inflammatory skin diseases
Mapping Immune Cell “Neighborhoods” in Psoriasis to Understand its Course
Posted on by Lawrence Tabak, D.D.S., Ph.D.
“Location, location, location.” While most of us know this phrase as a real estate adage, location—specifically that of various cell types—is becoming a key area of investigation in studying human disease. New techniques are enabling scientists to understand where certain cells are with respect to one another and how changes in their activity may affect your overall health.
In one recent example of the power of this approach, NIH-funded researchers [1] used a sophisticated method to map immune cells within human skin to get a more detailed picture of psoriasis, a common, chronic disease in which the immune system becomes overactive leading to skin inflammation. People with psoriasis develop patches of itchy, red, and flaky lesions on their skin, which can be mild to severe. For reasons that aren’t entirely clear, they’re also at higher risk for developing a wide range of other health conditions, including a unique form of arthritis known as psoriatic arthritis, diabetes, mental health issues, heart problems, and more.
The hope is that these newly drawn, precise maps of cellular “neighborhoods” in human skin will help chart the precise course of this disease to understand better the differences between mild and more severe forms. They may also yield important clues as to why people with psoriasis develop other health problems more often than people without psoriasis.
In the new study, a team including Jose Scher and Shruti Naik, NYU Langone, New York, analyzed immune cells within 25 skin samples from 14 volunteers, including those with active psoriasis, those with psoriasis but no active lesions, and people with healthy skin who do not have psoriasis. The researchers relied on a sophisticated approach called spatial transcriptomics [2] to map out what happens at the single-cell level within the samples.
In earlier approaches to single-cell analysis, researchers first would separate cells from the tissue they came from. While they could measure gene activity within those cells at the individual level, they couldn’t put things back together to see how they all fit. With spatial transcriptomics, it’s now possible to molecularly profile single cells to measure their activity in a tissue sample while also mapping their locations with respect to other cells.
The new study led to some intriguing findings. For instance, certain immune cells, specifically B cells, moved to the upper layers of the skin during active disease. That’s notable because prior studies had been unable to capture B cells in the skin adequately, and these cells are thought to play an important role in the disease.
Interestingly, the spatial cellular maps revealed inflammatory regions in both actively inflamed skin and in skin that appeared healthy. This finding highlights the fact that the inflammation that goes with psoriasis can affect the skin, and likely other parts of the body, in ways that aren’t easily observed. In future studies, the researchers want to explore how the presence of psoriasis and its underlying changes in immune cell activity may influence other organs and tissues beneath the skin.
Their fine-scale maps also showed increased gene activity in dozens of molecular pathways that are tied to metabolism and the control of lipid levels. That’s especially interesting because these factors are known to go awry in diabetes and heart conditions, which happen more often in people with psoriasis compared to those without. They also could see in their maps that this altered activity sometimes occurred in clear skin distant from any apparent lesions.
Having discovered such signals with potential consequences for other parts of the body, the researchers report that they’re working to understand how inflammatory immune cells and processes in the skin may lead to more widespread disease processes that affect other parts of the body. They plan to conduct similar studies in larger groups of people with and without active psoriasis lesions and studies following individuals with psoriasis over time. They’ll also explore questions about why people respond differently to the same anti-inflammatory treatment regimens.
To speed the process of discovery, they’ve made their maps and associated data freely available as a resource for the scientific community. About 7.5 million adults in the U.S. and millions more worldwide have psoriasis and associated psoriatic conditions [3]. The hope is that these maps will one day help to steer them toward a healthier future.
References:
[1] Spatial transcriptomics stratifies psoriatic disease severity by emergent cellular ecosystems. Castillo RL, Sidhu I, Dolgalev I, Chu T, Prystupa A, Subudhi I, Yan D, Konieczny P, Hsieh B, Haberman RH, Selvaraj S, Shiomi T, Medina R, Girija PV, Heguy A, Loomis CA, Chiriboga L, Ritchlin C, Garcia-Hernandez ML, Carucci J, Meehan SA, Neimann AL, Gudjonsson JE, Scher JU, Naik S. Sci Immunol. 2023 Jun 8;8(84):eabq7991. doi: 10.1126/sciimmunol.abq7991.
[2] Method of the Year: spatially resolved transcriptomics. Marx V. Nat Methods. 2021 Jan;18(1):9-14. doi: 10.1038/s41592-020-01033-y.
[3] Psoriasis Prevalence in Adults in the United States. Armstrong AW, Mehta MD, Schupp CW, Gondo GC, Bell SJ, Griffiths CEM. JAMA Dermatol. 2021 Aug 1;157(8):940-946. doi: 10.1001/jamadermatol.2021.2007.
Links:
Psoriasis (National Institute of Arthritis and Musculoskeletal and Skin Diseases/NIH)
Jose Scher (NYU Langone Health, New York, NY)
Shruti Naik (NYU Langone Health, New York, NY)
NIH Support: National Cancer Institute, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Center for Advancing Translational Sciences, National Institute of Allergy and Infectious Diseases
A More Precise Way to Knock Out Skin Rashes
Posted on by Lawrence Tabak, D.D.S., Ph.D.
