Class-switch recombination

As compared to DCs, B cells are very poor APCs and play a major role as source for antibodies. Upon stimulation by antigens and in the presence of T cells at the border of the T-cell-B-cell area, adjacent to follicles, B cells become antibody-secreting cells and eventually form a germinal center (GC) response. GCs are specialized follicles for B-cell expansion, somatic hypermutation, and class switch recombination, processes that are regulated by T cells, follicular DCs, and other cells. In this process of B-cell maturation, Tregs seem to play a critical role, as in several immune diseases, which are characterized by aberrant antibody... 

However, recent data obtained in humans also suggest direct actions of Tregs on B cells, as Lim et al. [31] have shown that isolated Tregs can suppress antibody production and the class switching recombination of B cells in the absence of T-helper cells. 

Iwasato, T., Shimizu, A., Honjo, T., Yamagishi, H. (1990). Circular DNA is excised by immunoglobulin class switch recombination. Cell 62, 143-149. 

The final stage of B cell differentiation where the BCR repertoire is shaped is the germinal centre (GC) reaction. In the T cell dependent GC reaction, the BCR is adapted for its cognate antigen by somatic hypermutation (SMH) and class switch recombination (CSR), both of which are driven by activation induced cytidine deaminase (AID). Since AID induces targeted point mutations in the CDRs of the Ig HCs and Ig LCs, this can dramatically alter the BCR affinity or even its specificity. As AID activity may also result in the formation of an autoreactive BCR, a stringent counterselection of such self-reactive B cells is required. By analysis in human of the BCR repertoire of post-GC IgG+ memory B cells, it was demonstrated that indeed new auto-reactive B cells develop by SHM whereas 20% of naive B cells is self-reactive, up to 40% of the IgG+ memory B cells expressed a true de novo created self-reactive BCR. Apparently, lack of T cell help prevents activation of these self-... 

Jung, S., Rajewsky, K., and Radbruch, A. (1993) Shutdown of class switch recombination by deletion of a switch region control element. Science 259, 984-987. 

CSR Cluster-situated regulator class-switch recombination... 

B.B., Crit. Rev. Immunol. 24, 297-320, 2004 Fiset, P.O., Cameron, L., and Hamid, Q., Local isotype switching to IgE in airway mucosa, J. Allergy Clin. Immunol. 116, 233-236, 2005 Min, I.M. and Seising, E., Antibody class switch recombination roles for switch seqences and mismatch repair proteins, Adv. Immunol. 87, 297-328, 2005 Apian, P.D., Causes of oncogenic chromosomal translocation. Trends Genet. 22, 46-55, 2006. 

Lieber MR, Yu K, Raghavan SC. Roles of nonhomologous DNA end joining, V(D)J recombination, and class switch recombination in chromosomal translocations. DNA Repair 2006 5 1234-1245. 

Dudley DD, Chaudhuri J, Bassing CH, Alt FW. Mechanism and control of V(D)J recombination versus class switch recombination similarities and differences. Adv Immunol. 2005 86 43-112. 

Harriman, W., Volk, H., Defranoux, N. and Wabl, M. (1993). Immunoglobulin class switch recombination. Annu. Rev. Immunol. 11, 361-384. 

Coker HA, Durham SR, Gould HJ Local somatic hypermutation and class switch recombination in the nasal mucosa of allergic rhinitis patients. J Immunol 2003 171 5602-5610. 

Muramatsu M, Kinoshita K, Fagarasan S, Yamada Y, Shinkai Y, Honjo T Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 2000 102 553-563. 

Kinoshita K, Harigai M, Fagarasan S, Muramatsu M, Honjo T A hallmark of active class switch recombination transcripts directed by I promoters on looped-out circular DNAs. Proc Natl Acad Sci USA 2001 98 12620-12623. 

Cameron L, Gounni AS, Frenkiel S, Lavigne F, Vercelli D, Hamid Q SeSp, and SeSy switch circles in human nasal mucosa following ex vivo allergen challenge evidence for direct as well as sequential class switch recombination. J Immunol 2003 171 3816-3822. 

Kleinjan A, Vinke JG, Severijnen LW, Fokkens WJ Local production and detection of (specific) IgE in nasal B-cells and plasma cells of allergic rhinitis patients. Eur Respir J 2000 15 491 497. Coker HA, Durham SR, Gould HJ Local somatic hypermutation and class switch recombination in the nasal mucosa of allergic rhinitis patients. J Immunol 2003 171 5602-5610. 

Fig. 1. Quantitative restriction analysis for the evaluation of class switch recombination in polyclonally activated B cells. The rearrangement of the Syl region is reflected by the disappearance of the S7l germline restriction fragment (). This is measured by determination of the ratio of hybridisation intensities of Sr, and a reference probe. The loss of Sy, is calculated from the comparison of intensity ratios in lane A (liver DNA) and B (activated B cells). Further details are given in Section 4.3.1. of this chapter.

In polyclonally activated B cells class switch recombination precedes or rapidly follows the switch in CH-gene expression. Switching by a differential RNA splicing mechanism would apply for a very short period, if at all. The frequency of cells expressing surface IgG3 begins to increase after day 3 of LPS stimulation and already by day 6 about half of the IgH loci of these cells have performed switch recombination. 

Class switch recombination is also found to take place in plasmacytoma and hy-bridoma cells. These rare variant cells can be detected in many cell lines at frequencies of 1(T4 to 1CT7 (see Section 2.2.5.). In all cases analysed so far intermediate CH genes have been deleted from the active IgH loci. Frequently, however, the recombination sites were outside of the switch region - most drastically in the IgD variants (see review [C]), there being no switch sequence in front of C5 [56], This could be the reason why in normal B cells switching from IgM to IgD is rare upon activation. 

It would seem from the present findings that the specificity of class-switch recombination is not mediated by consensus sequences in the S regions. It is more likely that the control of class-switching operates at the level of chromatin structure which may be influenced by repetitive sequences. 

Fig. 3. Programmed class switch recombination. Upon activation the B cell starts to secrete IgM, proliferate and perform class switch recombination. In early stages recombinations within and probably other S regions are found (not shown). In later rounds of replications recombinations between switch regions accompany the phenotypic switch. These recombinations occur on both, active and inactive, IgH loci of a cell. The active locus is not necessarily rearranged first. Frequently both IgH loci show recombination between the same switch regions, indicating a pr°8ramm ng inductive event.

Figure 6 Immunoglobulin heavy chain class switch recombination. (A) The murine heavy chain locus is shown before and after recombination from g. to yl, which results in expression of IgGl antibodies. Deleted sequences can be recovered in circular DNA molecules from B cells which have recently completed switch recombination. V, variable region C, constant region and S, switch region. (B) Examples of consensus G-rich repeats from some murine S regions...

Bloom s syndrome, the genetic disease resulting from deficiency in BLM helicase, is characterized by a predisposition to malignancy and also immunodeficiency. In individuals affected with Bloom s syndrome, production of immunoglobulin-producing plasma cells and class switch recombination is impaired.BLM helicase actively unwinds G4 Deficient unwinding... 

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