Fig. 4: Presumable role of M. catarrhalis in the pathogenesis of IgD⁺ NLPHL.

Costimulation of B cells characterized by IgD⁺ BCR and extraordinary long CDR3s by M. catarrhalis RpoC via the Fab fragment and MID/hag via the Fc fragment of their BCR. Naïve, mature IgD⁺ B cells with a BCR specific for RpoC encounter M. catarrhalis outer membrane vesicles. Binding of RpoC to the Fab and of MID/hag to the Fc region of membranous IgD induces activation of RpoC-specific IgD⁺ B cells, which is supported by CD4⁺ T cells particularly in patients with an HLA-DRB1*04 or DRB1*07 haplotype. The persistent or recurrent presence of M. catarrhalis presumably induces a germinal center reaction resulting in differentiation to memory B cells and plasmablasts and production of class-switched anti-RpoC serum antibodies and apoptosis of some germinal center cells due to disadvantageous mutations. The co-stimulatory effect of MID/hag through binding to the Fc part of IgD selects for retention of IgD on a fraction of the stimulated germinal center B cells. Meanwhile a clone acquires mutations in proto-oncogenes, tumor suppressor genes as well as chromosomal translocations and may transform into LP cells. However, the transformed IgD⁺ LP cells still gain growth advantage by the interaction of their BCRs with M. catarrhalis RpoC and MID/hag.