The NIH is committed to building a new era in medicine in which the delivery of health care is tailored specifically to the individual person, not the hypothetical average patient as is now often the case. This new era of “precision medicine” will transform care for many life-threatening diseases, including cancer and chronic kidney disease. But what about non-life-threatening conditions, like the aggravating rash on your skin that just won’t go away?
Recently, researchers published a proof-of-principle paper in the journal Science Immunology demonstrating just how precision medicine for inflammatory skin rashes might work [1]. While more research is needed to build out and further refine the approach, the researchers show it’s now technologically possible to extract immune cells from a patient’s rash, read each cell’s exact inflammatory features, and relatively quickly match them online to the right anti-inflammatory treatment to stop the rash.
The work comes from a NIH-funded team led by Jeffrey Cheng and Raymond Cho, University of California, San Francisco. The researchers focused their attention on two inflammatory skin conditions: atopic dermatitis, the most common type of eczema, which flares up periodically to make skin red and itchy, and psoriasis vulgaris. Psoriasis causes skin cells to build up and form a scaly rash and dry, itchy patches. Together, atopic dermatitis and psoriasis vulgaris affect about 10 percent of U.S. adults.
While the rashes caused by the two conditions can sometimes look similar, they are driven by different sets of immune cells and underlying inflammatory responses. For that reason, distinct biologic therapies, based on antibodies and proteins made from living cells, are now available to target and modify the specific immune pathways underlying each condition.
While biologic therapies represent a major treatment advance for these and other inflammatory conditions, they can miss their targets. Indeed, up to half of patients don’t improve substantially on biologics. Part of the reason for that lack of improvement is because doctors don’t have the tools they need to make firm diagnoses based on what precisely is going on in the skin at the molecular and cellular levels.
To learn more in the new study, the researchers isolated immune cells, focusing primarily on T cells, from the skin of 31 volunteers. They then sequenced the RNA of each cell to provide a telltale portrait of its genomic features. This “single-cell analysis” allowed them to capture high-resolution portraits of 41 different immune cell types found in individual skin samples. That’s important because it offers a much more detailed understanding of changes in the behavior of various immune cells that might have been missed in studies focused on larger groupings of skin cells, representing mixtures of various cell types.
Of the 31 volunteers, seven had atopic dermatitis and eight had psoriasis vulgaris. Three others were diagnosed with other skin conditions, while six had an indeterminate rash with features of both atopic dermatitis and psoriasis vulgaris. Seven others were healthy controls.
The team produced molecular signatures of the immune cells. The researchers then compared the signatures from the hard-to-diagnose rashes to those of confirmed cases of atopic dermatitis and psoriasis. They wanted to see if the signatures could help to reach clearer diagnoses.
The signatures revealed common immunological features as well as underlying differences. Importantly, the researchers found that the signatures allowed them to move forward and classify the indeterminate rashes. The rashes also responded to biologic therapies corresponding to the individuals’ new diagnoses.
Already, the work has identified molecules that help to define major classes of human inflammatory skin diseases. The team has also developed computer tools to help classify rashes in many other cases where the diagnosis is otherwise uncertain.
In fact, the researchers have launched a pioneering website called RashX. It is enabling practicing dermatologists and researchers around the world to submit their single-cell RNA data from their difficult cases. Such analyses are now being done at a small, but growing, number of academic medical centers.
While precision medicine for skin rashes has a long way to go yet before reaching most clinics, the UCSF team is working diligently to ensure its arrival as soon as scientifically possible. Indeed, their new data represent the beginnings of an openly available inflammatory skin disease resource. They ultimately hope to generate a standardized framework to link molecular features to disease prognosis and drug response based on data collected from clinical centers worldwide. It’s a major effort, but one that promises to improve the diagnosis and treatment of many more unusual and long-lasting rashes, both now and into the future.
Reference:
[1] Classification of human chronic inflammatory skin disease based on single-cell immune profiling. Liu Y, Wang H, Taylor M, Cook C, Martínez-Berdeja A, North JP, Harirchian P, Hailer AA, Zhao Z, Ghadially R, Ricardo-Gonzalez RR, Grekin RC, Mauro TM, Kim E, Choi J, Purdom E, Cho RJ, Cheng JB. Sci Immunol. 2022 Apr 15;7(70):eabl9165. {Epub ahead of publication]
Links:
The Promise of Precision Medicine (NIH)
Atopic Dermatitis (National Institute of Arthritis and Musculoskeletal and Skin Diseases /NIH)
Psoriasis (NIAMS/NIH)
RashX (University of California, San Francisco)
Raymond Cho (UCSF)
Jeffrey Cheng (UCSF)
NIH Support: National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Center for Advancing Translational Sciences
