Welcome to the next installment of our regular update where we report on research from the world of immunology, highlighting work from BSI members that has hit the headlines over the past few weeks.
Who's afraid of the big bad wolf? Small protein dampens down lupus pathology
Lupus is a complex autoimmune condition which affects around 30,000 people in the UK. Although its initial cause is unclear, disease pathology is due to the immune system recognising and mounting a response to cellular components such as DNA. Symptoms are varied and include fatigue, muscle and joint pain, skin rashes on the face or body, whereas more severe complications include kidney failure and pulmonary embolisms. Flare-ups of these symptoms have also been known to coincide with viral infections.
A team of scientists led by BSI member Professor Marina Botto at Imperial College London have recently discovered that deficiency of a protein called C1q may lead to development of lupus. C1q is a small protein which is part of the complement system, an arm of the immune system which destroys infected cells. Published in the journal Science, the team's research showed that in mice, C1q restrained the activity of cytotoxic T cells (a type of immune cell that propagates autoimmunity) by regulating the metabolism of the cell. This effect was reflected in humans, as C1q inhibited the activation, proliferation and function of cytotoxic T cells isolated from human volunteers. Additionally, virus-infected mice lacking C1q showed an over-exaggerated response by the cytotoxic T cells, which led to immune-mediated organ damage, similar to that seen in lupus.
Professor Botto said, “I’ve been working with lupus for many years, and we’ve only recently realised these cytotoxic cells – which have such a crucial role in protecting the body against viruses, may also play a key role in the disease.” She also explained that although the initial trigger for lupus is unknown, the condition could be sustained by viral infections that trigger an expansion of the cytotoxic T-cells, going some way to explain why symptom flare-ups often coincide with viral infections. Although this research is yet to be translated to humans, it sheds some light on the immune processes behind lupus and how these may be controlled.
Read the press release here.
Read the full article here: Ling et al. 2018 Science DOI: https://doi.org/10.1126/science.aao4555
Antibody light chains make light work of predicting MS progression
Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system whereby the immune system attacks the protective myelin sheath that covers neurons and facilitates the conduction of nerve impulses. Symptoms, which include muscle weakness, impaired vision and a lack of mobility, vary greatly from patient to patient. Some people also only experience a single ‘attack’ in their lifetime whereas others suffer numerous episodes, often leading to serious disability. Although there is no cure, the symptoms of MS are treatable. However, its variable nature makes it difficult to choose the appropriate treatment.
Scientists at the University of Birmingham, led by BSI Groups Secretary Dr John Curnow and Professor Mike Douglas, have discovered a way to predict the severity of the progression of the disease based on the ratios of certain types of antibody molecules in a patient’s spinal fluid. Antibodies are made up of a range of smaller components – two of which are the kappa (κ) chain and the lambda (λ) light chains. The team showed that having a low κ:λ ratio at diagnosis correlated with increased MS-related disability five years later. Although disease progression likely involved other factors, this work indicates that measuring κ:λ ratios at diagnosis may help doctors to tailor treatments for individual patients.
Commenting on the work Dr Curnow said, “Alongside improving our fundamental understanding of MS, this presents the opportunity to identify patients who are at higher risk of developing disability and may need more aggressive treatment. Similarly, it may be possible to identify patients at lower risk, who may be able to manage their condition more conservatively”. He also explained that more research was required to validate the findings, although if confirmed, this would lead to a simple test to identify patients with a poor prognosis. Clinicians would be able to then justify the use of highly effective therapies for these patients.
Read the press release here.
Read the full article here: Rathbone et al. 2018 Journal of Neurology, Neurosurgery and Psychiatry DOI: http://dx.doi.org/10.1136/jnnp-2018-317947
CRISPR-CAS9 offers new hope for tricky transfusions
Each year, 1.5 million units of blood are required to meet the transfusion needs of England alone. Currently, donor blood is matched with the recipient for the major blood group surface proteins, or antigens: A, B, O and RhD (Rhesus D). However, there are over 350 different red blood cell antigens that could trigger a rejection if they were to be mismatched with the recipient. Rejection occurs in around 2–5% of blood transfusion recipients, although this rises to 30% in sickle-cell disease (SCD) patients due to differences in red blood cell antigens between recipients of African descent and predominantly Caucasian donors.
A team of researchers at the University of Bristol have produced lab-grown red blood cells which lack a range of antigens responsible for the most common transfusion mismatching. To do this, they used cutting-edge CRISPR–CAS9 technology, a molecular tool derived from bacterial gene-editing systems, to delete the genes encoding the problematic antigens.
Although the researchers were keen to stress that the findings, published in the journal EMBO Molecular Medicine were preliminary, the work could lay the foundations for genetically altered blood which could be successfully transfused into patients, such as those with SCD, where mismatch and rejection is a common problem. Leader of the study, Dr Ashley Toye said "Blood made using genetically edited cells could one day provide compatible transfusions for a group of patients for whom blood matching is difficult or impossible to achieve within the donor population. However, much more work will still be needed to produce blood cells suitable for patient use."
Read the press release here.
Read the full article here: Hawksworth et al. 2018 EMBO Molecular Medicine DOI: https://doi.org/10.15252/emmm.20170845