Nature Sub-Journal Su Wenru/Zheng Yingfeng/Liu Xialin of Sun Yat-sen University discovered potential therapeutic targets for uveitis

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Uveitis is a serious autoimmune disease and a common cause of blindness; However, its individual cell dynamics and pathogenesis are still poorly
understood.

On October 3, 2022, Sun Yat-sen University Wenru Su, Yingfeng Zheng and Xialin Liu published a research paper entitled "Multicellular immune dynamics implicate PIM1 as a potential therapeutic target for uveitis" at Nature Communications, which is based on experimental autoimmune uveitis (EAU).
Single-cell RNA sequencing (scRNA-seq) was performed to identify disease-related changes in cellular composition and transcriptional regulation as disease progresses, as well as the disease-associated molecule PIM1
.

Inhibition of PIM1 reduces the proportion of Th17 cells and increases the proportion of Treg cells, possibly due to PIM1's regulation
of the protein kinase B (AKT)/Forkheadbox O1 (FOXO1) pathway.
In addition, inhibition of PIM1 reduces the pathogenicity of Th17 cells and reduces plasma cell differentiation
.
Importantly, in human uveitis Vogt-Koyanagi-Harada disease (VKH), the upregulation of PIM1 in CD4+ T cells and plasma cells is conservative, and inhibition of PIM1 reduces the expansion
of CD4⁺ T and B cells.
Overall, dynamic immune cell maps during uveitis were developed and hinted at that PIM1 may be a potential therapeutic target for VKH
.

Uveitis, an autoimmune eye disease involving the ciliary body, vitreous, choroid, and retina, is the leading cause of blindness and is characterized by recurrent inflammation
of the retina and uvea.
Uveitis is also a central nervous system (CNS) autoimmune disease that differs from autoimmune diseases of other organs or tissues due to the relative immune privileges of the CNS
.
After the diagnosis of uveitis, systemic and topical treatment with glucocorticoids with or without immunosuppressants is required to prevent irreversible loss
of vision.
Glucocorticoids, together with immunosuppressive drugs, cause a variety of side effects and have limited
efficacy.
Investigations into the underlying pathological mechanisms are needed to develop specific, safe and effective treatment options
for uveitis.
Abnormalities in various immune cells are a key factor
in autoimmune disruption in uveitis.
Among them, Th17 cells dominate the pathogenesis of EA
.
Transfer of autoreactive Th17 cells can induce EAU
in naïve mice.
In addition, there is growing evidence to support the disease-promoting role of B cells in EAUs, although not as well as T
cells.
However, there is a lack of regulation of CD4+ T cells and B cells and a clear description
of the changes associated with the progression of uveitis.
A dynamic map of immune dysfunction is needed to gain a deeper understanding of the pathological mechanisms
of uveitis.
Lymph nodes (LNs) are essential
for autoimmune processes.
As sites of interaction between various immune cells, especially T cells, B cells, and dendritic cells (DCs), LNs promote antigen presentation, immune cell activation, and autoimmune response initiation
.
Cervical drainage lymph nodes (CDLN) are the main lymph nodes
that promote effective drainage of macromolecules and immune cells from the central nervous system.
Thus, CDLNs may be production sites for autoreactive T cells and B cells against CNS autoantigens
.
Removing CDLN before induction of experimental autoimmune encephalomyelitis (EAE), a classic animal model of multiple sclerosis whose pathogenesis has many similarities with EAU17, significantly reducing disease severity
.
In this work, a comprehensive single-cell map of immune cells was constructed from CDLNs from EAU mice at different time points (days 0, 7, 14, and 21), depicting changes in
immune cell composition and gene expression as disease progresses.
In particular, single-cell data indicate that PIM1 is preferentially upregulated in Th17 cells, Th1 cells, Treg cells, and plasma cells (PC) during EA
.
Inhibition of PIM1 reduces the imbalance of Th17/Treg cell and PC differentiation, and inhibition of PIM1 reduces the pathogenicity
of Th17.
In addition, in human uveitis Vogt-Koyanagi-Harada disease (VKH), the upregulation of PIM1 in CD4+ T cells and plasma cells is conserved, and inhibition of PIM1 reduces the expansion
of CD4⁺ T and B cells.
The data suggest that targeting the PIM1 kinase may be a potential therapy
for VKH.
EAU study design and scRNA-seq analysis at multiple time points (Figure from Nature Communications) In summary, this study provides a comprehensive and dynamic single-cell profile of CDLN cells in multiple aspects of the immune system during uveitis, including cell ratios, DEGs, and enrichment pathways
.
The study identified PIM1 as an important regulator of Th17/Treg cell balance, Th17 cell pathogenicity, and PC differentiation during EA
.
PIM1/AKT/FOXO1 signaling may be an underlying mechanism of EAU pathogenesis, mediating imbalances between Th17 cells and Treg cells, and researchers believe that PIM1 inhibition may improve EA
.
These findings may extend to human uveitis, VKH, and other autoimmune diseases
of the central nervous system.

Informational message: https://doi.
org/10.
1038/s41467-022-33502-7

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