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▎Editor of WuXi AppTec's content team Vitiligo is an acquired autoimmune disease.
We are all familiar with the typical symptom of this disease-white spots on the skin
.
But surprisingly, until today, the cause of vitiligo is still a mystery
.
This has also limited the development of related therapies, and there has not yet been a treatment plan approved by the FDA
.
Scientists have learned that skin leukoplakia is produced by CD8+ T cells abnormally attacking autologous melanocytes, and interferon-gamma signals are essential for this process
.
But which cells are responding to the function of gamma interferon, previous studies have not given the answer
.
For vitiligo patients, who account for 0.
5% to 2% of the global population, it is particularly urgent to reveal the regulation mechanism of the disease
.
This week, in a study published in the journal Nature, the team of researcher Chen Ting from the Beijing Institute of Biological Sciences made an important breakthrough
.
This study reveals the cell types that play a key role in vitiligo and explains the preference for the location of vitiligo
.
More than 80% of patients with vitiligo are bilaterally symmetrically distributed, and this type is called non-segmental vitiligo
.
In order to explain the characteristics of this symmetrical distribution, the research team performed fluorescent staining on the skin samples of patients with vitiligo
.
They found that a large number of CD8+ T cells gathered at the junction of the skin lesion and the non-lesion area.
From this, it can be speculated that there is a recruitment mechanism in the pathogenesis of vitiligo, which coordinates the recruitment of CD8+ T cells at the junction of skin damage
.
Therefore, these cells can continue to attack the melanocytes in the healthy area, causing the depigmented area to gradually expand
.
▲A schematic diagram of the vitiligo-prone areas and the fluorescently stained skin damaged areas (picture source: reference [1]) Then, what kind of cells are used to achieve this recruitment mechanism? Different analytical methods all point to the same type of cell: fibroblasts
.
Fibroblasts are the most important cell component in the dermis.
The research team found that the specific genes of these cells are enriched in the interferon-gamma signaling pathway, and the downstream signals of interferon-gamma also mainly act on fibroblasts
.
In order to find out how fibroblasts function, the research team established a brand-new vitiligo-induced model mouse
.
Researcher Chen Ting said that the previous induction model methods were complicated and inefficient, and could not be used for complex genetic analysis
.
The latest induction model can knock out related genes in mice under different conditions and analyze them
.
Using this model, the research team knocked out the gamma interferon receptor gene in fibroblasts.
At this time, the mice no longer suffered from vitiligo, which further verified that the response of fibroblasts to gamma interferon is the key mechanism that causes vitiligo
.
To clarify the specific pathways by which fibroblasts respond to gamma interferon, it is necessary to find out which factors are abnormally expressed in the fibroblasts of vitiligo patients/mice
.
Researcher Chen Ting’s team found that compared with normal fibroblasts, the chemokines CXCL9 and CXCL10 have higher expressions in vitiligo patients and vitiligo model mouse fibroblasts
.
After knocking down the Cxcl9 or Cxcl10 gene, mouse fibroblasts lost the ability to recruit CD8+ T cells
.
▲Fibroblasts regulate the recruitment of killer CD8+ T cells through CXCL9/10 (picture source: Chen Ting's research group) So far, research has confirmed the key role of skin fibroblasts in skin autoimmune diseases and revealed their involvement in this process Key genes
.
At the same time, this study also discovered the determinants of preference for the location of the onset of vitiligo
.
Through the analysis of patients with non-segmental vitiligo, the research team found that the incidence of vitiligo varies greatly in different parts: the back of the hand and chest have the highest incidence, while the palm and upper limbs have the lowest incidence
.
Further research found that in areas with high morbidity such as the back of the hand, chest and back, the up-regulation of CXCL9 and CXCL10 were higher, and fibroblasts responded to gamma interferon to a higher degree
.
In the mouse model, the research team also found a similar pattern
.
These experiments show that the responsiveness of fibroblasts from different parts to gamma interferon not only determines their ability to recruit CD8+ T cells, but also determines the location preference of vitiligo
.
▲In fibroblasts, interferon gamma signal affects the content of killer CD8+ T cells (picture source: Chen Ting's research group) Researcher Chen Ting said that this study not only reveals the pathogenesis of vitiligo, but also for subsequent drugs and Clinical research also has a driving effect: "The model we have established is of great help to drug design and testing, and is expected to promote disease treatment in the future
.
Our research also performed a large number of single-cell sequencing analysis on patient samples.
These results are useful for future The classification of diseases and the design of clinical trials are of great value
.
"The causes of vitiligo are complex.
This study reveals the role of fibroblasts, but as researcher Chen Ting said, the regulatory mechanism of vitiligo is not limited to the functions of fibroblasts, such as the functions of neurons and regulatory T cells.
It has not yet been studied
.
Therefore, there is still a lot of room for exploring the pathogenesis of this common disease
.
We expect that future research will eventually find available therapies for at least tens of millions of patients around the world
.
The title of this article is "Anatomically distinct fibroblast subsets determine skin autoimmune patterns "paper published in the December 16" Nature "magazine
.
Beijing Institute of Biological sciences researcher Chen Ting and Beijing hospital, Chang Jianmin professor for co-corresponding author of the paper
.
Xu Zijian Beijing Institute of life sciences He and Chen Daoming are co-first authors
.
Reference materials: [1] Zijian Xu et al.
, Anatomically distinct fibroblast subsets determine skin autoimmune patterns.
Nature (2021), https://doi.
org/10.
