216 . H.-M. Schneider

inent factor; moreover their tendency to polymerize and their possible glycosylation might play a significant role with respect to the mechanism of tissue deposition. Why light chain fragments deposit in a granular electron-dense form as described in L.C.D.D., or form fibrils showing the characteristic spatial configuration of amyloid, remains unknown. One wonders if it is the aminoacid sequence of the light chain or the tissue factors that determines the type of deposition. As far as our case is concerned, it should be stressed that the two kinds of deposits can be associated in the same location, i.e. the media of small vessels.

AI amyloidosis and systemic light chain deposition dis­ease have been described in lymphoplasmacytic disorders, notably in multiple myeloma. In this case, there were no symptom of overt myeloma: however the patient's serum contained free kappa chains and the bone marrow sBowed predominantly kappa-containing plasma cells. This situa­tion is known in the so-called "light-chain" myeloma in

Received November 29, 1983 . Accepted September 10, 1984

which the prevalence of amyloidosis exceeds that m myeloma in general.

References 1 Gavenal 0, Noel LH, Droz 0, Leibowitch J (1980) Systemic

light chain deposition disease developing in the course of the lambda light chain myeloma. Brit Med J 282: 681-683

2 Glenner GG (1980) Amyloid deposits and amyloidosis. The ~ fibrilloses I. N Engl J Med 302: 1283-1292

3 Glenner GG (1980) Amyloid deposits and amyloidosis. The ~ fibrilloses II. N Engl J Med 302: 1333-1343

.. Preud'Homme JL, Morell-Maroger LM, Brouet JC, Cerf M, Mignon F, Guglielmi P, Seligmann M (1980) Synthesis of abnor­mal immunoglobulins in lymphoplasmocytic disorders with vis­cerallight chain deposition. Am J Med 69: 703-710

5 Randall RE, Williamson WC, Mullinax F, Tung MA, Still WJS (1976) Manifestations of light chain deposition. Am J Med 60:293-299

6 Shirah ana T, Benson MD, Cohen AS, Tamaka A (1973) Fibrillar assemblage of variable segments of immunoglobulin light chains. J ImmunolllO: 21-30

Key words: Multiple myeloma - Light chain deposition - Amyloidosis

Prof. J. P. Camilleri, Service d'Anatomie et de Cytologie Pathologiques, Hopital Broussais, 96, rue Didot, 75674 Paris Cedex 14, France

Letters to the Case

H.-M. Schneider Karlsruhe

Plasma cellular disorders, the so called plasma cell dys­crasias2

, may result in morbid manifestations by produc­ing increased and/or atypical immunoglobulins as well as by generalized amyloid deposits in the various organs. While this condition has been well known in the case of plasmocytomas, Glenner (1971) was the first able to dem­onstrate the relationship between irregular immunoglobu­lin production and amyloid deposits, which then led to the term light chain amyloidosis or AL amyloidosis.

This paper by Hofmann-Guilaine et al. deals with three of these essential factors. The case described presented with 1. a plasma cell dyscrasia of the light chain type without

demonstrable myeloma

2. granular light chain deposits at tubular and glomerular basement membranes and

3. amyloid deposits without demonstrable light chains in vessel walls.

As pointed out by the authors, obviously there is a direct relationship between the plasma cellular disorder, in­creased production of light chains and the amyloid deposits, although light chain deposits without amyloid as well as amyloid without light chains are found. Studies of the type and localization principles of the amyloidosis offer the following possible explanations regarding the presence of these constellations: 1. In plasma cellular disorders quite different fractions of

immunoglobulins may be observed, depending on the

type. For instance, immunoelectrophoresis has iden­tified complete M, A-type immunoglobulins while light chains have been found as Bence-Jones proteins (molecular weight 24,000-28,000) in the tubuli and, as described above, as granular deposits. But further­more, in quite a large percentage of all plasma cell dyscrasias light chain fragments (molecular weight 8,000-12,000) are observed which cannot be iden­tified in most cases because of their size, but which play a role of vital importance in the pathogenesis of amy­loidosis. It should be noted that the immunohistochem­ical demonstration of these fragments is possible only under special conditions since they do not carry the antigenic determinants necessary for normal antibody formation. As far as I know it is still unclear if the light chain fragments are produced by the disintegration of the immunoglobulins or of the light chains or if they are formed directly by the plasma cells as abortive types.

2. Initially the formal amyloidogenesis, i.e. the formation of fibrils with the ~-pleated sheet conformation, does not depend on the type of protein but the molecular weight of the amyloidogenic proteins3

• Only thus it is possible for quite different endogenic proteins, e.g. AA­protein, hormones, neurogenic products etc. as well proteins added iatrogenically4, to be included in the formation of amyloid. For the analysis of the present studies this fact is of particular importance, since due to their molecular weight only the light chain frag­ments may be amyloidogenic while the light chain pro­teins themselves do not enter into the formation of amyloid because of their comparatively large molecu­lar weight. This explanation is born out quite nicely by the immunohistochemical identification of light chains and the simultaneous lack of amyloid.

Letter to the Case . 217

3. The local factor is another essential component of the amyloidogenesis. The fibrillar ~-pleated sheet confor­mation can be produced only at certain structures of the organism. Here the myocytic basement membrane plays the vital role, probably in conjuction with the amyloid-P-component3

,5, while the type of amyloid protein does not matter. This then explains the findings of the present study that amyloid was found only around myocytic regions of the vessel walls and not along the tubular basement membranes, although here too, amyloidogenic proteins of the light chain fragment type are quite probably present - but cannot be detected due to their missing antigen determinants.

The findings of this study by Hofmann-Guilaine et al. thus confirm quite impressively our concept of the pathogenesis of amyloidosis, i.e. amyloid fibrils can be formed only by proteins of a particular molecular weight in conjunction with the local factor - the myocytic base­ment membrane.

References

1 Glenner GG (1971) Creation of "Amyloid" fibrils from Bence Jones proteins in vitro. Science 174: 712-714

2 Osserman EF (1961) The plasmocytic dyscrasias. Plasma cell myeloma and primary macroglobulinemia. Amer J Med 31: 671-675

3 Schneider H-M, Thoenes W (1982) Neue Aspekte der Amy­loidose. Klinische Wochenschrift 60: 583-592

4 Stoerkel et al (1983) Brief Communication. Iatrogenic, Insu­lin-Dependent, Local Amyloidosis. Laboratory Investigation

5 Stoerkel et al (1983) Manifestation and ultrastructural typ­ing of amyloid deposits in the heart. Virchows Archiv 401: 185-201

Privatdozent Dr. H.-M. Schneider, Direktor am Institut £iir Pathologie, St.-Vincentius Krankenhauser, Siidenstr. 37, Postfach 6604, 7500 Karlsruhe, FRG

Pathogenicity of Immunoglobulin Variable Regions: "V-Region Diseases"

Reinhold P. Linke Miinchen

1. Immunoglobulin-variable regions can be pathogenic. The idea that heavy chains, when not completed with light chains, are toxic to cells stems from observations on cell lines and B-cell neoplasias. Secretion of free heavy chains is observed only when the variable region is deleted1,4.

By contrast, free light chains are less harmful: light­chain secreting cell lines and myelomas or lymphomas are well known. The appearance of free light chains, however, is related to clinical complicationslO, some associated with amyloidosis3 and some with systemic light-chain depositsll.