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Cytokine - Receptor concepts

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Cytokine - Receptor concepts

Postby Saham » Fri May 21, 2010 5:22 pm

Hi
I am a MSc student of control engineering at Control and Intelligent Processing Center of Excellence-School of Electrical and Computer Engineering.
I'm working on the modeling and simulation of brain lesion dynamics in multiple sclerosis as my final thesis.I'm trying to get familiar with medical texts, so please forgive me for my probable mistakes in asking my questions.

Here i am asking about the binding of the cytokines to their receptors on the cell surface. I've faced with texts like for example interleukin-12 binds to its receptor on T cells and initiates a change in the cell performance. I want to know that:

Is there a unique IL-12 receptor (i mean one receptor), or many IL-12 receptors that distributed on the cell surface? If there is many, how it is quantitated on the cell surface (for example concentration of receptors on the cell surface)?

Consider that the cell is exposed to 2 different kinds of cytokines with 2 different effects (and maybe with opposite effects), and the two cytokines are presented around the cell with the same concentrations. Which one will determine the final performance of the cell? Is there any kind of stochastic phenomenon that determines the final task of the cell? Are the concentrations of receptors crucial for the fate of the cell? What will happen if we assume the case that the number of two different receptors (or concentrations of them) on the cell surface are also the same?

What do determine the High or Low affinity of the Receptor/cytokine binding? And does it play the crucial role for the fate of the cell? What will happen if the affinities of the two different cytokines are exactly the same?


I appreciate your taking the time to read or answer the questions.
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Re: Cytokine - Receptor concepts

Postby marla » Tue Jun 01, 2010 9:08 pm

I do not understand completely what are your doubts but I write all that I think can be helpful. If you have any questions only need to reply and I will answer.

Firstly, you need to know some general information about T Lymphocites. T Lymphocites are responsable of adaptive immune response. But this response is triggered by specific antigen recognition by T lymphocites. Otherwise, T lymphocites can be usefull in B cell activation and antibody production, here it’s named T helper cell, and this is known as adaptive immune response.

Talking about B cell activation, activated helper T cells secrete cytokines that act in concern with CD40 ( a type of tumor necrosis factor) to stimulate B cell proliferation and production of antibodies of different isotypes.

Cytokines serve two principal functions in antibody responses:
(1) Provide amplification mechanisms by augmenting B cell proliferation and differentiation
(2) They determine the types of antibodies produces by selectively promoting switching to different heavy chain isotypes.

When occur isotype switching we can have different inmunoglobulins that acts in the humoral response. Exist different types of inmunoglobulins, for example: IgM ( wich acts in the complement activation), IgG and it subclasses ( acts in Fc receptor-dependent phagocyte responses, complement activation, neonatal immunity or placental transfer), IgE (acts in immunity against helminthes (worms), mast cell degranulation or immediate hypersensitivity) and IgA (acts in mucosal immunity transport of IgA through epithelia).

The late events in helper T cell dependent antibody responses, including affinity maturation and the generation of memory B cells, occur in the germinal centers of lymphoid follicles. The affinity maturation is the process that leads to increased affinity of antibodies for a particular antigen as a T-dependent humoral response progresses. Follicular dendritic cells in the germinal centers display antigens, and the B cells that bind these antigens with high affinity are selected to survive.

Consider that the cell is exposed to 2 different kinds of cytokines with 2 different effects (and maybe with opposite effects), and the two cytokines are presented around the cell with the same concentrations. Which one will determine the final performance of the cell?

Different cytokines stimulate different kinds of T cells. T cells as I talk before, can act as heper T cells, when are this types of T cells it has four kinds identified: Th1, Th2, Tfh and Th17. So Different cytokines can made different functions in immune responses at same time. Because every cytokine can be use in different type of cells.

Is important to know that Cytokines are proteins secreted by different types of cells like:
(1) Lymphokines
(2) Chemokines
(3) Interferons
(4) Colony- stimulating factors
(5) Tumor necrosis factors

Every cell acts in different ways on T cell. So different cytokines has different functions in cell so they need to work together to have the final immune response. When Tumor necrosis factors are presented they determine the final performance of the cell because they induce a systemic inflammation and stimulate an acute phase reaction. When this occurs the cells suffer apoptosis and death.

What do determine the High or Low affinity of the Receptor/cytokine binding? And does it play the crucial role for the fate of the cell? What will happen if the affinities of the two different cytokines are exactly the same?

When are more receptor on the cell surface the affinity of the cytokine will be increase. Receptors has remarkable characteristics and are partly because of deficiency of cytokine receptors has now been directly linked to certain debilitating immunodeficiency states. In this regard, and also because the redundancy and pleiomorphism of cytokines are a consequence of their homologous receptors.
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Postby marla » Tue Jun 01, 2010 9:13 pm

I think that this book can be useful for you, you can get it online:
Cellular and Molecular Immunology By Abbas, Lichtman and Pillai
6th edition
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Re: Cytokine - Receptor concepts

Postby jonmoulton » Wed Jun 02, 2010 5:26 pm

Hi Saham,

"Is there a unique IL-12 receptor (i mean one receptor), or many IL-12 receptors that distributed on the cell surface? If there is many, how it is quantitated on the cell surface (for example concentration of receptors on the cell surface)?"

