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The Marvellous Multi-faceted Macrophages

Macrophages in a tissue culture dish

Macrophages in a tissue culture dish

What can macrophages do?

Most people know about the cleaning capabilities of macrophages but there is much more to macrophages than this.  Albeit, macrophages do ‘eat’ dead or damaged cells but what is not commonly known is that they do not just dissolve their ‘meal’, they  process their meal and then present it to T cells (another type of white blood cell) to show them the enemy for future reference. Macrophages also release signals calling for back up from other white blood cells. This, in general terms, is known as the inflammatory response. Macrophages also release toxic chemicals during inflammation, thereby destroying nearby tissues as well as the infecting pathogens (disease-causing organisms). These chemicals are oxidants: reactive oxygen species and nitric oxide. The very same oxidants health magazines warn people about and tell us we need to eat more anti-oxidants to counter.

They are also involved in the wounding-healing process and in the formation of blood vessels, both during ordinary foetal development and, then later in life, during disease (for example, in cancer). During the wound healing process, macrophages are the key regulators of repair, and involved in scar tissue (fibrosis) formation. They are in close contact with blood vessels during both development and during diseases such as wet age-related macular degeneration. Upon activation by cancer cells, macrophages release a variety of different types of proteins, many of which are important in cancer metastasis (spreading of cancer). The presence of a certain type of macrophage – tumour associated macrophage (i.e. TAM) correlates with poor prognosis in a variety of cancer types.

Macrophages play a pivotal role in diseases associated with low level chronic inflammation such as during cardiovascular disease, diabetes and cancer. These conditions have one thing in common – obesity. Obesity-induced chronic inflammation increases their risk. Recently, macrophages have been found in the fat around internal organs (known as visceral fat). The types of macrophages within the viscersal fat of a lean person and an obese person are different (the two types of macrophages are M1 and M2, more on this below). Fatty tissue sends signals (chemokines) to recruit and retain macrophages and these macrophages have a role in chronic inflammation and insulin resistance leading to type II diabetes.

Macrophages play a key role during cardiovascular disease. They are present in clogged arteries (atherosclerosis) within the plaques, affecting their stability where they ‘eat’ (phagocytosis) the lipoproteins. Once engorged, they turn into cholesterol-laden foam cells.  These macrophages seem unable to leave the plaque. They make inflammatory proteins, degrade their surrounding structures (by producing matrix-degrading proteases) which thin the cap on the plaque and eventually die. These dead cells make up the necrotic core of the plaque and contribute to its rupture. Unstable plaques are causal of myocardial infarction and stroke.

How do macrophages do this?

Courtesy of Dr. Volker Brinkmann, Max Planck Institute for Infection Biology, Berlin/ Germany

Macrophages act differently depending on their environment. When they are involved in inflammation, they are pro-inflammatory (also known as M1) but when they are involved in wound healing they are regulatory (also known as alternatively activated or M2). The macrophage behaviour depends on which signalling molecules are present in the tissue or organ. Some signalling molecules make macrophages into M1 while others make them into M2. One example of a signalling molecule (cytokine) that can make macrophages inflammatory is called tumour necrosis factor (TNF). Without TNF to activate them, macrophages cannot get rid of infections such as TB. When things go wrong and the immune system starts attacking the body (autoimmune disease) as in rheumatoid arthritis, Crohn’s and non-infectious uveitis (a disease affecting the eye and eventually leading to blindness), TNF is the culprit.

Other signalling molecules, such as IL-4 and TGFβ1, make them into M2 macrophages. M2 macrophages form scar tissue and produce a protein called VEGF that sends a signal to blood vessels encouraging them to make branches and more blood vessels. These macrophages turn off the inflammatory response.

These macrophage subsets are not distinct, there is overlap and macrophages can change their function depending on their environment.

Where do macrophages come from?

Monocytes and macrophages are very similar. Monocytes are formed in the bone marrow and then enter the blood stream. They circulate around the body in the blood until they are needed within a particular organ or tissue. These tissues make and secrete signalling molecules (known as cytokines or chemokines) which attract cells in from the blood. Once these monocytes leave the blood and enter tissues or organs, they turn into macrophages. These macrophages have different names depending upon which organ they are in. For example, in the kidneys they are called mesangial cells and in the eyes and brain they are called microglia.

