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AL amyloidosis

Tuesday 5 February 2008

In AL amyloidosis, a plasma-cell dyscrasia related to multiple myeloma, clonal plasma cells in the bone marrow produce immunoglobulins that are amyloidogenic.

In affected patients, 5 to 10 percent of bone marrow plasma cells (normal, @<@4 percent) have clonal dominance of a light-chain isotype on immunohistochemical staining and, in addition, produce urinary free monoclonal light chains (commonly termed Bence Jones proteins) of the dominant or isotype, usually excreting less than a gram of monoclonal protein per day.

When the amyloid-subunit proteins are submitted to amino acid–sequencing studies, the main constituent of AL deposits is the light-chain variable region and less frequently parts of the constant region or of the whole immunoglobulin. Why some immunoglobulin light chains form amyloid and others do not is unknown.

More than 50 monoclonal proteins have been isolated from the urine or tissue deposits of patients with AL amyloidosis. On the basis of clinical experience at several centers and the published sequences of AL amyloid proteins, the ratio of to light chains (1:3) is the reverse of that both in the normal state and in myeloma, in which the ratio is 3:2.

In addition, VI and I are the most common light-chain subgroups in patients with AL amyloidosis. Since VI light chains account for less than 5 percent of normal immunoglobulin but are found in a substantial fraction of AL amyloid proteins, the claim that all light chains in this subgroup are amyloidogenic has been made.21

The genetics of AL amyloidosis are currently being investigated. Among the known I light-chain amyloid sequences, a preponderance appear to be derived from one pair of variable region germ-line genes (O18–O8 and L18), suggesting that some germ-line genes or allelic variants may be more prone than others to mutations that give rise to amyloidogenic light chains.

In addition, the use of molecular genetics has enabled investigators to detect monoclonal cells containing the identical clonal immunoglobulin-gene rearrangement in the patient’s peripheral blood as found in his or her marrow plasma cells.

Pathogenesis

Only a small proportion of immunoglobulin light chains are amyloidogenic; for example, AL amyloidosis occurs in only 12 to 15 percent of patients with myeloma.

Certain structural features are related to amyloidogenicity: the isotype and the VVI variability subgroup (a homologous family of light-chain variable regions).

Two V gene segments — 6a and 3r — contribute equally to the encoding of 42 percent of amyloidogenic chains. The variable domains of light chains V(L), including the amyloidogenic chains, mutate during the immune response.

Some of these physiologic mutations can affect critical structural sites, destabilizing the domain and favoring the generation of an aggregation-prone state.

See also

- amyloidoses

  • familial amyloidosis

References

- Sanchorawala, V. (2006). Light-Chain (AL) Amyloidosis: Diagnosis and Treatment. CJASN 1: 1331-1341.