My first blog on immunology! (About time too…). As always, words in pink are in the glossary.
This post is going to outline the discovery by Tan et al (2016) of a unique type of antibody created by the novel DNA transposition of a gene, which could convey resistance to malaria. The medical significance of this is vast, as it could lead to the development of new vaccines and anti-malarial drugs.
Malaria is a disease caused by the protozoan parasite Plasmodium, that is transmitted by mosquito bites. There are 5 species of Plasmodium that infect humans, the most common and deadly being Plasmodium falciparum, which contributes towards the 500,000 deaths a year that are caused by malaria .
How does the body normally combat infection?
Part of the life cycle of Plasmodium involves reproduction within erythrocytes (red blood cells). During this time, the Plasmodium sticks proteins out of the surface of the erythrocyte, causing the cells to agglutinate and prevent entry into the spleen. These surface proteins are known as antigens. They can be recognised by the host’s immune system and trigger an immune response to remove the parasite. The largest group of malarial antigens are known as RIFINs, and contain ~150 genes.
How does the host detect antigens?
Antigens are detected by B cell antibodies; the soldiers of the adaptive immune system. Antibodies are mobile proteins, each with a binding site that is unique to a specific antigen. When an antibody detects its corresponding antigen, it gets cloned multiple times. These clones tag the protein containing the antigen, which is then detected by the pathogen-removing cells of the immune system. However, Plasmodium has avoided this fate by constantly producing a high number of varied antigens, making it difficult for the immune system to eradicate the parasite.
Newly discovered antibodies allow greater protection against malaria, through wider detection of antigens
This study by Tan et al (2016), discovered two individuals in a donor group that had a large insertion of DNA between the V and DJ segments of the antibody genes. These segments contribute towards the diverse antigen-recognition sites of the antibody. The insertion occurred once in each individual, and was propagated through stimulation and cloning of the antibody after detection of an antigen. The insertion, which was 100 amino acids long, was identified as coding for the collagen-binding LAIR-1 protein found on chromosome 19. The LAIR-1 insert uniquely conveys the ability to bind to a wide range of RIFIN antigens to the antibodies, and removes some of the specificity of regular antibodies.
The LAIR-1 insert had undergone several mutations, which meant it had lost the collagen binding ability and gained the ability to bind RIFIN antigen. These mutations were deemed vital, as artificially removing them prevented the antibodies from binding to RIFIN.
How did this insertion occur?
One proposed mechanism by which this transposition took place is RAG recombination, where enzymes chop out a gene, and transplant it elsewhere in the genome. RAG is used during antibody diversification, to create the wide array of antibodies that can match to any antigen. The target sequences that RAG use to hone in on a gene were found embedded on either side of the insertion, suggesting LAIR-1 had been cut out of chromosome 19, and transplanted into the antibody diversity genes in the ancestral B cell.
To investigate this theory further, Tan et al searched the genome to see if there was a copy of LAIR-1 missing from its usual place on chromosome 19. Chromosomes come in pairs, so if a gene is missing on one of the chromosomes, the functional protein can often still be made by the remaining gene on the other chromosome. However, neither copy of chromosome 19 was missing LAIR-1! So how did this gene mysteriously end up in the middle of an antibody gene sequence?
This gene transposition could have occurred by a previously unknown mechanism. It could also have been facilitated by irregular functioning of gene conversion or AID, both of which are utilised in the generation of antibodies.
Why is this important?
Tan et al speculate that this kind of novel insertion could be more frequent than currently thought, especially in areas which have endemic infection of Plasmodium falciparum. This discovery is undoubtably important, as it could ultimately lead to the development of a vaccine for malaria. It is unknown whether the individuals with these unique antibodies are completely resistant to malaria, but it is very likely that they are substantially more able to remove a persistent infection.
The paper: Tan et al. A LAIR1 insertion generates broadly reactive antibodies against malaria variant antigens. 2016. Nature. 592(7584): 105-109
Photo by: Flickr user Turkletom