N. R. StC. Sinclair

Fc-signalling in the modulation of immune responses by passive antibody.

Passive antibody can both suppress and augment immune responses. Until recently, there was virtual unanimity on the importance of the interaction of the Fc portion of modulating antibody with Fc‐receptors (Fc‐signalling), especially in experiments involving the suppression by antibody. Experiments reported in the last few years, that do not demonstrate the range of Fc‐portion/Fc‐receptor influences on the suppression of immune responses by passive antibody, have introduced new uncertainty into this field. The purpose of this paper is to review how the initial controversy on the influence of Fc‐signalling in inhibition by passive antibody was resolved. Old and new approaches are suggested that may help in resolving the current uncertainty engendered by recent experimental results that were interpreted to mean that passive suppressive antibody does not utilize the inhibitory FcγRIIB receptor. An understanding of the factors that influence negative Fc‐signalling is needed in order to optimize clinical therapies whose action depends on the suppressive property of antibody.

Co-stimulation and co-inhibition: equal partners in regulation.

Specific immune responses are controlled by two counterbalancing mechanisms—co‐stimulation and co‐inhibition. Antigen receptors determine specificity, activate co‐stimulation and/or co‐inhibition, and interact with these co‐stimulatory/co‐inhibitory mechanisms to dictate the direction of the immune response, either positive or negative. Co‐stimulatory or co‐inhibitory ligands interact with their specific receptors and may indicate the context in which antigen is perceived by lymphocytes. Ligation of antigen receptors may activate only co‐stimulatory or co‐inhibitory mechanisms, and thus may influence secondarily the direction of the immune response. Furthermore, the activity of a given co‐stimulator or co‐inhibitory receptor is modified depending on signalling via the antigen receptor. If neither co‐stimulators nor co‐inhibitors are present, lymphocytes, activated in response to antigen receptor signalling, produce low levels of effector elements and then revert to inactivity. Co‐inhibitors are defective in autoimmune disease.

The influence of T lymphocytes on antibody-induced B-cell suppression

IgG antibody complexxd with antigen can inhibit the B lymphocytes which produced the antibody. Helper T cells make factors which interfere with this feedback loop. Could the reversal by T-cell factors of the repressed stale induced in B cells by immune complexes be a physiological trigger of immunoglobulin production?

Clonalism - the Myth?

Two regulatory mechanisms, based on the contrasting concepts of imprinting (clonal theories and idiotypic networks) and of ongoing regulation of immune responses (by antigen and end products with specificity for antigen), give rise to different predictions and approaches to the question of autoimmunity and autoimmune disease. Both concepts have legitimacy, however, if a ranking in terms of explicative power must be given, ongoing regulation is more plausible since it accounts more fully for basic events in immune responses and in autoimmune phenomena. Many instructive findings have emerged from experiments based on this latter concept, furthermore, the approach has only received limited notice and, thus, has not yet been exhausted.

LYMPHOCYTE-DEPENDENT ANTIBODY AND RENAL GRAFT REJECTION

A patient with preformed cytotoxic lymphocyte-dependent antibody (L.D.A.) against the specific renal transplant donor rapidly rejected the grafted kidney. The characteristics of rejection were not those of hyperacute rejection due to cytotoxic complement-dependent antibody or of acute rejection is attributed to the cytotoxic activity of L.D.A. The avoidance of transplants based on positive crossmatches by the L.D.A. test or at least the carrying out of the L.D.A. crossmatch is advised.

