A crucial role for B cells in neuroinvasive scrapie
Authors: F Bootz
M A Klein
A J Raeber
E Flechsig
R M Zinkernagel
H Bluethmann
M Suter
U Kalinke
A Aguzzi
R Frigg
Journal: Nature (0)
Discipline: Multidisciplinary
Keywords: prion proteins; peripheral administration; kuru; iatrogenic Creutzfeldt-Jakob disease; bovine spongiform encephalopathy
Affiliations: Institute of Neuropathology, University of Zurich, Switzerland.

Abstract:  Although prion proteins are most efficiently propagated through intracerebral inoculation, peripheral administration has caused the diseases kuru, iatrogenic Creutzfeldt-Jakob disease (CJD), bovine spongiform encephalopathy (BSE) and new-variant CJD. The development of neurological disease after peripheral inoculation depends on prion expansion within cells of the lymphoreticular system. Here we investigate the identity of these cells by using a panel of immune-deficient mice inoculated with prions intraperitoneally: we found that defects affecting only T lymphocytes had no apparent effect, but that all mutations that disrupted the differentiation and response of B lymphocytes prevented the development of clinical scrapie. As an absence of B cells and of antibodies correlates with severe defects in follicular dendritic cells, a lack of any of these three components may prevent the development of clinical scrapie. However, we found that scrapie developed after peripheral inoculation in mice expressing immunoglobulins that were exclusively of the M subclass and without detectable specificity for the normal form of the prion PrPC, and in mice which had differentiated B cells but no functional follicular dendritic cells. We conclude that differentiated B cells are crucial for neuroinvasion by scrapie, regardless of the specificity of their receptors. 

