In almost all fields of health research, immunity is a hot topic. Dermatology is no exception. The skin has long been recognized as a major component of the human immune system. It serves as a physical barrier and is the primary defense against invading pathogens. Recently, however, research has shown that skin plays a much more involved role in maintaining homeostasis in the body, innate and adaptive immune responses, and has its own microbiome, which, like the bacteria in your digestive tract, impacts overall health.1
One of the concepts floating in research circles, especially in Europe, is the so-called “immunocompromised district.” It is understudied and sometimes misunderstood, though one expert who has written about it and observed it in clinical situations sees a lot of potential applications in dermatology.
“I see immunocompromised districts all over the place in my clinical practice,” said Robert Brodell, MD, professor and chair of the department of dermatology and professor of pathology at the University of Mississippi Medical Center. “There are areas of skin with higher or lower than normal immunity that contribute to localized cutaneous disease. This is a new concept that I use a lot.”
Brodell Syndrome
One of Dr Brodell’s earliest experiences with the immunocompromised district involved a patient who came to see his brother, an orthopedic surgeon. The patient had been admitted to the hospital through the emergency department 9 times about every 4 to 6 months. Each time he complained of redness and pain in his left leg, associated with fever, rigors, chills, and an extremely elevated white blood cell count.
The diagnosis was cellulitis was always made, despite the rash not having the typical appearance of cellulitis. Once the patient received antibiotics, his symptoms would always abate. But the infection would then recur. After 4 to 5 years of this routine, Dr Brodell noticed the patient had a scar on his left medial thigh extending almost to the knee.
“There was erythema with a feathered appearance centered on this scar,” said Dr Brodell. “It turns out the patient had had a venectomy for a coronary artery bypass graft 6 years before this. When you take that vein out of the medial thigh and use it on the heart to bypass coronary vessels, you destroy the major lymphatic structure that runs along the vein.” As a result, bacteria and their byproducts are cleared more slowly in this leg, and it becomes more susceptible to recurrent infection because the underlying immunity is compromised. This was the first case that made Dr Brodell think about immunocompromised districts.
Dr Brodell and his brother published a paper2 about the case, and his diagnosis, recurrent lymphangitic cellulitis syndrome (RLCS) was coined “Brodell’s Syndrome” by an Italian dermatologist, Vincenzo Ruocco, MD. Brodell’s paper also discussed the relationship between recurrent cellulitis of lower limbs and tinea pedis. “With normal immunity, any seeding of bacteria is taken care of by body’s natural defenses. But, when you have abnormal immunity because the major lymphatic vessel is missing, bacteria gets into leg and has nowhere to go. This produces the unusual hypersensitivity-like rash, which, in fact, is a form of cellulitis,” he said. “The patient will keep coming back until you clear the interdigital tinea and you are no longer seeding bacteria into that leg.”
About 3 in 10 Americans (29%) have at least 1 tattoo.5
Dermatological Voodoo
Although Dr Brodell recognized that recurrent infection in the heart patient’s leg was related to immunity, it was not until he was approached by Dr Ruocco that he started thinking about immunity and dermatology in an entirely different way. He saw recurrent lymphangitic cellulitis syndrome as a condition much like post-mastectomy angiosarcoma of Stewart-Treves. Both relate to regional lowering of immunity. Dr Ruocco, however, coined the term “immunocompromised” to refer to both higher-than-usual and lower-than-usual areas of immunity localized to the skin. That may seem counter-intuitive for many American doctors, who equate “compromised” only with a deficiency of immunity, but Dr Brodell says, “there is no reason compromised immunity has to be lowered.” Automimmune diseases such as Brunsting-Perry pemphigoid and amputation stump pemphigoid represent localized areas or districts with higher-than-normal immunity.
Nor are immunocompromised districts always anatomically induced, as with the case of cardiac patient or amputees. “There are a number of reasons why you could have both lower immunity or higher immunity in a localized area of the skin,” said Dr Brodell. In his paper,3 Dr Ruocco pointed out that an injury to a cutaneous area could also be caused not only by surgical or mechanical trauma, but burn, radiation dermatitis, herpetic infection, vaccination, and even tattooing. Though these mechanisms are all vastly different, they all have the end result of suppressing or disrupting immunity.