If a certain cell type is expressing a particular receptor, there are usually many examples of a given receptor type on a cell surface. It is possible that there will be a single receptor on the cell surface, but this is an unlikely case; it would be expected to occur just at the onset of expression as the first receptor arrives at the cell surface or would be expected to occur after expression has halted, as the receptors are being degraded by proteases during normal protein turnover and finally only one is left. Receptor concentrations can be roughly estimated by immunohistochemistry (e.g. fluorescent antibodies) but are more rigorously quantitated by Western blot (which requires a larger sample, more cells).

"Consider that the cell is exposed to 2 different kinds of cytokines with 2 different effects (and maybe with opposite effects), and the two cytokines are presented around the cell with the same concentrations. Which one will determine the final performance of the cell? Is there any kind of stochastic phenomenon that determines the final task of the cell? Are the concentrations of receptors crucial for the fate of the cell? What will happen if we assume the case that the number of two different receptors (or concentrations of them) on the cell surface are also the same?"

The downstream effects of the receptors will influence the response of the cell. Binding of the ligand (cytokine) to the receptor starts a signalling process in the cell, often a complex cascade of phosphorylation of other proteins. If the same population size of two different receptors with the same ligand affinity are exposed to the same concentrations of their respective ligands, it is the nature of the signal path that will determine which ligand elicits the greater response.

Binding of the ligand to the receptor is a stocastic phenomenon, as are all of the interactions in a signaling pathway. All molecular interactions involve chance. Concentrations of receptors influence the flow of signal through the signal path. Assuming concentrations of receptors are the same does not determine that the signal flow will be identical, as other factors such as the affinity of receptor and ligand or the nature of the signaling pathways come into play and affect the signal strength.

"What do determine the High or Low affinity of the Receptor/cytokine binding? And does it play the crucial role for the fate of the cell? What will happen if the affinities of the two different cytokines are exactly the same?"

Certainly the affinity is important for the fate of the cell, as the receptor-ligand affinity is one parameter of the signal path. Affinities can be directly measured by techniques like surface-plasmon resonance (for instance, using a Biacore instrument).
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Postby jonmoulton » Wed Jun 02, 2010 5:32 pm

"What do determine the High or Low affinity of the Receptor/cytokine binding?"

I don't think I addressed this adequately. The affinity is determined by the shape, flexibility and electrostatic topology of the receptor and its ligand -- in a molecular sense, how well they fit and how electrostatically sticky they are. The nature of the solvent has a strong influence on this affinity as well, though water will most likely be the dominant solvent just beyond the surface of a cell membrane. Specifically hydrogen bonding, dipole-dipole interactions and van der waals interactions tend to make the surfaces of ligand and receptor stick; exclusion of hydrophobic regions by water may also contribute to their complexation.
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Re: Cytokine - Receptor concepts

Postby Saham » Thu Jun 03, 2010 10:04 am

Thanks to "marla" and special thanks to "jonmoulton" for taking your valuable time to answer my questions.
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Re: Cytokine - Receptor concepts

Postby Nataly56 » Thu Jul 14, 2011 7:47 am

This is slightly out of my depth, but I can answer a few point that might help.
There are usually more than one receptor for a type of interleukin on the cell surface, however some interleukins, when they are bound cause the cell to express more receptors of a particular type of interleukin, and so increasing the chance of binding and activating intracellular signalling, the cast of IL12 i is the JAK_STAT pathway. It can also induce the decreased expression of other IL receptors, and sometimes cause the intracellular deactivation of other IL receptors. ( you would have to check exactly how as I can't remember!)
*As I understand it, T cells are all or nothing when it comes to IL signalling, which means they don't usually have two conflicting cytokine signals while being in an 'undecided' state. In other words, they usually receive a signal from one IL receptor, and they go down that pathway doing whatever they need to do, unless they get a signal telling them otherwise, often from a regulatory T cell that dampens down the immune response.
Plus it is not always just a single step signal, IL12 for example induces naive T cells to become Th0 cells, and then only after that to they become Th1 or 2 cells depending on what they encounter
Affinities are usually defined by the structure of the receptor, and with T cells the arrangement of alpha and beta chains whilst they mature in the thymus, therefore they will need very little of one cytokine to have an effect and a much higher concentration of another. This affinity regulation is important so the cell responds competently to the given situation. So if the concentration of two cytokines were the same, it would not matter as the key receptors with their own affinity for the cytokines with determine what happens.
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Re: Cytokine - Receptor concepts

Postby sunhan1985 » Fri Dec 21, 2012 2:27 am

As for my suggestion, you can do some biological experiments to determine the localization and distribution of your interested receptors with purchased specifc antibodies.
For example, immunohistochemistry is a useful rechnique. To get a reference, you can visit
http://www.immunohistochemistry.us/
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