What is type I MPGN as a consequence of type II cryoglobulinemia?
MPGN is a specific type of glomerular injury in which there is damage to the basement membrane from electron-dense deposits and an increase in the proliferation of endothelial cells and mesangial cells. Therefore, compared to MN, in which there is only thickening of the basement membrane due to immune complexes without cellular proliferation, MPGN is a more aggressive kidney injury. MN typically causes only the nephrotic syndrome, whereas MPGN causes nephrotic syndrome with an “active” urinary sediment showing red cells casts, granular casts, dysmorphic red cells, and kidney tubular epithelial cells.
The MPGN histology is type I MPGN, with immune complexes selectively located in the subendothelial space and mesangium. A reclassification of MPGN has occurred, and this category is now called immune complex mediated MPGN as compared to a separate category called complement mediated MPGN. Hepatitis C results in a unique production of cryoglobulin immune complexes that deposit in the subendothelial space, classifying this as a subset of immune complex MPGN.
The cryoglobulins in hepatitis C are so large that they cannot filter through the basement membrane, so they are trapped in the subendothelial space. Their size forces them to protrude into the lumen of the capillary, and it almost looks like there are thrombi in the glomeruli capillaries. The entire capillary lumen may become filled with the cryoglobulin complex.
Cryoglobulins are immune complexes comprising certain combinations of antibodies and antigens that precipitate on cooling and are classified based on the composition of the antibody involved and its target. When the antibody is composed of a single subtype (monoclonal), such as only an IgG or IgM, and precipitates in the cold, it is called type I cryoglobulinemia. This often results from a hematopoietic malignancy. If there is an antibody that is monoclonal (IgM or IgG) and it targets another antibody that is polyclonal (IgG), this is called type II cryoglobulinemia. This category used to be called essential cryoglobulinemia and is a characteristic of HCV. If there are two different polyclonal antibodies present that interact and form an immune complex, this is called type III cryoglobulinemia.
Once a patient is infected with hepatitis C, the immune system tries to neutralize the virus by producing IgG antibodies against the surface antigens of the viral capsid. Unfortunately, these antibodies do not neutralize the virus, but they do circulate in the blood of patients chronically infected with HCV. This is what is measured with the ELISA: non-neutralizing IgG antibodies against the hepatitis C capsid. What is unusual in HCV is that the patient will make a unique type of monoclonal IgM antibody (IgM k ) that directly targets the IgG the person has made against the viral envelope proteins. When one antibody attacks another antibody, this is called an anti-idiotypic antibody. The IgM that is made in patients with HCV is anti-idiotypic because it is directed against the IgG molecule. The cryoglobulin in HCV is composed of a monoclonal IgM k linking together polyclonal IgG and viral capsid envelope proteins. This crosslinking of antibodies to antibodies is why cryoglobulin is so large and obstructs the capillary lumen. It is unique from typical immune complexes in autoimmune syndromes like systemic lupus erythematosus, which are only composed of one antibody and one antigen. It is not known why only the clonal IgM heavy chain and only the kappa light chains are made by the stimulated B cells from hepatitis C.
