Pebbled paths to pathogenesis
Crystals and other precipitates can damage the kidney, lung, gall bladder, and the blood vessels. The resulting disorders thus share a common mode of origin, and LMU’s Hans-Joachim Anders argues that they should be viewed in this light.
Crystalline deposits and other insoluble substances play a role in the pathogenesis of many diseases, both acute and chronic. How broad is the spectrum?
Anders: The range is indeed quite large: Inhaled air-borne particles from the environment or from occupational exposures, can cause acute or chronic damage to the lung. Other organs are more likely to be damaged by particles that form within cells, such as misfolded proteins that are resistant to degradation by the cell’s disposal mechanisms and form abnormal deposits, as in Alzheimer’s or Parkinson’s, but also diabetes. Excretory organs such as the gall bladder and the kidney are especially at risk. Bile and urine undergo a process of concentration so as to conserve water, and this can lead to the precipitation of tiny crystalline particles, which serve as seeds for formation of larger granules or even stones, which can cause painful attacks of colic.
Why do crystals form in the first place?
Anders: In the excretory organs the problem arises mainly from the phenomenon of mineral hypersaturation: Water is progressively reabsorbed, and at some point the concentration of the salts becomes so high that they spontaneously interact to form crystalline structures that continue to grow to calculi and stones. In tissues, metabolic disorders or aberrant cell responses can prevent proteins from folding correctly into their normal functional shapes. Some misfolded proteins have a tendency to self-aggregate just like crystals, which can promote formation of microparticles of plaque-like deposits just like calculi and stones formed by minerals. Cholesterol crystals forming in the walls of the blood vessels and building atherosclerotic plaques isa well-known example.
That sounds as if they are involved about 50% of all medical conditions. Yet you prefer to focus on the commonalities between them rather than on the features that distinguish one from another. Why?
Anders: Studies on gout have shown that uric acid precipitates stimulate the secretion of pro-inflammatory molecules by activating a very specific signal pathway. Interestingly, the trigger is not the uric acid per se, but the crystalline particle itself. Since this first discovery chemically diverse particulates were found to promote inflammatory reactions via the same mechanism. And recently we identified that alsocrystal-mediated killing of cells involves a common molecular mechanism. That leads to the notion that a broad range of disorders, which differ widely in their clinical manifestations, are the consequence of very similar underlying mechanisms – and could perhaps be treated in similar ways.
How exactly does the body try to fight such microparticles?
Anders: Primarily by means of phagocytic cells, which actively take up dead cells and foreign particles and enzymatically degrade them into their basic components. However, crystals and misfolded proteins cannot always be digested in this way. Many microparticles are simply too bulky or long to be incorporated by phagocytes. These particles are then rather isolated by encapsulation, as in the case of the classical granulomas that form in lungs exposed to silicates. But this can lead to chronic inflammation and tissue scarring.
But cell death in response to exposure to crystals is not a passive process?
Anders: It has long been recognized from experiments on cell cultures that a certain fraction of the cells die when crystals are added. This was always regarded as being the result of a passive process. But it is observed not only with elongated particles that have sharp edges, but also with rounded particles with smooth contours. So it’s not a simple mechanic effect. We have now shown for several different types of crystals that cell death is indeed an actively regulated process. If a phagocyte is unable to destroy the crystal it has taken up, the degradating enzymes are released not into the vesicle surrounding the crystal but also into the cell cytoplasm. This then activates a specific signal pathway that induces cell death. The dying cell in turn releases a whole set of molecules that trigger inflammation. The upshot is a vicious circle of inflammation, followed by cell death, followed by further inflammation. For example, in the case of an attack of gout, the pain in the joint, which is the result of cell death and inflammatory reactions, gets worse over a period of hours until it reaches a peak. Similar phenomena occur in the kidney and other organs exposed to crystals.
So although crystallopathies differ in their etiology and manifestation, the immune system always resorts to the same signal pathways?
Anders: Exactly, this is our working hypothesis. More research will be needed in the coming years in order to test and verify this idea. Data that point to commonalities in the mechanisms that promote inflammation are relatively convincing. But we have a long way to go to confirm that the same holds for the process of cell death. Over the next few years we may be able to develop new therapeutic options for patients with crystal- and microparticle-associated disorders.
The New England Journal of Medicine 2016
Prof. Dr. med. Hans-Joachim Anders, nephrologist and rheumatologist, heads the Department of Nephrology at Medical Clinic IV at the inner city campus of LMU Medical Center.