B-cells aggravate autoimmune diseases

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Date: March 5, 2014
Source: Max-Planck-Gesellschaft
Summary:
Scientists may have discovered a fundamental aggravating factor in autoimmune diseases. If B-lymphocytes lack the protein PTP1B, the cells will become hyperactive for stimulatory signals and can thus promote an autoimmune attack. This study offers an additional explanation to how B-cells regulate an immune response.

Mice in which the scientists deactivated the PTP1B protein in B-cells have immune complex deposition (red) in their kidney. The same development could be observed in patients with rheumatoid arthritis (blue: cell nuclei).
Credit: © MPI f. Immunobiology and Epigenetics/ D. Medgyesi [Click to enlarge image]

Scientists in Freiburg may have discovered a fundamental aggravating factor in autoimmune diseases. If B-lymphocytes lack the protein PTP1B, the cells will become hyperactive for stimulatory signals and can thus promote an autoimmune attack. This study offers an additional explanation to how B-cells regulate an immune response.
In Germany, approximately 800,000 people suffer from rheumatoid arthritis. In this progressive disease, a person's own immune system attacks and destroys connective tissue. However, the most important factors governing the progress of the disease are still unknown. Now, scientists working with Michael Reth and David Medgyesi from the Max Planck Institute of Immunobiology and Epigenetics have identified a factor that may play a significant role.

Using genetic engineering, they deactivated the PTP1B protein in B-cells in the immune systems of mice. The B-cells then became much more responsive to activating signals and, in turn, served to reactivate the other cells.

PTP1B could therefore have a monitoring function in the B-cell-mediated immune response. Until now, B-cells were mainly known for producing antibodies after coming into contact with pathogens. Only recently is more and more accepted by researchers that B-lymphocytes possess important regulatory function in the immune system.

The current study now provides a new detail of this mechanism. A clinical investigation showed that B-cells in patients suffering from rheumatoid arthritis also produce unusually low amounts of the studied protein. In the patients' other cell types, and in healthy subjects, this was not the case. "This suggests that the protein plays a significant role in the development or the aggravated course of rheumatoid arthritis," says principal investigator Michael Reth. Reth is head of the Molecular Immunology department at the Max Planck Institute of Immunobiology and Epigenetics, as well as scientific director of the Centre for Biological Signalling Studies (BIOSS), a German Cluster of Excellence at the University of Freiburg.

In cases of rheumatoid arthritis in which conventional treatments are ineffective, patients can be treated with the drug Rituximab. The drug destroys all B-cells in the body and will thus at least halt the progress of the disease. "The B-cells produced after the Rituximab therapy possess similar amount of the PTP1B protein as cells in healthy people. This may contribute to the less severe autoimmune reaction," explains first author David Medgyesi. Long-term studies are required to determine whether these newly produced cells will lose the protein over time.

By the end of the 1990s, the laboratory headed by Michael Reth had already developed mice with B-cells in which specific genes could be knocked out using Cre-lox technology. In the meantime, this mouse strain is being used very successfully in over 200 laboratories around the world to study the functioning of the immune system.
Story Source:
The above story is based on materials provided by Max-Planck-Gesellschaft. Note: Materials may be edited for content and length.
Journal Reference:

1. D. Medgyesi, E. Hobeika, R. Biesen, F. Kollert, A. Taddeo, R. E. Voll, F. Hiepe, M. Reth. The protein tyrosine phosphatase PTP1B is a negative regulator of CD40 and BAFF-R signaling and controls B cell autoimmunity. Journal of Experimental Medicine, 2014; DOI: 10.1084/jem.20131196

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Max-Planck-Gesellschaft. "B-cells aggravate autoimmune diseases." ScienceDaily. ScienceDaily, 5 March 2014. <www.sciencedaily.com/releases/2014/03/140305111052.htm>.


J Exp Med. 2014 Mar 10;211(3):427-40. doi: 10.1084/jem.20131196. Epub 2014 Mar 3.
The protein tyrosine phosphatase PTP1B is a negative regulator of CD40 and BAFF-R signaling and controls B cell autoimmunity.
Medgyesi D1, Hobeika E, Biesen R, Kollert F, Taddeo A, Voll RE, Hiepe F, Reth M.
Author information
Abstract
Tyrosine phosphorylation of signaling molecules that mediate B cell activation in response to various stimuli is tightly regulated by protein tyrosine phosphatases (PTPs).

PTP1B is a ubiquitously expressed tyrosine phosphatase with well-characterized functions in metabolic signaling pathways.

We show here that PTP1B negatively regulates CD40, B cell activating factor receptor (BAFF-R), and TLR4 signaling in B cells. Specifically, PTP1B counteracts p38 mitogen-activated protein kinase (MAPK) activation by directly dephosphorylating Tyr(182) of this kinase. Mice with a B cell-specific PTP1B deficiency show increased T cell-dependent immune responses and elevated total serum IgG. Furthermore, aged animals develop systemic autoimmunity with elevated serum anti-dsDNA, spontaneous germinal centers in the spleen, and deposition of IgG immune complexes and C3 in the kidney.

