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Archive for the ‘Immunology’ Category

Infectious disease meets the epigenome

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The study of epigenetics (see Pharyngula’s excellent article) has allowed us to see biology and genetics through new eyes. The fact that heritable traits can be encoded in not only the nucleic acid sequences of As, Cs, Ts and Gs but also in the physical conformation of chromosomes and chemical modification of DNA has added a new level of complexity to our understanding of life. Covalent modifications to both DNA and associated histones and chromatin can result in the formation of active or repressed genetic regions; transcription of these genes found in that area is thus activated or repressed. Embryonic development, behaviour and cancer formation  have all been impacted by the discovery of this new genetic system wit deregulated epigentic processes leading to the development of these diseases – but what about in infection, immunity and pathogenesis of associated diseases?

Epigenetics: DNA, histones, ovalent modification and chromatin.

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Written by Connor

January 4, 2011 at 2:43 pm

Uncovering the biomedical and evolutionary importance of primate innate immunity

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Primates such as chimpanzees differ in the diseases that affect them – especially when we compare them to those that affect us. Progression to AIDs, cancer incidence, Alzheimers disease and malaria either do not affect or cause less severe diseases in non-human primates than they do in humans. So why are our primate cousins so differently affected by these particular diseases than we are? What causes these differences? Are they environmentally mediated? Behavioural? Molecular?

What does the innate immune system have to say about it?

The pathogenesis of disease is an important area of research when trying to understand the origins and progression of diseases. It depends on many variables – host specific, environmental or pathogen specific. A recent publication has sought to understand these differences from the point of view of host factors mainly the innate immune system. By comparing genome-wide gene expression patterns in primary immune cells (monocytes) cultured in vitro from groups of humans, chimpanzees and rhesus macaques and applying bioinformatic analysis to the results, the investigators were able to detect those genes whose expression is altered upon stimulation with lipopolysacharide (LPS), an important activator of the innate immune system. From this data set they could ask, functionally, what makes the human immune system different?

3,170 genes were seen to be differentially expressed with 793 changing in all three species indicating a conserved function. Other genes showed species-specific changes allowing researchers to ask what makes each species unique? More importantly what makes non-human primates different when it comes to diseases? There were 335 genes in the human monocytes that were expressed differently and these were divided between particular pathways.

What does this data have to say about specific diseases?

Those genes listed as being involved in viral infection were those most likely to be species-specific indicating the rapid adaptation of host immunity to fast-evolving viral pathogens. The data sheds light on the possible lo incidence of cancer in non-human primates by detecting the difference in apoptosis/cancer related genes – although the signifigance of monocyte gene expression when considering the whole-organism in diseases such as cancer is difficult to say. Most interestingly seen are those genes involved in HIV infection and AIDs  whose expression may explain why chimpanzees do not progress to AIDs or do so slowly.

Despite the problems in culturing non-human primate immune cells in vitro and the difficulties in controlling for environmental effects (different diets of primates), this study goes some way to understanding at a functional level what makes humans human from an immunological point of view. Although focussing on a single cell type, the monocyte, other cells may prove useful in investigating innate differences – as other cells also function in innate immunity – mucosal epithelium for one. This work paves the way for more detailed molecular analysis but also of more genome-wide work looking at other cells, other activators and pathogens (not LPS but HIV?). Understanding what makes humans different in a pathogenic light should focus not just on immunology at the gene expression level but also differences in epigenomics, behaviour, anatomy and cell biology.

 

 

Varki, Aijit. 2000. A Chimpanzee Genome Project is a Biomedical Imperitive. Genome Res. 2000. 10: 1065-1070. doi: 10.1101/gr.10.8.1065

Barreiro, Luis B., John C. Marioni, Ran Blekhman, Matthew Stephens, and Yoav Gilad. 2010. Functional Comparison of Innate Immune Signaling Pathways in Primates. Ed. Greg Gibson PLoS Genetics 6, no. 12 (December): e1001249. doi:10.1371/journal.pgen.1001249. http://dx.plos.org/10.1371/journal.pgen.1001249.

