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Table 1.
Inborn errors of immunity impacting IL-21 signaling and humoral immunity
GeneClinical featuresCellular defects and mechanisms of disease
IL2RG (X-linked) B+TNK SCID; recurrent, severe, and often fatal microbial infections; impaired B cell responses due to lack of T cell help Persistent B cell defect (poor responses in vivo, ↓ total and class-switched memory B cells) after HSCT in nonconditioned patients due to intrinsic B cell requirement of IL-21R/γc/JAK3 cytokine signaling 
JAK3 (AR) 
STAT3 (AD DN) S. aureus, Streptococcus pneumonia, and C. albicans infections; eczema; vascular/musculoskeletal/dental/ connective tissue defects; impaired humoral immunity; and hyper-IgE ↓Memory B cells in vivo; ↓ naive B cell plasmablast differentiation in vitro to IL-21; ↓ IL-21–dependent upregulation of IL2RA expression, impairing responses to IL-2; ↓ Tfh memory cells in vivo; ↓ Tfh cell generation from naive CD4+ T cells in vitro 
ZNF341 (AR) 
IL21R/IL21 (AR) Combined immunodeficiency; disseminated cryptosporidium infection, susceptibility to Pneumocystis jirovecii and fungal infections; impaired humoral immunity; hypogammaglobulinemia; increased serum IgE ↓ Total memory and class-switched memory B cells in vivo; ↓ naive B cell differentiation into plasmablasts in vitro to IL-21; ↓ Tfh memory CD4+ T cells in vivo; ↓ Tfh cells from naive CD4+ T cells in vitro 
GeneClinical featuresCellular defects and mechanisms of disease
IL2RG (X-linked) B+TNK SCID; recurrent, severe, and often fatal microbial infections; impaired B cell responses due to lack of T cell help Persistent B cell defect (poor responses in vivo, ↓ total and class-switched memory B cells) after HSCT in nonconditioned patients due to intrinsic B cell requirement of IL-21R/γc/JAK3 cytokine signaling 
JAK3 (AR) 
STAT3 (AD DN) S. aureus, Streptococcus pneumonia, and C. albicans infections; eczema; vascular/musculoskeletal/dental/ connective tissue defects; impaired humoral immunity; and hyper-IgE ↓Memory B cells in vivo; ↓ naive B cell plasmablast differentiation in vitro to IL-21; ↓ IL-21–dependent upregulation of IL2RA expression, impairing responses to IL-2; ↓ Tfh memory cells in vivo; ↓ Tfh cell generation from naive CD4+ T cells in vitro 
ZNF341 (AR) 
IL21R/IL21 (AR) Combined immunodeficiency; disseminated cryptosporidium infection, susceptibility to Pneumocystis jirovecii and fungal infections; impaired humoral immunity; hypogammaglobulinemia; increased serum IgE ↓ Total memory and class-switched memory B cells in vivo; ↓ naive B cell differentiation into plasmablasts in vitro to IL-21; ↓ Tfh memory CD4+ T cells in vivo; ↓ Tfh cells from naive CD4+ T cells in vitro 

AD, autosomal dominant; NK, natural killer.

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