<prompt> Answer this question truthfullyWhat is the underlying physiology or mechanism of cryoglobulinemia?  <response>: <reason> Cryoglobulins are proteins single or mixed immunoglobulins that precipitate from serum and plasma when cooled. They are produced due to chronic immune system activation and lymphoproliferation. Cryoglobulins have a tendency to redissolve on rewarming. The pathogenesis of cryoglobulinemia differs slightly based on the type of disorder and disease associations. The following are the major mechanisms involved in the pathogenesis of cryoglobulinemia:Type I cryoglobulinemia is usually seen in patients suffering from disorders of lymphoproliferation such as: Multiple myelomas MM Monoclonal gammopathy of undetermined significance MGUS Waldenstroms macroglobulinemia Chronic lymphocytic leukemia CLLThe solubility of proteins depends upon concentration, hydrophobicity, size and surface charge, as well as the solution temperature, pH and ionic strength. The following mechanisms have been proposed to be implicated in the precipitation of immunoglobulins in patients suffering from type I cryoglobulinemia:a Chronic immune stimulationThe lymphoproliferative and hematological disorders listed above lead to chronic activation of the immune system and production of higher concentrations of monoclonal immunoglobulins usually IgG or IgM at temperatures below 37 degrees celcius.b Aggregation of immunoglobulinsSelf aggregation through Fc fragment of immunoglobulins is the proposed mechanism of production of cryoglobulins in type I cryoglobulinemiai Modification of Ig heavy H and light L chainsAn abnormal glycosylation event in the heavy chain hypervariable region apparently leads to precipitation of immunoglobulins in type I cryoglobulinemia. ii Reduced concentration of sialic acidIncreased content of hydrophobic amino acids, decreased tyrosine and sialic acid residues has been known to lead to decreased solubility of immunoglobulins Ig. iii Deficiency of galactose in the Fc portion of the IgDecreased galactose concentration in the Fc portion of immunoglobulins leads to decreased plasma solubility of immunoglobulins. The terminal sialylation of these proteins is dependent on the presence of galactose residues, hence decreased galactose leads to decreased sialylation, which in turn promotes precipitation of immunoglobulins. The decreased glycosylation has also been linked to the increased nephrophilic nature of cryoglobulins.iv Somatic Ig mutationsSomatic hypermutation in the variable regions of the heavy VH and light chains VL may also contribute to the insolubility of immunoglobulins. Increased intraclonal VH andor VL gene diversity has been shown to be present in various patients suffering from hepatitis C associated mixed cryoglobulinemia. v Non-specific FcFc interactionsIt is important to note that these two different, yet highly representative, clinical syndromes generally reflect different types of underlying CG:MC is closely associated with hepatitis C infection and is thought to activate B lymphocytes by binding to CD81. 80-95 of patients with MC have circulating anti-HCV antibodies or circulating HCV RNA in the serum or within the cryoprecipitate. Polyclonal IgG anti-HCV have been noted in the cryoprecipitate as well. Approximately 50 of patients with chronic hepatitis C and 15 with hepatitis B will have circulating MC 12 Type II, 23 Type III. It is unclear what the antigen trigger is for production of the MC, but it is though that the hepatitis C viral RNA itself may be the factor since it is found in high quantities in the cryoprecipitate. 