Fig 1: Aire Deficiency in B Cells Promotes Humoral Autoimmunity and Compromises Cutaneous Anti-Candida Defense.(A) The cutaneous candidiasis infection model.(B and C) GMS stain of cutaneous C. albicans and skin fungal burden (CFU per mg of tissue) (mean ± SEM) in μMT recipient mice of Aire+/+ or Aire−/− donor B cells 4 d after infection. Bars: 1 mm (B, upper panels) or 100 μm (B, lower panels). **P < 0.01, by 1-tailed unpaired t-test.(D) ELISA of the levels (mean ± SEM) of autoantibodies binding to IL-17A, IL-17F and IL-22 in the sera of μMT recipient mice of Aire+/+ or Aire−/− donor B cells 4 d after infection. *P < 0.05, **P < 0.01, by 1-tailed unpaired t-test.(E) ELISA of the levels (mean ± SEM) of blocking activity of IL- 17A, IL- 17F and IL-22 to their receptors in the sera of μMT recipient mice of Aire+/+ or Aire−/− donor B cells 4 d after infection. *P < 0.05, **P < 0.01, ***P < 0.001, by 1-way ANOVA with Tukey’s post hoc test.(F and G) Flow cytometric and statistical analyses of IL-17A and IL-22 expression in cutaneous T cells of μMT recipient mice of Aire+/+ or Aire−/− donor B cells (n = 4 in each group) 4 d after infection and after ex vivo re-stimulation. The data are represented as mean ± SEM. *P < 0.05, by 1-tailed unpaired t-test.(H) Immunofluorescence analysis of Ly-6G (red) and DNA (blue) in cutaneous tissues surrounding the C. albicans infection site in μMT recipient mice of Aire+/+ or Aire−/− donor B cells 4 d after infection. The results in B–H represent 2 experiments, with 4 mice per group in each experiment. Bars: 160 μm (upper panels) or 40 μm (lower panels).(I) A simplified schematic of AIRE-mediated GC checkpoint of antibody diversification in B cells. At the T–B cell border of secondary lymphoid organs, B cells present antigens to and receive co-stimulation from DC-activated T cells, which also induce AIRE expression in B cells via CD40. The activated B cells enter the GC DZ and undergo SHM, proliferation and subsequent affinity selection by interacting with antigens on the surface of follicular dendritic cells (FDCs) in LZ. Low-affinity B cells will undergo apoptosis, whereas high-affinity B cells receive help from T follicular helper (TFH) cells to undergo CSR, and subsequently either re-enter the SHM–proliferation cycle in the DZ or exit the GC as plasma cells or memory B cells. AIRE in B cells limits autoantibody generation by restraining excessive AID activity in the GC.