Introduction to parry-romberg syndrome (PRS)

Parry-Romberg syndrome, or PRS, is a very rare disease in which tissues on one side of the face slowly shrink or atrophy over time. These atrophic lesions can not only affect surface skin appearance, but also deeper fat, muscle, and occasionally, bone layers. The syndrome evolves over several years, eventually plateauing, but it leads to irreversible changes in outward appearance.^1,2

The cause of this syndrome has never been found, but one strong and expanding area of research supports one prevailing theory: PRS as an autoimmune disease. In being an autoimmune disease, in short, this basically means one's own defence mechanism most likely causes this tissue damage. In this article, we'll dissect just what it means to be an autoimmune disease, and synthesise in-depth research across the sciences, applying this process to PRS.²

Understanding the immune system and autoimmunity

The function of a healthy immune system

The immune system is that body-specific defensive network, whose functioning at all times safeguards you from dangers outside in the form of viruses and bacteria. The most critical elements of this network are specialised white blood cells, of which B-lymphocytes and T-lymphocytes are two kinds.

• B-lymphocytes (B-cells): They serve as an arsenal and memory of the immune system. They are programmed to recognise specific germs and, upon activation, they produce proteins in the form of antibodies. Antibodies are highly specific molecules and can stick to an invader, neutralise it, or mark it to be destroyed by other immune cells³
• T-lymphocytes (T-cells): The first-line soldiers and field generals of the immune system. Some T-cells, also referred to as cytotoxic T-cells, have been pre-programmed to recognise and eliminate cells in the body that have been injured or infected. Other T-cells offer general guidance to the immune response⁴

Defining autoimmunity

Autoimmunity occurs when this network of defences makes an erroneous judgment call. The immune system, which can otherwise distinguish between one's own cells ("self") and foreign threats ("non-self"), becomes disoriented. It misidentifies healthy, normal cells as threats and attacks those cells. It's this friendly fire that causes inflammation and tissue damage in autoimmune disease.¹

The link to scleroderma

For an understanding of evidence supporting autoimmunity in PRS, it would be helpful to know of an associated disease, scleroderma. Scleroderma is an autoimmune disease, which causes fibrosis—scarring and hardening of skin and internal organs.⁵ PRS today is widely included within localised scleroderma disease spectrums and often co-exists in association with one named morphea en coup de sabre. This closeness of clinical relation provides an ideal setting for an understanding of common autoimmune mechanisms in action.^1,2,6

Scientific evidence for an autoimmune basis in PRS

Histopathological evidence: Immune cells in affected tissues

One of the most powerful direct evidence originates from histopathology, or tissue study under microscopy. When researchers procure a small piece of involved skin from someone suffering from PRS, they inevitably find it to be tightly filled with B-cells and T-cells. The occurrence of these white blood cells in a location in which they do not exist in normal circumstances can only be evidence of an active and inflammatory response by the immune system at the very site of atrophy in tissues.

The role of B-cell dysregulation

Other studies have confirmed B-cells in scleroderma-spectrum disease patients as hyper-activated and operating abnormally. As well as to produce antibodies, B-cells operating in excess secrete chemical signals in the form of cytokines.^7,8  Cytokines are proteins that instruct other cells to act in certain ways. In PRS, B-cells have been shown to secrete excessive amounts of pro-fibrotic cytokines, including IL-6 and TGF-β. These specific messengers tell skin cells (fibroblasts) to enter overproduction, producing too much scar tissue. This reaction, known as fibrosis, causes the tissue to become hardened and contracted.^3,7,8

The role of cytotoxic T-cells

While B-cells lay the foundation for scarring, it's T-cells who could be causing initial damage. In an influential 2020 paper, scientists diligently counted, one by one, each of the different kinds of immune cells directly in the patient's own skin in early scleroderma. What they saw was that the most common of these immune cells were cytotoxic T-cells, whose number one job in life is to destroy other cells.⁴

The study provided significant pictorial evidence to demonstrate that these cytotoxic T-cells were attacking and inducing apoptosis—the programmed cell death process—on endothelial cells. ⁴ These are regular cells that line thin body vessels in minute detail. This blood vessel attack could be an initial process in closing down nutrient supplies and bringing about the following wasting away of surrounding muscle and fat tissues.

