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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.

People

Tim Vyse

Professor of Molecular Medicine

Projects

Omics in SLE
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

    Sex and autoimmunity
    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

      Infection autoimmunity
      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

        Publications

          Awards

          Access a full list of Professor Vyse's research funding 

          Activities

          13th European SLE Meeting 2022

          The Immunogenetics team is organising the 13th European SLE Meeting

          People

          Tim Vyse

          Professor of Molecular Medicine

          Projects

          Omics in SLE
          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

            Sex and autoimmunity
            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

              Infection autoimmunity
              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

                Publications

                  Awards

                  Access a full list of Professor Vyse's research funding 

                  Activities

                  13th European SLE Meeting 2022

                  The Immunogenetics team is organising the 13th European SLE Meeting