434 7e FORUM D ' IMMUNOLOGIE

can expect only the binding of complexed antibodies. Such an inter- action usually results in the shedding and/or endocytosis of the ligand- receptor complexes, and such receptor down-regulation can again render the t ransformants defenceless.

J. F. Marcelletti, P. del Guercio and D. H. Katz:

Perhaps one of the more intriguing notions to come out of this Forum, at least from our point of view, is tha t FeR (and IBF) which recognizes a particular isotype of Ig may not be composed of just a single or few discrete structures, but rather m a y exist as a mul t imember family of receptors. Certainly, this concept was a cornerstone for the working model for isotype-specific regulation of anti- body synthesis proposed by us, and we believe tha t sufficient experimental data exists to warrant its serious consideration. Moreover, similar views were expressed by Dafiron and Frid- man, as well as by Gergely el al. While the issue remains to be settled, the possibility tha t FcR and IBF may exhibit a finer specifci ty and broader repertoire than originally anticipated suggests a very interesting complexity for Fc-related immunoregulatory inter- actions.

The work described by MeGhee el al. and by K. Ishizaka regarding the functional capacity of FcR + T-cell clones clearly indicate tha t such cells can exhibit either isotype-speeifie enhancement or suppression depending upon the conditions of induction or analyses. While the generality of these results remains to be established, such results help to explain certain appa- rently conflicting observations. For example, Lynch and associates have established tha t mice bearing IgE- secreting cell lines exhibit large num- bers of FeRn+ T cells of the Lyt-2 + phenotype, and have suggested tha t such cells m a y be involved in suppres- sion of tha t isotype of antibody. We have established tha t Lyt-2 + T cells

(FcR~ +) can be induced to secrete a

~ otentiating IgE-binding factor. Per- aps this is another case of a multi-

functional cell exhibiting desperate activities depending upon environ- mental conditions.

Along these same lines is the notion tha t a given FcR + cell can regulate secretion of multiple isotypes of anti- body, and perhaps other immune functions as well. This seems some- what intuitive considering that a fair proportion of normal lymphocytes can express FcI~ for multiple isotypes of lg. However, the experimental work done with hybridoma lines such as T~D~ discussed by Adachi et al. add validity to such an idea. What now must be considered is the concept tha t a signal relevant to production of a particular isotype of Ig will not be delivered via an IBF which may bind to that class of antibody (e. ~j. IgE), but rather via an IBF specilic for yet another Ig isotype (e. ~q. IgM).

A comment is appropriate concern- ing the idea tha t the meaningful Fc-related processes which take place on the cell surface may involve multi- signal events rather than simple receptor-tigand binding. From a theo- retical point of view, this certainly could be the case in IBF-mediated regulation of cellular function as emphasized by R. Lynch as well as by ourselves. However, the ra ther remarkable experimental observations described by Gergely el al. and by Waldschmidt and Vitetta clearly indi- cate that multi-signal events may be the rule ra ther than the exception in immunoregulation involving the Fc portion of the lg molecule.

Finally, a general observation made by a large number of participants in this Forum is tha t a large variety of cells express FcR. Of course, it seems reasonable (from our slightly biased point of view) that lymphocytes should express such receptors. How- ever, why should such an array of non- immune cells also express these types of receptors ? We feel tha t the answer to this question may be tha t FcR are actually receptors for self. As pointed out by Da0ron and Fridmau, the concentrations of the various classes

REGULATORY FcR 435

of Ig are among the most stable para- meters in normal plasma. Immuno- globulin may well serve as an extre- mely stable self-reference point upon which an FcR + cell can gauge other cellular activities.

a. P. l~evillard:

The concept of isotypic network is now emerging from a patchwork of independent studies dealing with inter- actions between immunoglobulin heavy-chain isotypic determinants and a variety of stereospecific soluble or cell-surface-bound ligands. Most of the apparent heterogeneity of the data, and possibly some weakness in the hypotheses that can be put forward at present, rely on the fact tha t many of the ligands are still poorly characterized and merely defi- ned by their source and/or restricted isotypic specificity. Moreover, the bio- logical effects of those ligands are analysed in systems that involve complex cellular interactions, and very little is known of the possible outcome of in vivo administration of biological moieties tha t selectively alter the expression of Ig heavy chain genes in vitro.

There are still a great deal of struc- tural studies to be performed with the help of DNA recombinant technology applied to IgBF before any clinical evaluation of those products can be at tempted in diseases associated with selective Ig class or subclass deficiency or excess. Yet cellular pharmacology provides numerous examples of fami- lies of molecules with predictable bio- logical effects that were efficiently used a long time before their specific recep- tors had been fully characterized. In this respect, the immunoglobulin heavy chains offer the great advantage of being completely sequenced at the gene and at the protein levels. Hence, the use of synthetic peptides as second signals of polyclonal B-cell activation (Morgan el al.) 11] or as inhibitors of antibody-dependent cell cytotoxicity (Gergely et at., this Forum) could be

applied to other models of isotype- specific interactions. It may represent a straightforward approach in the ana- lysis of the structure-function rela- tionship of Fc determinants.

The simple model of an isotypic regulatory loop such as [Ig -~ expres- sion of FcR and release of IgBF -+ positive or negative effect on Ig production by B cells] is no longer acceptable in view of the complex cellular interactions so elegantly deci- phered by Ishizaka and coworkers and by Marcelletti el al. That compa- rable interactions may apply to iso- types other than IgE is suggested by at least two series of findings.

1) Induction of enhanced Fell expression upon incubation of peri- pheral blood lymphocytes with lgA or IgG, or with IgE as pointed out by Spiegelberg and Thompson, has not been regularly reproduced in several laboratories. Variables such as Ig concentration, degree of aggregation or polymerization, subclass distribu- tion, temperature and duration of exposure, etc., may be of critical importance, as shown by the demons- t rat ion that aggregated IgG or anti- gen/antibody complexes modulate F e b expression on B cells [21 or T cells [3, 4].

2) Some of the IgBF may bear at least two binding sites: one for iso- typic determinants of the Ig molecules and the other for an acceptor site on FcR-positive cells. This was postu- lated for IgEBF by Marcelletti el al. in the present Forum. It was consi- dered by Fridman el a!. that IgGBF might trigger an r off, signal on B cells by bridging together la determinants and surface Ig [5]. Moreover, we have shown that IgGBF purified by immu- noabsorption on IgG from cell-free supernatants of peripheral blood lym- phocytes could bind to about 60% of Fc-fB-positive but not to Fc-Aq- negative lymphocytes, as shown by the formation of passive erythrocyte- antibody rosettes 16].

Finally, as suggested by DaCron and Fridman, the isotypic regulatory network may represent an open and highly interconnected system. Only