examples of this–autoimmune diseases and ecological approaches to the
microbiome.
If the perspective presented here is correct, then autoimmunity is a physiological
process, which plays indispensable roles in the organism. Autoimmune diseases
must be perceived not as the result of the sudden appearance of an undesirable
autoimmune reaction (in the tradition of Ehrlich’s“horror autotoxicus”)andelim-
ination of immune cells responding to the self, but as the consequence of
a perturbation in the (cell-mediated, tissue-mediated, or system-mediated) regula-
tion of immunological processes that include, as a normal component, responses to
endogenous elements (Wing and Sakaguchi 2010). This means that, contrary to
what has been done over the last decades, thefirst question of researchers interested
in understanding autoimmune diseases should perhaps be not so much“what
triggers an immune response against the self ?”(e.g., why do self-reactive effector
Tcellsdevelopinthisorganism?)as“which aspect of the regulatory machinery that
normally keeps autoimmune responses in check has been disturbed, and why?”
(e.g., why do regulatory T cells no longer downregulate the activity of potentially
harmful autoreactive Tcells?). The two strategies differ. Thefirstactsatthelevelof
effector cells and consists in preventing the development of autoreactive cells.
The second acts at the level of the cells that regulate the activity of effector cells;
acknowledging the physiological nature of autoimmunity, it consists in preventing
the switch from physiological autoimmunity to pathologicalautoimmunity. One
can speculate that many factors could play a role in this disturbance of regulatory
mechanisms (especially regulatory T cells), including excessive hygiene in indus-
trialized societies (Bach 2002), modification of the microbiota, and disorganization
of the extracellular matrix in local tissues.
The second example of a therapeutic consequence of the renewed concep-
tion of immunity and individuality in recent immunology concerns the micro-
biota. Recognizing that most living things harbor myriad microbes, most of
which do not harm their hosts, a key clinical goal becomes to manage these
microbial communities instead of trying to kill all microbes. The develop-
ment of such ecological approaches in medicine is a difficult task because the
microbiota is in fact made of several highly complex local ecosystems in
which any perturbation is likely to have unpredictable consequences. That
being said, recent success with faecal transplantation in people infected with
Clostridium difficile(van Nood et al. 2013), despite major potential limits in
other contexts (Pamer 2014), suggests that such approaches are of increasing
interest to clinicians. Another approach in the same vein is to determine to
what extent, in a context of antibiotic resistance, it will be possible to
manipulate components of the microbiota to protect a host against pathogens
(Pamer 2016).
Philosophy of Immunology 27