Last week Science has an update on differential antigen processing by DCs including a key sentence on immature DCs:
Cultured immature DCs capture antigen but only process and present it on MHC II after exposure to inflammatory stimuli or TLR ligation.
Although the authors were not aware of current allergy research, they perfectly summarize how vitamin D renders DC immature, while hygiene (infections or LPS farm exposure ) may antagonize it.
Most people in the field search Pubmed but there is another site that I frequently visit – the European patent database that often have more concise information. Look at current allergy patents – the last one will definitely work you may also use a big plastic bag ;-)
Be aware that being cynical is probably bad for your heart.
You may renember the homunculus – a projection of body functions on brain areas. There is an interesting clinical extension stemming from 69 stroke patients of which 15 immediately, easily and permanently quit smoking. One patient said that his “body forgot the urge to smoke”. Sure, this analysis may still be somewhat confounded by the fact that certainly more areas are usually destroyed – but there are interesting approaches that could be followed up, the authors speculate about influencing sensory airway representation, neurotransmitter therapy and monitoring of smoking cessation programs. So stroke may help to quit smoking but I think there are better ways to do that. Seems that Science won this race with Nature. Yea, yea.
Don’t miss the follow up.
The Korea Herald writes – as noticed by Hsien Hsien Lei
The government yesterday released a set of new regulations to ban or restrict genetic tests in 20 categories amid ethical concerns over DNA tests … According to the new guidelines, DNA labs will be banned from conducting tests in 14 categories including body mass, intelligence, strength, propensity for violence, longevity, mental health, diabetes, blood pressure and asthma.
Although I do not believe that genetic testing for “asthma genes” will make any sense without the context of scientific studies, I think that such regulations are overdue – at least when genetic testing does not provide any benefit but may pose harm. If you have asthma or not, is a clinical question – and the answer will be an appropriate treatment or not. If you ever will get asthma is a question that nobody can answer. Even if genetic prediction will be ever possible, there is still no preventive measurement (at least by Jan 18, 2006, 16:14:23) . Yea, yea.
My previous work on vitamin D focused mainly on allergy but according to new research of Bosse et al vitamin D also stimulates bronchial smooth muscle and airway remodeling
Genetic variants in the vitamin D receptor (VDR) gene were recently associated with asthma. The biological mechanisms explaining this association is unknown, but are likely to involve many cell types given the pleiotropic effect of its ligand … The most significant network of up-regulated genes included genes involved in morphogenesis, cell growth and survival as well as genes encoding structural proteins, which are potentially involved in airway remodelling.
Another study published more or less at the same time by Wittke shows
Conversely, WT splenocytes, Th2 cells and hematopoetic cells induced some symptoms of experimental asthma when transferred to VDR KO mice, but the severity was less than that seen in the WT controls … Lipopolysaccharide (LPS) induced inflammation in the lungs of VDR KO mice was also less than in WT mice. Together the data suggest that vitamin D and the VDR are important regulators of inflammation in the lung…
In a previous paper I have questioned if LPS
nanogram exposure on the pulmonary epithelium will supersede the gram-wise exposure on the gut mucosa.
This may indeed work as now shown by Eyal Raz in a commentary in Nature Immunology where previous TLR studies
typically reproduce the splenic version of innate immunity (the spleen is used here as a metaphor for the sterile internal environment).
In the lung only the alveolar space is thought to be sterile while macrophages should not be in a constant state of activation (as inflammation would compromise gas exchange).
There are now several indicators for a lung-specific regulation of innate immunity: TLR9 is expressed in human plasmacytoid dendritic cells while TLR4 is only on myeloid DCs; TGFB-ß mediated crosstalk between alveolar macrophages and epithelial cells seems to be unique in the lung; in addition indeolamine induction or surfactant production is not found elsewhere. Yea, yea.
A new series of pro- and con editorials in the Am J Res Crit Care Med discusses the question why in some instances mouse models have “misdirected resources and thinking”. You may have noticed that I have only rarely used animals for research; the authors of this editorial have collected empirical data on the exploding use of murine models. Despite their attractiveness from a technological point, they are often useless because
I am sure there are even more arguments – I suggest that the authors deserve the Felix-Wankel price.
15 Dec 2006: The BMJ has 6 more examples about the discordance between animal and human studies: steroids in acute head injury, antifibrinolytics in haemorrhage, thrombolysis or tirilazad treatment in acure ischaemic stroke, antenatal steroids to prevent RDS and biphosphonate to treat osteoporosis.
