distal Vκ genes (p = 0.0006), with a higher frequency of somatic hypermutation of rearrangements employing Jκ5 compared to baseline in memory B cells. The use of Vλ rearrangements in regenerating B cells was also biased toward use of Vλ genes of the proximal cassette. In general, reemerging CD27+ Ig light chain genes were substantially more highly mutated than before RTX therapy (p < 0.0001, baseline vs during reconstitution).
  
  
  CONCLUSIONS
  Our data indicate that RTX therapy leads to generation of distinct Vκ/Jκ and Vλ/Jλ gene repertoires consistent with replenishment of antigen-experienced B cells by germinal centers. At baseline, the imprints of receptor revision appeared to be more striking, which indicates that receptor revision is active in patients with RA and can be reduced by RTX.
authors.affiliation: Department of Rheumatology and Clinical Immunology, Medizinische Klinik und Poliklinik II, Oberdürrbacherstr. 6, 97080 Würzburg, Germany.
authors.forename: Arumugam
authors.initials: A
authors.lastname: Palanichamy
authors.forename: Khalid
authors.initials: K
authors.lastname: Muhammad
authors.forename: Petra
authors.initials: P
authors.lastname: Roll
authors.forename: Stefan
authors.initials: S
authors.lastname: Kleinert
authors.forename: Thomas
authors.initials: T
authors.lastname: Dörner
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Tony
mesh_terms: D000328:Adult; D058846:Antibodies, Monoclonal, Murine-Derived / Q000009:adverse effects*; D018501:Antirheumatic Agents / Q000009:adverse effects*; D016175:B-Lymphocyte Subsets / Q000276:immunology; D005260:Female; D015328:Gene Rearrangement, B-Lymphocyte, Light Chain; D005803:Genes, Immunoglobulin; D018858:Germinal Center / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D006801:Humans; D017578:Immunoglobulin Class Switching; D007145:Immunoglobulin kappa-Chains / Q000235:genetics*; D007146:Immunoglobulin lambda-Chains / Q000235:genetics*; D007156:Immunologic Memory; D008875:Middle Aged; D011947:Receptors, Antigen, B-Cell / Q000235:genetics; D000069283:Rituximab
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D018501:Antirheumatic Agents; D007145:Immunoglobulin kappa-Chains; D007146:Immunoglobulin lambda-Chains; D011947:Receptors, Antigen, B-Cell; D000069283:Rituximab