Mechanisms of disease: monoclonal immunoglobulin deposition. Amyloidosis, light chain deposition disease, and light and heavy chain deposition disease.
All forms of MIDD are related to the presence of an expanded clone of B-cell origin that is producing an Ig product, usually, but not exclusively an L-chain, which is predisposed to deposit in tissues, with or without some degree of processing. The nature of the processing is currently unclear, although limited proteolysis is likely to play a major role in most, but not all, patients. Diagnosis is made by the identification, using immunohistochemical techniques, of the monoclonal Ig nature of the deposited material, which may be fibrillar and Congo red-positive (AL and AH), or more amorphous and Congo red-negative (LCDD and LCHDD). Present modalities of therapy are similar or identical to those employed in multiple myeloma, attempting to eliminate the monoclonal cell population responsible for the production of the precursor of the deposited protein. A variety of ancillary therapeutic measures may be employed to treat problems associated with the failure of specific organs produced by the deposition. The details of how the uniformly soluble precursor molecule is converted to an essentially insoluble aggregate that compromises the function of the tissue in which it is formed are not yet known. It is still not possible to construct a potential "unified field theory" governing the deposition of intact Igs or their fragments. It is likely, as appears to be the case in other forms of amyloid unrelated to Ig, that many proteins contain, within their sequence, peptides that are capable of forming insoluble beta sheet-like structures. When these peptides are isolated from their surrounding molecular environment--either by proteolysis in the test tube, by a mutational change that predisposes them to limited proteolysis; or by a point mutation, deletion, or some other structural modification (as glycosylation), which alters their molecular context without proteolysis--and are present in sufficient concentration, they become less soluble under physiologic conditions. It is likely that the site of deposition depends upon the site of synthesis, but to a lesser extent than the protease profile and the physicochemical make-up of the affected tissues. Better understanding of the latter factors is necessary for the development of better modes of treatment.
Buxbaum
J
J
Medical Service, New York Department of Veterans Affairs Medical Center, New York.
D000686:Amyloidosis / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000378:metabolism*; D006362:Heavy Chain Disease / Q000276:immunology*; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000378:metabolism*; D007674:Kidney Diseases / Q000276:immunology / Q000473:pathology; D010265:Paraproteinemias / Q000276:immunology*
D000911:Antibodies, Monoclonal; D007147:Immunoglobulin Light Chains