trust but verify

Innate immune system detects the pathogen invasion and alerts adaptive immune system to its presence. However it is not always clear whether adaptive immune system should be alerted to the presence of any dose of pathogenic inoculum. May be innate immune system can handle low dose of pathogenic inoculum alone? However, what if innate immune system tries to handle the pathogen alone, fails doing it and alerts adaptive immune system too late when pathogenic onoculum become too large? The exact balance that will increase protective immunity and at the same time reduce tissue damage will depend on many variables, many of them still unknown.

If you are interested to know more about the complex interaction between innate and adaptive immune systems, I will recommend reading the following research article published in Nature Immunology a few weeks ago. In this study by Nadine Honke et al. (1), the authors first showed that in mice, intravenously injected (i.v.) vesicular stomatitis virus (VSV) is rapidly captured and cleared from the bloodstream by tissue macrophages. However, interestingly, the authors could detect the presence of live virus only in spleen tissue. Specifically, live virus was maintained in specialized macrophages called marginal zone macrophage that are identified by staining for CD169 marker. In contract, live virus could be recovered from all tissue examined from wild-type mice depleted of macrophages or from mice deficient in IFN-α receptor. These results suggested that CD169+ macrophages have some unique properties that allow them to maintain live virus in wild-type mice. The authors showed it may be related to higher expression of IFN-α signaling inhibitor Usp18 in CD169+ macrophages as compared to other tissue macrophages, for example, F4/80+ macrophages. Indeed, expression of VSV was absent in CD169+ macrophages from Usp-18 deficient mice. In other words, CD169+ macrophages “intentionally” inhibit IFN-α signaling in order to maintain live virus. Why is that? The authors explained this puzzle by observation that VSV-specific T cell and IgG response were reduced in Usp-18 deficient mice. Moreover, Usp-18 deficient mice became very susceptible to i.v. Injected VSV. Usp-18 deficient mice harbor far less live virus in the spleen at early time point post infection (at 7h) and harbor far more live virus in brain at late time point post infection (at 7 days). In addition, the authors showed that live virus primed VSV-specific adaptive immune response more efficiently compared to inactivated VSV. The authors concluded that “deliberate” maintenance of replication-competent virus in CD169+ macrophages gives enough time or antigenic material for efficient priming of protective adaptive immune response, while inactive virus is far inferior in providing signals necessary for efficient priming of protective adaptive immune response.

However, there are several holes in the story. The authors did not show results whether (1) VSV-specific T cells response was reduced in mice depleted of CD169+ macrophages or (2) whether mice depleted of CD169+ macrophages became more susceptible to VSV. Without these controls the whole concept of the paper will be misleading.

David

1. http://www.nature.com/ni/journal/vaop/ncurrent/full/ni.2169.html

gut instinct is depressing

does Immune system has any role besides protecting the body from infections? In my opinion, the answer is probably NO. Once in a while, however, you may find a study claiming otherwise (for example, study claiming that adaptive immune system improves neuron function and memory (1). These type of studies are usually based on observations derived from mice with a defective immune system (missing one or several components of immune system). The main challenge to these type of conclusions is the fact that because normal body harbors myriad varieties of microbes (in the gut, skin, oral cavity, etc.), then even a simple alteration of immune system may indirectly affect other tissue's function though its direct (missing)impact on microbiota. In order to properly address the involvement of immune system in other tissues function experiment should be carried out in the absence of microbiota, for example, in germ-free mice.

If you interested to know more whether immune system could affect other tissue's function and also to illustrate my point, I will recommend reading the following paper that appeared recently in Nature Medicine. This study, by Shulzhenko N and Morgun A et al., looked at intestinal tissue function in the absence of B cells (2). Using several lines of B cell or immunoglobulin (Ig) knock-out (KO) mice and gene microarray analysis, they found that there was very similar changes of intestinal tissue in mice missing B cells or IgA compared to wild type littermates (Fig 2c). In general, genes involved in defense were up-regulated and genes involved in metabolism were down-regulated in B cell KO mice compared to wild type littermates. This may have implied that B cells modulate intestine tissue function. However, to rule out indirect effect of microbiota, they carried out the same experiment in germ-free B cell KO or germ-free wild type mice. As expected, the difference in gene expression of intestinal tissue between B cell KO and wild type mice disappeared on germ-free background (Fig 3c,d). Of note, similar down-regulation of intestinal tissue metabolism occurred in both B cell KO and RAG KO mice (that lacks T cells as well) but it did not occur on germ-free background. These data suggested that improper activation of adaptive immune system in the absence of B cells were not responsible for down-regulation of intestinal metabolism and that microbiota was involved. Because gene expression profile of B cell KO mice was very similar to gene expression profile of intestinal tissue derived from mice with intestinal epithelial-specific deletion of GATA4 transcription factor, the authors concluded that altered microbiota (as a result of lack of B cells/IgA) directly affected intestine tissue metabolism. They also supported this conclusion by profiling gene expression of isolated intestinal epithelial cells from B cell KO mice and using mouse intestinal cell line treated with different inflammatory stimuli. In my opinion, the caveat of this interpretation is the fact that (a) gut tissue contains diverse set of innate immune cells (for example, lymphoid-tissue inducer-like cells) that could have affected gut metabolism and (b) intestinal epithelial cells isolated from B cell KO mice might had already received signals from these innate immune system (and not directly from microbiota) (in Fig. 5c). In my opinion, the better way to support their conclusion would have been to isolate intestinal epithelial cells from germ-free mice and treat them with different microbes or their components.

Overall, this study is one of best example of how proper experimental approach reveals the hidden effect of microbiota on intestinal tissue in the absence of one component of immune system, in this case the absence of B cells (and IgA).

David

1. http://www.nature.com/neuro/journal/v9/n2/full/nn1629.html

2. http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.2505.html

A freak of Nature

Today I am going to introduce a new discussion topic I call “right paper wrong journal”.

Scientist are looking for two things in the journal editor: integrity and good judgment. In many occasions, we have a situation when a publication of a particular paper represents editor's less than a good judgment. By judgment here I mean a relevance and a value paper brings to the journal readers. Paper can be well designed and properly done but it may not make a significant contribution for the knowledge advancement. 

Here is the example of such paper that was recently published in Nature (Nature is widely regarded a the world's most prestigious science journal). In this paper by Christine Moussion and Jean-Philippe Girard (1), the authors showed that in vivo a proper maintenance of lymph node (LN)-specific endothelial cells, called high endothelial venules (HEV), requires their interaction with dendritic cells through lymphotoxin-β receptor. As a functional outcome, the authors showed that in the absence of dendritic cells LNs had reduced cellularity due to a reduced capacity of lymphocytes to adhere to the HEV and enter the LN. However, no data is provided how this changes would have affected any meaningful immunological response. Any way, absence of dendritic cells by itself (independent of HEV functionality) will make an initiation of antigen-specific immune response almost impossible. Is there any reason why this paper could have not be published in Journal of Immunology?

David

(1) http://www.nature.com/nature/journal/vaop/ncurrent/full/nature10540.html