Immune repertoire

The immune repertoire, is defined as, the number of different sub-types an organism's immune system makes, of any of the 6 key types of protein, either immunoglobulin or T cell receptor.

In most vertebrates, immune systems have 6 key types of proteins, which help the immune system recognise viruses, germs, etc. The 6 main types are: immunoglobulins (2), and T cell receptors (4). Immunoglobulin proteins consist of 2 parts, a light chain and a heavy chain. T cell receptors come in 4 types, labelled alpha, beta, gamma and delta.

In an organism, each of the 6 types of protein, in fact consists of a large number of sub-types, all differing slightly from each other. In one organism, There can be tens of thousands, or millions of different sub types of each of the 6. The differences are not obvious, and require complex research to detect, e.g. DNA sequencing, or antigen binding tests.

Every day, we are exposed to a wide range of disease causing organisms. thus, how well our immune system is able to detect them—depends on how many sub types of the proteins, it is able to produce. An immune system that produces a wide variety, will likely have one or two subtypes that recognise any germ we are exposed to. An immune system that produces just a few, will likely miss or "not see" certain germs or viruses—and these could then go on, unchallenged, to cause disease.

Immune repertoire is defined, as the number of sub-types that exist in an organism's immune system, of one or other of the 6 key types of proteins, in a certain "compartment" of the immune system (i.e. a certain set of cells from the immune system).

How large is the immune repertoire?

A few researchers have measured immune repertoires for humans, but as the task until recently was technically difficult, it was seldom attempted. Estimates will depend on the precise type or 'compartment' of immune cells studied; and the protein studied.

  • Pasqual et al. JEM (2002) publication showed that the expected billions of combinations were over-estimated. The authors described the genetic spatio temporal rule which governs the TCR locus rearrangements and were able to demonstrate for the first time that the V(D)J rearrangements are not random, hence resulting in a smaller V(D)J diversity.[1]
  • Dare et al. (2006) estimated repertoire for TCR gamma genes, in CD8+CD45RO+ memory T cells in blood, as 40,000–100,000 sub-types, in 3 healthy young adults. In healthy older adults, (over 75) they found smaller repertoires, being 3,600; 5,500; 14,000 and 97,000.[2]
  • Artsila et al. (1999) estimated repertoire for TCR alpha and TCR beta in CD4+/CD8+ T-cells, as approx 100,000.[3]

How is the immune repertoire generated

  1. The repertoire is generated, by immune system cells (lymphocytes) cutting a bit of DNA from 2 or 3 parts of the genome, and joining them together in different combinations. Each part of the genome, has only a few different pieces of DNA that can be used. But the different combinations of these, give a massive range of total sequences.
  2. Following that, the repertoire is edited. Cells whose protein would cause an immune reaction with the body, are removed. Cells which actually detect an invading organism, become more numerous. And cells with new types, may be added

Factors affecting immune repertoire

  1. age: the immune system develops over life, as stem cells mature, and generate their own maybe unique, gene sequences
  2. what diseases you are exposed to. When exposed to a disease, your body can create further sub types of proteins that recognise the virus, and thus fine tune the immune response. Also after the disease is gone, cells which recognised it, tend to hang around in the body.
  3. immune memory. generally after one has had a disease, the cells whose genes recognise the disease, are allowed to persist for many years in the body.
  4. old age—there is some evidence, that cells with existing subtypes die off, and are not replaced by new subtypes.[4]
  5. genetic disease (primary immunodeficiency: a few genetic diseases, people don't have the genes for the 6 immune proteins; or don't have the genes to do the splicing. Thus they can't generate the immune repertoire, or have a reduced one
  6. Treatments that seriously affect the immune system e.g. bone marrow transplant and cancer treatment—in these your entire bone marrow—[which is the source of the immune system]—is wiped out, to clear the body of cancer (which can often spread to the marrow). After that you get a transplant in of cancer-free marrow, from a donor, or from yourself when you were in remission. These basically have to re-generate the immune repertoire again.

Measuring immune repertoire.

the general problem

There is an interesting mathematical problem—if a set of objects consists of a large number of sub types—how does one count how many sub types there are? For instance, if you have a bag of balls, and they come in a range of colours—how can you work out, how many different colours there are in the bag?

Where there are only a few colours—say 4—it's easy. You just keep examining balls, one at a time, until you are happy you've seen all the colours. The same old ones keep coming up time and time again. And you just count the different types.

Where there are say 30–50 different colours—it is more difficult. A large number of balls need examining, and comparing one to another. Anyone who has ever tried collecting say football cards, knows that in order to be sure you have seen all of them—you need to open a very great number of packs.

Where there could be say several thousand colour types—the problem of finding out how many types there are, becomes challenging. Sampling and sorting and counting types—becomes difficult, involve a lot of work.

Yet this is the problem encountered in some areas of biology. For instance, health of an ecosystem, might depend on presence of thousands of species. An immune system's ability to detect disease, might require hundreds of thousands of different types of cells.

how to do it

For immune systems, there are four approaches.

  1. Use a low-resolution technique to catalogue cell types, and use that as an index of overall repertoire. In ecology, the analogy would be cataloguing animals at the genus level, rather than species. This assumes diversity of one, reflects diversity of the other. It can pick up severe losses in diversity, large enough to knock out whole classes of things. It is perhaps less able to show, when the number of different things in a class is reduced.
  2. look at a lot of individual cells, and count or estimate the total number of sub types that must be present. Thus if you look at 100 cells and find 50 subtypes—then look at another 100 cells, and are now up to 60 subtypes—and then another 100 cells, and are now up to 65 there is a mathematical approach that predicts the total number of subtypes present. In the past, it took a tremendous amount of effort to obtain DNA sequences from the genes; this is now becoming easier with "next generation " sequencing, where it is possible to sequence tens of thousands of these genes, from a blood sample, simultaneously, for a few hundred dollars.
  3. Look at a few sub types, work out how common each is, and thus work out the total number of sub types you expect. Thus if you find 1 makes up a hundredth of the immune system—you might expect the immune system to consist of 100 subtypes.[2]
  4. Clinical tests to assess presence of the normal range of cell types. If one type is entirely missing—say B-lymphocytes—then an entire subset of the immune repertoire may be missing. See Primary immunodeficiency.

Why does immune repertoire matter?

  1. The problem is interesting, of developing methods to count numbers of sub-types present—when there are a great many sub types.
  2. The actual size, is the key test of one of the basic theories in immunology, namely MacFarlane Burnet's theory of clonal selection. This theory—now some decades old—postulated that the immune system had to include a very large number of sub types. That number, until recently, has not been measured directly.
  3. Numerous treatments are coming into use, which affect the immune system—there is a need to measure repertoire, to monitor these effects. And also to develop treatments, to increase repertoire, e.g. using cytokines as drugs.
  4. If a persons immune repertoire is low—say as a result of a cancer treatment which as a side effect, knocks out their immune system—they'll be unusually susceptible to diseases. In fact, one of the limiting factors, in developing cancer treatment, is this—it means patients have to be nursed carefully for some time in sterile environments until the immune system recovers. And if they are unlucky enough to get infected while the immune system is down—the infections can be life-threatening. Any way to make the immune system recover faster, would be useful.
  5. Other areas of biology, also involve great variety and diversity. E.g. in a square km of rainforest, there may be several hundred species of trees, or insects. A litre of ocean water, may contain a high diversity of plankton plants and animals. A cubic cm of soil, will contain many different types of bacteria and fungi. High diversity, is a key characteristic of all these.
  6. It may be useful, to have methods to measure these large numbers, to put a number on diversity, for its own sake, so we have a better idea how large the diversity is. Also, to use as bench marks. A fall from 1000 species to 10, we can readily detect. A fall from 1000 species to 500, is also a significant change—but the methods to detect this change, would be extremely complex.
  7. Research on the immune system repertoire, may develop methods of sampling and statistics, to directly assess diversity in ecology. It may be that this too, is best approached, through genetic markers and high throughput sequencing—rather than more traditional taxonomy.

Future developments

Next generation sequencing may have a large impact.[5] This can obtain thousands of DNA sequences, from different genes, quickly, at the same time, relatively cheaply. Thus it may be possible, to take a large sample of cells from someones immune system, and look quickly at the range of sub-types present in the sample. The ability to obtain data quickly from tens or hundreds of thousands of cells, one cell at a time, should provide a good idea, of the size of the person's immune repertoire. These large-scale adaptive immune receptor repertoire sequencing (AIRR-seq) data require specialized bioinformatics pipelines to be analyzed effectively[6]. Many computational tools are being developed for this purpose. The Immcantation framework provide a start-to-finish analytical ecosystem for high-throughput AIRR-seq data analysis[7][8]. The AIRR Community is community-driven organization that is organizing and coordinating stakeholders in the use of next-generation sequencing technologies to study immune repertoires[9]. In 2017, the AIRR Community published recommendations for a minimal set of metadata that should be used to describe an AIRR-seq data set when published and deposited in a public repository[10].

