Monthly Archives: November 2009

Synovial fibroblasts spread Rheumatoid Arthritis to other joints

New research shows that rheumatoid arthritis synovial fibroblasts help spread destructive arthritis to other joints in the body, according to research by Lefevre and colleagues published online on the 8th November in the journal Nature Immunology.

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease that can affect many tissues and organs, but mainly causes inflammation in the lining of the joints. RA is an autoimmune disease and is caused by abnormal immune responses whereby the body’s own immune system attacks itself. About 1% of the population in developed countries suffer from RA, and it leads to progressive joint destruction resulting in chronic pain, loss of mobility and loss of function of the joint. One of the key features of RA is it usually starts in one or two joints and then spreads to most joints in the body. The researchers wanted to understand what host factors are involved in the spread of disease. They were particularly interested in special cells called rheumatoid arthritis synovial fibroblasts (RASFs), which are present in high numbers in rheumatoid synovium (lining of the joint) and had previously been shown to contribute to the progression of RA by attaching to, invading and degrading cartilage and bone.

The researchers used a SCID mouse model of RA. SCID mice have a severe immunodeficiency and cannot mount a humoral or cellular immune response therefore you can graft tissues from another species (in this case human cartilage and RASFs or rheumatoid synovium) subcutaneously (under the skin) and it will not reject it. This means the researchers could study the biology of RA and how it spreads over a long period of time. Using this in vivo model they showed not only that human RASFs attached to, invaded and degraded co-implanted cartilage but also could spread through the mouse body to another cartilage implant on the other side of the mouse (contralateral implant). Experiments that inject RASFs 2 weeks after surgical cartilage implantation suggests that RASF migration was due to neovasculisation (formation of micro blood vessels) of the cartilage and not due to the surgery itself or wound healing. The researchers then implanted rheumatoid synovium as a natural source of RASFs. These “natural” RASFs also migrated to, invaded and degraded the RASF-free cartilage contralateral implant. The organs of 20 mice used in the implant experiments were examined to determine the route of RASF migration; the majority of human RASFs were found in the spleen but no RASFs were detected in the lungs, intestines, heart, liver or skin distant from the implants. Human RASFs were also found in mouse joints and ear cartilage and PCR analysis revealed that human RASFs were present in the bloodstream of experimental mice. Finally, the researchers showed that RASFs are able to transmigrate through cell monolayers, which is an important requirement for entering and leaving the bloodstream at sites of disease or to access distal sites.

This work shows that the characteristic progressive joint destruction seen in RA is in part due to RASFs, which can migrate long distances and spread the destructive arthritis from one primary joint to other joints in the body. More work is needed to understand if other cellular factors are involved in RASF migration. This could provide clues for new drug targets to prevent the spread of RA, which is hugely important since the cause of RA is unknown and there is currently no known cure.

ResearchBlogging.org
Lefèvre, S., Knedla, A., Tennie, C., Kampmann, A., Wunrau, C., Dinser, R., Korb, A., Schnäker, E., Tarner, I., Robbins, P., Evans, C., Stürz, H., Steinmeyer, J., Gay, S., Schölmerich, J., Pap, T., Müller-Ladner, U., & Neumann, E. (2009). Synovial fibroblasts spread rheumatoid arthritis to unaffected joints Nature Medicine DOI: 10.1038/nm.2050

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Hitting the headlines this week

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Interventions in childhood and adolescence reduce teenage pregnancy

Interventions in early childhood and adolescence help reduce teenage pregnancy and could be included in public policy according to a systematic review by Angela Harden and colleagues published free in the British Medical Journal last week.

The United Kingdom and United States have high teenage pregnancy rates, and although early parenthood can be positive it is also associated with a wide range of adverse health and social issues. Sex education and better sex health services have traditionally been used to reduce teenage pregnancy rates but recent research suggests they are not effective on their own. This has led to efforts to address the social and economic difficulties associated with early pregnancy and parenthood.

The researchers conducted a systematic review, including a statistical meta-analysis (combines all the results in one analysis), to examine the quality of ten trials that investigated interventions to prevent early parenthood and five qualitative studies that examined young people’s views on early parenthood in the UK. They found that teenage pregnancy rates were 39% lower in individuals that received an intervention (like pre-school education, parent training or promotion of self esteem) compared to those that received standard practice or no intervention at all. Three common themes emerged from the qualitative studies that contributed to early parenthood; including dislike of school, poor material circumstances and unhappy childhood, and low expectations for the future.

Childhood and adolescent programmes providing learning support to boost interest in school, guidance and social support to address an unhappy childhood and career development and work experience to increase aspirations in young people could all be useful to reduce teenage pregnancy. These strategies could be included in public policies to effectively address social disadvantage and teenage pregnancy. The researchers found only a limited amount of data on programmes to reduce teenage pregnancy so more work is needed to study the effectiveness of these interventions in preventing early parenthood.

