Anti-phosphocholine (PC) antibodies are known to provide protection against challenge with virulent Streptococcus pneumoniae. X-linked immune deficient (Xid) mice fail to produce anti- PC antibodies even after immunization with S. pneumoniae. Consequently, Xid mice are extremely susceptible to infection with S. pneumoniae. PC-specific B cells appear to undergo clonal deletion in Xid mice; however, a new thymus-dependent form of PC, 6-(O-phosphocholine) hydroxyhexanoate (EPC), can rescue PC-specific B cells from the bone marrow presumably by providing T-cell help before clonal deletion. Analysis of PC-specific IgG hybridomas from Xid mice revealed utilization of several V-D junctional variants of the VH1 gene segment rearranged to different D and JH gene segments. The majority of Xid anti- PC antibodies exhibit an Asp ~ Gly 95H replacement at the V:D junction. These Gly 95H VH1 variants associate with ?1C L-chains to produce anti-PC antibodies that: 1) have low relative affinity for PC; 2) are heteroclitic for nitrophenylphosphocholine; and 3) fail to bind to or provide protection against S. pneumoniae. Single prototypic V-D variants of the T15-id (Asp 95H), M603-id (Asn 95H) and M167-id (Asp 95H - Ala 96H) were also induced in Xid mice. The M603-like and M167-like antibodies bound to and protected against S. pneumoniae even though they exhibited Ka's for PC which were lower than T15-id+ antibodies. These data demonstrate that small changes in the V-D junctional sequence of the T15 (VH1) heavy chain alter L-chain usage and the structure of the PC binding-site so that the PC expressed on S. pneumoniae is no longer recognized.
