Abstract
IgM antibodies (Abs) are thought to play a major role in humoral immunity but only at the early stage of the primary immune response. However, two subsets of IgM+ memory B cells (MBCs), one with high affinity gained by means of multiple somatic hypermutation (SHM) and the other with low affinity and no SHMs, are generated through the germinal center (GC)-dependent and GC-independent (non-GC) pathway, respectively, after immunization with (4-hydroxy-3-nitrophenyl)acetyl (NP)-chicken γ-globulin. Surprisingly, an analysis of antibody-secreting cells reveals that a large amount of anti-NP IgM Ab with few SHMs is secreted during the recall response, indicating that only non-GC MBCs have terminal differentiation potential. Since secondary IgM Abs are capable of binding to dinitrophenyl ligands, they likely provide broad cross-reactivity in defense against microbial infection.
Highlights
The (4-Hydroxy-3-nitrophenyl)acetyl (NP)-hapten system of the C57BL/6 mouse is advantageous for studying the structural bases of Ab affinities since anti-NP Abs are largely encoded by the V186.2 gene, as well as by minor genes such as V23, J558.55, and V124, referred to as Vanalogs[1]
By leveraging the NP system with a strong understanding of Ab affinity maturation, hapten-chromophore proteins with different numbers of hapten molecules, such as NPhi- or NPmed-allophycocyanin (APC), have often been used to estimate the relative affinities of BCRs6,7. Using these NP-APCs, Hara et al showed that there are two subsets of IgM+ memory B cells (MBCs) in the spleens of mice immunized with NP-chicken γ-globulin (NP-CGG): one expressing BCRs with increased affinities due to somatic hypermutation (SHM), similar to those of IgG1+ MBCs acquired through a germinal center (GC) reaction, and the other expressing BCRs lacking SHMs that are supposedly generated through the GC-independent pathway[7]
Phase III starts with secondary immunization, which induces MBC activation followed by MBC differentiation into Ab-secreting cells (ASCs) that secrete secondary Abs
Summary
The (4-Hydroxy-3-nitrophenyl)acetyl (NP)-hapten system of the C57BL/6 mouse is advantageous for studying the structural bases of Ab affinities since anti-NP Abs are largely encoded by the V186.2 gene, as well as by minor genes such as V23, J558.55, and V124, referred to as Vanalogs[1]. By leveraging the NP system with a strong understanding of Ab affinity maturation, hapten-chromophore proteins with different numbers of hapten molecules, such as NPhi- or NPmed-allophycocyanin (APC), have often been used to estimate the relative affinities of BCRs6,7 Using these NP-APCs, Hara et al showed that there are two subsets of IgM+ memory B cells (MBCs) in the spleens of mice immunized with NP-chicken γ-globulin (NP-CGG): one expressing BCRs with increased affinities due to SHM, similar to those of IgG1+ MBCs acquired through a germinal center (GC) reaction (referred to as MBCGC), and the other expressing BCRs lacking SHMs that are supposedly generated through the GC-independent (non-GC) pathway (referred to as MBCnon-GC)[7]. Since neither primary IgM Abs nor affinity-matured IgG1 Abs bind to DNP, the broad cross-reactivity observed is considered to be characteristic of secondary IgM Abs, and their immunological role is discussed
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