Written by Connor

January 3, 2011 at 9:50 pm

A mothers love declines – a measles vaccine problem?

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Worldwide, measles virus infection accounts for around 200,000 deaths annually; the importance of which is emphasized given the availability of a highly effective vaccine. Vaccine effectiveness, however, is a complex matter and is subject to many problems – a major one being transfer of maternal antibodies to children during early life, a form of natural passive immunity. Although these antibodies are there for a reason and do protect offspring from infections in early life, bridging the gap until they can synthesize their own antibodies, they have been shown to inhibit the activity to certain vaccines – measles vaccine is an example (see figure below).

Antibody concentrations in child following birth showing decline in attenuation (infection attenuation)

During early childhood, maternal antibody concentrations begin to wane and eventually reach such a level as to offer little protection from microbial challenge. These antibodies however are able to dampen the ability of a child to develop protective immunity following vaccination; it is this ‘window of opportunity’ that is responsible for a great number of measles virus infections and fatalities every year. The development of an effective vaccination strategy to get around this blocking effect would therefore be of great medical interest.

Recently, Kim et al (2010) publish their investigations into understanding how and why measles virus infection, in the presence of specific antibody results in the inhibition of a protective response following vaccination. Prior to this study it was unknown whether in this situation, MeV-specific B cells were being generated at all or whether they simply failed to secrete neutralizing antibody. The group used a rat model of MeV infection and simulated maternal antibody effects by passively transferring MeV specific antibodies and measuring the immunological outcomes. They demonstrated that there is a specific failure of B cells to secrete protective antibody in the presence of transferred antibody.

B cells will only secrete antibody when 3 signals are triggered:

1.     B-cell receptor/antigen interactions

2.     B – cell/ T-cell interactions

3.     Action of soluble mediators (for example: cytokines like interferon)

Kim et al hypothesized that in this model, where both signals 1 and 2 were active, inhibition of antibody secretion may be accounted for by the interference with certain soluble mediators. This idea was attractive providing the great deal of evidence showing MeV obstruction of interferon production – a pathway that normally results in the robust development of innate and adaptive immune responses. This results in two major problems involving antibody-specific inhibition of protective immune responses (maternal antibody) combined with MeV’s natural ability to inhibit the development of immunity; cases which are shared during the ‘window of opportunity’.

To this effect, the group developed a novel vaccine vector to circumvent wild-type measles interferon inhibition. Using reverse-genetics technology, they incorporated a MeV antigen gene, the haemagglutinin (HN) glycoprotein into the Newcastle Disease virus (NDV) genome as an extra gene, generating NDV-HN. NDV is an avian virus that induces high concentrations of IFNs upon infection allowing for the possibility of an effective measles vaccine in the presence of measles antibody.

The investigation confirmed the group’s predictions in that NDV-HN induced much higher levels of IFN in rat tissues when compared to MeV and that this led to development of MeV-specific neutralizing antibodies in the presence of transferred antibody. This work further verified that role that the restoration signal 3, in the form of alpha-IFN allows for B-cell secretion of antibody in in vivo and in vitro systems.

Given how medically important vaccination has been in protecting populations from often fatal and serious infectious disease and the troubles that arise when maternal antibody concentrations drop, any work developing vaccine technology to avoid these difficulties should be welcomed. Kim et al. confirmed the basis for the immunological blocks in generating MeV antibodies and began the development of a novel vector system to rationally provide protection. The results in this rat model, although not specifically applicable to the human situation, are promising in that it provides a logical framework to advance vaccine technology and prevent thousands of childhood deaths worldwide.

Kim D, Martinez-Sobrido L, Choi C, Petroff N, García-Sastre A, Niewiesk S, Carsillo T. (2011) Induction of Type I Interferon Secretion through Recombinant Newcastle Disease Virus Expressing Measles Virus Hemagglutinin Stimulates Antibody Secretion in the Presence of Maternal Antibodies. J Virol. 2011 Jan;85(1):200-7. PMID: 20962092

Written by Connor

December 17, 2010 at 10:43 pm