1038/s41586-021-04221- 8
We are all familiar with the typical symptom of this disease-white spots on the skin
.
But surprisingly, until today, the cause of vitiligo is still a mystery
.
This has also limited the development of related therapies, and there has not yet been a treatment plan approved by the FDA
.
Scientists have learned that skin leukoplakia is produced by CD8+ T cells abnormally attacking autologous melanocytes, and interferon-gamma signals are essential for this process
.
But which cells are responding to the function of gamma interferon, previous studies have not given the answer
.
For vitiligo patients, who account for 0.
5% to 2% of the global population, it is particularly urgent to reveal the regulation mechanism of the disease
.
This week, in a study published in the journal Nature, the team of researcher Chen Ting from the Beijing Institute of Biological Sciences made an important breakthrough
.
This study reveals the cell types that play a key role in vitiligo and explains the preference for the location of vitiligo
.
More than 80% of patients with vitiligo are bilaterally symmetrically distributed, and this type is called non-segmental vitiligo
.
In order to explain the characteristics of this symmetrical distribution, the research team performed fluorescent staining on the skin samples of patients with vitiligo
.
They found that a large number of CD8+ T cells gathered at the junction of the skin lesion and the non-lesion area.
From this, it can be speculated that there is a recruitment mechanism in the pathogenesis of vitiligo, which coordinates the recruitment of CD8+ T cells at the junction of skin damage
.
Therefore, these cells can continue to attack the melanocytes in the healthy area, causing the depigmented area to gradually expand
.
▲A schematic diagram of the vitiligo-prone areas and the fluorescently stained skin damaged areas (picture source: reference [1]) Then, what kind of cells are used to achieve this recruitment mechanism? Different analytical methods all point to the same type of cell: fibroblasts
.
Fibroblasts are the most important cell component in the dermis.
The research team found that the specific genes of these cells are enriched in the interferon-gamma signaling pathway, and the downstream signals of interferon-gamma also mainly act on fibroblasts
.
In order to find out how fibroblasts function, the research team established a brand-new vitiligo-induced model mouse
.
Researcher Chen Ting said that the previous induction model methods were complicated and inefficient, and could not be used for complex genetic analysis
.
The latest induction model can knock out related genes in mice under different conditions and analyze them
.
Using this model, the research team knocked out the gamma interferon receptor gene in fibroblasts.
At this time, the mice no longer suffered from vitiligo, which further verified that the response of fibroblasts to gamma interferon is the key mechanism that causes vitiligo
.
To clarify the specific pathways by which fibroblasts respond to gamma interferon, it is necessary to find out which factors are abnormally expressed in the fibroblasts of vitiligo patients/mice
.
Researcher Chen Ting’s team found that compared with normal fibroblasts, the chemokines CXCL9 and CXCL10 have higher expressions in vitiligo patients and vitiligo model mouse fibroblasts
.
After knocking down the Cxcl9 or Cxcl10 gene, mouse fibroblasts lost the ability to recruit CD8+ T cells
.
▲Fibroblasts regulate the recruitment of killer CD8+ T cells through CXCL9/10 (picture source: Chen Ting's research group) So far, research has confirmed the key role of skin fibroblasts in skin autoimmune diseases and revealed their involvement in this process Key genes
.
At the same time, this study also discovered the determinants of preference for the location of the onset of vitiligo
.
Through the analysis of patients with non-segmental vitiligo, the research team found that the incidence of vitiligo varies greatly in different parts: the back of the hand and chest have the highest incidence, while the palm and upper limbs have the lowest incidence
.
Further research found that in areas with high morbidity such as the back of the hand, chest and back, the up-regulation of CXCL9 and CXCL10 were higher, and fibroblasts responded to gamma interferon to a higher degree
.
In the mouse model, the research team also found a similar pattern
.
These experiments show that the responsiveness of fibroblasts from different parts to gamma interferon not only determines their ability to recruit CD8+ T cells, but also determines the location preference of vitiligo
.
▲In fibroblasts, interferon gamma signal affects the content of killer CD8+ T cells (picture source: Chen Ting's research group) Researcher Chen Ting said that this study not only reveals the pathogenesis of vitiligo, but also for subsequent drugs and Clinical research also has a driving effect: "The model we have established is of great help to drug design and testing, and is expected to promote disease treatment in the future
.
Our research also performed a large number of single-cell sequencing analysis on patient samples.
These results are useful for future The classification of diseases and the design of clinical trials are of great value
.
"The causes of vitiligo are complex.
This study reveals the role of fibroblasts, but as researcher Chen Ting said, the regulatory mechanism of vitiligo is not limited to the functions of fibroblasts, such as the functions of neurons and regulatory T cells.
It has not yet been studied
.
Therefore, there is still a lot of room for exploring the pathogenesis of this common disease
.
We expect that future research will eventually find available therapies for at least tens of millions of patients around the world
.
The title of this article is "Anatomically distinct fibroblast subsets determine skin autoimmune patterns "paper published in the December 16" Nature "magazine
.
Beijing Institute of Biological sciences researcher Chen Ting and Beijing hospital, Chang Jianmin professor for co-corresponding author of the paper
.
Xu Zijian Beijing Institute of life sciences He and Chen Daoming are co-first authors
.
Reference materials: [1] Zijian Xu et al.
, Anatomically distinct fibroblast subsets determine skin autoimmune patterns.
Nature (2021), https://doi.
org/10.
1038/s41586-021-04221- 8
