?…what was Neuroimmunology like when you started your career…
When I started my scientific career in the early 1970s, I could not forebode that I’ll end up as a Neuroimmunologist: neuroimmunology simply did not exist then. The CNS was deemed an immunological no-go tissue – shielded by the tight blood-brain barrier from peripheral immune surveillance. Also, EAE, Experimental Allergic (not Autoimmune!) Encephalomyelitis was around. But its pathognomonic round cell infiltrates were considered as the result of some allergic response to myelin plus adjuvant. Finally, MS was an idiopathic virus disease. An autoimmune pathogenesis was excluded by the absence of demonstrable autoantibodies (the criteria of autoimmunity at that time). Anyway, MS was a disease without any known therapy, other than vitamins and corticoids for acute relapses.
Equally barren was the field of autoimmune research. The 1970s were dominated by an overly strict version of Burnet’s clonal selection theory, which had it that autoimmunity (then represented by humoral autoantibodies) was due to factors like a pathological mutation of immune cells, or by the accidental opening of barriers surrounding sequestered tissues (including the CNS). Self-reactive immune cells were thought to disappear during the development of the immune system.
Now we know that Burnet’s concept (which did not know yet of T and B cell dichotomy) stood the test of time, but only partly. In particular, autoreactive T cell clones are efficiently purged during intrathymic shaping of the repertoire, but this process is by no means complete. The mature immune repertoire abounds with organ specific T cell clones, which in homeostasis are confined to an innocuous state of silence, sleepers. Upon pathological activation, they start to attack “their” target tissue. In addition, there are autoreactive T cell clones with regulatory function, self-reactive Treg’s.
?…what have the transformative technical changes been…
The list of transformative technical (and conceptual) changes is never-ending. I focus on the most radical game changers.
The first technological revolution (apart from the Xerox copier!) I witnessed was the appearance of Len Herzenberg’s FACS, initially a huge machine operated by a devoted physicist. It became the basis for distinguishing the diversity of immune cells subsets. FACS based cell sorting and analysis facilitated cloning and propagation of (auto-) antigen specific immune cells, another major technological progress. Next came the monoclonal antibody technology with all its impact on topics ranging from cell biology to clinical therapy, and the generation of transgenic animals. Also worth mentioning are newly developed imaging technologies, such as two-photon microscopy and genetic fluorescent cell markers, which now allow following fate and function in the living animal. Most recently, of course, single cell transcriptome profiling and CRISPR- based transgenesis are game-changers warranting mention.
Although not commissioned here, I can’t help commenting on ideological changes I witnessed over time. I saw concepts mushrooming all of a sudden, staying in the limelight for a while before their silent demise. One spectacular example was Jerne’s idiotype/anti-idiotype network theory, an intellectually alluring concept, which, unfortunately failed the test of time (“… what initially appeared as an exciting new perspective of the immune system is now viewed as a scientific vagary, and is largely abandoned “ Klaus Eichmann). Another, even more amazing example is the roller-coaster fate of regulatory T cells. Originally known as suppressor T cells fell this subset out of grace for a while, became a taboo cell. However, suppressor cells experienced a brilliant resurrection, though under a new name, now regulatory T cells, Tregs. After the gene underlying their regulatory function (FoxP3) had been identified, Tregs have been resurged as key elements in immune homeostasis as well as actors in a diversity of pathological conditions. They are now credited as agents in tissue repair and targets of clinical therapy.
These episodes, along with others, have taught me that fashion not only dictates our daily dress code but also profoundly imprints our scientific thinking, experimenting and writing.
?… what discovery has surprised you most….
Just a few examples from diverse fields: structures and mechanisms of antigen recognition by adaptive T cells (MHC, peptide TCR) came unanticipated; immune reactivity of the CNS tissues, with particular function of microglia; the beneficial therapeutic effect of anti-CD20 MAbs in relapsing-remitting MS, a disease that was deemed so T cell-dependent; and finally the classification of NMOSD and MOGAD as demyelinating autoimmune conditions separate from MS came to me as surprises. Finally, allow me to mention one of our own observations, namely the potential role of the intestinal microbiota in the pathogenesis of CNS (and other) autoimmune conditions – this was truly unexpected
?… what are your expectations for the future…
My best guess: The future will come with surprises that at present cannot be forecasted. So, what can be predicted at present? As a boy, in the 1960s, I had been an avid reader of futurist pamphlets that predicted, how the future world would look, say in 1990. I read that, then, we all would be carrying little motors on our back with propellers enabling us to hop individually from Munich to Paris and back. This did not materialize; instead, we now are living with Microsoft, Apple and Amazon. I learned the lesson, and now hesitate to predict a future too far ahead.
Joining the crowd, I anticipate individualized medicine, antigen specific therapies of autoimmune disease (in particular MS!). We will not only treat people efficiently, but we will be able to prophylactically avert the risk of disease. This will be reached using, easy to predict, artificial intelligence, high-tech lab instruments, in vitro organ/tissue generation, and, of course, we all will travel with propellers on our back.
?… where do you think the field is getting to…