|[Frontiers in Bioscience 1, a46-58, August 16, 1996]|
A STUDY OF THE INTERACTIONS OF AN IMMUNOGLOBULIN LIGHT CHAIN
WITH ARTIFICIAL AND B-LYMPHOCYTE MEMBRANES.
Jonathan S. Wall1, Fayad M. Ayoub2, and Paul S. O'Shea
1 Human Immunology & Cancer Program, University of Tennessee
Medical Center at Knoxville, 1924 Alcoa Highway, Knoxville, TN
2 Department of Biological & Chemical Sciences,
University of Essex, Colchester, Essex, England U.K.
2 Department of Biological & Chemical Sciences, University of Essex, Colchester, Essex, England U.K.
Received 01/11/96; Accepted 05/29/96; On-line 08/16/96
It is well known that the light chain components of human immunoglobulins may become a pathogenic agent in immuno-proliferative disorders such as multiple myeloma (1, 2). The overproduction of monoclonal IgLCs may induce many clinical complications (3) which include systemic deposition of amyloid cast formation especially in the kidneys (4, 5, 6, 7), an elevated erythrocyte sedimentation rate and serum viscosity (8) and in some cases a generalised immunosuppression (9, 10). The mechanisms which give rise to these effects are uncharacterised, and the possibility of a specific "ligand-receptor" type interaction also remains to be identified.
It has been demonstrated that the properties of free IgLCs, include possible protease activity similar to that of serine proteases (11, 12); the ability to activate the complement cascade via the alternative pathway (13); to bind chemotactic factors (14) and opioid peptides (15); antigen binding activity in the monomeric form (16, 17) as well as species and antigen cross reactivity (18). Perhaps the most important, potential of IgLCs is to modulate the immune system by functioning as an anti-idiotypic antibody (19), or possibly by induction of natural immuno-suppressive agents.
All these studies reaffirm the importance of the interactions of IgLCs, and imply that monomeric forms of IgLCs can act in a specific or multi-reactive manner. Presumably this occurs by the high-affinity associations which involve residues in the three complementarity-determining domains in the variable region of the IgLC. In this respect, the reactivity of monomeric IgLCs is unexpected. On the other hand, a far more favourable situation can be envisaged with the dimeric forms, which have been shown by X-ray crystallography to resemble the Fab region of whole Igs. In such a configuration, the two variable regions associate to form a pseudo-antigen binding cleft (20).
An excess of monoclonal IgLCs associated with multiple myeloma has been found to affect the immuno-competency of patients, many of whom develop systemic immuno-suppression (9, 10). This was investigated by Wearne and co-workers (21, 22, 23, 24), who expounded the phenomenon as Light Chain Isotype Suppression (LCIS), due to the specific suppression of normal Igs containing the light chain of the same isotype as the paraprotein. This interesting suggestion was criticised by King et al (25) who in a study of 25 multiple myeloma patients found no evidence of LCIS. However, in light of the data presented in recent reports (16, 17, 18, 19), the possibility exists that IgLCs may contribute to an immuno-suppressive mechanism. The means by which this may be achieved may include: suppression mediated via an anti-idiotypic network; by displaying specificity to, and thereby inactivation of a membrane antigen involved in lymphocyte proliferation, differentiation or Ig synthesis; or by inducing the production of natural immuno-suppressive cytokines, by an as yet unspecified mechanism.
The immuno-suppressive effects of IgLCs, by virtue of induction of suppressive cytokines, may be related to the immuno-modulatory properties of intravenous immunoglobulin (IvIg), (26). These studies demonstrated a decrease in all lymphocyte subsets and a 41% decrease in the total peripheral blood lymphocyte count. The mode of action of this treatment is still unknown and is undergoing investigation. Ling et al (27), have assessed the effects of IvIg treatment on interferon gamma and interleukin-6 in patients with secondary generalised epilepsy, and have shown a rapid increase in the plasma concentrations of both cytokines. The induction of these two proteins may be an important factor. It has been demonstrated that interferon gamma causes a down regulation of interleukin-6 receptors on human B-lymphocytes (28, 29) and in synergy with interleukin-7 (which is abundant in the bone marrow stem-cell environment), arrests proliferation and differentiation of murine pre-B cell lines and induces apoptosis in these cells (30).
The interactions of IgLCs with a membrane surface has received little attention. A low-affinity, high capacity, receptor for IgLCs has been demonstrated in the rat and human renal proximal tubular brush-border cells (31, 32). This receptor however, is thought to be an endocytic scavenger involved in the resorption and catabolism of free light chains and small molecular weight proteins (31, 33). The possibility that a membrane-IgLC interaction can occur in the absence of a classical proteinacious receptor has, until now, not been considered. In light of the multi-functional potential of IgLCs, in this report we examined the biochemical aspects of interactions of these molecules.