Tag Archives: viral genome

Q&A: What is the difference between innate and adaptive immunity?

antigen binding siteTo a immunologist, the host immune system is separated into two main branches: innate and adaptive immunity. Here, we will briefly discuss the difference between the two:

The commonality – While both innate and adaptive immunity has the goal to mount an effective response against pathogens, one is less specific than the other against infection.

The difference – Innate immunity is a general response whereas adaptive immunity is specific to a particular antigen

The innate immunity is the first line of defense. It is there even before the infection. The innate immunity consists of phagocytic cells, barriers, and antimicrobial compounds. The innate immunity presents the pathogen antigen to initiate adaptive immunity.

The adaptive immunity depends on the antigen presented from the innate immunity arm of the immune system. Unlike innate immune response, it mounts responses to specific antigenic challenges.

In the next issue, we will discuss more about the mechanisms of innate immunity.

Other article: Virus prevents beer from getting spoiled

Stealing gene from viruses to form placenta in dogs and cats

If there weren’t viruses, our cats and dogs would not develop a placenta. A group of researchers from France discovered that in cats and dogs, the gene syncytin, responsible for creating a placenta, is stolen from retroviruses. Syncytin is highly conserved within species in the carnivora. In other words, there is a little DNA variation in the syncytin sequence. By comparing syncytin in species, the gene is stolen from viruses about 70-80 million years ago. Interestingly, syncytin is identified as an envelope gene that belongs to a provirus (provirus means a virus genome integrated into cat’s or dog’s genome). An envelope gene codes for an envelope protein. Go to the figure below: envelope protein is important in binding to cells for the virus to enter the cell. Stealing env gene from viruses is, therefore, an important mechanism for mammals to evolve. Evolution is a slow process. It depends on mutations that give rise to characteristics that may convey fitness to a particular species. By stealing an entire gene from viruses, mammals essentially skip the slow process of accumulating mutations. The researcher wrote,

“Therefore, it seems that, on several occasions in the course of mammalian evolution, env genes from endogenous retroviruses have been co-opted by their host to participate in the formation of the placenta”

The researchers also asked an interesting question after correlating the syncytin gene with the envelope gene of retroviruses. Can viruses use syncytin gene from cats and dogs as their envelope (see figure to see where the envelope protein is) to enter the cell? This group of researchers made virus mutants with cats’ or dogs’ syncytin as their envelope protein (envelope protein is responsible for binding to specific receptor to enter the cells). Then, they measured the number of viruses produced to see if syncytin is functional. In Figure C, you can see that viruses with either cat’s and dog’s syncytin can replicate in cat and dog’s cell. In sum, syncytin gene is still a functional envelope gene for virus replication.

Humans also have syncytin.

What if there are no viruses on Earth? Life would probably be developed with a difference mechanism. Given the slow rate of evolution, forming a placenta is quite unlikely.

Proc Natl Acad Sci U S A. 2012 Feb 14;109(7):E432-41. Epub 2012 Jan 17.
Ancestral capture of syncytin-Car1, a fusogenic endogenous retroviral envelope gene involved in placentation and conserved in Carnivora.
Cornelis G, Heidmann O, Bernard-Stoecklin S, Reynaud K, Véron G, Mulot B, Dupressoir A, Heidmann T.

An immune approach to treat multiple sclerosis

The immune system is the guard against pathogens; however it can be turned against us causing immune-mediated diseases. So far, there are several autoimmune diseases recognized, including inflammatory bowel disease and Multiple sclerosis (MS). Multiple sclerosis is an immune-mediated demyelinating disease affecting the central nervous system (CNS). In the United States, the prevalence of multiple sclerosis is 85 per 100000 people. To date, there are a few experimental models that resemble the pathology of multiple sclerosis, including experimental autoimmune encephalomyelitis (EAE) and theiler virus (TMEV). In EAE model, the demyelination is induced by the injection of foreign peptides which promote inflammatory response in the central nervous system. In the case of TMEV, the viral replication begins in astrocytes, microglia and macrophage in the grey matter. At a later stage of infection, the virus persists in macrophage in the white matter. The persistence is believed to initiate a prolonged inflammatory response from T helper cells, which ultimately leads to the demyelinating disease in the white matter. As the pathology of both mouse models closely resembles MS in humans, these two models are used extensively to study the role of immune system in promoting demyelination.

