G-CSF drives autoinflammation in APLAID

Abstract

Missense mutations in PLCG2 can cause autoinflammation with phospholipase C gamma 2-associated antibody deficiency and immune dysregulation (APLAID). Here, we generated a mouse model carrying an APLAID mutation (p.Ser707Tyr) and found that inflammatory infiltrates in the skin and lungs were only partially ameliorated by removing inflammasome function via the deletion of caspase-1. Also, deleting interleukin-6 or tumor necrosis factor did not fully prevent APLAID mutant mice from autoinflammation. Overall, these findings are in accordance with the poor response individuals with APLAID have to treatments that block interleukin-1, JAK1/2 or tumor necrosis factor. Cytokine analysis revealed increased granulocyte colony-stimulating factor (G-CSF) levels as the most distinct feature in mice and individuals with APLAID. Remarkably, treatment with a G-CSF antibody completely reversed established disease in APLAID mice. Furthermore, excessive myelopoiesis was normalized and lymphocyte numbers rebounded. APLAID mice were also fully rescued by bone marrow transplantation from healthy donors, associated with reduced G-CSF production, predominantly from non-hematopoietic cells. In summary, we identify APLAID as a G-CSF-driven autoinflammatory disease, for which targeted therapy is feasible.

The hypermorphic PLCγ2 S707Y variant dysregulates microglial cell function – insight into PLCγ2 activation in brain health and disease, and opportunities for therapeutic modulation

“…However, when repeated in the hiPSC-derived microglia, no change in IL-1β secretion, as well as a decrease in TNF-α secretion was observed. Recently, granulocyte-colony stimulating factor (G-CSF) has been identified as a main driver of APLAID [14]. Further work is needed to determine if G-CSF is also elevated in APLAID microglia, and to what role this would have on the CNS function.…”

“…The term APLAID (autoinflammation and PLCγ2-associated antibody deficiency and immune dysregulation) was coined to categorise the genetic, clinical and functional findings of the PLCγ2 S707Y variant [3]; subsequently, this classification has been extended to other PLCγ2 variants which also confer strong hypermorphic PLCγ2 enzymatic activity and cause a spectrum of APLAID-related autoimmune phenotypes in this monogenic, dominantly inherited disorder [9][10][11][12][13]. Furthermore, it has recently been demonstrated that most of APLAID symptoms can be recapitulated in PLCγ2 S707Y/+ mice [14].…”

Mind bomb 2 limits inflammatory dermatitis in Sharpin mutant mice independently of cell death

“…G-CSF enhances wound healing in animal excisional wound models ( 31 ) and in patients with dystophic epidermolysis bullosa or radiation-induced moist desquamation of the skin ( 32 ). Yet, G-CSF also promotes autoinflammatory skin pathology in phospholipase C gamma 2-associated antibody deficiency and immune dysregulation (APLAID) ( 33 ). Loss of MIB2 in the context of the cpd mutation reduced the abundance of G-CSF in the skin that correlated with enhanced dermatitis severity, suggesting G-CSF acts to promote wound healing in this inflammatory dermatitis model.…”