At the Institut Curie, Inserm, in collaboration with colleagues from Dynavax, researchers are closing in on some of the mysteries of how the human body defends itself from attack. There are a few ways the human body faces attack. One source of attack is from the outside via viruses and bacteria and another is from within, through a dysfunction of its own cells resulting in autoimmune diseases, tumors and cancer. There are a couple of responses the body activates when triggered by those attacks. One is innate immunity, a response that is rapid but devoid of memory; the other is adaptive immunity, which is a response that takes longer to put into place but is more specifically targeted.
In the presence of viral or bacterial attack an essential prerequisite to the properly functioning innate immunity is the “turning on” of the protein PI3-kinase. Once PI3-kinase is activated, the immune response is triggered, leading to the production of type 1 interferons, the spearhead of innate immunity, which destroys the body’s invaders. This discovery opens up new therapeutic prospects since it may suggest ways of restoring the function of innate immunity, which, in autoimmune diseases is overactivated and in certain cancers is inhibited.
While innate immunity is always on guard to detect and destroy abnormal cells, tumor or bacterial/viral, it has no memory. The long-term adaptive immunity then comes into play, and though it takes longer to initiate, it teaches the immune system to recognize and destroy a specific invader.
Plasmacytoid dendritic cells are the body’s “sentinels” and are responsible for not only recognizing an invader, but for making the decision whether to trigger an innate immune (immediate, no memory) response or an adaptive (longer initiation, adapts itself in the best ways to destroy a specific invader) immune response.
Whatever the response, the presence of an intruder stimulates the TLR receptor inside the dendritic cells. Only then is the choice made between the two t ypes of immune of response. The PI3-kinase is activated and turns on a whole cascade of proteins inside a cell. Information on the presence of an intruder in the body is thus transmitted to its final destination, in the cell’s nucleus, where the protein IRF-7 (transcription factor) modifies the expression of specific genes and so alters the cell’s behavior. In this specific case, IRF-7 induces the production of type 1 interferons (interferon-alpha, for example), which will bring about the destruction of the virus and strongly activate various cells of the immune system.
In certain autoimmune diseases, like systemic lupus erythematosus(3) or Sjögren’s syndrome, this innate response goes haywire and is overstimulated, which leads to an abnormal defense reaction of the immune system that causes it to attack the body’s own cells, tissues or organs. In some cancers, on the other hand, the innate response is virtually absent. It may be that the cancer cells are able to block the PI3-kinase signaling pathway.
Vassili Soumelis, MD, PhD, at the Institut Curie and his collaborators hope that, in time, they can develop new treatments for use in autoimmune diseases and oncology. By acting on PI3-kinase, it may be possible to adapt the innate response, so as to inhibit it in the treatment of autoimmune diseases and boost it in cancer treatment.
First published in the February 18, 2008, issue of the Journal of Experimental Medicine.
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