Selected articles October 2016
Resistin – possible immune regulator
Resistin Gene Expression is Downregulated in CD4+ T Helper Lymphocytes and CD14+ Monocytes in Rheumatoid Arthritis Responding to TNF-α Inhibition
I. Nagaev, M. Andersen, M. K. Olesen, O. Nagaeva, J. Wikberg, L. Mincheva-Nilsson and G. N. Andersen
In this paper by Scandinavian researchers it is shown that the inflammatory cytokine resistin (resistance to insulin) has pro-inflammatory as well as proresolving roles in active rheumatoid arthritis.
Rheumatoid arthritis is a debilitating autoimmune disease, which affects about 1% of the population in Western countries. Rheumatoid arthritis is T cell mediated, implying activation and expansion of auto-reactive T cells, their migration into the synovia and induction of local inflammation with monocyte activation, leading to cartilage damage and bone resorption.
In recent years, the cytokine resistin has attracted attention as a pro-inflammatory cytokine in rheumatoid arthritis.
The main finding presented in this paper is that resistin gene expression in CD4+ T cells is susceptible to changes in the cytokine environment, which indicate that resistin may have other properties than “just” being a pro-inflammatory cytokine secreted by monocytes. Considering this, the authors assume that resistin synthesis may be used by CD4+ T cells to direct the immune response into regulatory and/or effector Th1, Th2, Th17.
– Interestingly, we found a correlation between fold change in resistin and TGFβ gene expressions in monocytes, which points to a connection between the regulation of these two genes, says Marlene Andersen, first author of the paper.
Marlene shares the first authorship with Ivan Nagaev, who did all the biochemistry experiments in the study.
– I’m a medical doctor and Ph.D. student at Aalborg University and at present fulfilling my specialist training at North Denmark Regional Hospital to become a rheumatologist.
Furthermore, Marlene Andersen is a member of the “Scandinavian Melanocortin Study Group” of Grethe Neumann Andersen, with whom this study is done in collaboration.
– During the work that led to this paper, I have mostly enjoyed the rewarding cooperation with my amazing main supervisor, Grethe Neumann Andersen. She always shares her wisdom, knowledge and experience.
As TGFβ is important in the maintenance of immune tolerance, the findings presented here support the view that resistin may have an immune regulatory function.
– Our next step will be to study resistin gene expression in the context of a panel of cytokine gene expressions discriminating between Th1, Th2, Th17 and regulatory response in various leukocyte subsets from DMARD naïve patients with rheumatoid arthritis of recent onset, Marlene Andersen concludes.
On the HLA-DR-presence on T cells
Presence of HLA-DR Molecules and HLA-DRB1 mRNA in Circulating CD4+ T Cells (pages 211–221)
A. L. S. Revenfeld, R. Steffensen, L. H. Pugholm, M. M. Jørgensen, A. Stensballe and K. Varming
Here, Danish researchers elaborate on the longstanding observation of HLA-DR being present on T cells.
It has been observed for more than four decades that T cells in peripheral blood can present MHC class II (MHCII) molecules on their outer surface and that the number of MHCII+ T cells increases upon activation. In line with this, one of the three human MHCII isotypes, called HLA-DR, is frequently used as a T cell activation marker along with other molecules, such as CD69 and CD25. Nonetheless, the functional role and significance of HLA-DR on human T cells is not fully determined and the unequivocal confirmation of an endogenous expression or a protein acquisition from other immune cells is absent.
The present study was carried out to elucidate the physiological details of HLA-DR on T cells as well as to obtain novel information about a possible endogenous expression.
Anne Louise Revenfeld, the first author of the paper, carried out the work that led to this publication as a part of her PhD, which she finalized about a year ago.
– The topic of my thesis was HLA-DR in relation to T cells and the article addresses some of the initial questions we wanted to answer. I think that the strength of our investigation is based on the combination of highly tailored protein and transcript analyses, which elucidate the phenomenon on different levels simultaneously
Especially one technique was very dear to Anne Louise during this work.
– My major interest was definitely centered on the flow cytometric work, as this is a fantastic and indispensible technique, when working with immunological research.
With her work, Anne Louise and her colleagues show that the characteristics for the presence of HLA-DR on T cells differ from when it is found on antigen-presenting cells.
– Since a lot of the expected functionality of HLA-DR on T cells has been deduced from what we know from its function on antigen-presenting cells, we question that this knowledge might simply be extrapolated to T cells. Hence, we do not immediately believe that HLA-DR-presenting T cells are antigen-presenting cells. In addition, the use of HLA-DR as an activation marker for T cells is questioned, and this is rather important because many laboratories still use HLA-DR in this context without relating their findings to something functional (e.g. WHY it is present on T cells and what does this mean for the pathological/physiological issues that are investigated?). With our results we hope that this practice may be re-evaluated.
Anne Louise Revenfeld is currently a postdoctoral researcher, doing mainly research about basic immunological mechanisms with a focus on CD4+ T cells.
– We continue to work with HLA-DR in the context of T cells during my postdoctoral work. Ultimately, it is the possible functionality of this phenomenon that we are interested in. Consequently, functional investigations have been initiated. We hope to show that HLA-DR is connected to regulatory functions of T cells and our work in this context also involves the role of extracellular vesicles produced by cells of the immune system, as means of communication and regulation.