Tag Archives: ige

IL33, allergy and helminths: Shot in the leg?

Ever since the NEJM paper in 2010 that showed an IL33/ST2 association there are always new studies. Grotenboer 2013 did a functional annotation of the gene and it’s receptor in humans while there is no more doubt about the involvement of IL33 in human allergy.  Right now IL33 suppression is even used as an experimental screening test for allergic reactivity with ongoing phase II studies of anti-IL33 or anti ST2. Good IL33 reviews can be found for example in frontiers in immunology by Tataori et al. or in nature immunology by Smith. These reviews do not tell you so much about the regulation but this has recently elucidated by Gour et al. who describe a tropomyosin–dectin-1 interaction of the human host. Why is tropomyosin such a frequent target of human IgE?

Muscle protein tropomyosin is an important IgE target in a number of nematode infections; Onchocerca volvulus ; Ascaris lumbricoides; Anisakis simplex; and tropomyosin from the blood fluke Schistosoma mansoni is also a human IgE antigen. Tropomyosin is highly conserved across many invertebrates and is responsible for much of the IgE cross-reactivity between Ascaris and dust-mites.

I haven’t found any good  answer to this question. As tropomyosin affects contractility – this seems like “shooting into the leg” of worms whenever they attempt to invade.
Maybe Gour et al. did not know the earlier dissertation from Berlin that already showed a reduced inflammation in the OVA mouse model by administration of recombinant tropomyosin.

The broad cross reactivity to tropomyosin gives rise to the question if helminth tropomyosin could induce allergic reactions to itself and/or tropomyosin of different organisms. Considering the fact that filarial nematodes express tropomyosin on their surface […] and that the continuing turnover of microfilariae confronts the host with relevant amounts of tropomyosin makes this question even more appropriate.

The worm seems to be attacked by anti-worm-surface-tropomyosin IgE whenever the worm tries to invade  the epithelium during an acute infection. During invasion extracellular IL33 is cleaved into a shorter form with enhanced activity attracting more immune cells.
During chronic infestation nothing happens as long as the worm does not invade and doesn’t trigger any IL33 alarmin. As there is continuous tropomyosin antigen antigen contact, the host is slowly desensitzed, clearing IgE in favor of IgG4.

Is this also a model that explains allergy? We don’t know the details but maybe this antigen recognition / response system is being disturbed where allergens like Der p1 mimicking a worm infection by tropomyosin can trigger the allergic reaction in particular as Der p1 a cysteine protease also mimicks an invasion signal.

The most significant improvement in Snow Leopard

(at least for scientists) is the possibility to annotate PDFs. Sorry, the screenshot originates from one the most stupid papers that I read over the past years but it nicely shows Continue reading The most significant improvement in Snow Leopard

Try to stay away from rants and comparisons

for living then longer … This might be a good rule for private life (and even for a scientific career) but not so much for the progress of science.
There is another allergy gene paper on FCER1A and RAD50. FCER1A has some tragedy as the authors believed for many years in FCER1B (and others in FCER2).
Another tragedy comes with the second gene – Continue reading Try to stay away from rants and comparisons

Hans Selye: Ancestor of the allergy vitamin hypothesis

I spent a lot of time in libraries verifying bibliographic lists as I expected that somebody else could have had the idea of allergy induction by vitamin D before — in particular when being closer to the introduction of vitamin D supplements. Fortunately Science Magazine now offers a fulltext search of their archives (what is currently not possible with old Nature volumes). I could locate about 70% of the computer hits when searching manually the Science index for vitamin and hayfever. The loss of about one third could be mainly attributed to the fact that extra supplement pages have only occasionally preserved in the libraries that I have visited for this project (Marburg, Berlin, München STABI + TUM, Garching). Text recognition is also limited, so my results may be preliminary.

What I found this afternoon in the library at TUM Garching Continue reading Hans Selye: Ancestor of the allergy vitamin hypothesis

Pax5 and allergy

Transcription factor Pax5 is a key regulator for the B cell lineage (it may even be reponsible for redifferentiation from B to T cells according to new research from the Busslinger lab). As human CD23a, the low affinity IgE receptor, has a functional Pax-5-binding site, there could be a relationship to allergy inheritance. So far I have only looked into Pax-8 while Pax-5 might be even more important.

Lymphopoetin and allergy

This is to convince me that the thymic stromal lymphopoietin (TSLP) is a master switch in allergy

15 Aug 2004

Skin-specific overexpression of TSLP resulted in an AD-like phenotype, with the development of eczematous lesions containing inflammatory dermal cellular infiltrates, a dramatic increase in Th2 CD4+ T cells expressing cutaneous homing receptors, and elevated serum levels of IgE.

5 Jun 2006

Topical application of the physiologically active ligand [1{alpha},25-(OH)2D3; calcitriol] of the vitamin D receptor, or of its low-calcemic analog MC903 (calcipotriol; Dovonex), induces TSLP expression in epidermal keratinocytes, which results in an atopic dermatitis-like syndrome.

22 Jan 2007

TSLP, synergistically with interleukin 1 and tumor necrosis factor, stimulates the production of high levels of Th2 cytokines by human mast cells (MCs) … TSLP is released by primary epithelial cells in response to certain microbial products, physical injury, or inflammatory cytokines.

23 Jan 2007

Proinflammatory TNFalpha or IL-1alpha and Th2 (IL-4 or IL-13) cytokines synergized to induce the production of TSLP in human skin explants … Our data provide the first evidence of TSLP induction and subsequent DC activation in human skin.

25 Feb 2007

Mice with an IEC[intestinal epithelial cell]-specific deletion of IKKbeta show a reduced expression of the epithelial-cell-restricted cytokine thymic stromal lymphopoietin in the intestine and, after infection with the gut-dwelling parasite Trichuris, fail to develop a pathogen-specific CD4+ T helper type 2 (TH2) response and are unable to eradicate infection. Further, these animals show exacerbated production of dendritic-cell-derived interleukin-12/23p40.

June 2007

… (TSLP) and interleukin-7 share a common receptor chain, IL-7Rα … The gene encoding the IL-7Rα chain is polymorphic, and investigation of inhalation allergic patients compared with controls showed significant association with two alleles at position +1237 and +2087.

Aug 2007

… TSLP represents a master switch of allergic inflammation at the epithelial cell and dendritic cell interface.

IL4 cluster revisited

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.

il4cluster.png