Instead of protecting us, the immune system can sometimes go awry, as in the case of autoimmune disorders and allergies. An Ludwig-Maximilian-Universitaet (LMU) in Munich group has dissected how mast cells modulate their calcium levels to maintain the immune response under control.

The immune system defends us against attack by germs and viruses and also helps to eliminate cancer cells. The innate immune system is responsible for the initial detection and destruction of invasive pathogens.

There are situations, but in which immune responses may be misdirected, causing the machine to focus its firepower to the wrong targets - either the human body's own proteins (in the case of autoimmune disorders ) or on intrinsically benign foreign tissues (in the case of allergies).

Currently a team of researchers led by LMU immunopharmacologist Susanna Zierler and pharmacologist Ingrid Boekhoff in the Walther Straub Institute of Pharmacology and Toxicology has now shown that the action of certain ion-channel proteins in mast cells plays a significant role in preventing allergic and anaphylactic reactions and ensuring that immune responses don't overshoot.

Mast cells are present in almost all organs in the human body and modulate the initiation and resolution of inflammatory reactions mounted by the immune system as a means of combating infections and metabolic dysregulation.

Immune reactions are highly complex procedures, which must be carefully targeted. <span style="color: #ff6600;"><a style="color: #ff6600;" href="https://www.en.uni-muenchen.de/news/newsarchiv/2020/zierler_ionenkanal.html">This usually means that immune cells have to be capable of detecting particular signals that interact with receptor proteins on the cell surface and converting them to clearly defined sets of molecular interactions that result in the activation of the proper response at the ideal time and in the right place.</a></span>

Among the reactions triggered within the cell are adjustments in the levels of positively charged ions including calcium, sodium and potassium. It ends up that rapid and transient changes in ion concentrations are essential for the activation of many types of resistant cells.

It's apparent that cells modulate intracellular levels of the ions principally via proteins called ion channels and ion pumps, however these flows are regulated in the context of immune reactions is not known in detail.

<span style="color: #ff6600;"><a style="color: #ff6600;" href="https://www.en.uni-muenchen.de/news/newsarchiv/2020/zierler_ionenkanal.html">The research groups led by Susanna Zierler and Ingrid Boekhoff have , within the framework of the Collaborative Research Center TRR-152 funded by the DFG, characterized the functions of ion channels which regulate the concentration of free calcium in mast cells.</a></span>
Like most other cell types, mast cells achieve it by activating the release of calcium from intracellular stores. The endoplasmic reticulum (ER) is the greatest storage organelle for calcium .

However, other intracellular organelles, such as the mitochondria (the cell's power stations) along with also the lysosomes (intracellular waste disposal units), can also supply calcium ions on demand.

Every one these intracellular compartments are delimited by membranes where technical ion channels are added.

<em>These results show that perturbation of the sensitively regulated equilibrium that controls the level of intracellular calcium ions in mast cells can lead to drastic allergic and anaphylactic reactions."-Susanna Zierler, immunopharmacologist, Ludwig Maximilian University of Munich</em>

Endolysosomal membranes, for instance, include a protein that belongs to the family called two-pore stations (TPCs). Zierler, Boekhoff and their colleagues report that among these, TPC1, plays a significant part in regulating changes in the intracellular distribution of calcium ions between endolysosomes along with the ER.

They shown that selective genetic knockout or pharmacological inhibition of TPC1 in mast cells in mice alters the equilibrium between the quantities of calcium stored within such organelles.

Crucially, this change is associated with a notable increase in the secretion of histamine, which then triggers a severe allergic reaction, on both the cellular and systemic levels.

The identification of this TPC1 station protein as an important regulator of mast-cell action and histamine secretion has obvious therapeutic implications.

"The study pinpoints the TPC1 channel as a promising drug target for the treatment of allergic and mast-cell-dependent disorders," states Zierler. Overall, concentrated pharmacological charge of the ion stations in immune cells has great potential for the treatment of infections, allergies and maybe even leukemias.
<div class="content-src-label"><strong>Source:</strong></div>
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<span style="color: #ff6600;"><a style="color: #ff6600;" href="https://www.en.uni-muenchen.de/news/newsarchiv/2020/zierler_ionenkanal.html" target="_blank" rel="noopener noreferrer">Ludwig Maximilian University of Munich</a></span>

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<div class="content-src-label"><strong>Journal reference:</strong></div>
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Arlt<em>.,</em><em>E., et al. </em>(2020) TPC1 deficiency or blockade augments systemic anaphylaxis and mast cell activity. <em>Proceedings of the National Academy of Sciences</em><span style="color: #ff6600;">. <a style="color: #ff6600;" href="https://doi.org/10.1073/pnas.1920122117" target="_blank" rel="noopener noreferrer">doi.org/10.1073/pnas.1920122117</a>.</span>

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