Cl- regulates cryoglobulin structure: a new hypothesis for the physiopathological mechanism of temperature non-dependent cryoprecipitation

Cryoglobulins are pathological cold-precipitable immunoglobulins associated with a number of infectious, autoimmune and neoplastic disorders. Patients, when exposed to low temperatures, show symptoms related to intravascular precipitation of such immunoglobulins. The formation of cryoaggregates induced by exposure to cold temperature is the key pathogenetic mechanism. The subsequent intravascular precipitation can account for some clinical signs of peripheral vasculitis, but fails to explain the precipitation of cryoglobulins in regions where no significant temperature changes take place. We studied, in vitro, the activity of different ions on temperature-dependent aggregation of cryoglobulins and found that the concentration of Cl- present in solution is the most important variable that controls the size and the rate of formation of aggregates, both at low temperature and at 37degreesC. We suggest that chloride anion could be the most important factor involved in the pathogenesis of events in visceral regions, such as in the kidneys, where no temperature changes occur but where the local Cl- concentration changes to maintain blood electrolytic homeostasis and acid-basic equilibrium. Moreover, identification of a specific structural domain responsible for Cl- binding may provide new targets for drugs selectively designed to interfere with cryoglobulin aggregation.