Tag Archives: pv

The main physical manisfestation of the P/P diseases is the presence of blisters on the skin and mucous membranes. Underlying those blisters are numerous molecular processes including recognition of keratinocyte cells of the skin and cell death. But how these blisters actually form, that is, what is the order of events leading up to their formation, has not been clear. A recent study by scientists Parviz Deyhimi and Payam Tavakoli suggests that in pemphigus vulgaris (PV), cell death comes first, then the formation of blisters (Journal of Oral Pathology and Medicine, doi: 10.1111/jop.12022).

The blisters that form in PV are referred to as lesions, or suprabasal vesicles, because of where they are found within the layers of the epidermis (supra meaning above, so above the basal layer, see Figure 1a). Because they are found so deep within the tissue, the blisters formed and PV disease itself is considered more severe than pemphigus foliaceus, where the blisters appear within the granular layer. The lesions formed during PV and in other mucocutaneous autoimmune blistering diseases are formed when the rogue antibodies formed during disease recognize proteins found at junctions formed by keratinocyte cells interacting with one another. The loss of these junctions that generates the tear in the skin is called acantholysis. Acantholysis is more than a tearing of the skin.

There is also cell death (also called apoptosis) within the lesions. But it has been unclear when and where apoptosis occurs with relation to acantholysis and to recognition of the junctions by antibodies generated by the immune system of the patient. Besides the ordering of events, it has been unclear which of the various types of apoptosis are at play. In the intrinsic pathway of apoptosis, a cell essentially commits suicide because of an internal trigger, perhaps as part of a genetic program as occurs during cell or tissue development. In the extrinsic pathway, the trigger to commit suicide is external. Perhaps this is where the antibodies of PV patients play a role, then? At least two models, both with excellent experimental support, exist for the ordering of events.

The first suggests that apoptosis is a late event in pemphigus and that it is not required for acantholysis and blister formation, while the second suggests that apoptosis occurs early, before significant acantholysis. A related viewpoint to the second is that the two occur simultaneously, though independently, though evidence exists for apoptosis actually causing acantholysis. For instance, chemical inhibitors of apoptosis have been shown to prevent lesion formation and a time-course study has shown that apoptotic cells were present before blisters in pemphigus foliaceus. The current authors looked at tissue samples from 25 patients with oral lesions due to PV. They used immunohistochemistry, the same technique that is used to diagnose PV.

Looking closely for regions where normal lesion-free tissue was adjacent to lesions, so-called peri-lesional regions, they found that 100% of the cells within lesions had fragmented DNA, the hallmark of apoptosis. In the adjacent normal tissue (in the parabasal region) of most of the samples, 75% of the cells had the marker of apoptosis. Looking at the acantholytic cells within the lesion, the result was strikingly close to 75%, at 76% and at the roof of the vesicle, it was even higher, at 80%. Given the presence of apoptotic cells in the lesion-free patient tissue, the authors concluded that apoptosis is not a late event, but an early one that may cause acantholysis. Recognizing that the structural damage (acantholysis) and death (apoptosis) of keratinocytes are mediated by the same molecular players – the caspase enzymes.

Research led by Sergei Grando has proposed a novel theory of“apoptolysis”, combining the two terms. The work of Deyhimi and Tavakoli supports this model and suggests that once a threshold level of apoptotic cells exist in the basal cell layer, somewhere north of 80%, then a lesion will form. According to the authors, conventional therapy of PV consisting of high-dose corticosteroids is based on the hypothesis that acantholysis leads to apoptosis, so it will be critical to unravel the current results and to determine if treatments might be tailored differently in the future. How apoptosis leads to formation of blisters and how antibodies to desmogleins may promote apoptosis is still under investigation, but one additional piece of information from the current work is that based on the absence of another cell death marker, Bax, the authors suspect the extrinsic cell death pathway.

The pieces to the pemphigus puzzle are beginning to be unraveled. Driven by the fact that the more we learn about the molecular events leading up to blisters, the more chances there will be to intervene before debilitating blisters can occur.

In the days after being told that you have one of the diseases in the Pemphigus/Pemphigoid family, when you’re running around filling prescriptions for your new, huge, seven-day pill container, it’s hard to feel hopeful.

Maybe you’ve been looking for answers for months – and getting the wrong ones. Maybe you’re finding it a challenge to take care of ordinary everyday things, like brushing your teeth because of painful oral lesions. Or you don’t know how to explain to friends that you’re miserable and not feeling up to your usual activities.

That’s how it was for me. By the time I was diagnosed with PV nearly three years ago, I’d consulted five different doctors over five months and had a medicine cabinet filled with failed ointments, pills and rinses.

Because my symptoms were so widespread, and because the doctors I saw were not familiar with Pemphigus, I’d been told I had everything from allergies to cold sores to possibly cancer.

It was weird hearing doctors, whom I instinctively trusted, tell me that this or that was going on with me, and turn out to be wrong, time after time. Each doctor focused on his or her special area of expertise, ignoring the symptoms that didn’t fit.

I remember calling one doctor to complain the medicine she’d prescribed wasn’t working, and she told me I was using it incorrectly.

