Disease relevance of Immunoglobulin Class Switching

• Induced overexpression of AID in CH12F3-2 B lymphoma cells augmented class switching from IgM to IgA without cytokine stimulation [1].
• The SCID but not the RAG-2 gene product is required for S mu-S epsilon heavy chain class switching [2].
• Oligoclonal protein bands and Ig isotype switching in multiple myeloma treated with high-dose therapy and hematopoietic cell transplantation [3].
• Furthermore, immunoglobulin isotype class switching of WT1 antibodies from IgM to IgG occurred in conjunction with disease progression from refractory anemia (RA) to RA with excess of blasts (RAEB), and further to RAEB in transformation (RAEB-t) in MDS patients [4].
• Analysis of clonotypic isotype class switching (CSR) in Waldenström macroglobulinemia (WM) and IgM monoclonal gammopathy of undetermined significance (MGUS) reveals a normal initial phase of B-cell activation as determined by constitutive and inducible expression of activation-induced cytidine deaminase (AID) [5].

High impact information on Immunoglobulin Class Switching

• IL-13 was first recognized for its effects on B cells and monocytes, where it upregulated class II expression, promoted IgE class switching and inhibited inflammatory cytokine production [6].
• These isotype deficiencies correlated with a deficiency in accumulation of transcripts from and class switching to affected CH genes [7].
• The data support the notion that TGF-beta and IL-4 can direct isotype-specific class switching [8].
• Transgenic mice carrying an immunoglobulin mu heavy chain transgene exhibit isotype switching of the transgene [9].
• The endogenous immunoglobulin heavy chain locus resides on mouse chromosome 12, which shows that transgene isotype switching can occur between two different chromosomes even though normal antibody gene switching has generally been thought to occur within one chromosome [9].

Chemical compound and disease context of Immunoglobulin Class Switching

• The murine B cell lymphoma CH12.LX, which bears cell surface IgM specific for the phosphatidyl choline epitope of sheep red blood cells, is capable of spontaneous isotype switching in vitro [10].

Biological context of Immunoglobulin Class Switching

• Activation-induced cytidine deaminase (AID), which is specific to B lymphocytes, is required for class switch recombination (CSR)--a process mediating isotype switching of immunoglobulin--and somatic hypermutation--the introduction of many point mutations into the immunoglobulin variable region genes [11].
• These results suggest that CD40 is essential for T cell-dependent immunoglobulin class switching and germinal center formation, but not for in vivo T cell-dependent IgM responses and T cell-independent antibody responses [12].
• Although Ku is required for immunoglobulin class switching, how CD40 signal transduction is coupled to Ku is still unknown [13].
• Deficiencies of the Msh2 protein or the Smu tandem repeat (SmuTR) sequences each reduce isotype switching in mice by about 2- to 3-fold [14].
• To investigate regulation of human immunoglobulin heavy chain expression, we have cloned DNA downstream from the two human Calpha genes, corresponding to the position in the mouse IgH cluster of a locus control region (LCR) that includes an enhancer which regulates isotype switching [15].

Anatomical context of Immunoglobulin Class Switching

• In both cell types, LPS induces transcription specifically through the germ-line gamma 2b locus before gamma 2b class switching [16].
• Crosslinking of CD40 on B cells induces, in the presence of lymphokines, immunoglobulin class switching from IgM to IgG, IgA or IgE [17].
• The data reported herein demonstrate that platelets, via CD154, induce dendritic cell maturation, B cell isotype switching, and augment CD8(+) T cell responses both in vitro and in vivo [18].
• LTalpha-/- mice immunized with sheep red blood cells (SRBC) produced high levels of antigen-specific IgM but no IgG in either primary or secondary responses, demonstrating failure of Ig class switching [19].
• The most well-studied ligands of TLRs expressed on B cells include the lipopolysaccharides (for TLR4) and CpG-containing DNAs (for TLR9), which induce and/or co-stimulate B cells to undergo proliferation, class switching and differentiation into antibody-secreting cells [20].

Associations of Immunoglobulin Class Switching with chemical compounds

• Cyclosporin A inhibited IL-4-driven CD40 ligand-dependent IgE isotype switching in PBMC but did not inhibit IgE synthesis induced by CD40 mAb plus IL-4 [21].
• Class switching of alloantibody to a high-affinity IgG response is also highly dependent on C3 [22].
• To investigate the role of germline transcription and/or transcripts in heavy chain class switching, we have replaced the germline I gamma 2b promoter and I exon in ES cells with an expressed neomycin resistance gene [23].
• Allergen drives class switching to IgE in the nasal mucosa in allergic rhinitis [24].
• Gamma 3 gene-disrupted mice selectively deficient in the dominant IgG subclass made to bacterial polysaccharides undergo normal isotype switching after immunization with polysaccharide-protein conjugate vaccines [25].

Gene context of Immunoglobulin Class Switching

• Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene [26].
• ELISPOT assays confirmed the reciprocal patterns of IFN-gamma or IL-4 production by T cells in similar frequencies in the respective groups of mice, and antibody analysis confirmed the presence of Th2-mediated isotype switching in the knockout mice [27].
• These results indicate that GH and IGF-I induce IgE and IgG4 production by class switching in an IL-4- and IL-13-independent mechanism [28].
• The data indicate that MMR proteins are directly involved in class switching and that the role of Msh2 differs from that of Mlh1 and Pms2 [29].
• Examination of Msh6- and Msh3-deficient mice in class switching reveals overlapping and distinct roles of MutS homologues in antibody diversification [30].

Analytical, diagnostic and therapeutic context of Immunoglobulin Class Switching

• Role for mismatch repair proteins Msh2, Mlh1, and Pms2 in immunoglobulin class switching shown by sequence analysis of recombination junctions [29].
• These data imply that Lyn is involved in B cell triggering by CD38 ligation plus IL-5 for isotype switching [31].
• These results identify T-bet as a selective transducer of IFN-gamma-mediated IgG2a class switching in B cells and emphasize the importance of this regulation in the pathogenesis of humorally mediated autoimmunity [32].
• Although K030 harbored antibodies to ML-IAP at the time of study entry, multiple courses of vaccination over 4 years increased antibody titers and elicited isotype switching [33].
• CT and rCTB, in the presence of IL-2, significantly increased IgA isotype switching at the clonal level in populations of purified and LPS-activated murine surface IgA- spleen B cells, as determined by ELISA, enzyme linked immunospot assays, and limiting dilution analysis [34].

References