19 Dec 2006: Another pitfall paper
31 Dec 2006: A blog on animal welfare
25 Apr 2007: Call for better mouse models
15 Jul 2018: Of Mice, Dirty Mice, and Men: Using Mice to Understand Human Immunology
7 Jan 2023: A review concluding that The vitamin D system in humans and mice: Similar but not the same
Clemens von Pirquet (1874-1929) was the first to introduce “Allergie” into clinical medicine by characterizing an altered immune reaction of the body to foreign substances. The famous paper was published 1906 in the “Münchner Medizinische Wochenschrift (MMW)” Volume 53, page 1457-1458.
AB Kay published a nice essay on “100 years of Allergy: can von Pirquet’s word be rescued?” that includes an English translation of the above paper. The MMW has a contemporary obituary of Meinhard von Pfaundler (1872-1947) who was one of the earlier directors of the Münchner Haunersche Kinderspital.
Finally, the “Wiener Klinische Wochenschrift” has a CV of Clemens von Pirquet, showing his way to Baltimore and Breslau back to Vienna until his tragic end by committing suicide together with his mentally ill wife.
Just found at the HUM MOLGEN bulletin board a link to Fable, a new automated literature extraction system. Fable is pretty fast and can output gene lists. Sure, the screenshot below shows only those genes that I mentioned in the abstract, but this is not so bad as the most important genes wil be placed there.
BTW, the number of reviews on asthma genetics have been falling to less than 50% after closing the Asthma Gene Database. Maybe this new service will help to re-establish the former output of reviews ;-) yea, yea.
I am interested in 5q31 and the IL4 cluster since I met David Marsh in the lobby of a hotel in Heidelberg around 1993. David was one of the founding fathers of asthma genetics and I renember how he vividly told me that he has a forthcoming Science paper on the IL4 cluster and IgE. The cluster is still one of the best allergy regions where the signalling through IL4 and IL13 now gets more interest than the work of any of his competitors.
Nature genetics now has an update on the 3-dimensional resolution of the genomic region. It is not cristallographic work as might be expected but a nice study of the chromatin structure that is leading to a coordinated expression of these cytokines. SATB1 (special AT-rich sequence binding protein 1) is thought to anchor specialized sequences letting DNA loops come into interaction. I wonder if there might be even a direct physical interaction of the IL4 and IL13 promotor and if there will be any SNP influencing that interaction? David (who died of brain cancer in 1998) would have really liked this work. Yea, yea.
The Hotel Dieu in Paris has been one of the first pediatric hospital in the world (see my photo of the hospital entrance). I recall from the detailed history of allergic diseases by Schadewaldt that at the beginning of the last century it was difficult to presen the students a case of the Bostock hayfever.
The disease was so rare that it took more than one week to find a child with the typical symptoms. Yea, yea.
I am detailing in a forthcoming paper in “Allergy”, that the contradicting results found with ADAM33 (the first positionally cloned asthma gene) probably results from a rather poor design of all follow-up studies.
It does not make so much sense to repeat over and over the same few SNP marker; instead a full resquencing of the linkage region would be necessary. From the analysis of public LD maps it is even possible that neighboring genes may be responsible for the observed associations.
I have also doubts if the SNP-centric view is always leading to success. BTW there is a new database of over 400,000 non-reduandt indels of which 280,000 are validated by comparison with other human or chimpanzee genomes (see Mills et al., the indels are available in dbSNP under the “Devine_lab” handle).
A new study now shows directly that personal exposure of particles is linked to asthma symptoms. Children carried pollution monitors in their backpacks on the way to school where PM2.5 ranged from 20 to 50 micrograms per cubic meter. Although only around 10 percent of the total mass of particles was diesel soot, it was this that was most closely linked to the children’s asthma. This nicely complements results of our study in Munich in 1989/1990 which was the first survey indirectly linking car exhaust and airway symptoms in children. Mechanisms how this happens are not very well known – for a discussion of the biphasic response see our paper of a mouse model, yea, yea.
Having read again Beutlers 2004 TLR review, I am always fascinated by the flexible response and the hourglass response effect. On the outside there is the microbial universe and inside are the many strategies to fight infection, but all goes through a single bottleneck. What is the reason behind? To calm down but strike when necessary?
