Fig. 5.41 Structureofamyloid.(A)Aschematicdiagramofanamyloidfibershowingfourfibrils(therecanbeasmanyassixineachfiber)woundaroundoneanotherwithregularlyspacedbindingoftheCongoreddye.(B)Congoredstainingshowsapple-greenbirefringenceunderpolarizedlight,adiagnosticfeatureofamyloid.(C)Electronmicrographof7.5-to10-nmamyloidfibrils.(From Merlini G, Bellotti V: Molecular mechanisms of amyloidosis. NEnglJMed349:583–596, 2003.)
Many other proteins also can deposit as amyloid in a variety of clinical settings. Some of the most clinically important examples are mentioned in the following section.
Amyloidosis results from abnormal folding of proteins, which assume a β pleated sheet conformation, aggregate, and deposit as fibrils in extracellular tissues. Normally, intracellular misfolded proteins are degraded in proteasomes and extracellular protein aggregates are taken up and degraded by macrophages. In amyloidosis, these quality control mechanisms fail and fibrillar proteins accumulate outside of cells. The proteins that form amyloid fall into two general categories (
Fig. 5.42 ): (1) normal proteins that have an inherent tendency to associate and form fibrils, particularly when produced in increased amounts; and (2) mutant proteins that are prone to mis-folding and aggregation. The mechanisms of deposition of different types of amyloid are discussed next along with classification.
Because a given form of amyloid (e.g., AA) may be associated with diverse clinical settings, we will follow a classification that takes into account clinical and biochemical features (
Table 5.16 ). Amyloid may be systemic (generalized), involving several organ systems, or it may be localized to a single organ, such as the heart. On clinical grounds, the systemic pattern is subclassified into primary amyloidosis when it is associated with a clonal plasma cell proliferation, or secondary amyloidosis when it occurs as a complication of an underlying chronic inflammatory or tissue-destructive process. Hereditary or familial amyloidosis constitutes a separate, heterogeneous group with several distinctive patterns of organ involvement.
Primary Amyloidosis: Plasma Cell Proliferations Associated With Amyloidosis. Amyloid in this category is of the AL type and is usually systemic in distribution. This is the most common form of amyloidosis, with approximately 2000 to 3000 new cases each year in the United States. It is caused by a clonal proliferation of plasma cells that synthesize abnormal Ig molecules. The AL type of systemic amyloidosis occurs in 5% to 15% of individuals with multiple myeloma, a plasma-cell tumor characterized by excessive production of free immunoglobulin light chains (Chapter 12). The free, unpaired κ or λ light chains (referred to as Bence Jones protein) are prone to aggregating and depositing in tissues as amyloid. Since the majority of myeloma patients do not develop amyloidosis, however, it is clear that not all free light chains are equally likely to produce amyloid. For unknown reasons, λ light chains are approximately six times more likely to deposit as amyloid than κ light chains.
Most persons with AL amyloid do not have multiple myeloma or any other overt B cell neoplasm; such cases have been traditionally classified as primary amyloidosis, because their clinical features derive solely from the effects of amyloid deposition rather than formation of tumor masses. In virtually all such cases, however, monoclonal immunoglobulins or free light chains, or both, can be found in the blood or urine. Most of these patients also have a http://ebooksmedicine.net (e.g., misfolded protein)
Monomers assemble to form ˜-sheet structure