IL-13 and hepatic gluconeogenesis

When I started learning about immunology I held a conviction that the immunity serves only to combat infections and pathogens. Perhaps the major change I have acquired in my understanding of immune processes is that the function of the immune system could be more permeating and extend to broader activities than just the defense. What we call the immune system works in situations well beyond the strict response to pathogenic organisms. It does not necessarily fight foreign entities as it may accommodate them (in case of microbiota) and also it has the intriguing links with the metabolism. I have found a publication that adds an interesting voice in support of such more general role of the immune system. It turns out that the cytokine IL-13 which is an important player in Th2 branch of immunity may influence how our body maintains one of the most important metabolic indicators.

The link:

Authors show data that mice deleted for gene encoding IL-13 display the impaired control of glucose level in the blood. Such defect appears to be a systemic one since it comprises both the increased production of glucose by liver cells as well as the reduced glucose uptake by muscles. Additionally, investigators delve into the molecular mechanism that underlies the IL-13-dependent control over the glucose production in the liver. It turns out that the transcription factor STAT3 could be the mediator between IL-13 signaling and genes involved in hepatic gluconeogenesis. Other than that authors attempt to identify the cellular population which may be responsible for the release of IL-13 in the liver and suggest that these could be NKT cells.

I am not really sure if it is sound to speculate in such way but there is at least the theoretical possibility that the exposure to parasites that provoke Th2-skewed response (like helminths) could protect from developing type II diabetes. The only problem is that relatively benign organisms inhabit the gastrointestinal tract and their influence may not extend to the liver whereas those that infect systemically (like Schistosoma mansoni) are too dangerous to be treated as a therapeutic agent. However, schistosome eggs are already applied as support in the treatment of excessive gut inflammation. May they be helpful in the regulation of glucose level?

Stanya KJ, Jacobi D, Liu S, Bhargava P, Dai L, Gangl MR, Inouye K, Barlow JL, Ji Y, Mizgerd JP, Qi L, Shi H, McKenzie AN, & Lee CH (2013). Direct control of hepatic glucose production by interleukin-13 in mice. The Journal of clinical investigation, 123 (1), 261-71 PMID: 23257358


Schistosoma mansoni evacuates its eggs through Peyer’s patches

Schistosomes are parasitic worms that live in the blood and have a complicated life cycle. The sexual form inhabits vertebrates (humans included) whereas the other stages infest fresh water snails. Adult worms tend to chronically infect their host (sometimes for many years) but for the propagation they have to be able to release their eggs to the outer environment. These blood parasites are remarkably invisible to the immune system; however, their eggs are known to induce the immune response. How such ability may connect to the propagation issue is the subject of the recent publication.

The link:

Authors study how Schistosoma mansoni, which is an endemic human parasite present in many tropical regions of the world, may excrete its eggs through the intestinal barrier (schistosome species vary between utilization of the intestinal and urinary tracts as the evacuation routes for eggs). It looks like to this end the parasite uses the lymphatic structures encountered in the lower portion of the small intestine – Peyer’s patches. The presence of mature schistosome eggs is apparently able to remodel the vasculature around Peyer’s patches and introduce changes to the cellularity of these intestinal lymphatic structures. Moreover and crucially, in the strain of mice that harbors no Peyer’s patches the egg excretion is visibly reduced and more eggs appear to be backwashed into the host tissue where they form granulomas.

For a number of years schistosome eggs have been hyped as the “taming agent” of the over-reacting immune system. It is well known that they possess the modulatory influences over a number of inflammatory conditions that afflict the gastrointestinal tract. I wonder if such an ability to modulate may be due to the described peculiar interaction of schistosome eggs with their hosts’ Peyer’s patches. From the schistosome point of view eggs need to get out. Thus the parasite may have evolved to drive the immune reaction to its eggs because of the necessity to utilize immune structures for the egg excretion.

