Immunogenetics

The aims of the Immunogenetics group are to understand the pathology, clinical outcomes and disease mechanisms of autoimmunity using genetics. The group focuses on the autoimmune disease, systemic lupus erythematosus (SLE). SLE is a unique autoimmune disease in that any organ in the body can be targeted. It primarily affects young women, particularly those who have non-European ancestry. The disease involves abnormalities of both the innate and adaptive immune systems and has a strong genetic component.

Members

Tim Vyse

Professor of Molecular Medicine

Functional genomics of SLE

Genome-wide associations studies (GWAS) have revealed more than 100 SLE susceptibility loci. In most cases the mechanisms by which these genetic factors elevate the risk of disease is unknown. We are combining both genetic and functional approaches to address these questions. Through genetic studies in multiple ancestries in SLE, we can fine map the association signals and using techniques such as Mendelian randomisation to infer the likely causal functional effects that underpin the genetics. By studying gene expression using single cell RNA sequencing, proteomics and massively parallel sequencing we can gain further insight the functional effects of risk alleles for SLE. This project involves internal collaboration with David L Morris and Deborah Cunninghame Graham

Role of X chromosome in female bias in autoimmunity

Almost all autoimmune diseases show sexual dimorphism with a striking female bias that is most marked in SLE (10:1). The cause of the bias has historically been attributed to ‘hormones’, which undoubtedly can influence immune function. However, several lines of evidence indicate a role for the X chromosome too. Gene expression in females from the X chromosome is usually regulated by random inactivation. This process is subject to perturbation by non-random skewing and loss of full inactivation on a regional bias. We are investigating both these processes in B cells in SLE to determine whether they are dysregulated. We have recently shown that a novel SLE risk gene, CXorf21 (TASL) is upregulated by SLE risk alleles, the gene also escapes X inactivation hence females have a higher dose of this disease risk gene, which acts in a viral sensing pathway that is activated in SLE. This project involves internal collaboration with Deborah Cunninghame Graham

Balance between risk of autoimmunity and infection risk in population

Why autoimmune genetic risk alleles persist in a population has long been subject to speculation. One hypothesis is that such disease risk alleles provide some protection against common infections. This has been difficult to substantiate because genetic studies of infectious disease are highly confounded. The COVID pandemic allows a unique opportunity to study host genetics in the setting of ‘new’ infectious agent. We have compared the genetics of SLE and COVID outcome and found evidence for strong genetic correlation between the two traits: both positive and negative factors were identified. We are actively following this up by using both genetic data from different ancestral populations and by acquiring epidemiological data of common infection frequency in a population cohort to compare infection incidence and severity with polygenic risk scores for common autoimmune diseases. This project involves internal collaboration with David L Morris

