Anti-IgG3 monoclonal antibody [DyLight® 633]

Background Signal transducer and activator of transcription 3 hyper-IgE syndrome (STAT3-HIES) is caused by heterozygous mutations in the STAT3 gene and is associated with eczema, elevated serum IgE, and recurrent infections resembling severe atopic dermatitis, while clinically relevant specific IgE is almost absent. Methods To investigate the impact of STAT3 signaling on B-cell responses, we assessed lymph node and bone marrow, blood B and plasma cell subsets, somatic hypermutations in Ig genes, and in vitro proliferation and antibody production in STAT3-HIES patients and healthy controls. Results Lymph nodes of STAT3-HIES patients showed normal germinal center architecture and CD138(+) plasma cells residing in the paracortex, which expressed IgE, IgG, and IgM but not IgA. IgE(+) plasma cells were abundantly present in STAT3-HIES bone marrow. Proliferation of naive B cells upon stimulation with CD40L and IL-4 was similar in patients and controls, while patient cells showed reduced responses to IL-21. IgE, IgG1, IgG3 and IgA1 transcripts showed reduced somatic hypermutations. Peripheral blood IgE(+) memory B-cell frequencies were increased in STAT3-HIES, while other memory B-cell frequencies except for IgG4(+) cells were decreased. Conclusions Despite impaired STAT3 signaling, STAT3-HIES patients can mount in vivo T-cell-dependent B-cell responses, while circulating memory B cells, except for those expressing IgG4 and IgE, were reduced. Reduced molecular maturation demonstrated the critical need of STAT3 signaling for optimal affinity maturation and B-cell differentiation, supporting the need for immunoglobulin substitution therapy and explaining the high IgE serum level in the majority with absent allergic symptoms.

Despite the reported high heterogeneity of the human immune response to tuberculosis (TB), new studies may contribute to the understanding of Mycobacterium tuberculosis immunopathogenesis. To investigate the patterns of humoral response during latent (LTBI) and active TB, we evaluated specific IgG subclasses' response, by ELISA, to a set of mycobacterial antigens (Rv2029c, Rv2031c, Rv2034, Rv2628, Rv3353c ESAT6: CFP10, and the new chimeric PstS1(285-374): CFP10) in plasma samples from exposed uninfected controls (ExC, n = 24), LTBI (n = 61), and TB (n = 15) donors. In general, the TB group showed statistically higher levels of IgG1, and lower levels of IgG3. Keeping specificities >= 90%, the highest sensitivity for TB detection was observed for IgG1ESAT6: CFP10 (93.3%), followed by IgG2-Rv3353 (86.7%), IgG1-Rv3353 (69.2%) and IgG1-PstS1(285-374): CFP10 (53.3%). The combinatory of high IgG1-ESAT6: CFP10, followed by low IgG2-Rv3353c titers increased the specificity for TB detection to 100%. Only IgG3-ESAT6: CFP10 showed statistical differences between ExC and LTBI, detecting 50% of the LTBI donors. For the first time, higher levels of IgG2-PstS1(285-374): CFP10 and IgG2Rv3353 were observed in LTBI and ExC, as compared with a lower or absent immunoreactivity among TB. This study demonstrates differential modulation of subclasses' profiles for the stages of infection, which may contribute to the further development of new diagnostic tools.