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Tissue antibody repertoire9/12/2023 ![]() Serum IgG is also present in CD40/CD40L-deficient mice ( 38) and in patients with X-linked hyper-IgM syndrome ( 39). ( 36) showed that LPS given to young mice resulted in IgG-producing cells, and this group would later identify these as short-lived IgG3 plasma cells in the splenic marginal zone (MZ) ( 37). For example, low levels of IgA can be found in early human fetuses ( 32, 33, 34) as well as IgG transcripts ( 35). Evidence for an alternative mechanism comes from several observations, including our own. The dependence of CSR on cytokines from T cells responding to environmental Ags raises the question of how CSR proceeds in Ag-deprived fetal piglets. Polarization of naive CD4 T cells toward Th1 or Th2 cytokine profiles is often paralleled by the expression of certain IgG subclasses and influenced by the type of Ag or microbe-associated molecular pattern (MAMP) encountered by the APC ( 31). Certain cytokine profiles favor switching to certain subclasses or isotypes ( 24, 25, 26, 27, 28, 29, 30). Switching increases when cells are caused to proliferate, which appears to accelerate the expression of AID ( 22) and is heavily influenced by activated T cells and the cytokines they secrete ( 23). CSR requires cleavage of switch regions comprised of highly repetitive sequence motifs followed by ligation to cleaved downstream switch regions and subsequent repair mediated by activation-induced cytidine deaminase (AID) ( 18, 19, 20, 21). These also include germinal center formation, expression of CD40L (CD154) on activated T cells, repertoire diversification by somatic hypermutation, and, of course, changes in relative isotype/subisotype expression. It is likely that similar differences in biological functions and relative expression will be found among Ig subclasses in animals that have been less well studied.ĬSR is one of several temporally coincident events that characterize the maturation of adaptive immune responses to thymus-dependent Ags. The 13 rabbit IgA subclasses also differ in their distribution among tissues ( 11), suggesting anatomically related differences in function. Similar physiological differences are seen with IgA subclasses in which human IgA1 is relatively more prevalent in blood than secretions ( 6), perhaps because it is more susceptible to IgA proteases than IgA2 ( 9, 10). The subclass called IgG1 in cattle is the predominant IgG in all exocrine fluids and comprises 90% of the IgG in colostrum but only 50% of serum IgG ( 7, 8). The four IgG subclasses of laboratory rats and mice also exhibit differences in biological function and physiological distribution. IgG3 is also a powerful activator of complement. IgG1 accounts for nearly three-fourths of total serum IgG, and both IgG1 and IgG3 decorate phagocytic cells because of their high affinity for FcγR1. Four IgG subclasses occur in humans, and these possess different biological characteristics. Similar duplication has resulted in 13 subclasses of IgA in rabbits ( 5) and two subclasses of IgA in humans ( 6). Gene duplication in various mammals has lead to multiple subclasses of IgG in rodents, humans, domesticated ruminants, horses, swine, camelids, and guinea pigs ( 1, 2, 3, 4). We hypothesize that long-hinged porcine IgG3 may be important in preadaptive responses to T cell-independent Ags similar to those described for its murine namesake. The age and tissue dependence of IgG3 transcription paralleled the developmental persistence of the IPP, and its near disappearance corresponds to the diversification of the preimmune VDJ repertoire in young piglets. Except for IgG3 in the IPPs and mesenteric lymph nodes, no stochastic pattern of Cγ expression during development was seen in animals from mid-gestation through 5 mo. Lymphoid tissues from late term fetuses revealed a similar expression pattern. Most surprising was the finding that IgG3 accounted for half of all Cγ transcripts in the ileal Peyer’s patches (IPPs) and mesenteric lymph nodes but on average only ≃5% of the clones from the thymus, tonsil, spleen, peripheral blood, and bone marrow of newborns. However, relative transcription of allelic variants of IgG1 randomly deviate from the 1:1 ratio expected in heterozygotes. Studies revealed that among the six Cγ genes, allelic variants of IgG1 comprised 50–80% of the repertoire, and IgG2 alleles comprised <10% in nearly all tissues. Our data from ≃12,000 Cγ clones from >60 piglets provide the first report on the relative usage of all known porcine Cγ genes in fetal and young pigs. Fetal piglets offer an in vivo model for determining whether Ag-independent IgG subclass transcription proceeds in a manner that differs from subclass transcription in pigs exposed to environmental Ags and TLR ligands.
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