Another doctor simply increased the dose of what he’d given me, and a third told me that if a certain cream didn’t work in two weeks, I should come back and be biopsied for cancer.
Frustrating!

Scary!

Finally I saw a doctor who said the magic words, “I don’t know what it is,” and referred me to a great dermatologist, who biopsied me and put a name to my condition. Under his care I began the slow uphill journey back to health.

For me, the hardest part was not the discomfort of eating or washing my hair or the harsh side effects from medications, unpleasant as they were. It was the sad sense that I’d lost something precious and my life would never be the same.

As I learned how to cope with PV over time I found out that, like other major life events, this experience offered a unique opportunity to grow and learn more about myself.

Some encouraging words, for those new to this journey:

1. You will feel better, a little at a time. Celebrate the small steps as your health improves each day, each week and each month.
2. Remember P/P is just a small part of who you are. While it may loom large right now, it will command less of your attention as time goes on.
3. Keep a health journal. I found it extremely helpful – especially in those foggy prednisone days when I got lost in the middle of sentences – to record everything health-related in a notebook.
I wrote down the details of every doctor visit, the questions I wanted to remember to ask, the answers I got, symptoms and feelings, medication doses and so on. I’ve now had my notebook for three years, and it’s so handy for keeping track of lab work, bone density scans and other treatments that occur at regular intervals.
Writing things down also keeps them from swirling endlessly around in your mind and is helpful when talking to your doctor.
4. De-stress any way you can. At the 2012 IPPF Patient Meeting in San Francisco, we learned about the chemicals released by stress that aggravate autoimmune disorders.
My favorite way to get rid of excess stress is by doing yoga. I also enjoy walking, and when I don’t have time for either of those, a few long, deep breaths do wonders.
5. Count on your friends at the IPPF. There’s a wealth of help at the IPPF. You can get one-on-one support from a trained Peer Health Coach, ask questions on the discussion forum or join the active email group.
Online resources, dial-in Town Hall meetings with IPPF’s doctor-researchers, and annual Patient Conferences are other options. I made the mistake of waiting too long before getting involved with this fantastic organization.
6. Give back. Share a tip that worked for you or just lend an ear to help someone else who’s newer to P/P than you. See #5 for places you can jump in.

The 175 genes that were found to be significantly differentially expressed between cases and controls were used as input for pathway analysis with the ingenuity pathway analysis software. The network that was given the most significant P-value and the highest-scored functional pathways is shown. The network was found to be related to ST18 (marked in green). © 2012 Society for Investigative Dermatology

The recent buzz in the pemphigus and pemphigoid community stems from the publication of “Population-Specific Association between a Polymorphic Variant in ST18, Encoding a Pro-Apoptotic Molecule, and Pemphigus Vulgaris” in the Journal of Investigative Dermatology (available online, March 2012).

Despite the fact that pemphigus most often affects adults, it seems a large extent may be genetically determined. Indeed, the disease sometimes runs in families. Also, the deleterious antibodies implicated as a major cause of the disease can be found in healthy relatives of patients. And finally, the disease prevalence is highly population-dependent. For example, it is up to 40 times more common in Jewish as compared with non-Jewish populations.

The delineation of the genetic basis of a disease can reveal unknown aspects of its pathogenesis, which in turn is likely to point to novel therapeutic targets. To tackle the genetic basis of pemphigus vulgaris, Dr. Ofer Sarig and Eli Sprecher (Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel) led a collaboration with Ibrahim Saleh (co-Principle Investigator), Detlef Zilliekens, Michael Hertl and Markus M. Nöthen (Germany); Dedee Murrell (Australia), Aviv Barzilai, Henri Trau, Reuven Bergman, Ariel Darvasi, Karl Skorecki, Dan Geiger and Saharon Rosset (Israel).

Over the past two years, they assessed on a global (“genomic”) level the possibility that specific genetic variants may predispose to pemphigus vulgaris. They identified genetic variations in a gene called ST18 associated with the increased incidence of pemphigus vulgaris in Jewish and Egyptian patients. The fact that patients of German origin did not demonstrate the same trend suggests that the ST18 variants shows an increased risk for the disease in a population-specific manner. Carriers of the genetic changes have a 6-fold elevated risk of developing the disease. These genetic variations are associated with an increase in the expression of ST18 in the skin. Since ST18 is known to promote programmed cell death, increased expression of this protein may render the skin tissue more susceptible to the deleterious effects of the pathogenic antibodies.

Prof. Eli Sprecher is Director of Dermatology at The Tel Aviv Sourasky Medical Center in Israel.

What started as a posting of the story on Facebook quickly spread to the P/P Email Discussion Group where the talk turned to quicker diagnosis, better treatments, and a cure. Dr. Sprecher said, “The greatest reward for a physician involved in basic research like me is the feedback we get from our patients. This goes much deeper than anything else.” The P/P Community continues to be high-spirited and focused on researching this discovery and hopes more information is available at the IPPF’s Fifteenth Annual Meeting in Boston, May 18-20. 2012.

This step along the path of better understanding disease susceptibility and pathogenesis sheds new light on the genetic association of pemphigus vulgaris. Future work is still needed to more towards better genetic tools that impact disease management and targeted therapies.

But today, we are one step closer than we were yesterday.