Research projects in Vinuesa’s group
The Humoral Immunity Autoimmunity Group is investigating the cellular and molecular
events that regulate production and selection versus elimination
of memory B cells, which is of critical importance to understand how best to
harness immune responses against infection, and to mitigate against
autoimmunity. Our team has recently discovered the roquin gene, a key piece
in what appears to be a crucial pathway for repressing formation of
lupus autoantibodies and development of diseases resembling type 1 diabetes
and rheumatoid arthritis. Our research aims to illuminate the cause of these
diseases and identify more specific and effective therapeutic approaches.
This project was initially funded by the Wellcome Trust and is now integrated
within the Genes in Immunity and Tolerance Consortium - Large RO1 of the National
Institutes of Health: (Dr C Vinuesa, Dr G Hoyne, Dr. Ed Bertram, Dr J Cyster,
Prof L Lanier, Prof A Weiss, Prof C Goodnow). Mutagenesis, mapping and gene
identification are performed at the ANU, and screen development and detailed
analysis performed jointly at the ANU and the University of California San Francisco.
1. Investigating how a mutation in the roquin gene causes
lupus: Di Yu, Hu Xin, Vicki Athanasopoulos, D Silva, C Goodnow, C Vinuesa.
Roquin acts cell-autonomously within T cells to suppress ICOS expression and
accumulation of T follicular helper (TFH) cells. The interaction of ICOS (inducible
costimulator) with its ligand ICOSL is also essential during T cell-dependent
B cell differentiation within germinal centres: mice and humans lacking ICOS
have defective germinal centre formation and anamnestic antibody responses.
Our preliminary data indicate ICOS protein expression is tightly controlled
by Roquin to prevent autoimmunity. Dr Vicki Athanasopoulos (postdoctoral fellow)
has shown Roquin localises to cytoplasmic stress granules, which are sites
of regulation of mRNA metabolism, and a CCCH RNA-binding domain suggest Roquin
targets are RNA-binding proteins that may be involved in regulating mRNA stability
and/or translation. Di Yu (PhD student) and Hu Xin (MSc student) are currently
investigating the regulation of ICOS expression by ICOS and the possibility
this occurs at a posttranscriptional level and may combine the processes of
ubiquitylation and control of mRNA stability. D. Silva (Research Fellow) is
exploring whether Roquin may also repress activation of B cells reactive against
self-nuclear antigens. This project is funded by the NH&MRC.
2. Roquin prevents autoimmune diabetes through a novel
tolerance pathway: D. Silva, Jennifer Hogan, C Vinuesa.
Work by Dr Diego Silva, (Research Fellow), has revealed Roquin also plays
a critical role in peripheral T cell tolerance to pancreatic antigens and
is a potent suppressor of autoimmune diabetes. His current focus is to dissect
the relative role of Roquin in repressing self-reactive T cells, dissecting
its involvement in maintenance of anergy vs Treg suppression. This project
is funded by the NH&MRC.
3. Translational study: human genetics of systemic autoimmunity
(SLE and type 1 diabetes) based on mouse mutagenesis: M Linterman, N Simpson,
C Angelucci, A Wilson, G Huttley, C Goodnow, J Harley, M Cook, C Vinuesa.
Vinuesa’s group is currently investigating whether genetic defects in
the Roquin pathway may account for a fraction of patients with SLE or type
1 diabetes. This work is being carried out by Michelle Linterman, a PhD student,
in collaboration with John Harley (OMRF, US). In partnership with Dr Matthew
Cook, they have launched in the last year the “APOSLE” study,
with the aims of establishing an Australian DNA collection from patients with
SLE that can be screened for mutations in candidate lupus genes. Other lupus-susceptibility
genes identified through our autoimmunity mouse ENU screen will also be studied
as potential human lupus candidate alleles.
4. Molecular analysis of memory B cell formation in
germinal centres: Di Yu, I MacLennan, C Goodnow, C Vinuesa,
Germinal centres are specialized sites of B cell proliferation and receptor
gene hypermutation, where high affinity foreign-antigen specific B cells are
stringently selected to form memory cells and plasma cells. While these processes
are critical for long-term immunity to infection, and our previous work has
shown they are also stringent steps for deleting self-reactive B cells, little
is known about the underlying molecular and cellular mechanisms. By sorting
germinal centre B cells destined to form memory, and matched control germinal
centre cells that are blocked in differentiation to memory cells, we have
used Affymetrix microarrays to identify a set of memory-associated genes.
Remarkably, many of these have not previously been found to be expressed in
immune cells, but are known for their roles in synaptic plasticity and memory
in the nervous system. Di Yu (PhD student) has confirmed the differential
pattern of expression of a group of genes found in normal centrocytes undergoing
T cell-driven selection, but not expressed in centrocytes from sterile germinal
centres. This project is pursuing the immunological functions of these memory
genes.
5. Elucidating the role of the autoimmune modulator
Roquin and TFH cells in the prevention of Experimental autoimmune encephalomyelitis:
D. Silva, Joseph Ng, C. Vinuesa.
While mice with dysfunctional Roquin develop autoimmune diseases including
diabetes, they are protected against experimental autoimmune encephalitis
(EAE), a mouse model of multiple sclerosis. In this project, Joseph Ng (Honours
student) and Diego Silva (Research Fellow) are studing the mechanism by which
Roquin modulates the immune response in EAE and the involvement of a subset
of immune cells, follicular helper T cells, in inducing protection. This work
is funded by Multiple Sclerosis Research (Australia).
6. Role of follicular T helper cells in rheumatoid arthritis:
Matthew Cook, Natalia Botelho, D Matthis, C Benoist and C Vinuesa.
Rheumatoid Arthritis is a systemic autoimmune disease that attacks the synovium
in the joints and leads to progressive joint inflammation and destruction. It
is a chronic, and often terribly debilitating disease and to date is incurable.
The K/BxN mouse model revealed a critical role for antibodies in triggering
murine arthritis. Using this model Natalia Botelho (Honours student) is currently
investigating the possibility that roquin, through its repression of T follicular
helper cells and self-reactive germinal centre B cells, negatively controls
autoimmune arthritis development.