COVID-19 and systemic lupus erythematosus genetics: A balance between autoimmune disease risk and protection against infection
Wang, Y., Guga, S., Wu, K., Khaw, Z., Tzoumkas, K., Tombleson, P., Comeau, M. E., Langefeld, C. D., Cunninghame graham, D. S., Morris, D. L., Vyse, T. J. & Sirugo, G. (ed.), 3 Nov 2022, In: PLoS genetics. 18, 11, p. e1010253 e1010253. Research output: Contribution to journal › Article › peer-review. DOIs: https://doi.org/10.1371/journal.pgen.1010253
Comprehensive genetic and functional analyses of Fc gamma receptors influence on response to rituximab therapy for autoimmunity
MATURA Consortia & MASTERPLANS Consortia, Dec 2022, In: EBioMedicine. 86, 104343. Research output: Contribution to journal › Article › peer-review. DOIs: https://doi.org/10.1016/j.ebiom.2022.104343
Age acquired skewed X Chromosome Inactivation is associated with adverse health outcomes in humans
Roberts, A., Morea, A., Amar, A., Zito, A., El-Sayed Moustafa, J., Tomlinson, M., Bowyer, R., Zhang, X., Christiansen, C., de Oliveira Costeira, R. C., Steves, C., Mangino, M., Bell, J., Wong, C., Vyse, T. & Small, K., Nov 2022, (Accepted/In press) In: eLife. Research output: Contribution to journal › Article › peer-review
Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with TRAF3 mutations
Rae, W., Sowerby, J. M., Verhoeven, D., Youssef, M., Kotagiri, P., Savinykh, N., Coomber, E. L., Boneparth, A., Chan, A., Gong, C., Jansen, M. H., du Long, R., Santilli, G., Simeoni, I., Stephens, J., Wu, K., Zinicola, M., Allen, H. L., Baxendale, H., Kumararatne, D., & 17 othersGkrania-Klotsas, E., Scheffler Mendoza, S. C., Yamazaki-Nakashimada, M. A., Ruiz, L. B., Rojas-Maruri, C. M., Lugo Reyes, S. O., Lyons, P. A., Williams, A. P., Hodson, D. J., Bishop, G. A., Thrasher, A. J., Thomas, D. C., Murphy, M. P., Vyse, T. J., Milner, J. D., Kuijpers, T. W. & Smith, K. G. C., 12 Aug 2022, In: Science Immunology. 7, 74, p. eabn3800 eabn3800. Research output: Contribution to journal › Article › peer-review. DOIs: https://doi.org/10.1126/sciimmunol.abn3800
Complement C4, the Major Histocompatibility Complex, and Autoimmunity
Vyse, T. J. & Tsao, B. P., Aug 2022, In: Arthritis and Rheumatology. 74, 8, p. 1318-1320 3 p. Research output: Contribution to journal › Editorial › peer-review. DOIs: https://doi.org/10.1002/art.42119
Major histocompatibility complex and SLE
Fernando, M. M. A. & Vyse, T. J., 1 Jan 2021, Lahita’s Systemic Lupus Erythematosus. Elsevier, p. 5-24 20 p. Research output: Chapter in Book/Report/Conference proceeding › Chapter › peer-review. DOIs: https://doi.org/10.1016/B978-0-12-820583-9.00020-8
A plausibly causal functional lupus-associated risk variant in the STAT1-STAT4 locus
Patel, Z. H., Lu, X., Miller, D., Forney, C. R., Lee, J., Lynch, A., Schroeder, C., Parks, L., Magnusen, A. F., Chen, X., Pujato, M., Maddox, A., Zoller, E. E., Namjou, B., Brunner, H. I., Henrickson, M., Huggins, J. L., Williams, A. H., Ziegler, J. T., Comeau, M. E., & 49 othersMarion, M. C., Glenn, S. B., Adler, A., Shen, N., Nath, S. K., Stevens, A. M., Freedman, B. I., Pons-Estel, B. A., Tsao, B. P., Jacob, C. O., Kamen, D. L., Brown, E. E., Gilkeson, G. S., Alarcón, G. S., Martin, J., Reveille, J. D., Anaya, J. M., James, J. A., Sivils, K. L., Criswell, L. A., Vilá, L. M., Petri, M., Scofield, R. H., Kimberly, R. P., Edberg, J. C., Ramsey-Goldman, R., Bang, S. Y., Lee, H. S., Bae, S. C., Boackle, S. A., Graham, D. C., Vyse, T. J., Merrill, J. T., Niewold, T. B., Ainsworth, H. C., Silverman, E. D., Weisman, M. H., Wallace, D. J., Raj, P., Guthridge, J. M., Gaffney, P. M., Kelly, J. A., Alarcón-Riquelme, M. E., Langefeld, C. D., Wakeland, E. K., Kaufman, K. M., Weirauch, M. T., Harley, J. B. & Kottyan, L. C., 1 Jul 2018, In: Human Molecular Genetics. 27, 13, p. 2392-2404 13 p. Research output: Contribution to journal › Article › peer-review. DOIs: https://doi.org/10.1093/hmg/ddy140
Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic diseases
Acosta-Herrera, M., Kerick, M., González-Serna, D., Wijmenga, C., Franke, A., Gregersen, P. K., Padyukov, L., Worthington, J., Vyse, T. J., Alarcón-Riquelme, M. E., Mayes, M. D. & Martin, J., 2019, In: Annals of the rheumatic diseases. 78, 3, p. 311-319 9 p. Research output: Contribution to journal › Article › peer-review. DOIs: https://doi.org/10.1136/annrheumdis-2018-214127
Genetic overlap between autoimmune diseases and non-Hodgkin lymphoma subtypes
Din, L., Sheikh, M., Kosaraju, N., Smedby, K. E., Bernatsky, S., Berndt, S. I., Skibola, C. F., Nieters, A., Wang, S., McKay, J. D., Cocco, P., Maynadié, M., Foretová, L., Staines, A., Mack, T. M., de Sanjosé, S., Vyse, T. J., Padyukov, L., Monnereau, A., Arslan, A. A., & 72 othersMoore, A., Brooks-Wilson, A. R., Novak, A. J., Glimelius, B., Birmann, B. M., Link, B. K., Stewart, C., Vajdic, C. M., Haioun, C., Magnani, C., Conti, D. V., Cox, D. G., Casabonne, D., Albanes, D., Kane, E., Roman, E., Muzi, G., Salles, G., Giles, G. G., Adami, H. O., Ghesquières, H., De Vivo, I., Clavel, J., Cerhan, J. R., Spinelli, J. J., Hofmann, J., Vijai, J., Curtin, K., Costenbader, K. H., Onel, K., Offit, K., Teras, L. R., Morton, L., Conde, L., Miligi, L., Melbye, M., Ennas, M. G., Liebow, M., Purdue, M. P., Glenn, M., Southey, M. C., Din, M., Rothman, N., Camp, N. J., Wong Doo, N., Becker, N., Pradhan, N., Bracci, P. M., Boffetta, P., Vineis, P., Brennan, P., Kraft, P., Lan, Q., Severson, R. K., Vermeulen, R. C. H., Milne, R. L., Kaaks, R., Travis, R. C., Weinstein, S. J., Chanock, S. J., Ansell, S. M., Slager, S. L., Zheng, T., Zhang, Y., Benavente, Y., Taub, Z., Madireddy, L., Gourraud, P. A., Oksenberg, J. R., Cozen, W., Hjalgrim, H. & Khankhanian, P., 1 Oct 2019, In: Genetic Epidemiology. 43, 7, p. 844-863 20 p. Research output: Contribution to journal › Article › peer-review. DOIs: https://doi.org/10.1002/gepi.22242
Nucleolin acts as the receptor for C1QTNF4 and supports C1QTNF4-mediated innate immunity modulation
Vester, S. K., Beavil, R. L., Lynham, S., Beavil, A. J., Cunninghame Graham, D. S., McDonnell, J. M. & Vyse, T. J., 1 Jan 2021, In: Journal of Biological Chemistry. 296, 100513. Research output: Contribution to journal › Article › peer-review. DOIs: https://doi.org/10.1016/j.jbc.2021.100513