Homeostatic regulation of T cell trafficking by a B cell–derived peptide is impaired in autoimmune a

[melihtas]

http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.3842.html
Full Text is behind paywall.

Homeostatic regulation of T cell trafficking by a B cell–derived peptide is impaired in autoimmune and chronic inflammatory disease

Abstract
During an inflammatory response, lymphocyte recruitment into tissue must be tightly controlled because dysregulated trafficking contributes to the pathogenesis of chronic disease. Here we show that during inflammation and in response to adiponectin, B cells tonically inhibit T cell trafficking by secreting a peptide (PEPITEM) proteolytically derived from 14.3.3 zeta delta (14.3.3.ζδ) protein. PEPITEM binds cadherin-15 on endothelial cells, promoting synthesis and release of sphingosine-1 phosphate, which inhibits trafficking of T cells without affecting recruitment of other leukocytes. Expression of adiponectin receptors on B cells and adiponectin-induced PEPITEM secretion wanes with age, implying immune senescence of the pathway. Additionally, these changes are evident in individuals with type 1 diabetes or rheumatoid arthritis, and circulating PEPITEM in patient serum is reduced compared to that of healthy age-matched donors. In both diseases, tonic inhibition of T cell trafficking across inflamed endothelium is lost. Control of patient T cell trafficking is re-established by treatment with exogenous PEPITEM. Moreover, in animal models of peritonitis, hepatic ischemia-reperfusion injury, Salmonella infection, uveitis and Sjögren's syndrome, PEPITEM reduced T cell recruitment into inflamed tissues.

Article about the paper:
http://www.birmingham.ac.uk/news/latest/2015/04/Newly-discovered-pathway-200415.aspx

Newly discovered pathway reveals how our immune system is regulated; gives hope for serious chronic diseases

Researchers from the University of Birmingham have identified an important new way in which our immune systems are regulated, and hope that understanding it will help tackle the debilitating effects of type 1 diabetes, rheumatoid arthritis and other serious diseases.

The team discovered a novel pathway that regulates the movement of pathogenic immune cells from the blood into tissue during an inflammatory response.

A healthy, efficient immune system ordinarily works to damp down inflammation and carefully regulate the magnitude of the response to infection and disease. In diseases such as diabetes and arthritis, as well as when we age, our immune system becomes less stringently regulated and this can lead to an exaggerated inflammatory response – allowing inappropriate access of immune cells to vulnerable tissues. The new study shows that beneficial effects of the new pathway are lost in these diseases, as well as during normal ageing.

The study, published in Nature Medicine, details how a key molecule regulates this aspect of our immune response. Importantly, the team were then able to show how the addition of this molecule to immune cells from patients with diabetes and arthritis could regain control of the movement of their immune cells, thereby reversing the pathogenic changes seen in these diseases.

 

[anciendaze]

This is one paper I would like to read in full.

 

[anciendaze]

I've had a look at the full paper, and find a great deal of interest. This strikes me as a major discovery which would not have been made if they had been limited by simple models of immune function. The 14-unit polypeptide they found is a fragment of a known protein with the catchy name of 14.3.3 zeta/delta. They still have not identified the enzyme which performs proteolysis to extract this.

That parent protein had previously been noticed as a suspicious bystander in a number of diseases, but was not itself implicated. (I found this in a paper on protein-protein interaction networks. See figure 2.)

The starting point for their investigation was a circulating hormone called adiponectin. This is involved in both oxidation of fatty acids and regulation of glucose. It is known to be involved with both immune and metabolic pathways. A connection with inflammation is very interesting here, since it plays a role similar to leptin, which has already been implicated in several aspects of ME/CFS.

The researchers were interested in the recruitment of T-cells into endothelial tissues, something which shows up in a wide range of chronic disease states. Even so, the story was not simple. They had to discover that B-cells were also needed, though not because of antibodies, and how B-cells were able to signal to memory T-cells which then regulated recruitment of other T-cells more closely associated with pathology. (I had previously been watching for work on recruitment of CD8+ T-cells to endothelial tissues.)

They also helped to explain the way rituximab works in a number of chronic inflammatory diseases. If production of the polypeptide they found, dubbed PEPITEM, has been exhausted depletion of B-cells will not increase the problem, since they were not performing their regulatory function anyway. When these cells are replaced by fresh cells the signalling will improve, (provided the stem cells in bone marrow from which B-cells are derived are not damaged.)

The exciting possibility no one had anticipated is that direct intervention using exogenous PEPITEM can break the cycle of tissue damage and recruitment of more T-cells quickly. This is particularly interesting because this is a naturally-occurring molecule already found in healthy humans.

 

[natasa778]

The exciting possibility no one had anticipated is that direct intervention using exogenous PEPITEM can break the cycle of tissue damage and recruitment of more T-cells quickly. This is particularly interesting because this is a naturally-occurring molecule already found in healthy humans.

Thanks for that summary! The authors have also filed a patent for this, which could hold details (or speculations) not given in the paper?

Claims: A method for treatment and/or prophylaxis of a condition associated with T cell mediated chronic inflammatory disease by administration, to a patient, of a peptide comprising N'-SVTEQGAELSNEER-C {SEQ ID NO: 1) or an analogue thereof that inhibits T cell migration.
2, A method according to claim 1 , wherein the condition is selected from the group consisting of T ceil auto-reactivity, T cell mediated chronic inflammatory disease and autoimmune disease.
3, A method according to claim 1 or 2, wherein the condition is diabetes mellitus (type I).
4, A method according to claim 1 or 2, wherein the condition is selected from the group consisting of: juvenile onset diabetes; rheumatoid arthritis; Crohn's disease; atherosclerosis; psoriasis; inflammatory and fibrotic liver disease(s) including steatohepatitis and cirrhosis; and uveitis.
etc

 

[anciendaze]

Thanks for that summary! The authors have also filed a patent for this, which could hold details (or speculations) not given in the paper?

