TABLE 1.
Pathways shown in Figure 1.
| Key | Pathway | Sex difference or sex steroid regulation or XCI effect |
|---|---|---|
| A | ssRNA virus damages lung epithelium | • Sex differences in expression of viral entry receptors |
| B | Damaged epithelium releases chemokines, alarmins and cytokines to recruit or activate innate immune cells such as DCs, monocytes, neutrophils and ILCs/NKs | • Sex differences in IL-33 production were reported |
| • AR promotes development of IL-33 producing stromal cells (in visceral adipose tissue) | ||
| C1 | ssRNA activates TLR7-TASL signaling that results in production of IFN-I and proinflammatory cytokines | • ERα activity promotes pathways involving IRF5 leading to increased IFN-I |
| • X-linked TLR7 and CXORF21 expression is increased by incomplete XCI in females | ||
| C2 | Activated ILC2s produce IL-5 that recruits eosinophils and amphiregulin that promotes tissue repair | • Females harbor more ILC2s than males |
| • ILC2 numbers and function are attenuated by AR activity | ||
| • Overall amphiregulin levels are increased in males and by AR activity | ||
| D | Activated cDCs transit to LNs and present Ag to naïve T cells. Inflammatory monocyte-derived DCs infiltrate lung tissue | • ER activity regulates DC differentiation and function |
| E1 | Activated CD8+ T cells differentiate to cytotoxic effectors or memory cells | • AR activity promotes faster contraction of CTL after viral clearance, promoting faster recovery |
| • AR activity limits IFNγ production | ||
| E2 | CD4+ T cells differentiate to Th1 cells that produce IFNγ and promote viral clearance | • X-linked CXCR3 subject to incomplete XCI leading to biallelic expression in females |
| • T cell CXCR3 promotes antiviral activity | ||
| • ER activity promotes CD4+ T cells functional responses | ||
| • AR activity reduces Th1 differentiation | ||
| E3 | CD4+ T cells promote B cell activation and Ab production | • X-linked CD40LG subject to incomplete XCI leading to biallelic expression in females |
| • CD40L enhances T-B interactions and T cell survival | ||
| E4 | Regulatory T cells attenuate immune responses and promote CD8+ T memory cell differentiation | • ER activity promotes FOXP3 expression and regulatory T cell activity |
| • AR activity may promote regulatory T cell numbers and amphiregulin production during the resolution phase | ||
| F | B cells produce Abs specific for viral proteins | • Biallelic TLR7 expression due to incomplete XCI increases quantity and quality of virus-specific Abs |
| • ERα activity promotes class switch recombination and somatic hypermutation via effects on BCR signaling and Aicda expression | ||
| • AR activity decreases Ab levels |