Hypogammaglobulinaemia occurs in Fas-deficient MRL-lpr mice following deletion of MHC class II molecules

Fas (CD95)‐mediated apoptosis in B and T cells is deficient in both human autoimmune lymphoproliferative syndrome and in MRL‐lpr mice, a model for systemic lupus erythematosis (SLE). Autoimmune disease in these mice is associated with polyclonal B cell activation, increased serum immunoglobulin and autoantibodies. In non‐autoimmune mice MHC class II is not required for normal serum immunoglobulin expression, and previously we have shown using MHC class II‐deficient MRL‐lpr mice (MRL‐lpr Ab−/−) that generation of specific antibodies to DNA requires MHC class II‐directed T cell help. In contrast, in the present study we demonstrate that MRL‐lpr Ab−/−mice also have a profound reduction of total serum immunoglobulin levels, suggesting abnormal polyclonal regulation of B cells by MHC class II‐directed T cells occurs in the autoimmune MRL‐lpr strain. This abrogation of immunoglobulin production does not occur in MHC class II‐deficient non‐obese diabetic (NOD) mice, nor in MHC class I‐deficient NOD or MRL‐lpr mice. Reduced immunoglobulin levels in MRL‐lpr Ab−/− mice were not due to a lack of B cells or to an increased loss of circulating immunoglobulin, but were associated with reduced numbers of surface IgG‐positive B cells. These results define a general abnormal regulation of B cells in MRL‐lpr mice through a process requiring MHC class II, and suggest that Fas deficiency may allow expansion of totally T‐dependent B cells.

Cell-mediated cytotoxicity against syngeneic tumors

Abstract Spleen cells from DBA/2 mice bearing the DBA/2 P815X mastocytoma for approximately 2 weeks can be stimulated in vitro by mastocytoma cells to generate cytotoxicity measured as 51 Cr release from mastocytoma cells in a 4-hr assay. These cytotoxic cells will not kill allogeneic cell lines but will kill a series of first transplant generation syngeneic tumors. T cells are involved in that treatment of the responding or the cytotoxic cell populations with either anti-T or anti-theta antibody + complement will abrogate all cytotoxicity. Anti-Ly 2.1 antibody + complement treatment of either responder cells (prior to the in vitro culture with irradiated tumor cells) or effector cells after culture markedly decreases cytotoxicity whereas treatment with anti-Ly 1.1 was more effective prior to culture compared to its effect on cytotoxic cells per se. These T cells are in the small lymphocyte class and occur either singly or in aggregates. Suppression of antisyngeneic tumor cytotoxicity by antibody inhibits preferentially the expression of cytotoxicity in the aggregate fractions.

Reply: Some Afterthoughts – Pragmatic and Philosophical

Conditions under which one searches for Fc‐signalling determine the success in finding it. A major condition is that one must have enough T cells to drive a T‐cell‐dependent response, but not enough T‐cell activity to obscure the Fc‐signalling. Antigen‐masking and destructive phagocytosis of antigen occur. Under conditions and in areas of the body where T‐cell activities are limiting and Fc‐signalling can not be blocked, Fc‐signalling may be observed. The balance between costimulation and coinhibition is a major determinant in immune responsiveness, because costimulation and coinhibition interfere with each other.

IMMUNOSUPPRESSIVE FACTORS ASSOCIATED WITH TUMORS

Chemically-induced murine lymphomas often contain viral agents which are demonstrable by:- 1) the induction of tumors with acellular preparations derived from these lymphomas (1–7), 2) the virally-encoded antigens which are present on these lymphomas (8, 9), 3) the anti-viral antibodies which can be found in hosts bearing these lymphomas (9), and 4) the direct isolation from recently induced lymphomas of a virus which can be detected in tissue culture (10–12, B. Williams, personal communication and reported in 7). These viruses may be important in the initial induction of the lymphoma or may enter and be carried along as a passenger once the lymphomas have been established in the original host or as a transplant line. Using the well-established experience that virtually all murine lymphomas contain putatively oncogenic viruses, we successfully demonstrated an increased resistance to challenge by chemically-induced syngeneic lymphoma cells following immunization of the prospective hosts with an allogeneic tumor cell line which was induced by an oncogenic acellular preparation obtained from the original chemically-induced syngeneic lymphoma (13).

Can B‐Cell Signalling be Understood?

Hie therefore, Robin, overcast the night; The starry welkin cover thou anon With drooping fog as black as Acheron; And lead these testy rivals so astray, As one come not within anothers way. William Shakespeare, A Midsummer Nights Dream Act III, Scene II