Antibody response elicited by T-dependent and T-independent antigens in gene targeted κ-deficient mice

Abstract

Animal models substantially contribute to the understanding of the pathogenesis of various human diseases, including those associated with genetic defects. Our study investigated the characteristics of antibody responses elicited by T-dependent and T-independent antigens in mice rendered kappa-deficient by targeted deletion of the J kappa C kappa gene segments. It is known that in normal murine species the kappa repertoire dominates the antibody repertoire (kappa/lambda ratio = 95:5). Our results indicate that the kappa gene deletion causes the alternative usage of lambda 1 (93%) and lambda 2 (7%) light chains, confirming previous studies demonstrating that in kappa-deficient mice all B cells express Ig lambda receptors. The anti-trinitrophenylbenzene (TNP) response in K-/- mice was compensated for by lambda 1 and lambda 2 bearing Igs. However, isoelectric focusing analysis of anti-TNP antibodies showed a considerably more restricted pattern of lambda anti-TNP antibodies in K-/- as compared with kappa antibodies in normal mice. No major differences were observed in the affinity for the hapten of kappa or lambda 1 or lambda 2 mAbs obtained from 129/Sv and K-/- mice. Furthermore, lambda 1 and lambda 2 chains can reconstitute the expression of an idiotype (460Id) borne on kappa anti-TNP antibodies. The 460Id was detected both in polyclonal and monoclonal anti-TNP antibodies obtained from K-/- mice. Our results clearly showed that the kappa anti-TNP repertoire is compensated by the lambda repertoire even though the latter is clonally restricted in K-/- mice.

Antibody response against poly (Glu60Ala30Tyr10) terpolymer and bacterial levan in ϰ‐deficient mice

“…1 F). This is in contrast to our previous observations with the TI antigens TNP-LPS and TNP-Ficoll, where a good A2 response was observed in K-/-mice [7].…”

“…Taking advantage of this model, we have previously studied the anti-TNP response of K-/-mice to theTNP hapten presented either as aT-independent (TI) or T-dependent (TD) antigen. The lack of x anti-TNP antibodies was compensated for by h l and h2 anti-TNP antibodies, although IEF analysis showed a considerably more restricted pattern of h anti-TNP Ab in K-/-as compared to x antibodies in normal mice [7].…”

Evolution of V genes: DNA sequence structure of functional germline genes and pseudogenes

“…Second, utilization of germline IgkV genes decreases with distance from the IgkJ locus (Cox et al 1994). Third, in mice incapable of expressing IgkV by targeted deletion of the IgkJ-IgkC gene segments, the antibody response to TNP (normally > 95% utilizing IgkV genes) now utilizing IgIV genes had similar affinity and idiotype (460-Id) to normal (Pricop et al 1994). Fourth, when human IghV and IgkV mini-locus transgenes (each containing four V genes plus human D, J, and C elements) were introduced into mice unable to produce endogenous heavy-and kappa light chains, the transgenic mice produced human antibodies upon immunization with human CD4 and IgE (Lonberg et al 1994) and somatically hypermutated the rearranged human V regions.…”

The Primary Antibody Repertoire of κ‐Deficient Mice is Characterized by Non‐Stochastic Vλ1 + VH Gene Family Pairings and a Higher Degree of Self‐Reactivity

“…In addition, evidence for positive selection, revealed by restricted V H þ V L pairing in the available l B-cell repertoire, exists [31]. Furthermore, V l genes have been observed to effectively reconstitute the immune response to influenza virus by developing neutralizing antibodies in JC k D mice [39] and, also, to other thymus dependent and independent antigens [32,40]. The experiments outlined here demonstrate the ability of an exclusively l-light-chain-expressing peripheral B-cell repertoire to generate NAAb specificities in the circulating immunoglobulin pool, although at higher levels (probably as a result of endogenous selection processes on the available restricted germline diversity).…”