Retracted: No

PubPeer comments:
 The first line of defense against all pathogens is the immune system. It was therefore expected, with a high degree of plausibility, that this would apply to prions as well. This study has completely changed that perception, and can rightly be considered paradigm-shifting. Aguzzi and colleagues have investigated all immune-deficiency mouse models available at the time, including both innate and adaptive immunity (B-cell deficiency, T-cell deficiency, interferon deficiency, and others). They found that removing the B-cells would block neuroinvasion. Hence this means that prions can subvert the immune system and utilize it to gain access to the brain. This discovery has had enormous impact on public health policies during the mad-cow disease crisis, and is shaping prion prophylaxis to the present day. See figure 1: the crucial image is the absence of histopathology in mMT knockout mice ![file] , 
 Am I the first one to notice that Dr Aguzzi has recently acquired an anonymous admirer of his work? What s the risk associated with signing your name to your public admiration? https: pubpeer.com publications CB801D32D9D844A0F58E3218B50635#1 https: pubpeer.com publications 0B4BCDE6304A57C98F0A303AE278C7#1 https: pubpeer.com publications 58C5E795F4F965ADFC1CABDD9438F2#1 , 
 This seminal paper showed for the first time that B-cells are important during peripheral stages of prion disease. Ablation of B-cell differentiation proved neuroprotective when mice were received prions via intraperitoneal, but not intracerebral injection. Moreover, mice lacking both B- and T-cells remained healthy after peripheral inoculation while mice lacking only T-cells did succumb to prion disease similar to wild-type mice, suggestive of a B-cell specific effect. This study paved the way for further, important studies on prion neuroinvasion, especially regarding the complex interplay between B-cells, follicular dendritic cells and prions. ![] , 
  Medicago Murex seems surprised to learn that there are people who think it important and worthwhile to comment positively on papers that have been important to their work. As for  Carex Hystericina s anonymity, I would rate it similarly to the anonymity of  Medicago Murex : both are unnecessary and a bit silly. , 
 #2 I ve reported these comments as they do appear to be a form of  astroturfing . , 
 Here is Adriano Aguzzi, the senior author of the paper discussed above. I am pleased (and also quite amused) that a study dating back from almost three decades is inciting such strong emotions among both admirers and detractors. Here I wish to provide some context to this discussion. This study was conducted in the middle of the Mad Cow Disease crisis. There are certain interesting parallels to the current CoV2 pandemic. Scientific knowledge was incomplete, and public health policy had to navigate by sight. Like today, many mistakes were made which in hindsight appear obvious - yet back in the days the facts were not clear by any means. I wish to state that the implicit conclusion that many people (including myself) drew from this study was **wrong. ** It was plausible, granted, but it was incorrect. The data themselves are robust, and were reproduced in my studies by us and by others. The problem is that the requirement for B-cells to achieve neuroinvasion seemed to suggest that prions piggyback on lymphocytes in order to reach the brain. Because I was convinced that B-lymphocytes would acquire prions directly, I advocated loudly for universal leukodepletion of blood units. This procedure removes all lymphocytes from blood, and I thought that it would decrease the likelihood of prion transmission through transfusions. Dr. Bernadette Healey (at that time CEO of American Red Cross) asked me to come to Washington and defend my position, which I did. My impassionate speech was apparently quite convincing, and both the USA, the United Kingdom and many other countries adopted universal leukodepletion. However, just 2 years thereafter, my lab showed that is not the case . It turned out that B-cells are in reality crucial for the maintenance of follicular dendritic cells, which in turn represent the main factories of prions within the body. Hence B-cells are crucial for prion neuroinvasion, but the reason why they are required is not that they transfer prions from one place to the other. In the end, even if I was probably wrong in my argument, it appears that leukodepletion was a good thing after all. It was shown in many follow-up studies that cellular components of the blood (even if not necessarily B cells) transport prions. Indeed in those years several individuals have contracted prion infections after transfusion with blood units that had not been depleted of lymphocytes. Conversely, after the introduction of leukodepletion, not a single person anywhere in the world ever became sick with prions as a consequence of blood transfusion. Therefore I conclude that I was probably wrong u2013 but at the same time I may have been right for the wrong reason! Today, many years after everything was said and done, my take is that this anecdote shows how science progresses in the u201cPopperianu201d sense of the word: through progressive falsification of working hypotheses. We generate data, construct a hypothesis, then perform additional experiments which contradict that hypothesis, then formulate a refined hypothesis, and so on. This was the case for the u201cprionemiau201d (the contamination of the blood supply with prions). I am pretty sure that we will see similar instances in the case of CoV2. , 
 Why do you think they are astroturfing? Are positive comments not allowed on pubpeer? , 
 Dear  Castostomus Leopoldi , did you find any factually wrong statements in the comments that you complain about? If you did, pubpeer is the right place to point them out! I am not an expert but I couldn t find anything misleading. Quite on the contrary, I think it s good that people discuss old pre-internet papers that have foundational to a specific field of research. , 
 @ #7  In the past few weeks someone (anonymous) has developed a strong interest in promoting Dr. Aguzzi s bibliography on pubpeer. These anonymous compliments appear, as far as I can tell, only on articles authored by Dr. Aguzzi. I might agree with you that positive comments could be important, but when they are made anonymously, to me, and I imagine to most people, they smell like astroturf. That smell is especially strong in this case since Dr. Aguzzi has a long list of other articles on pubpeer with very critical comments: https: pubpeer.com search?q=aguzzi *. The critical comments in that list are also anonymous but that doesn t bother me since the comments point out facts and not the opinions of the anonymous commenters on the importance of Dr. Aguzzi s work. I personally think PubPeer should ban anonymous compliments but they rarely take my (anonymous) opinions into account :-) * note that it s maybe convenient for Dr Aguzzi that you will now have to scroll down that list I pasted above to find the critical comments of his work. , 
 I am a younger PI at one of the world s top institutions. I have written positive commentaries about important work carried out by scientists in the neurodegeneration field (which I know well) including Aguzzi, Soto, Weissmann and several others, and will continue to do so whenever appropriate. It is in the nature of pubpeer to excoriate serious scientists who have made seminal contributions over three decades or more. And of course, if mistakes were made, they should be pointed out and redressed. But I think that it is fair to provide some perspective and to also acknowledge the work that was done well and has had a positive impact on the field. As for the anonymity, my motives are clear. In view of the extremely bilious environment populating pubpeer, I am afraid that revealing my identity would make me a target by the vengeful mob. Indeed, the mob starts often shitstorms which are at least as disruptive as the ire of some Nobel Prize winners - if not worse. Like it or not, we all must watch our backs, students and PIs alike. The commenter s request that PubPeer should ban (!) compliments speaks volumes about his real intents, and they are different from e.g. the journal clubs at my instution, where we celebrate excellent science rather than taking it down. I feel sorry for those colleagues who only know scorn, envy and malice as a means of promoting themselves, and my positive comments are meant to counteract this trend. , 
 #6 Dr. Aguzzi: Thank you for responding to comments on this thread. Yes, it does seem as some commenters here admire your body of work, and most commenters (anonymous or not) appreciate both supportive and critical posts, and really just prefer that they are substantive in nature. To that end, would you be able to respond to several credible (to me) threads which express concerns about papers where you are a co-author or senior author? Here are a few that seem to me to be worth a response: https: pubpeer.com publications 6C9662B7F4B3BF3771614F8C1F52B4 https: pubpeer.com publications 0F5804DCEBED850344C541FE2847FC https: pubpeer.com publications 841806329CBD4CD2593E83C5E369EA ,