Related article: Fight against multiple sclerosis, a battle against demyelination

An important group of immune signaling molecules is cytokines. Cytokines are secreted by numerous cells. They are responsible for communicating between cells and directing the differentiation of T cells. In MS patients, IL-12 is locally expressed in the CNS. Its level is higher in the cerebrospinal fluid and plasma during active disease. Functionally, IL-12 is secreted by antigen-presenting cells. (see left)When antigen presenting cell recognizes a foreign particle through toll-like receptor 3 (TLR3), it turns on a cascade that phosphorylates IRF5. Phosphorylated IRF5 is then shuttled into the nucleus to activate the transcription of IL-12. Secreted IL-12 then binds to IL12 receptor on naïve T cells to induce the differentiation into Th1 cells and the release of proinflammatory IFN-g. There is also another cytokine found in MS patients that might be related to the induction of demyelination. Weiner et al. found a higher IL-23 level in the dendritic cells extracted from MS patients. IL-23 is a hetero-dimer that shares p40 subunit with IL-12. Despite the partial similarity between IL-12 and IL-23, IL-23 is functionally distinct inducing naïve T cells to differentiate into Th17 cells. So, if you are kind of confused at this point, all you have to know is that IL-12 makes Th1 and IL-23 makes Th17 cells. And both Th1 and Th17 are proinflammatory T cells. There is another subset of T cells that are anti-inflammatory known as the regulatory T cells, which counteract the inflammation. But we are not going to about regulatory T cells today.

So, how does this link to deriving an effective therapy for MS? IL-12 and IL-23 are inducing T cells to differentiate into proinflammatory T cells. What if we inhibit IL-12 and IL-23? Do we stop the inflammation? And indirectly stop the demyelination?

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The way to inhibit IL-12 and IL-23 is to generate antibodies against them. As I mentioned before, both cytokines share the p40 subunit. Thus, it seems feasible to treat demyelinating diseases with anti-p40 antibodies. Treating EAE models with antibodies against IL-12 and IL-23 works well. An antibodies-treated EAE mouse gets less demyelination.

There is a human clinical trial conducted by Segal et al. which they give a varying amount of antibodies (ustekinumab) against p40 to MS patients. However, they didn’t find a significant difference in alleviating demyelination in treated and placebo groups. It is discouraging to hear that antibodies against p40 don’t work on MS, as it has improved inflammation for other autoimmune diseases, such as psoriasis and inflammatory bowel disease. However, the researchers are trying to figure out the reason why antibodies didn’t work. There are a few suggestions made so far to explain this finding. One, the antibodies is 150kDa in molecular weight. It is possible that antibodies can’t cross the blood brain barrier to get to the CNS. Another possible explanation is that the recruited MS patients are in a much later stage of MS. Th1 and Th17 proinflammatory T cells are already recruited and accumulated in the CNS. So, blocking the induction of differentiation into Th1 and Th17 wouldn’t be a big help to MS patients at the late stage. Recruiting MS patients at an earlier stage of MS might give us a different result.

Deriving a drug for immune-mediated disease is a challenge, as we have to understand the cause of immune response. But we are closer than ever before as we continue to investigate the cause of MS.

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J Immunol. 2006 Jun 15;176(12):7768-74.

IL-23 is increased in dendritic cells in multiple sclerosis and down-regulation of IL-23 by antisense oligos increases dendritic cell IL-10 production.

Vaknin-Dembinsky A, Balashov K, Weiner HL.

Lancet Neurol. 2008 Sep;7(9):796-804.

Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised, dose-ranging study.

Segal BM, Constantinescu CS, Raychaudhuri A, Kim L, Fidelus-Gort R, Kasper LH; Ustekinumab MS Investigators.

Typo: corrected: cytokines are a group of molecules, not ‘one of the key immune molecules’ 09142012