Therapeutic evidence: response to immunosuppression

Another good argument in favour of an autoimmune cause is treatment efficacy. The drugs, which have been proven to stop active PRS, suppress or modulate the immune system. Familiar drugs like methotrexate work by generally suppressing immune function. More specific biologic drugs have been made. Rituximab, for example, an antibody to B-cells, depletes B-cells and is used to treat scleroderma. In an otherwise treatment-resistant case of PRS published in 2020, PRS stopped progressing once treated with secukinumab, an antibody to the pro-inflammatory cytokine IL-17. These therapies would not be efficacious if not due to an active autoimmune role of the immune system.^3,9,10

Implications for treatment and future research

Current treatment paradigms

It becomes critical to diagnose PRS as an autoimmune disease, as it alters the entire treatment strategy. Instead of only facing cosmetic restoration ex post facto, the medical treatment in PRS, more than anything, shifts to early therapy. With treatment through the active, inflammatory phase of disease, physicians attempt to reverse the immune attack and salvage as much as atrophic tissue as possible.

Future directions in research

This information is also contributing to new treatment leads. When scientists know exactly which cells and cytokine pathways are responsible, they can create more specific therapies. The best would be to come up with therapies to block the harmful elements of the disease process responsible for PRS, without affecting the healthy elements of the immune system. This would allow for more specific therapies and less in the way of side effects. Future research will also focus on identifying credible biomarkers to aid in earlier diagnosis and to individualise treatment for the patient.

Summary

Parry-Romberg Syndrome (PRS) is an uncommon condition of progressive, gradual shrinkage or atrophy of tissues on one side of the face. Although PRS's cause has not been proven, scientists' current best theory is that PRS is an autoimmune disease, whereby one’s own body’s immune system attacks otherwise healthy facial cells unjustly. This can be concluded through multiple critical proof points.

The histological examination of involved skin reveals evidence of an ongoing inflammatory assault in the form of an aggregate of immune cells, including B-cells and T-cells. Research has shown that overactive B-cells in related disorders secrete chemical communications known as cytokines, promoting scarring and stiffening of tissue, also called fibrosis. Moreover, studies have also shown that detrimental cytotoxic T-cells can initiate the process by killing normal endothelial cells of small blood vessels. This autoimmune cause is also supported by reactions to therapies to lower the functioning of the immune system, such as methotrexate and newer biologic drugs. This understanding has shifted treatment direction to support early treatment in an attempt to cease the aggression of the immune system and reduce atrophy. 

FAQs

What is parry-romberg syndrome in simple terms?

Parry-Romberg syndrome is a very rare disorder in which, gradually, over years, on one side of the face, skin, fat, and in some cases, muscle and bone reduce in size. The process slowly stops, but it can't be reversed.

What does it mean to describe PRS as an "autoimmune" disease?

An autoimmune disease happens when your disease-fighting system, which should defend you against infection, becomes confused and attacks healthy tissues in your own body. In PRS, it's believed this misguided attack focuses on facial tissues, causing inflammation and progressive atrophy typical of the syndrome.

What is the scientific evidence for this participation of the immune system?  

There are certain significant indicators as well. At first, there are certain immune cells (T-cells and B-cells) in skin samples that have been involved, but they would not be there in these regions under normal circumstances. Secondly, studies tell us certain T-cells may be destroying cells of tiny blood vessels, and hyperactive B-cells release chemical signals requesting scarring. Lastly, medications designed to calm down an over-aggressive kind of immune system have succeeded in halting disease progression.