Elimination of activating Fcγ receptors in spontaneous autoimmune peripheral polyneuropathy model protects from neuropathic disease

Abstract

Spontaneous autoimmune peripheral polyneuropathy (SAPP) is a reproducible mouse model of chronic inflammatory peripheral neuropathy in female non-obese diabetic mice deficient in co-stimulatory molecule, B7-2 (also known as CD86). There is evidence that SAPP is an interferon- γ , CD4+ T-cell-mediated disorder, with autoreactive T-cells and autoantibodies directed against myelin protein zero involved in its immunopathogenesis. Precise mechanisms leading to peripheral nerve system inflammation and nerve injury including demyelination in this model are not well defined. We examined the role of activating Fc-gamma receptors (FcγRs) by genetically ablating Fcγ-common chain (Fcer1g) shared by all activating FcγRs in the pathogenesis of this model. We have generated B7-2/ Fcer1g-double null animals for these studies and found that the neuropathic disease is substantially ameliorated in these animals as assessed by behavior, electrophysiology, immunocytochemistry, and morphometry. Our current studies focused on characterizing systemic and endoneurial inflammation in B7-2-null and B7-2/ Fcer1g-double nulls. We found that accumulation of endoneurial inflammatory cells was significantly attenuated in B7-2/ Fcer1g-double nulls compared to B7-2-single nulls. Whereas, systemically the frequency of CD4+ regulatory T cells and expression of immunosuppressive cytokine, IL-10, were significantly enhanced in B7-2/ Fcer1g-double nulls. Overall, these findings suggest that elimination of activating FcγRs modulate nerve injury by altering endoneurial and systemic inflammation. These observations raise the possibility of targeting activating FcγRs as a treatment strategy in acquired inflammatory demyelinating neuropathies.

Single-cell multi-omics of human clonal hematopoiesis reveals that DNMT3A R882 mutations perturb early progenitor states through selective hypomethylation

“…3a, Supplementary Table 3). FCER1G, TYROBP and TNFRSF4, are known to be involved in proinflammatory signaling [68][69][70][71][72][73][74][75][76] , consistent with previous reports suggesting that CH clones display enhanced proinflammatory signatures 24,26,41,[77][78][79][80][81] . In another example, we identified upregulation of the prosurvival oncogene PIM2, downstream of STAT signaling, in mutated LMPPs, recently implicated as a target for eradicating chemotherapy-resistant chronic myeloid leukemia stem cells 82 (Supplementary Table 3).…”

Immunomodulatory effects of intravenous and subcutaneous immunoglobulin in chronic inflammatory demyelinating polyneuropathy: An observational study

“…Finally, CD32a + classical monocytes were similarly reduced in CIDP patients after IVIg and SCIg treatment. CD32a is an essential activating immunoglobulin receptor that promotes phagocytosis in autoimmune diseases such as rheumatoid arthritis or systemic lupus [28, 29], and its deletion, amongst other immunoglobulin receptors, was shown to protect from peripheral nerve inflammation in an animal model of CIDP [30]. Therefore, it can be assumed that the reduction of CD32a + phagocytic classical monocytes also plays a therapeutic role in CIDP.…”

Diagnostic biomarker for type 2 diabetic peripheral neuropathy via comprehensive bioinformatics analysis

“…Studies have demonstrated that FCER1G was upregulated in different stages of the sciatic nerve and dorsal root ganglia (DRG) of diabetic mice 25 and contributed to the generation of neuropathic pain in rats 26 . The elimination of activating FCER1G ‐dependent Fc gamma receptors (FcγRs) reduced nerve injury by altering endoneurial and systemic inflammation 27 . SYK is widely expressed in hematopoietic cells and is involved in a variety of cellular processes by coupling activated immunoreceptors to downstream signaling events.…”