ETH Zürich, Switzerland

An infection biologist points out an outstanding issue in mucosal immunology.

The gut immune system can distinguish between harmless commensal microorganisms and dangerous pathogens, and attenuates its response to the former to avoid dangerous chronic inflammation. The mechanisms that maintain this hyporesponsiveness are just beginning to be unravelled.

Dendritic cells, the key organizers of appropriate immune responses, actively sample commensal microbes. In organs other than the gut, this would trigger a strong immune response, and the responsiveness of intestinal dendritic cells to microbes is thought to be thwarted by anti-inflammatory molecules released by gut cells. But the situation could be much more complex: hyporesponsiveness might be restricted to certain 'microbe-associated molecular patterns' (MAMPs), such as lipopolysaccharides, large molecules attached to the outer membrane of many bacteria.

Linda Klavinskis of Kings College London and her team have analysed the MAMP-responsiveness of dendritic cells migrating from gut tissue to local lymph nodes. Surprisingly, these cells do respond to harmless Bacillus spores and most MAMPs — but not lipopolysaccharides (V. Cerovic et al. J. Immunol. 182, 2405–2415; 2009). Does this suggest that hyporesponsiveness of intestinal dendritic cells is transient? The maintenance of hyporesponsiveness in the gut mucosa, patterns of MAMP-hyporesponsiveness, and localization and timing of MAMP responses will be important topics for future research.

Unfortunately, unactivated dendritic cells are hard to isolate from the gut mucosa. In situ analysis of dendritic-cell responses to gut microbes in intact tissue holds much promise. Technical advances in multicolour two-photon microscopy, fluorescently tagged microbes, and transgenic mice expressing cell-type and response-specific fluorescent reporter proteins will be instrumental in this key area of biology.

Posted by Brendan Maher at 07:31 PM | Permalink | Comments (0) | TrackBacks (0)

Burnham Institute for Medical Research, La Jolla, California

A structural biologist has great expectations for llamas' small antibodies.

Llamas aren't just unusual and exotic looking: their antibodies are also a reason for much excitement. Made entirely of heavy chains, they are about half the size of those found in humans and many other vertebrates, which are normally composed of both heavy and light chains. When it comes to therapeutic applications, these larger antibodies are hard to store and deliver. But llama and other camelid antibodies demonstrate superior heat-stability and solubility, without compromising affinity or specificity, making them an attractive alternative.

Robin Weiss of University College London and his colleagues isolated three llama antibodies, known as 'neutralizing' antibodies, that can broadly prevent multiple HIV subtypes from infecting cells (A. Forsman et al. J. Virol. 82, 12069–12081; 2008). They began by creating an antibody library from two llamas immunized with the HIV gp120 antigen. To select for neutralizing antibodies, antibodies were raised against one HIV subtype but cross-screened against multiple subtypes. The researchers also included a competitive elution step to select antibodies that can compete with binding by CD4, the primary HIV receptor on human T cells. It remains to be seen how these neutralizing antibodies fare in animal studies and where they bind in atomic detail.

Intriguingly, there have been reports of several potent, broadly neutralizing human antibodies (for example, F10 and CR6261 against influenza's haemagglutinin) in which only heavy chains are involved in antigen binding — reminiscent of the situation of llama antibodies. These studies corroborate that the heavy chain alone can mediate broad neutralizing activity, and invite speculation that this may be a special strategy engaged by the human immune system to reach cryptic binding sites. Llama antibodies may be even better suited for those hard-to-reach targets.

Posted by Brendan Maher at 01:55 PM | Permalink | Comments (1) | TrackBacks (0)

Imperial College, London.

A crystallographer takes a jaunt into immunology.

Although I spend most of my time exploring a landscape formed by atoms and bonds, I know it is healthy to make occasional journeys into less familiar territories, and I was intrigued to spot a paper on the curious interplay between infection and immunity in cattle with foot-and-mouth disease virus (FMDV).

