Every time an intruder ‘violates’ the front doors and attacks the human organism, a silent war with our defenses is triggered. There is a front line that takes the field, “subtracts material from the enemy” and ensures that efforts can be “directed towards the production of heavy means of defense and the reconstruction of what is left ‘under the rubble’ of the inflammation “. The architects of this important strategic operation are special, ‘ancient’ soldiers: the molecules of innate immunity. And the scientist Alberto Mantovani uses this “image taken from the war context” to describe their actions. “Actions that leave a trace and, if well measured, can guide the action of doctors”. What can be defined as an ‘anatomy’ of innate immunity, a chapter that reveals all the secrets of soluble molecules which according to experts “act like real ‘primitive antibodies'”, bears the signature of a team of Italians.
It is a review that has earned the pages of the ‘New England Journal of Medicine’. It was curated by Mantovani, scientific director of Humanitas and professor emeritus of Humanitas University, and Cecilia Garlanda, head of the Laboratory of Experimental Immunopathology of Humanitas and professor of Humanitas University, together with a group of researchers. In recent decades, the team has led several discoveries on this front and takes stock of the knowledge of this class of molecules and the potential they offer for the diagnosis and treatment of infections, autoimmune and neurodegenerative diseases. The first molecules of innate immunity were isolated nearly a century ago and are now used clinically as diagnostic and prognostic indicators of inflammation.
“They are a well-established clinical diagnostic tool – highlights Garlanda – Their level in the blood, as Covid-19 has also demonstrated, allows us to measure the inflammatory state and has great diagnostic and prognostic value for many infectious, inflammatory or autoimmune diseases. However, the research data of recent years tell us that these molecules can do much more: not only as precision prognostic markers, but as therapeutic targets that are still largely unexplored”. Some studies carried out by researchers at the Irccs Humanitas Clinical Institute have made it possible to learn more about innate immunity. Today, the experts recall, we know that these molecules, once activated by encountering a pathogen, play a leading role: they fight the infection, recognizing the intruder, signaling it and hindering its action like ‘primitive antibodies’ , and coordinate tissue regeneration, because the war that the body unleashes against viruses, fungi or bacteria, like any conflict, leaves behind a lot of damage.
“We felt it was important to share all the knowledge on the molecules of our first line of defense for the benefit of doctors and future generations of clinicians, who find themselves using them for diagnosis and therapy, sometimes without having full perception of their potential – explains Mantovani – The molecules of innate immunity are in fact the protagonists of some important defense actions when the body is under inflammatory attack, as occurs in sepsis or in the case of major traumas, but also in neurodegenerative or autoimmune diseases”. The review on Nejm adds to the three that Mantovani wrote for ‘Nature’ and ‘The Lancet’ and which today represent a firm point of consensus on the discipline.
The soluble molecules of innate immunity are a large group of molecules with a complex and diversified action, not always easy to study due to their soluble nature. They operate outside and independently of the cells that produced them, moving through the body primarily through the blood system. Many of them are normally found in tissues, where they carry out their passive surveillance activity waiting for an emergency situation to arise, i.e. when the body recognizes the presence of a pathogen and/or tissue damage. When this happens, a cascade of chemical and cellular messages allow the alarm signal to spread from the tissue where the anomaly has been recognized throughout the body, activating a real state of systemic alert: the ‘acute phase response’ ‘.
The soluble molecules of the innate immunity play a fundamental role in this response and act in concert with the cells of the innate immunity (macrophages, neutrophils, natural killer cells, and so on). “Unlike the latter, however – continues Mantovani – the soluble molecules of innate immunity have long been underestimated”.
“Far from being the mere product of the state of inflammation that characterizes the body’s first line of defense against an aggression – Mantovani points out – they activate some defensive actions: they attach themselves to the microbes or to the diseased cells, signaling them to the immunity cells or eliminating them directly; they produce metabolic and hormonal changes that hinder the action of pathogens (such as the reduction of circulating iron, a fundamental molecule for ‘the aggressors’); they regulate not only the state of inflammation, but also the coagulation process and of regeneration which is essential to restore the functioning of tissues and organs once the infection has been neutralized”.
But what is the potential of these ‘ancient’ antibodies? As Garlanda explained, this potential can also be therapeutic. At the beginning of 2022, the Humanitas group of researchers led by Garlanda and Mantovani, in collaboration with the team of Elisa Vicenzi of the Irccs San Raffaele Hospital in Milan, demonstrated the ability of one of these molecules (Mbl) to bind to the protein Spike of Sars-CoV-2 in all its variants and to block the virus. Not only that: patients who have some mutated versions of Mbl would have a greater risk of developing severe forms of Covid-19.
“If it is true that the action of innate immunity is less specific than that put in place by adaptive immunity – the body’s second line of defense, tailor-made for the threat to be faced and of which antibodies are part – today we know that the soluble molecules of innate immunity act as real ‘primitive antibodies'”, conclude the two scientists. The research turns on its spotlight: several preliminary clinical studies are now testing the effectiveness of these molecules as potential supportive therapies for infectious, inflammatory, autoimmune and neurodegenerative diseases.