The ratios of different types of macrophages vary in healthy and ill people and mice. Illness includes people with an infection, autoimmune disease, cardiovascular disease and obese people.

Here is a (short) list of future offerings:

  • Macrophages and fat tissue
  • Atherosclerosis
  • The importance of TNF
  • Age-related macular degeneration

Sources:

ResearchBlogging.org
Tarnjit Khera (2014). The Marvellous Multi-faceted Macrophages Scitkk.Wordpress.com
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New virus (MERS-CoV) cases increasing

Another case of Middle East respiratory syndrome coronavirus (MERS-CoV) was confirmed in the Middle East on 12th March:  a 68 years old man fell ill in the UAE on 1st March, was hospitalised on 3rd March and is now recovering. He had no contact with any known case but he does own a farm where he has contact with animals, including camels. The other two latest cases occurred in late February in Saudi Arabia. MERS-CoV causes severe acute respiratory illness. The first case was a Saudi national. The virus from this patient was isolated from his lungs in The Netherlands.

Cases of MERS-CoV

MERS-CoV was first confirmed as a new disease in September 2012 and since then there have been 189 cases and 82 deaths in total, although the number of people with a mild version of the illness who do not seek medical attention is unknown. Only three cases have been reported in children under 5 years of age. The WHO has received reports of laboratory-confirmed cases in the Middle East, France, Germany, Tunisia and the UK. In these countries the patients were either transferred for care of the disease or returned from the Middle East and subsequently became ill. In France, Tunisia and the UK transmission of the illness has occurred between people in close contact (either at home or in the work place) who had not been to the Middle East.

MERS-CoV infection can cause very severe pneumonia, septic shock and multi-organ failure resulting in death. It is more likely to be mild in individuals who do not have any underlying conditions. The disease starts with a fever and cough, chills, sore throat, muscle and joint pain, followed by difficulty in breathing and pneumonia. Roughly 33% of the patients also suffered from vomiting and diarrhoea. The incubation period is about 5-14 days before the onset of symptoms.

So far, antivirals have not been successful in treating the disease. Various drugs have been screened in cell cultures but there is no clinical data to support their use in humans. However, research using monkeys has found two promising agents: ribavirin and interferonα-2b.

Where did the virus come from?

Coronaviruses are a large family of viruses causing a range of illnesses in humans, from the common cold to SARS. Viruses of this family also cause a number of animal diseases. MERS-CoV is a type of coronavirus which had not been identified in humans prior to 2012.  The MERS-CoV infecting humans is genetically close to coronaviruses found in hedgehogs and bats. A genetic sample from a bat matched 100% with the first human patient. Neturalising antibodies against MERS-CoV or similar viruses, but no viral genetic material, has been described in camels. It is not clear whether the bats can infect the camels or whether humans can be infected by both bats and camels carrying the virus. Data suggests MERS-CoV could have emerged as early as 2009.

Worryingly, there has been an increase in the number of cases with over 60% of the patients being male. This higher number of patients verses females could just be down to low number of cases or something more concerning.

Sources:

http://currents.plos.org/outbreaks/article/state-of-knowledge-and-data-gaps-of-middle-east-respiratory-syndrome-coronavirus-mers-cov-in-humans-2/

http://www.cdc.gov/coronavirus/MERS/

http://en.wikipedia.org/wiki/Middle_East_respiratory_syndrome_coronavirus

http://www.who.int/csr/disease/coronavirus_infections/faq/en/

Tarnjit Khera (2014). New virus (MERS-CoV) cases increasing Scitkk.wrodpress.com

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MMR’s successor – MMRV

What is MMRV?

MMRV is the quadruple vaccination against measles, mumps and rubella (MMR; more here) and chicken pox (also known as varicella). Varicella vaccination (developed in Japan) has been used in Japan for twenty years and in the USA since 1995. In 2006, the varicella vaccination was combined with MMR to make MMRV. MMRV was licensed in 2005 and is a routine vaccination in many countries including the USA, Germany and Australia. The advantages of this are to reduce the number of injections and therefore increasing acceptance and uptake, hence increasing coverage. Two injections of MMRV give 94% efficiacy against chicken pox.