Joseph D. Turner,Priyanka Narang,Mark C. Coles,Adrian P. Mountford (2012). Blood Flukes Exploit Peyer’s Patch Lymphoid Tissue to Facilitate Transmission from the Mammalian Host PLOS Pathogens

IgE class switching occurs in germinal centers

IgE antibody response is known to accompany infections with helminths. Organisms like Schistosoma mansoni, Nippostrongylus brasiliensis, Heligmosomoides polygyrus or Brugia malayi are able to induce the substantial class switching to IgE and increased levels of IgE serum antibody. IgE antibodies are also associated with allergies, asthma and generally Th2 effector responses. The other murine antibody class connected to Th2 is IgG1. Despite the importance of IgE response not all facts linked to basic IgE biology are entirely clear.  For example, it is not sure whether class-switching to IgE takes place in or outside germinal centers. Another elusive issue is the hypothetical presence of separate IgE memory population. There were some suggestions that IgE class switching needs to go through IgG1 intermediates and that IgE memory is maintained in IgG1 compartment. The recent publication uses IgE-reporter mouse strain to challenge the notion that IgE response occurs exclusively in tight connection with IgG1.

The link:

Authors use the fact that the secreted and membrane forms of antibody are translated from different mRNA splice variants. The IgE reporter strain they employ has the GFP sequence inserted downstream of exon that encodes the cytoplasmic domain of membrane IgE thus connecting the fluorescent signal with the membrane antibody version. Additionally, the IgE locus of reporter mice contains 52-amino acid region (called M1) derived from human antibody. Such approach allows detecting GFP signal as approximation of IgE membrane variant synthesis and subsequently verifying the presence of IgE with antibody against M1.

To confirm the validity of this strain for in vivo studies authors employ in vitro cultures with IgE response promoting factors (anti-CD40 and IL-4). It is established that GFP-positive population can be divided into GFPint and GFPhi subsets. The presence of soluble IgE correlates with appearance of GFPhi cells and only GFPhi fraction stains positively with anti-M1 antibody. Additionally, GFPhi cells express much more of IgE mature transcript than GFPint population which contains numerous cells positive for IgG1 presence. It is therefore concluded that only GFPhi fraction encloses IgE-switched cells.

To monitor how IgE-switched population comes into existence authors use the infection with Nippostrongylus brasiliensis. They aim to detect the germinal center (B220+IgDGL7+CD95+) and memory (B220+IgD+GL7CD38hi) compartments inside GFPhi (and thus IgE-switched) subset by flow cytometry. At the initial phase of infection all GFPhi cells bear features characteristic for germinal centers. At later stages some of them transform into memory cells. The appearance of IgE germinal center and memory populations occurs at the same time as analogous IgG1 subsets. Authors interpret these data as ruling against the possibility of IgG1 transitional stage for IgE-switched cells. Investigators also confirm the functionality of IgE memory population by adoptive transfer strategies. Additionally, the publication contains data about in vivo generation of IgE-secreting plasma cells and visualizations of germinal centers with IgE-switched cells (plus IgE memory and plasma cells) in lymph nodes of infected mice.

My first reaction after reading this paper was that of astonishment. Did they know so little about IgE response not to be sure whether there are IgE-switched cells inside germinal centers? The included data do not show anything very new or unexpected. They just extend basic facts from B cell biology for the IgE population.  Investigators show in the convincing way that IgE memory and plasma compartments derive from germinal center reaction and that memory IgE cells contribute to faster antibody response on re-infection. On the whole this is very interesting stuff which illustrates how many gaps are still in our knowledge.

Talay, O., Yan, D., Brightbill, H., Straney, E., Zhou, M., Ladi, E., Lee, W., Egen, J., Austin, C., Xu, M., & Wu, L. (2012). IgE+ memory B cells and plasma cells generated through a germinal-center pathway Nature Immunology, 13 (4), 396-404 DOI: 10.1038/ni.2256