FMDV, a highly contagious pathogen that can cause lameness, low weight and decreased milk production, is a scourge of agricultural livestock around the world. Although the acute phase of infection is rarely fatal, infection may persist in animals that have apparently recovered, creating a viral reservoir that some fear could contribute to the spread of disease. Nicholas Juleff and colleagues, from the United Kingdom's Institute for Animal Health, report a fascinating discovery that may have unlocked the secret of FMDV persistence.

They used an array of molecular techniques to search for traces of virus in tissues from the mouths and throats of infected cattle (N. Juleff et al. PLoS ONE 3, e3434; 2008). In a carefully controlled study, they found evidence of intact, non-replicating virus particles trapped by immune cells called follicular dendritic cells within the germinal centres of lymph nodes. Strikingly, virus was present for at least 38 days post infection, even though it was undetectable in surrounding tissues.

The retention of intact virus within germinal centres is likely to have a role in stimulating the long-lasting immune response of white blood cells that is characteristic of viral infections (but not current vaccine preparations) and echoes a pattern previously seen for HIV infection. The authors suggest that this capture may inadvertently also be responsible for preserving intact viruses capable of infecting susceptible cells as they come into contact with germinal centres. A causal relationship has yet to be firmly established but the paper illuminates a clear pathway by which to check this out.

Posted by Maxine Clarke at 08:53 AM | Permalink | Comments (0) | TrackBacks (0)

Albert Einstein College of Medicine, New York City

A biologist considers a link between jumping genes and immune-system enzymes.

Many viruses present a fierce threat to the body. They contain nucleic acids that, when free to roam in a cell's cytoplasm, elicit an immune response involving proteins called interferons. Pairings of the nucleic-acid residues cytosine and guanine are especially good at this, unless they carry a chemical modification in the form of a methyl group. This modification is the norm for 'jumping genes', or retrotransposons, which can move around the human genome and were probably once viral genes themselves.

A team led by Daniel Stetson at the University of Washington in Seattle has uncovered a useful twist to this tale. While searching for proteins that interact with cytoplasmic nucleic acids, the researchers came across Trex1. Mutated versions of Trex1 are known to cause chilblain lupus in humans, and in mice lead to autoimmune myocarditis, whereby the immune system attacks the heart. Stetson et al. say that mice lacking Trex1 have huge numbers of retrotransposons in their heart muscles.

Critically, the authors' molecular surveys reveal that Trex1 suppresses the rate at which jumping genes move around. This indicates that Trex1 protects the body from misidentifying its own parts as 'foreign' by degrading retrotransposons and thus preventing them from overloading the system (D. B. Stetson et al. Cell 134, 587–598; 2008).

That jumping genes have the potential to overwhelm the system in this way was unexpected. Most experts had assumed that the addition of methyl groups took care of quenching them. But if retrotransposons are made at a rate that triggers inflammation, as Stetson and his colleagues' experiments propose, it could open up a whole new avenue for research. Everyone studying lupus and related diseases should be excited.

Posted by Anna Petherick at 05:11 PM | Permalink | Comments (0) | TrackBacks (0)

INSERM, Paris

An immunologist applauds a protein that prunes intolerant white blood cells.

Spreading tolerance is a worthy cause. In the body, newly made white blood cells are rendered tolerant to the many thousands of native proteins. But, like any complex process, this one is not foolproof, and when it goes wrong intolerant white cells cause autoimmune disease.

One way that the tolerancespreading system can fail is by not having enough 'field agents' to pick off intolerant dissenters. Regulatory T lymphocytes (Treg), a type of white blood cell, are these field agents. They find and suppress other white cells that react to healthy parts of the body. Although it is known that people with low Treg levels tend to have autoimmune diseases, how the cells function has been unclear. Recently, however, researchers in Japan shed light on this mystery.

