It only takes absent-minded observation of your skin to see some of the busy inner workings of your body. Just think of the blueish bruises and red scrapes from your skin’s collisions with the outside world, or the white pus-filled ejections of unwanted material. But when it comes to the outside coming in, you tend not to see anything: your skin seems to be the sturdy walls that form a crude barrier against larger intruders.
New research, however, reveals an active army hidden within this fortress. It turns out the skin has its own, semi-autonomous immune system ready to fight off stealthy infections at the first point of entry to our bodies. This system, a pair of new studies published in Nature says, can actively produce the proteins known as antibodies which counteract anything our bodies recognise as a threat, like foreign microbes or toxins.
Immune responses in the skin are completely normal during an infection. But the new observation that healthy skin builds up its own defence in preparation for an attack is a surprise to researchers.
“It was very exciting!” Prof Michael Fischbach and Dr Djenet Bousbaine – co-authors of the new studies, and bioengineers at Stanford University in the US – told BBC Science Focus. “We already knew that skin microbes could induce one arm of the immune system (T cell responses), and that such responses could be redirected against new antigens.
“Our discovery that skin microbes also induced an antibody response (another arm of the immune system) allowed us to develop topical vaccines against diseases such as tetanus.”
The research comes as particularly good news for those with needle phobia. Future vaccines could be delivered directly to the skin instead of being injected beneath its surface, paving the way for needle-free vaccines.
“People have worked on the development of skin vaccines before but these are based on different principles – for example, the use of microneedles in the form of patches,” said Fischbach and Bousbaine.
“Our vaccine strategy is different because it leverages the intimate relationship established over millions of years of coevolution between our skin microbes and our immune system.”
Frontline immunity
The discovery hinged upon 2015 research that showed the skin of mice could produce protective immune cells known as T cells in response to bacteria.
For that experiment, a common and harmless bacterium, Staphylococcus epidermidis, was introduced to the skin of mice raised without any microbes – and the T cells built up the animals’ immunity to it.
In fact, the skin’s response to the bacterium was much stronger than they expected. Why? The scientists behind the new studies, some of whom were also involved in the 2015 research, may now have the answer.
When they conducted mice experiments again, they found their answer: B cells were also activated – the immune cells that trigger the production of antibodies. The researchers discovered that these antibodies lasted for over 200 days, providing immunity for the duration of that time.
It’s the same response to what happens in our bloodstreams when we get ill or receive a vaccine – yet the frontline of this battle was the skin itself.
Astonishingly, the response happened even when the scientists disabled the mice’s lymph nodes – the clusters of immune system cells found all over our bodies that filter out harmful substances.
A new vaccine
After discovering that the skin has its own immune system, the researchers wondered whether they could use this system to develop a new type of vaccine.
Their second study revealed that S. epidermidis could be genetically modified – by altering the proteins in its DNA – to resemble foreign proteins that the body would want to fight off.
Applying a real toxin directly to the skin does not produce an immune response, since the fortress does not let it in. But, since S. epidermidis can ‘colonise’, or get inside, the skin, engineering the bacterium to appear like the toxin allowed the scientists to get behind this defence – and introduce some training material for its army to practice on.
Prompted by the engineered S. epidermidis, the skin successfully produced an immune response in the mice’s bloodstreams and mucous membranes (the moist tissues that line the body’s respiratory, digestive and reproductive canals, like the lining of the nose).
When the researchers exposed the mice to a foreign protein like the tetanus toxin, this immune response protected them – even though the dose should have been fatal.
Mucous matters
The discovery could be the breakthrough needed to develop vaccines that directly produce antibodies in key ‘mucosal’ areas, like the insides of our noses and mouths (places where mucus is typically found).
Such vaccines would be made from the engineered S. epidermidis – with its proteins swapped for those of harmful pathogens – and applied to the skin in the form of a cream.
The body would be given a chance to train against the pathogens in the areas that they first reach us and activate those defensive walls. A vaccine like this could help to stop respiratory infections, like COVID, from developing before they even get into our bodies.
This would be a major asset in stopping severe diseases before they reach pandemic potential.
“Vaccines are typically injected intramuscularly and provide long-term systemic immunity. However, they are less efficient at generating immunity at the site of infection: mucosal surfaces,” said Fischbach and Bousbaine, who incidentally began this research in the summer of 2020.
“With poor mucosal immunity, vaccinated individuals can still become infected and transmit disease, thereby reducing the herd immunity benefits of a vaccine program.
“We showed that our vaccination strategy induces both local (skin and nasal, S. epidermidis is also a natural inhabitant of the nares) and systemic responses thus potentially providing not only protection against severe diseases but also against infection and transmission.”
Creams are also cheap to make and easy to distribute – and don’t need a healthcare worker to administer them.
Yet, successful as they were, these studies were conducted on mice. A long road of research lies ahead before the researchers can confirm similar responses will be seen in humans, but Fischbach and Bousbaine are hopeful.
Next, they are working on a vaccine for non-human primates and hope to start clinical trials in 2028.
About our experts
Michael Fischback is the Liu Family Professor of Bioengineering at Stanford University, in the US, and the director of the Stanford Microbiome Therapies Initiative. His research has been published in Nature, Nature Communications, and Cell.
Dr Djenet Bousbaine is a postdoctoral scholar in bioengineering at Stanford University in the US. Her research has been published in Nature, Science, and Frontiers in immunology.
Read more: