Transitional B cells in early human B cell development – time to revisit the paradigm?
Martin, V., Wu, Y.-C, Townsend, C., Lu, H-C., Silva O ’ Hare, J., Mozeika, A., Coolen, A., Kipling, D., Fraternali, F., Dunn- Walters, D.K.
Frontiers in Immunology Dec 2;7:546. http://journal.frontiersin.org/article/10.3389/fimmu.2016.00546
As part of our studies on early B cell development in ageing we looked at the repertoire of antibody genes in four different cell populations. We had previously thought that the sequence of cell types went from preB cell, to immature B cell in the bone marrow to Transitional B cell, to Naive B cell in the blood. We can see evidence of a steady accumulation, or a steady loss, of certain antibody genes as we move along this pathway. This reflects the changing repertoire to remove potentially autoreactive cells before they reach the stage where they can be dangerous. However, there are very many instances where the transitional cell population looks like the “odd one out”. Therefore perhaps this population as a whole is not the precursor of naive cells that follows from immature cells. In all likelihood there will be precursors of naive cells in there, since there is strong evidence from other groups to suggest this. However, in a normal individual we think that there are many other cells in this population with a different function altogether.
Significant differences in physicochemical properties of human immunoglobulin kappa and lambda CDR3 regions.
Catherine L. Townsend, Julie M.J. Laffy, Yu-Chang Wu, Joselli Silva O ’ Hare, Victoria Martin, David Kipling, Franca Fraternali, Deborah K. Dunn-Walters
Front. Immunol., Sept 27;7:388 2016 http://journal.frontiersin.org/article/10.3389/fimmu.2016.00388/full
There are two loci in the genome for antibody light chain genes, called kappa and lambda. We analysed rearranged kappa and lambda light chain genes to see if their CDRL3 regions were different. We find that they are different, that most (but not all) differences are encoded in the germline V and J regions, and that the enzyme that adds N nucleotides into the CDR3 regions (of both heavy and light chain) shows a small amount of variability between different people. Since the size of the CDR3 affects the antibody structure and larger sizes have been associated with autoreactive antibodies (see next publication) then individual variation in N nucleotide addition may be important for individuals with respect to autoimmune disease.
Promiscuous antibodies characterised by their physico-chemical properties: from sequence to structure and back.
Laffy JM, Dodev T, Macpherson JA, Townsend C, Lu HC, Dunn-Walters D, Fraternali F.
Prog Biophys Mol Biol. 2016 Sep 14. pii: S0079- 6107(16)30047 -5. doi: 10.1016/j.pbiomolbio.2016.09.002.
We have found that we can’t always find significant differences in antibody gene usage between two different populations (for example between old antibodies and young antibodies in a particular age group). However, just looking at gene use may not always be the best way of looking for differences. The actual structure of an antibody is what determines how it binds to antigens. Together with our MABRA partners, in particular Franca Fraternali, we have done some preliminary work looking at antibody CDRH3 regions. These are the regions we think are more important in antigen binding. We find that “sticky” antibodies - that are promiscuous and bind a number of different antigens - have a CDR3 structure that sticks out from the surface of the antibody and is often in a structure called “Beta sheet”. This structure is less flexible than and “alpha helix” structure.
A Reassessment of IgM Memory Subsets in Humans.
Bagnara D, Squillario M, Kipling D, Mora T, Walczak AM, Da Silva L, Weller S, Dunn-Walters DK, Weill JC, Reynaud CA.
J Immunol. 2015 Oct 15;195(8):3716-24. doi: 10.4049/jimmunol.1500753. Epub 2015 Sep 9.
In this paper, with colleagues in France, we are investigating the different populations of B cells and what the relationship between tissue B cells in the spleen is with the B cells that circulate in the blood. This is important because most often we can only get blood to study. However, much of the combat zone between pathogens and the immune system is actually in tissues. If we can understand the relationship between the two then it helps us to understand what is happening in the tissues even though we may only be looking at the blood.
The ageing human B cell repertoire: a failure of selection?
Clin Exp Immunol. 2016 Jan;183(1):50-6. doi: 10.1111/cei.12700.
A review paper addressing possible causes of the changes in B cell repertoire with age.
Statistical mechanics of clonal expansion in lymphocyte networks modeled with slow and fast variables
A Mozeika and ACC Coolen
(submitted to J Phys A, PDF)
Ageing of the B-cell repertoire.
Martin V, Bryan Wu YC, Kipling D, Dunn-Walters DK.
Philos Trans R Soc Lond B Biol Sci. 2015 Sep 5;370(1676). pii: 20140237. doi: 10.1098/rstb.2014.0237.
Another paper from Vicky’s thesis work. Showing some key differences in the older B cell repertoire which may mean the B cells are responding in a different way in the older person.
Age-related aspects of human IgM+ B cell heterogeneity.
Martin V, Wu YC, Kipling D, Dunn-Walters DK.
Ann N Y Acad Sci. 2015 Jul 7. doi: 10.1111/nyas.12823. [Epub ahead of print]
A paper from Vicky’s thesis work. Using the CyTOF to measure multiple markers at once on the surface of B cells she found that the levels of IgM vary quite a lot. In a specialised subset of B cells that we think are important in innate responses to bacterial infections we see some major differences in older people.
Immunoglobulin light chain allelic inclusion in systemic lupus erythematosus.
Fraser LD, Zhao Y, Lutalo PM, D'Cruz DP, Cason J, Silva JS, Dunn-Walters DK, Nayar S, Cope AP, Spencer J.
Eur J Immunol. 2015 Aug;45(8):2409-19. doi: 10.1002/eji.201545599. Epub 2015 Jun 24.
Monoclonal paraprotein influences baseline B-cell repertoire diversity and perturbates influenza vaccination-induced B-cell response.
Tete SM, Kipling D, Westra J, de Haan A, Bijl M, Dunn-Walters DK, Sahota SS, Bos NA.
Exp Hematol. 2015 Jun;43(6):439-47.e1. doi: 10.1016/j.exphem.2015.02.005. Epub 2015 Mar 18.
Well done Sarah for this paper, showing the effect of monoclonal gammopathy on B cell responses.
Immunoglobulin kappa variable region gene selection during early human B cell development in health and systemic lupus erythematosus.
Hehle V, Fraser LD, Tahir R, Kipling D, Wu YC, Lutalo PM, Cason J, Choong L, D'Cruz DP, Cope AP, Dunn-Walters DK, Spencer J.
Mol Immunol. 2015 Jun;65(2):215-23. doi: 10.1016/j.molimm.2015.01.017. Epub 2015 Feb 17.
Redemption of autoantibodies on anergic B cells by variable-region glycosylation and mutation away from self-reactivity.
Sabouri Z, Schofield P, Horikawa K, Spierings E, Kipling D, Randall KL, Langley D, Roome B, Vazquez-Lombardi R, Rouet R, Hermes J, Chan TD, Brink R, Dunn-Walters DK, Christ D, Goodnow CC.
Proc Natl Acad Sci U S A. 2014 Jun 24;111(25):E2567-75. doi: 10.1073/pnas.1406974111. Epub 2014 May 12.
Faculty of Health and Medical Sciences, Duke of Kent Building, University of Surrey,
Guildford, GU2 7XH