ResearchBlogging.org
Harden, A., Brunton, G., Fletcher, A., & Oakley, A. (2009). Teenage pregnancy and social disadvantage: systematic review integrating controlled trials and qualitative studies BMJ, 339 (nov12 1) DOI: 10.1136/bmj.b4254

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M cells, gatekeepers or gateway to the gut

Glycoprotein 2 is the M cell receptor for type I pili on bacteria and is important for the immune response to these bacteria, according to research by Hase and colleagues published last week in the journal Nature.

The mucosal immune system is one of the largest components of our immune system and is hugely important for protecting mucosal surfaces (like our gastrointestinal tract) from harmful pathogens. Our guts are home to trillions of commensal bacteria which live quite happily there causing us no harm whatsoever. The gastrointestinal tract is protected from these bacteria (or other damaging substances) by a layer of tightly packed epithelial cells which form a barrier against any bacteria or molecules penetrating the gut. However, Microfold (M) cells are specialised intestinal cells located over mucosal lymphoid tissue called Peyer’s patches which are potential entry points into the host. M cells sample microorganisms or molecules in our gut and help transport them across the epithelial cell barrier (a process called antigen transcytosis) to deliver to professional immune cells (like macrophages, T cells or dendritic cells) to stimulate a protective immune response. In essence, M cells act like CCTV cameras to survey the gut area for anything that is out of the ordinary, or potentially harmful, and then present them to our immune system (essentially the police and the law courts) to sort those bad ‘uns out.

Previous work had shown that antigen transcytosis by M cells is important for mucosal immune responses but little was known about the mechanism involved. The researchers used microarray to scan the entire genome for specific molecules associated with M cells and found that glycoprotein 2 (GP2) was expressed in M cells in both human and mouse Peyer’s patches. Using immunoelectron microscopy they showed that GP2 was localised to the apical surface of M cells (the surface exposed to the commensal bacteria in the gut). Furthermore, they found that GP2 bound a variety of commensal and pathogenic enterobacteria (Escherichia coli, Salmonella enterica serovar Enteritidis and Salmonella Typhimurium), and more specifically bound to FimH expressed in the bacterial type I pilus (filamentous projections on the bacterial surface which are important for adhesion). Three-dimensional imaging revealed that GP2 accumulates around E. coli and S. Typhimurium as they are internalised in M cells and deletion of GP2 in mice reduced the uptake of type-I-piliated bacteria. After bacteria are translocated through M cells in a GP2-dependent manner they were captured by dendritic cells. Furthermore, GP2 was important for induction of mucosal immune responses against specific bacterial antigens (proteins that stimulate an immune response). Bacteria deficient in FimH lost the ability to bind GP2, had reduced entry into Peyer’s patches and induced a weak helper T cell and antibody immune response. Similarly, mice lacking GP2 had reduced helper T cell and antibody immune responses after challenge with bacteria expressing FimH.

This paper highlights the biological importance of GP2-dependent M cell antigen transcytosis as part of immunosurveillance in the intestine for bacteria expressing FimH. More work is needed to fully understand exactly what happens to the bacteria after they are delivered to immune cells and tissues by the M cells. Finally, M cells are thought to be a promising target for oral vaccinations to induce a protective immune response and this work shows that GP2 may be a possible vaccine target.

Although M cells act as a great surveillance system for the gut there are always a few bacteria that abuse the system. Shigella is one particular deviant bacterium that cannot normally invade the apical surface of intestinal epithelial cells and so uses the M cells to breach the epithelial cell barrier and gain access to their basolateral surface. Here, they can successfully invade, replicate in the intestinal epithelium, and wreak havoc on the gut by causing shigellosis or bacillary dysentery.

ResearchBlogging.org
Hase, K., Kawano, K., Nochi, T., Pontes, G., Fukuda, S., Ebisawa, M., Kadokura, K., Tobe, T., Fujimura, Y., Kawano, S., Yabashi, A., Waguri, S., Nakato, G., Kimura, S., Murakami, T., Iimura, M., Hamura, K., Fukuoka, S., Lowe, A., Itoh, K., Kiyono, H., & Ohno, H. (2009). Uptake through glycoprotein 2 of FimH+ bacteria by M cells initiates mucosal immune response Nature, 462 (7270), 226-230 DOI: 10.1038/nature08529

Further reading

Jang, M.H. et al., (2004) Intestinal villous M cells: An antigen entry site in the mucosal epithelium. Proceedings of the National Academy of Sciences, 101, p.6110-6115.

Schroeder, G.N. and Hilbi, H. (2008) Molecular pathogenesis of Shigella spp.: Controlling host cell signalling, invasion and death by Type III secretion. Clinical Reviews Microbiology, 21, p.134-156.

