A Major Subset of Mutated CLL Expresses Affinity-selected and Functionally Proficient Rheumatoid Factors

Distinct groups of autoantigens as drivers of ocular adnexal MALT lymphoma pathogenesis

“…Six of 124 OAML (5%) expressed a stereotyped RF BCR, five of which were belonging to one of three stereotyped RF groups. Previously, we repeatedly confirmed that recombinantly produced IgMs of these three groups indeed displayed strong mono-reactive binding to IgG ( Fig 1B ) ( Bende et al, 2005 , 2016 , 2020 ; Hoogeboom et al, 2010 , 2013b ; Janssen et al, 2021 ). One case (OAMZL44) was unique as it expressed an IGHV3-74-encoded BCR, which was highly homologous to an RF-producing memory B-cell clone (D1 P3) that we had isolated by antigen-specific sorting with labeled IgG of a peripheral blood mononuclear cell sample of a donor who had been immunized with Rhesus(D)-mismatched red blood cells ( Fig 1B ).…”

“…The IgMs of OM8 and OAMZL3 were not encoded by stereotyped RF IGHV rearrangements, whereas OAMZL44 expressed the here newly defined stereotyped RF IGHV3-74/IGKV4-1 combination. RF mono-reactivity has previously also been demonstrated by us for an immunological subset of M-CLL ( Hoogeboom et al, 2013b ; Janssen et al, 2021 ; Bende et al, 2022 ). However, in contrast to our previous findings on subsets of M-CLL, we did not observe binding of OAML IgMs with any viral, bacterial, or fungal antigens ( Hoogeboom et al, 2013a ; Bende et al, 2022 ).…”

“…Identical and similar amino acids are highlighted in red and blue, respectively. Reference A: PMID 33778415 ( Janssen et al, 2021 ), Reference B: PMID: 2439644 ( Newkirk et al, 1987 ), Reference C: Bende, unpublished. (C) IGHV amino acid sequences of two homologous IGHV4-34-expressing OAMLs.…”

“…However, primary CLL tumor cells of some OAML IGHV-homologous CLLs of the ERIC consortium were obtained, that is, one CLL of stereotyped subset #31, three of #148B, two of #202 and one of #273 ( Fig 5A ). These primary CLL cells were stimulated in culture to secrete CLL-derived IgM, as described previously ( Hoogeboom et al, 2015 ; Janssen et al, 2021 ). Of note, OAMZL12 VH-CDR3 is >65% homologous with CLL subset #148B members, for example, DE-02-0294-H1, ID84, and D33 (Table S3).…”

“…The level of poly-reactivity of the three OAML IgMs, however, was substantially lower than that of two selected poly-reactive IgMs retrieved from U-CLLs. Six of the 124 OAML IGHVs (5%) were stereotyped high affinity RFs ( Bende et al, 2005 , 2016 , 2020 , 2022 ; Hoogeboom et al, 2010 , 2013b ; Janssen et al, 2021 ). Three of the produced 23 (13%) OAML IgMs displayed strong mono-reactive RF activity in an IgG ELISA.…”