IgG4 and IgE Transcripts in Childhood Allergic Asthma Reflect Divergent Antigen-Driven Selection

Abstract

The physiologic function of the “odd” Ab IgG4 remains enigmatic. IgG4 mediates immunotolerance, as, for example, during specific immunotherapy of allergies, but it mediates tissue damage in autoimmune pemphigus vulgaris and “IgG4-related disease.” Approximately half of the circulating IgG4 molecules are bispecific owing to their unique ability to exchange half-molecules. Better understanding of the interrelation between IgG4 and IgE repertoires may yield insight into the pathogenesis of allergies and into potential novel therapies that modulate IgG4 responses. We aimed to compare the selective forces that forge the IgG4 and IgE repertoires in allergic asthma. Using an IgG4-specific RT-PCR, we amplified, cloned, and sequenced IgG4 H chain transcripts of PBMCs from 10 children with allergic asthma. We obtained 558 functional IgG4 sequences, of which 286 were unique. Compared with previously published unique IgE transcripts from the same blood samples, the somatic mutation rate was significantly enhanced in IgG4 transcripts (62 versus 83%; p < 0.001), whereas fewer IgG4 sequences displayed statistical evidence of Ag-driven selection (p < 0.001). On average, the hypervariable CDRH3 region was four nucleotides shorter in IgG4 than in IgE transcripts (p < 0.001). IgG4 transcripts in the circulation of children with allergic asthma reflect some characteristics of classical Ag-driven B2 immune responses but display less indication of Ag selection than do IgE transcripts. Although allergen-specific IgG4 can block IgE-mediated allergen presentation and degranulation of mast cells, key factors that influence the Ag-binding properties of the Ab differ between the overall repertoires of circulating IgG4- and IgE-expressing cells.

Unlike in Children with Allergic Asthma, IgE Transcripts from Preschool Children with Atopic Dermatitis Display Signs of Superantigen-Driven Activation

“…GAPDH gene products were amplified as positive control. For primer sequences, see Kerzel et al (2) and Rogosch et al (12). PCR products were purified by gel electrophoresis.…”

Persistence of the Eosinophilic Phenotype in Preschool Children with Mild Bronchial Asthma

“…В [10,13,[16][17][18]. Уровень IL-4 ИнМ у детей группы БА превышал таковой у детей группы сравнения как в начале (в 14,3 раза), так и в конце исследования (в 13,7 раза).…”

“…Уровень IL-4 ИнМ у детей группы БА превышал таковой у детей группы сравнения как в начале (в 14,3 раза), так и в конце исследования (в 13,7 раза). Следует отметить, что IL-4 является ростковым фактором B-клеток и переключает продукцию IgM на IgE, IgG4 [13,[17][18][19][20].…”

B-cell antibody class switchings are pressuromodulated events: Part II, gene recombination

“…In atopic allergic disease, antigen-specific serum IgE antibody is present; it is a product of multiple sequential indirect CSRs at the intracellular pressures at which there is maximal expression of somatic hypermutation (SHM) enzymes [4], as is the case in atopic rhinitis [20,43], asthma [44,45] and venom sensitivity [46,47].…”

“…In bee venom sensitization and asthma for example, over time there is a shift from somatically hypermutated specific IgE to specific IgG4 [45][46][47]. The IgG4 is less mutated than IgE which CSR equivalently, probably since the PRDM1-induced drop in B-cell pressure to between 0.10 and 0.12 units is transient during the perinadir when SHM enzyme APOBEC3H is expressed [4].…”