Kajsa Wing, now at the Karolinska Institute in Stockholm, and her colleagues focused on the protein CTLA-4, which is preferentially expressed by Treg cells and forms part of a rheumatoid arthritis drug called Abatacept. They bred mice without CTLA-4 on the surface of their Treg cells. The animals appeared healthy until maturity, then quickly developed autoimmunity. So CTLA-4 is needed for the field-agent system to operate, and merely expressing it in smaller quantities on other sorts of white blood cell isn't enough. Wing et al. then discovered that CTLA-4 on Treg cells interacts with and diminishes two proteins, CD80 and CD86, on the surface of dentritic cells, which show other white cells what to hunt (K. Wing et al. Science 322, 271–275; 2008).

All of this confirms that CTLA-4 should provide a means of treating autoimmune diseases. Blocking CTLA-4 should improve the capacity of dendritic cells to present dangerous native cells to the immune system. Clinical trials for cancer treatments that do just that are already under way. Now we have a clearer idea how they work.

Posted by Anna Petherick at 05:06 PM | Permalink | Comments (0) | TrackBacks (0)

University of Cambridge, UK

A zoologist traces flu across the globe.

In winter, everybody recognizes a stuffy nose, a fever and an achy body as influenza. But experts still grapple with where the flu virus goes during the summer. One theory has it that flu lays low, holding out until the following season in a small number of asymptomatic people. Another idea — that flu strains tend to become extinct locally but shift around geographically — carries more weight. A recent paper by Derek Smith of the University of Cambridge, UK, and his colleagues helped nail the latter hypothesis by plotting the results of antigen-binding assays and genetic sequencing of more than ten thousand viruses on a map (C. A. Russell et al. Science 320, 340–346; 2008).

The researchers call this approach 'antigenic cartography'. Their antigenic time charts contain data crunched from the portion of the World Health Organization's enormous 'Global Influenza Surveillance Network' database that details strains classified as 'H3N2' between 2002 and 2007. First, they confirm flu's source–sink dynamics by showing that winter flu strains are more closely related to (and thus more likely to have evolved from) strains found elsewhere than to last season's local contagion. Second, the team pinned down H3N2's spread. Temperate regions are regularly seeded by strains from east and southeast Asia, where many strains circulate continuously and asynchronously in a pattern probably driven by varying climatic conditions.

These findings suggest that close surveillance of emerging strains in east and southeast Asia could enable us to predict those that will later affect the rest of the world. Yet it also poses a question: why do flu strains not return to this region after spending time (and thus evolving) elsewhere? Now that we know where new strains come from, we need to find out why they never go back.

Posted by Anna Petherick at 03:19 PM | Permalink | Comments (0) | TrackBacks (0)

Harvard Medical School, Boston, Massachusetts

An immunologist muses about inflammation through cell interactions.

I spend my lab hours trying to understand what prompts T cells — a type of white blood cell — to specialize. Some T cells produce soluble molecules that rattle the immune system into an inflamed state; other cells generate molecules that calm the system back down.

Upon infection, cells such as macrophages — another type of white blood cell — produce soluble molecules called interleukins that direct the fate of the responding T cells. An emerging curiosity in the field is which interleukins make certain T cells become pro-inflammatory, and which cause other T cells to become anti-inflammatory. This decision is crucial for determining whether an immune response induces or suppresses inflammation.

Recently, investigators have turned their attention towards an interleukin known as IL-27. This is produced by activated macrophages and was initially thought to induce IFN, a signalling molecule that activates macrophages even more.

But work by Nico Giraldi and his colleagues at Genentech in South San Francisco, and other groups, has recast IL-27 as a molecule that primarily directs T cells to suppress inflammation. In a paper published in March, Giraldi's team confirmed that IL-27 acts in this way because it causes CD4+ and CD8+ T cells to make the anti-inflammatory IL-10, and does not work through an alternative pathway (M. Batten et al. J. Immunol. 180, 2752–2756; 2008). Mice with Listeria infections or autoimmune tissue inflammation in their brains and spinal cords generated fewer IL-10-producing T cells when they lacked an IL-27 receptor. Whether an analogous interaction occurs in humans is not known, but, if it does occur, this research could become medically useful.

Posted by Maxine Clarke at 09:19 AM | Permalink | Comments (0) | TrackBacks (0)