Selected articles, February 2014
How tumours evade the immune system
Angiostatic Effects of NK Cell-Derived IFN-c Counteracted by Tumour Cell Bcl-xL Expression
R. P. A. Wallin, V. S. Sundquist, E. Bråkenhielm, Y. Cao, H.-G. Ljunggren & A. Grandien
We all know that cytotoxic cells kill their target cells. But in this paper the authors conceptually show that cytotoxic cells also have an important role in fighting tumours and possibly also infections by influencing the tissue environment.
Reports have been published that tumours are selected to resist T-cell immune attacks by a variety of mechanisms including recognition and cytotoxic killing.
Proteins of the anti-apoptotic BCL-2 family such as BCL-XL have long been seen to be upregulated in many types of tumours. These proteins block the mitochondrial pathway of apoptosis and it is believed that BCL-XL protects the tumor cells from various cell death stimuli in the harsh environment of the growing tumour.
Started 15 years ago
Robert Wallin, the first author of that study, reveals that the work started almost 15 years ago, when he was a PhD student, together with Valentina Screpanti.
– We continued the work as post docs and eventually, almost 15 years after the start, the study is now finished, Robert Wallin tells.
He was until recently a group leader and associate professor at the Karolinska Institutet, but is now responsible for education development at a new life science institute in Jakarta, Indonesia, International Institute for Life-Sciences.
Robert Wallin and Valentina Screpanti worked as PhD students together in a project concerning the role of apoptosis in T and NK cell killing of infected cells and tumour cells. They found that BCL-XL protects a tumour, in vivo, from NK cell activity, but did not understand the mechanism, more than that it was not protection against the cytotoxicity of the NK cells. Valentina later found that the activity of NK cells inhibit blood-vessel expansion in the tumour in an IFN-g dependent way and that BCL-XL enables the tumour to grow in spite of the lower oxygen and nutrient supply.
Lymphocytes are important in tissue remodelling
– One interesting aspect of publishing this study is that we can draw the attention to this potentially important field, says Robert Wallin.
A few articles were published over ten years ago about the fact that another immune cell could inhibit vessel expansion in a similar way, but not much has happened since.
– I believe that the role of lymphocytes in tissue remodelling in inflammation and in tumours is an interesting field to study, Robert Wallin concludes.
On the relationship between influenza and type 1 diabetes
Antibodies to Influenza Virus A/H1N1 Hemagglutinin in Type 1 Diabetes Children Diagnosed Before, During and After the SWEDISH A(H1N1)pdm09 Vaccination Campaign 2009–2010
M. Svensson, A. Ramelius, A.-L. Nilsson, A. J. Delli, H. Elding Larsson, A. Carlsson, G. Forsander, S. A. Ivarsson, J. Ludvigsson, I. Kockum, C. Marcus, U. Samuelsson, E. Örtqvist and Å. Lernmark, the Better Diabetes Diagnosis (BDD) study group
Different viruses have been implicated in the triggering and promoting of islet autoimmunity and progress to the onset of clinical disease, but the exact role they play is still uncertain. In light of the reports on increased incidence of narcolepsy after the Swedish vaccination campaign against A(H1N1)pdm09 2009-2010, the researchers in this study wanted to investigate whether the vaccination may had altered any characteristics of type 1 diabetes in newly diagnosed children. They also determined the levels of A/H1N1-HAAb in a standard radio binding assay, a method commonly used to detect islet autoantibodies.
Type 1 diabetes is a complex disease
The etiology to type 1 diabetes is complex, and includes both genetic and environmental factors. At present, type 1 diabetes is viewed as a two-step disease. The first step is the triggering of islet autoimmunity in the genetically at-risk (HLA-DQ8, HLA-DQ2 or both), which is reflected by the appearance of islet autoantibodies. The second step is the developing of clinical disease, which may require many years to manifest. However, it is known that a higher number of autoantibodies predicts the disease progress, so that patients with multiple autoantibodies progress faster to clinical onset.
Matilda Svensson is a medical student who joined the research team in 2012 when she was working on a project as part of a summer course at Lund University. This summer project is what led to the publication.
– The study design was initiated before I joined the project, Matilda Svensson tells me. All raw data had been collected, and my task was to, together with Ahmed Delli, compile it and perform the necessary statistical analysis.
– We found that the youngest children (<3 years of age) had significantly lower frequency of A/H1N1-HAAb than older children (divided into age groups 3<6, 6<9, 9<13 and 13-18 years), which probably cannot only be explained by a lower vaccination coverage in this age group.
Vaccination may accelerate or delay progress into type 1 diabetes
The group also found that children carrying HLA-DQ2 (not together with HLA-DQ8) may have had lower frequencies of A/H1N1-HAAb, which is a new finding. Nothing was found that pointed towards an increased number of patients diagnosed with type 1 diabetes the winter season of 2009-2010 compared to seasons before and after. However, when comparing children diagnosed before, during and after the vaccination campaign, it was found that frequencies and levels of two islet autoantibodies (GADA and ZnT8QA) were increased among patients diagnosed during (GADA and ZnT8QA) and after (ZnT8QA) compared to them diagnosed before the vaccination campaign. Also, less children than expected in the youngest age group (<3 years of age) carrying the highest genetic risk (HLA-DQ2/8), where diagnosed after the vaccination campaign. These findings allowed the group to speculate that the vaccination (or the virus itself) may have accelerated, or delayed, progression into clinical disease in different children, depending on their age, HLA-DQ genotype, islet autoantibody status and possible other factors.
– This was all new to me, and I enjoyed the whole working process. How the results from the statistical analyses opened up for new angels and questions and the continuous revision, that finally resulted in a finished product, Matilda Svensson concludes.
What is the Better Diabetes Diagnosis study group?
The Better Diabetes Diagnosis (BDD) study is a nationwide prospective cohort study that recruits new-onset diabetes patients who are less than 18 years old at time of diagnosis. Today are all paediatric medical centres in Sweden participating in the BDD study. The BDD study started recruiting new incident patients of type 1 diabetes from May 1st, 2005 and is still ongoing. Children who are less than 18 years old at the time of diagnosis were included, and the diagnosis is confirmed based on clinical criteria and follow up after six months of onset.
For each newly diagnosed child, blood samples are collected within 3 days of diagnosis for specific risk testing of HLA genotyping and islet autoantibody assays. At the same time blood samples are collected for biochemical and metabolic parameters, which are tested at the referring clinical centre and a specific nurse-based questionnaire is filled. The questionnaire records demographical variables as well as clinical and family medical histories, and also involves information about the patient’s origin for two generations.