The aims of the group are to use a multi-omic approach to understand the functional consequences of risk loci for autoimmune disease. The primary focus of the group focuses is 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
Faculty Lead for Doctoral Student Welfare
Projects
Functional annotation of the Ikaros transcription factors in autoimmune disease
Genome-wide associations studies (GWAS) have revealed that three members of the Ikaros family of transcription factors are associated with SLE. These proteins primarily act as lymphocyte regulatory factors. The focus of the project is to discover the biological mechanism by which these transcription factors act, by using genetic fine-mapping in multi-ancestry datasets, gene expression using single-cell RNA sequencing and epigenetic strategies, including ChIP-Seq. This project involves an internal collaboration with David Morris and Timothy Vyse.
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 an internal collaboration with Timothy Vyse.
OX40 and OX40L: biomarkers of disease activity for SLE
The OX40-OX40L co-stimulatory signal is a pivotal checkpoint within the immune system. These two molecules, expressed on lymphocytes, are both genetic risk factors for multiple autoimmune diseases, including Systemic Lupus Erythematosus (SLE). The risk alleles at both loci are cis-eQTLs correlated with increased expression of their cis-gene. Using a multi-omic approach we are seeking to discover whether 1) blocking the OX40-OX40L using an OX40:Fc fusion protein will reverse the transcriptomic and proteomic changes from co-stimulation. 2) increased levels of the soluble proteins in the serum of SLE patients is correlated with increased disease activity. This project is a collaboration with Timothy Vyse and Cambridge Digital Health Ltd.
Publications
Awards
Access a full list of Dr Cunninghame Graham's funding
Activities
UK Universities Mediation Working Group
People
Faculty Lead for Doctoral Student Welfare
Projects
Functional annotation of the Ikaros transcription factors in autoimmune disease
Genome-wide associations studies (GWAS) have revealed that three members of the Ikaros family of transcription factors are associated with SLE. These proteins primarily act as lymphocyte regulatory factors. The focus of the project is to discover the biological mechanism by which these transcription factors act, by using genetic fine-mapping in multi-ancestry datasets, gene expression using single-cell RNA sequencing and epigenetic strategies, including ChIP-Seq. This project involves an internal collaboration with David Morris and Timothy Vyse.
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 an internal collaboration with Timothy Vyse.
OX40 and OX40L: biomarkers of disease activity for SLE
The OX40-OX40L co-stimulatory signal is a pivotal checkpoint within the immune system. These two molecules, expressed on lymphocytes, are both genetic risk factors for multiple autoimmune diseases, including Systemic Lupus Erythematosus (SLE). The risk alleles at both loci are cis-eQTLs correlated with increased expression of their cis-gene. Using a multi-omic approach we are seeking to discover whether 1) blocking the OX40-OX40L using an OX40:Fc fusion protein will reverse the transcriptomic and proteomic changes from co-stimulation. 2) increased levels of the soluble proteins in the serum of SLE patients is correlated with increased disease activity. This project is a collaboration with Timothy Vyse and Cambridge Digital Health Ltd.
Publications
Awards
Access a full list of Dr Cunninghame Graham's funding
Activities
UK Universities Mediation Working Group
Our Partners
University College London
Cambridge Digital Health
Group lead
Faculty Lead for Doctoral Student Welfare