B lymphocyte maturation in Wegener's qranulomatosis: A comparative analysis of VH genes from endonasal lesions

Jan Voswinkle*, A. Mueller, J. A. Kraemer, P. Lamprecht, K. Herlyn, K. Holl-Ulrich, A. C. Feller, S. Pitann, A. Gause, W. L. Gross

*Corresponding author for this work
119 Citations (Scopus)


Background: Anti-neutrophil cytoplasmic antibodies (ANCA) directed against proteinase 3 (PR3) are highly specific for Wegener's granulomatosis (WG). Evidence for a pivotal role of PR3-ANCA in the induction of vasculitis has been demonstrated. B cell clusters have been observed within endonasal biopsy specimens. Objectives: To determine whether B cell selection and maturation take place in granulomatous lesions of WG. Methods: Granulomatous lesions and the immunoglobulin (VH) gene repertoire from nasal tissue of six WG patients-two active and two smouldering localised WG (ANCA negative, restricted to respiratory tract), plus one active and one smouldering PR3-ANCA positive generalised WG-were characterised by immunohistochemistry, polymerase chain reaction, cloning, DNA sequencing and database comparison. Results: B lymphocyte-rich, follicle-like areas were observed proximal to PR3 positive cells and plasma cells in granulomatous lesions; 184 VH genes from these granulomatous lesions were compared with 84 VH genes from peripheral blood of a healthy donor. The mutational pattern of VH genes from active WG resembled memory B cells. Structural homologies of VH genes from granulomatous lesions to PR3-ANCA encoding genes were detected. Significantly more genes (55%, 45%, and 53%, respectively) from active WG compared with the healthy repertoire carried mutations to negatively charged amino acids within the binding site coding regions, favouring affinity to the positively charged PR3. Conclusions: Selection and affinity maturation of potentially PR3-ANCA producing autoreactive B cells may start in granulomatous lesions, thereby contributing to disease progression from ANCA negative localised to PR3-ANCA positive generalised WG.

Original languageEnglish
JournalAnnals of the Rheumatic Diseases
Issue number7
Pages (from-to)859-864
Number of pages6
Publication statusPublished - 07.2006

Research Areas and Centers

  • Academic Focus: Center for Infection and Inflammation Research (ZIEL)


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