As always, I remind people that patent claims are deliberately broad, in hopes of covering any possible variations and derivative implementations of the idea. If this becomes as valuable as I suspect, there will be other attempts to break this claim. One problem here is that the entire peptide sequence was already part of a database of protein sequences, but this particular subsequence was not specifically identified. I would guess that others who have done protein sequencing will be going through their old data to show that they had already found this in healthy controls. It would surprise me if no one had encountered this before.

This would not be enough to break this patent, but it would weaken claims of novelty and originality. As always, once attorneys are involved, the outcome becomes uncertain. You might also try to compute the on-going income pharmaceutical companies currently derive from poorly effective treatments for the conditions listed. A battle to delay introduction of new and effective treatments which might end that income stream could be a rational choice by companies without such a patent.

 

[Ecoclimber]

New pathway reveals how immune system is regulated, gives hope for chronic diseases

Date: April 20, 2015
Source: University of Birmingham

Summary:
An important new way in which our immune systems are regulated has been uncovered by researchers, giving hope that understanding it will help tackle the debilitating effects of type 1 diabetes, rheumatoid arthritis and other serious diseases.

Researchers from the University of Birmingham have identified an important new way in which our immune systems are regulated, and hope that understanding it will help tackle the debilitating effects of type 1 diabetes, rheumatoid arthritis and other serious diseases.

The team discovered a novel pathway that regulates the movement of pathogenic immune cells from the blood into tissue during an inflammatory response.

A healthy, efficient immune system ordinarily works to damp down inflammation and carefully regulate the magnitude of the response to infection and disease. In diseases such as diabetes and arthritis, as well as when we age, our immune system becomes less stringently regulated and this can lead to an exaggerated inflammatory response -- allowing inappropriate access of immune cells to vulnerable tissues. The new study shows that beneficial effects of the new pathway are lost in these diseases, as well as during normal aging.

The study, published in Nature Medicine, details how a key molecule regulates this aspect of our immune response. Importantly, the team were then able to show how the addition of this molecule to immune cells from patients with diabetes and arthritis could regain control of the movement of their immune cells, thereby reversing the pathogenic changes seen in these diseases.

Professor Ed Rainger, from the University of Birmingham, explained, "Our immune system becomes progressively less effective over the years and this can become harmful leading to disease. Being able to understand the link between aging and pathology will help us to reduce the risk of ill health associated with increasing age."

"Our discovery of this new pathway is very exciting. Not only does it reveal new ways in which our bodies control inflammation, it also indicates that we may be able design new drugs to reverse the disease and age specific loss of this pathway."

"The fact that the new pathway is relevant to both diabetes and rheumatoid arthritis, which are quite different diseases, implies a broad applicability to many chronic inflammatory and autoimmune diseases. This is an area of research we are keen to follow, and will be working with doctors from other specialities to determine whether this is the case and whether new therapies might be more broadly applicable"

The global healthcare landscape is undergoing a significant shift, with some populations experiencing a sharp increase in life expectancy. However, an aging population comes with a rise in the prevalence of debilitating diseases, which in turn passes on a significant burden to the patients, their families and their health service providers.

Professor Rainger added, 'The link between the decline of this pathway and normal aging is also very interesting, as this is a natural process. It means that patients with diseases such as rheumatoid arthritis may have accelerated decline of this pathway so that individuals as young as 20 have the immune function of 70 year olds. If we can identify patients at risk of developing this disease we may be able to artificially restore some vigour to their immune systems and reduce the burden of disease for the individual patient as well as their families and the NHS.''

The next step is to use the findings in clinical studies that will investigate the viability of treatments and therapies targeting this pathway.

Professor Peter Weissberg, Medical Director at the British Heart Foundation, said: "This is a superb piece of research that appears to have identified a new way to regulate chronic inflammation. It helps to explain why autoimmune diseases like rheumatoid arthritis become more common with age."

"It remains to be seen whether these findings will have any direct relevance to cardiovascular disease. However, coronary heart disease tends to be more common in people with chronic inflammatory conditions such as rheumatoid arthritis, so if this research leads to better treatments for these conditions, it might be expected that this will lead to fewer heart attacks in these patients."

Journal Reference:

1. G Ed Rainger et al. Homeostatic regulation of T cell trafficking by a B cell–derived peptide is impaired in autoimmune and chronic inflammatory disease. Nature Medicine, April 2015 DOI: 10.1038/nm.3842

Cite This Page:

University of Birmingham. "New pathway reveals how immune system is regulated, gives hope for chronic diseases." ScienceDaily. ScienceDaily, 20 April 2015. <www.sciencedaily.com/releases/2015/04/150420122939.htm>.

Another Paper from authors interesting concept:

THE PEPTIDE INHIBITOR OF TRANS-ENDOTHELIAL MIGRATION, PEPITEM, A NOVEL IMMUNE REGUALTORY AGENT, CONTROLS T-CELL TRAFFICKING DURING INFLAMMATION, A TONIC INHIBITORY PATHWAY THAT IS LOST IN CHRONIC DISEASE

M Chimen, H M McGettrick, C Yates, A Martin, F Barone, L Walker, C Buckley, G Nash, P Narendran, G E Rainger University of Birmingham doi:10.1136/heartjnl-2013-304019.187