In a clinical setting, we observed that B cells of rheumatoid arthritis patients have significantly reduced PTP1B expression. Our data suggest that PTP1B plays an important role in the control of B cell activation and the maintenance of immunological tolerance.

 

[natasa778]

Great! Great start!!

Now to the question of why PTP1B levels were reduced in the first place. IF this was due to something that is not eliminated by Rituximab/B cell depletion, then it is all over again after a while

Long-term studies are required to determine whether these newly produced cells will lose the protein over time.

 

[Bob]

"The B-cells produced after the Rituximab therapy possess similar amount of the PTP1B protein as cells in healthy people. This may contribute to the less severe autoimmune reaction," explains first author David Medgyesi.

That's interesting.

 

[Ren]

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[Ema]

High dose IVIG can also slow or halt autoimmune diseases. I wonder if it is because the donor antibodies express more of this protein.

 

[natasa778]

B-cells in patients suffering from rheumatoid arthritis also produce unusually low amounts of the studied protein

I am willing to bet something like this is behind the low levels.

 

[Cosma]

PTP1B seems like a HUGE marker to me, as it explains alot of aspects of CFS.


1- impaired activation of AMPK
CFS:

CONCLUSION:
EPS is an effective model for eliciting muscle contraction and the metabolic changes associated with exercise in cultured skeletal muscle cells. We found four main differences in cultured skeletal muscle cells from subjects with CFS; increased myogenin expression in the basal state, impaired activation of AMPK, impaired stimulation of glucose uptake and diminished release of IL6. The retention of these differences in cultured muscle cells from CFS subjects points to a genetic/epigenetic mechanism, and provides a system to identify novel therapeutic targets.

PTP1B:

Thus, neuronal PTP1B inhibition results in decreased hypothalamic AMPK activity, isoform-specific AMPK activation in peripheral tissues, and downstream gene expression changes that promote leanness and increased energy expenditure. Therefore, the mechanism by which PTP1B regulates adiposity and leptin sensitivity likely involves the coordinated regulation of AMPK in hypothalamus and peripheral tissues.
http://mcb.asm.org/content/29/16/4563.full

2- B cells
CFS:

Chronic fatigue syndrome (CFS) is a heterogeneous disorder of unknown aetiology characterized by disabling fatigue, headaches, sleep disturbance and several other symptoms. The onset of CFS may follow a viral infection or period of stress. Patients with CFS do not have hypogammaglobulinaemia, predisposition to recurrent bacterial infections or symptoms of autoimmunity. To date, defects in B cell numbers or function have not been shown in the literature. However, treatment with anti-B cell therapy using Rituximab has recently shown benefit to CFS patients. We therefore postulated that patients with CFS had a subtle humoral immune dysfunction, and performed extended B cell immunophenotyping. We undertook a detailed characterization of the proportions of the different B cell subsets in 33 patients with CFS fulfilling the Canadian and Fukada criteria for CFS and compared these with 24 age- and gender-matched healthy controls (HC). CFS patients had greater numbers of naive B cells as a percentage of lymphocytes: 6·3 versus 3·9% in HC (P = 0·034), greater numbers of naive B cells as a percentage of B cells: 65 versus 47% in controls (P = 0·003), greater numbers of transitional B cells: 1·8 versus 0·8% in controls (P = 0·025) and reduced numbers of plasmablasts: 0·5 versus 0·9% in controls (P = 0·013). While the cause of these changes is unclear, we speculate whether they may suggest a subtle tendency to autoimmunity.

PTP1B:

If B-lymphocytes lack the protein PTP1B, the cells will become hyperactive for stimulatory signals and can thus promote an autoimmune attack.

In Germany, approximately 800,000 people suffer from rheumatoid arthritis. In this progressive disease, a person’s own immune system attacks and destroys connective tissue. However, the most important factors governing the progress of the disease are still unknown. Now, scientists working with Michael Reth and David Medgyesi from the Max Planck Institute of Immunobiology and Epigenetics have identified a factor that may play a significant role. Using genetic engineering, they deactivated the PTP1B protein in B-cells in the immune systems of mice. The B-cells then became much more responsive to activating signals and, in turn, served to reactivate the other cells.
In cases of rheumatoid arthritis in which conventional treatments are ineffective, patients can be treated with the drug Rituximab. The drug destroys all B-cells in the body and will thus at least halt the progress of the disease. “The B-cells produced after the Rituximab therapy possess similar amount of the PTP1B protein as cells in healthy people.
https://www.mpg.de/7977816/autoimmune_diseases_b-cells

3- leptin
CFS:

Self-reported fatigue severity was significantly correlated with leptin levels in six of the participants with CFS and one healthy control, supporting our primary hypothesis. The machine learning algorithm distinguished high from low fatigue days in the CFS group with 78.3% accuracy.

PTP1B:

Mice lacking the protein-tyrosine phosphatase PTP1B are hypersensitive to insulin and resistant to obesity. However, the molecular basis for resistance to obesity has been unclear. Here we show that PTP1B regulates leptin signaling. In transfection studies, PTP1B dephosphorylates the leptin receptor-associated kinase, Jak2. PTP1B is expressed in hypothalamic regions harboring leptin-responsive neurons.