“I noticed in a number of patients I had that they were getting flat warts in the black dye of their tattoos, and very rarely in other colors,” said Dr Brodell. “A traditional way of thinking about that would be, okay there must be HPV in the dye. This can certainly happen with atypical mycobacteria that occurs in tattoos from contaminated dye. But HPV is extremely hard to culture, and there is nothing to make you think anything in ink would sustain this virus. I wondered if nanoparticles in black dye were creating an immunocompromised district in the skin only where the black dye is located. When you then expose that area to the wart virus, where does it grow? The area where you have suppressed immunity.”
In another clinical case, he saw a patient with an owl tattoo that had been placed many years earlier. In just the past few months the owl’s eyes became scaly, elevated, and itchy. “The patient thought it was voodoo. But, the eyes were a different color ink then was used elsewhere in the tattoo,” said Dr Brodell. Biopsy results revealed cutaneous sarcoidosis and the patient was found to have hilar adenopathy typical of pulmonary sarcoidosis. This is an example of increased immunity localized to a district of the skin containing a specific tattoo dye.
There are 2.1 million people living with limb loss in the USA, and that number is expected to double by 2050.6
Applying What We Know
Dr Brodell helped author another paper about the phenomenon of cutaneous sarcoidosis (CS) presentations. In patients with the disease, more than one-third experience it in a localized area of the skin.4 In addition to the patient with the owl tattoo, he observed such sarcoidal plaques occurring in 20-year-old scars that suddenly became elevated when the patient developed sarcoidosis. “In fact, if you have a patient with an old flat scar that suddenly thickens, think cutaneous sarcoidosis,” said Dr Brodell. As with certain colors of tattoo ink, the infection may be localized to the area with lowered immunity, in this case, the scar tissue.
“In dermatology, one of the many concepts we use is portal of entry. When we see an infection we ask ourselves, ‘How did infection get into the skin?’ The idea that immunity can play a role in localized areas of the skin is something we all should be exploring—and not just for reactive treatments and therapies, but for preventative ones, as well,” he said.
Understanding the complex role immunocompromised districts play in skin infections may eventually help us build better tools for fighting certain dermatologic conditions. “If you can diminish immunity and that is leading to warts growing in black dye tattoos, why could not someone develop colorless nanoparticles that could be injected into the skin as a targeted treatment for localized skin disease?” said Brodell. “Perhaps then we could avoid using systemic agents such as corticosteroids.” This potential for future therapies does not look compromised at all.
References
1. Mann ER, Smith KM, Bernardo D, Al-Hassi HO, Knight SC, et al. (2012) Review: Skin and the Immune System. J Clin Exp Dermatol Res S2:003. doi: 10.4172/2155-9554.S2-003
2. Brodell LA, Brodell JD, Brodell RT. Recurrent lymphangitic cellulitis syndrome: A quintessential example of an immunocompromised district. Clin Dermatol. 2014 Sep-Oct;32(5):621-7. doi: 10.1016/j.clindermatol.2014.04.009.
3. Ruocco, V. The immunocompromised district: How the pieces of the puzzle gradually fell into place. Clin Dermatol. 2014 Sep-Oct; 32(5):549-52. doi: 10.1016/j.clindermatol.2014.04.019.
4. Mahoney J, Helm SE, Brodell RT. The sarcoidal granuloma: A unifying hypothesis for an enigmatic response. Clin Dermatol. 2014 Sep-Oct;32(5):654-9. doi: 10.1016/j.clindermatol.2014.04.013.
5. Source: https://theharrispoll.com/tattoos-can-take-any-number-of-forms-from-animals-to-quotes-to-cryptic-symbols-and-appear-in-all-sorts-of-spots-on-our-bodies-some-visible-in-everyday-life-others-not-so-much-but-one-thi/
6. Ziegler-Graham, K. et al. Estimating the Prevalence of Limb Loss in the United States: 2005 to 2050. Am Arch Rehabil Ther. 89(3):422-9 · April 2008. doi: 10.1016/j.apmr.2007.11.005.