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Research scientist revealed to be Belle du Jour

Belle du Jour, the once anonymous blogger behind the popular Diary of a London Call Girl blog, which spawned a TV show starring Billie Paper and several books, has today been revealed as Dr. Brooke Magnanti, a research scientist working for the Bristol Initiative for Research of Child Health.

 

Speaking to India Knight in the Sunday times, Magnanti reveals she chose prostitution to fund her life in London whilst writing up her PhD thesis in informatics, epidemiology and forensic science. With little spare time on her hands because she was “still making corrections and preparing for the viva” and money running out fast Magnanti pondered on the perfect profession that “doesn’t require a great deal of training or investment to get started, that’s cash in hand and that leaves me spare time to do my work in”. Her solution was working as a £300/hour escort.

 

Belle’s blog has been accused of glamourising sex work and the revelations that “Belle” is in fact an intelligent and well-educated woman demonstrates that sex workers come from all walks of the life. However, this tale also highlights the perils of undertaking an academic career in scientific research. Doctoral work in any field is an all-consuming affair where the final months of writing up require an other-worldy and single-minded devotion to one thing and one thing only. Finishing. Add to that, the horrors of endless corrections to your thesis, counting your pennies because your funding has run out and finding a job in the highly competitive field of science (a job which can be poorly funded with little stability) and it’s pretty easy to imagine the state of mind when struggling for money that leaps from science to sex work.

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Pneumonia is world’s biggest childhood killer

Pneumonia is an acute respiratory infection of the lungs caused by viruses, bacteria and fungi. Despite pneumonia being treatable and preventable, estimates suggest that over 2 million children die every year from pneumonia, making it the leading cause of childhood death worldwide.

On the 2nd November the World Health Organisation and the United Nations Children’s Fund launched the Global Action Plan for Prevention and Control of Pneumonia (GAPP) to raise awareness of the devastating death toll from pneumonia and call on governments, public health policy-makers, charities, non-governmental organisations and the public to work together to implement their action plan.

The GAPP aims to:

  • protect children from pneumonia by providing an environment with low risk of pneumonia (strategies include increasing hand-washing or providing adequate nutrition)
  • prevent pneumonia in children (with vaccinations against the microorganisms that cause it such as Streptococcus pneumonia and Haemophilus influenzae b)
  • Treat children sick with pneumonia with the correct healthcare and antibiotics.

If successful their plan could save 5.3 million children from dying of pneumonia by 2015.

A new “Health in Action” article in this week’s PLoS Medicine by Enarson and colleagues describes efforts by the government in Malawi to introduce a national programme to cut childhood deaths from pneumonia. This strategy, known as standard case management (or SCM), aims to ensure that children with pneumonia in Malawi receive effective treatment, like antibiotics and oxygen therapy.

The SCM strategy for treatment of children with pneumonia in Malawi was based on a similar programme established by the International Union against Tuberculosis and Lung Disease. This was a cost-effective health intervention that has been successfully used to prevent and control tuberculosis in 190 countries. To improve the management of severe and very severe pneumonia in children admitted to district hospitals (accessible to the whole population) the Child Lung Health Programme (CLHP) for pneumonia in Malawi focused on:

  • getting lasting commitment from the government to sustain the health programme
  • establishing diagnosis and treatment based on the SCM
  • teaching clinical staff the SCM
  • safeguarding uninterrupted supplies of standardised drugs and equipment needed for pneumonia treatment
  • recording and reporting clinical outcomes of pneumonia
  • supervising and evaluating the programme

The CLHP in Malawi has been in place since 1999 and was funded by the Malawi government and support from the Bill and Melinda Gates foundation. The CLHP was gradually scaled-up across the entire country over the next 5 years. Between Oct 2000 and Dec 2005, the CLHP successfully trained 312 health workers (including nurses and medical assistants) in SCM and there was a consistent increase in the numbers of children receiving pneumonia treatment in district and central hospitals. Furthermore, the proportion of children dying from pneumonia dropped from 18.6% to 8.4%. The CLHP is now successfully maintained by the Malawi government after the end of external funding for the project. However, there are still ongoing challenges that need to be addressed, such as a shortage of healthcare workers and the effects of malnutrition, malaria, HIV/AIDS and anaemia on the outcome of pneumonia infection.

The reduction of child mortality by two-thirds by 2015 is a major challenge set by the United Nations Millenium Development goals and programmes, like the CLHP in Malawi to reduce deaths from pneumonia, will make a significant contribution to this goal.

Enarson, P., Gie, R., Enarson, D., & Mwansambo, C. (2009). Development and Implementation of a National Programme for the Management of Severe and Very Severe Pneumonia in Children in Malawi PLoS Medicine, 6 (11) DOI: 10.1371/journal.pmed.1000137
ResearchBlogging.org

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