Children given the MMRV are more likely than children given MMR to have a fever which might suggest a more rigorous immune response.  The greater worry is the associated increase in febrile seizures within two weeks of vaccination although the increase was only 8 children out of 10,000 children (for MMRV) to 3. 5 children per 10,000 children (for MMR). This increase in febrile seizures is small and only occurs in children between 12-23 months; after the age of two years there is no significant difference. Although febrile seizures are frightening for parents, there is no risk of any long-term harm to the child.  There is also worry over an universal chicken pox vaccination increasing the likelihood of shingles later in life (only people exposed to chicken pox virus can get shingles) but the rate of shingles had been increasing in the USA, and other countries, before the introduction of the varicella vaccine and did not accelerate when the vaccine was introduced. This suggests to me that there is no link between shingles and the vaccine and therefore this is a needless worry.

Why immunise against varicella in the UK?

The world health organisation recommends routine vaccination to be considered in countries that can afford it and where it is a relatively important public health concern, a socio-economic problem and where at least 85% coverage is achievable. Varicella is considered a mild disease in children and compared to measles and mumps it is. In the USA, where records of chicken pox cases are kept, evidence shows that its introduction has benefitted the economy when the loss of work hours while parents look after a sick child and the hospitalisation costs verses the cost of the vaccine are compared.

Per 100,000 people Top - number of cases Bottom - hospitalisations in red and deaths in green

Per 100,000 people
Top – number of cases
Bottom – hospitalisations in red and deaths in green

Will introducing a new vaccine into the UK be a problem?

MMR uptake rates are still not at 95% in the UK, which is what the WHO recommends. Introducing MMRV, especially with the associated scaremongering around febrile seizures, may reduce uptake further. People still worry about ingredients in the vaccine (e.g. can they be given to children with an egg allergy?), the age of the child (two years or over is considered ideal), how long the vaccination lasts and the potential increase in another more deadly strain developing. These diseases are considered to be too mild and uncommon to warrant vaccination by a lot of people. Parents usually quote a second or third hand experience of an MMR-vaccine link, vaccine failure or adverse events. Several parents who rejected MMR had direct experience of caring for children with autism. Tony and Cherie Blair refusing to confirm the immunisation status of their child did nothing to alleviate parents’ fears.

Parents, falsely, seem to believe in the benefits of natural immunity and how it can be boosted by good nutrition. They also, erroneously, think exposure to low levels of disease causing bugs will boost immunity (they seem to be misunderstanding the hygiene-hypothesis). Although true to an extent, this does not apply to measles, mumps and rubella.

How to introduce a new vaccine?

Parents want GPs to provide impartial advice and give them a leaflet outlining the facts. They do not want to be judged and assumed to be stupid when in fact a lot of parents who do not give their child MMR on time are actually highly educated. Views on disease severity are based on personal experience rather than facts and exposure to increased disease susceptibility is motivation to vaccinate (e.g. in ethically diverse communities or during foreign holidays). Parents use official information leaflets to educate themselves about the disease and adverse symptoms and the decision to vaccinate is an emotional one rather than logical.

Trust in health professionals and vaccine policy is central to acceptance therefore effective communication comparing the facts of disease and vaccine risks in perspective is key. As parents think two years is a better age for immunisations, catch-up campaigns can target 24-36 month olds when parents may be more willing to vaccinate. Face-to-face contact by non-judgemental health providers, whether it is the GP, practice nurse or health visitor, is required.

Although controversial, compulsory vaccination should be considered. This will protect children who cannot be immunised for health reasons and children less than 12 months old for whom these vaccines do not work.

Epetition – Introduction of MMRV vaccine in the UK

http://epetitions.direct.gov.uk/petitions/62315

Sources:

Protection against varicella with two doses of combined measles-mumps-rubella-varicella vaccine versus one dose of monovalent varicella vaccine: a multicentre, observer-blind, randomised trial.

Prevention of varicella: Update of recommendations for use of quadrivalent and monovalent varicella vaccines in children.

Economic evaluation of the routine childhood immunisation program in the United States, 2009.

UK parents’ decision-making about measles-mumps-rubella (MMR) vaccine 10 years after the MMR-autism controversy: A qualitative analysis.

Varicella Vaccination in Japan, South Korea, and Europe.

 

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Tarnjit Khera (2014). MMR’s successor – MMRV Scitkk.WordPress.com

Creative Commons Licence
Scitkk by Tarnjit Khera is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
Based on a work at Scitkk.wordpress.com.
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