References

  1. ↑ Pasqual, N; Gallagher, M; Aude-Garcia, C; Loiodice, M; Thuderoz, F; Demongeot, J; Ceredig, R; Marche, PN; Jouvin-Marche, E (2002). "Quantitative and qualitative changes in V-J alpha rearrangements during mouse thymocytes differentiation: implication for a limited T cell receptor alpha chain repertoire". J. Exp. Med. 196: 1163–73. doi:10.1084/jem.20021074. PMC 2194109. PMID 12417627.
  2. 1 2 Dare, R; Sykes, PJ; Morley, AA; Brisco, MJ (2006). "Effect of age on the repertoire of cytotoxic memory (CD8+CD45RO+) T cells in peripheral blood: The use of rearranged T cell receptor gamma genes as clonal markers". Journal of immunological methods. 308 (1–2): 1–12. doi:10.1016/j.jim.2005.08.016. PMID 16325196.
  3. ↑ Arstila, TP; Casrouge, A; Baron, V; Even, J; Kanellopoulos, J; Kourilsky, P (1999). "A direct estimate of the human alphabeta T cell receptor diversity". Science. 286 (5441): 958–61. doi:10.1126/science.286.5441.958. PMID 10542151.
  4. ↑ Blackman, MA; Woodland, DL (2011). "The narrowing of the CD8 T cell repertoire in old age". Current Opinion in Immunology. 23 (4): 537–42. doi:10.1016/j.coi.2011.05.005. PMC 3163762. PMID 21652194.
  5. ↑ Khan TA, Friedensohn S, de Vries AR, Straszewski J, Ruscheweyh HJ, Reddy ST (2016). "Accurate and predictive antibody repertoire profiling by molecular amplification fingerprinting". Sci. Adv. 2: e1501371. doi:10.1126/sciadv.1501371. PMC 4795664. PMID 26998518.
  6. ↑ Yaari, Gur; Kleinstein, Steven H. (2015-11-20). "Practical guidelines for B-cell receptor repertoire sequencing analysis". Genome Medicine. 7: 121. doi:10.1186/s13073-015-0243-2. ISSN 1756-994X.
  7. ↑ Heiden, Vander; A, Jason; Yaari, Gur; Uduman, Mohamed; Stern, Joel N. H.; O’Connor, Kevin C.; Hafler, David A.; Vigneault, Francois; Kleinstein, Steven H. (2014-07-01). "pRESTO: a toolkit for processing high-throughput sequencing raw reads of lymphocyte receptor repertoires". Bioinformatics. 30 (13): 1930–1932. doi:10.1093/bioinformatics/btu138. ISSN 1367-4803. PMC 4071206.
  8. ↑ Gupta, Namita T.; Heiden, Vander; A, Jason; Uduman, Mohamed; Gadala-Maria, Daniel; Yaari, Gur; Kleinstein, Steven H. (2015-10-15). "Change-O: a toolkit for analyzing large-scale B cell immunoglobulin repertoire sequencing data". Bioinformatics. 31 (20): 3356–3358. doi:10.1093/bioinformatics/btv359. ISSN 1367-4803. PMC 4793929.
  9. ↑ Breden, Felix; Prak, Luning; T, Eline; Peters, Bjoern; Rubelt, Florian; Schramm, Chaim A.; Busse, Christian E.; Heiden, Vander; A, Jason (2017). "Reproducibility and Reuse of Adaptive Immune Receptor Repertoire Data". Frontiers in Immunology. 8. doi:10.3389/fimmu.2017.01418. ISSN 1664-3224.
  10. ↑ Rubelt, Florian; Busse, Christian E; Bukhari, Syed Ahmad Chan; Bürckert, Jean-Philippe; Mariotti-Ferrandiz, Encarnita; Cowell, Lindsay G; Watson, Corey T; Marthandan, Nishanth; Faison, William J (2017-11-16). "Adaptive Immune Receptor Repertoire Community recommendations for sharing immune-repertoire sequencing data". Nature Immunology. 18 (12): 1274–1278. doi:10.1038/ni.3873.
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