Yves Borel

Autoantibody to an Immunoregulatory Inducer Population in Patients with Juvenile Rheumatoid Arthritis

The human inducer (T4(+)) and reciprocal cytotoxic/suppressor (T5(+)/T8(+)) subsets have been defined by monoclonal antibodies. In the present study, we examined the relationship of naturally occurring anti-T cell autoantibodies found in patients with active juvenile rheumatoid arthritis (JRA) to these subsets. In one approach, normal T cells were treated with anti-T4 or anti-T8 to eliminate the corresponding subset of cells and then analyzed for reactivity with JRA sera. It was found that JRA sera were reactive with only 15% of an enriched cytotoxic/suppressor population, whereas they reacted with 37% of an enriched inducer population. In reciprocal studies, JRA(+) T cells were eliminated with JRA sera and complement and the residual T cells (JRA(-)) reacted with monoclonal antibodies and indirect immunofluorescence on a fluorescence-activated cell sorter. As expected, the JRA sera and complement treatment of unfractionated T cells markedly diminished the T4(+) subset, whereas there was a concomitant increase in T cells reactive with anti-T5 and anti-T8. A similar diminution in T4(+) T cells was found in the circulating peripheral T cell compartment of patients with active JRA who possessed the JRA antibody. Functional studies demonstrated that removal of the JRA(+) population of T cells diminished phytohemagglutinin and soluble antigen proliferative responses, both of which were previously shown to be functions of T4(+) T cells. More importantly, in the absence of JRA(+) T cells, pokeweed mitogen-stimulated immunoglobulin production was markedly enhanced, despite the concomitant increase in T5(+)/T8(+) cytotoxic/suppressor cells. These results suggest that the JRA serum may define a Qal-like antigen found predominantly on the human inducer population which could activate suppressor and/or other feedback regulatory cells.

Systemic lupus erythematosus in childhood: Clinical manifestations and improved survival in fifty-five patients☆

A retrospective review of 55 patients with systemic lupus erythematosus (SLE) (45 girls and 10 boys) under age 18 (median age of onset; 12.2 years) seen at the Childrens Hospital Medical Center (Boston, Mass.) over the past 20 years was done. Clinical presentation was similar to previous series, but atypical presentation was common. Certain unusual presentations (such as isolated hematopoietic abnormalities) often occurred and delayed diagnosis for years in some cases. The frequency of ARA clinical classification of SLE was different in children as compared to adults. We observed depression of lymphocyte count in many patients and encountered elevations of hepatic enzyme levels in others. Of the 55 patients reviewed, 9 have died and 8 have been lost to follow-up. Of the rest, 21 have mild to moderate disease and 17 have inactive or minimally active SLE, after a median length of follow-up of 8.8 years. In severe cases, using either corticosteroids and/or cytotoxic agents, a favorable prognosis was obtained. Our cumulative 5- and 10-year survival of 92 and 85%, respectively, equals or exceeds that of previous reports of childhood SLE.

Haptens Bound to Self IgG Induce Immunologic Tolerance, While When Coupled to Syngeneic Spleen Cells They Induce Immune Suppression

the four nucleosides adenosine, guanosine, cytosine, and thymine riboside adenosine, guanosine, cytosine and thymine riboside linked to keyiiole limpet haemocyanin (NZBXNZW)Fi dinilrophenyl dinitrcphenyl linked to keyhole limpet haemocyanin dinitrophenyi linked to mouse gammaglobulin guanosine guanosine linked to IgGja guanosine linked to keyhole limpet haemocyanin human gammaglobulin keyhole limpet haemocyanin 7-methylguanosine 7-meihylguanosine linked to keyhole limpet haemocyanin plaque forming cell<s) sheep red biood cells T cell dependent T cell independent

Treatment of lupus nephritis in adult (NZB + NZW)F1 mice by cortisone-facilitated tolerance to nucleic acid antigens.

Adult female (NZB + NZW)F1 mice were treated with cortisone, cortisone with tolerogen (isologous NZB IgG-nucleosides conjugates) or cortisone with isologous IgG free of nucleosides. Other treatments also included tolerogen or isologous IgG alone, and cortisone together with denatured DNA. All untreated mice died by 10 mo of age. Cortisone prolonged the survival rate. This effect was further improved by combined treatment of cortisone and tolerogen. Prolonged survival was accompanied by a decrease in proteinuria. Other treatments failed to influence either survival or proteinuria. Although cortisone did not prevent the appearance of antibody to denatured DNA, cortisone and tolerogen suppressed them in most of the animals. Preexisting antibody to denatured DNA was reduced by cortisone and cortisone and tolerogen, but not by cortisone and IgG. In contrast, antibody to native DNA bore no relationship to therapy. Animals living beyond 1 yr of age, regardless of the treatment, fall into three histopathological categories: (a) severe nephritis, as in untreated animals, (b) moderate nephritis (with absence of severe alteration of the glomerular basement membrane, i.e. the histological counterpart of prolonged survival), (c) minimal nephritis. In a small number of animals treated with cortisone or cortisone and IgG and in 6/20 animals treated with cortisone and tolerogen, minimal lesions as judged by light, fluorescent, and electron microscopy were found. These last mice were in good health at 15-16 mo of age, twice the life-span of untreated mice. In conclusion, these data suggest that tolerance to nucleic acid antigens facilitated by cortisone offers a promising new approach to treat established murine lupus nephritis.

A novel technique to link either proteins or peptides to gammaglobulin to construct tolerogens.

In order to extend the concept of constructing tolerogens (i.e., compounds which induce immunologic tolerance), we developed a novel method to covalently link either protein or peptide to isologous gammaglobulin. We used disuccinimidyl suberate (DSS) for preparing protein conjugates in solution in a novel use of this reagent. We tested the efficacy of this method in two different experimental models: in the first, we found that administration of pigeon cytochrome C conjugated to mouse IgG in vivo induces T cell unresponsiveness in vitro. In the second, we induced unresponsiveness to factor VIII light chain both in newborn and, more importantly, in adult mice already immune to factor VIII. We hope that this simple method will provide a powerful tool to construct tolerogens useful in the specific treatment of either allergic or autoimmune diseases.

In vitro nucleoside specific immune response by lymphocytes from systemic lupus erythematosus.

The in vitro immune response of systemic lupus erythematosus (SLE) lymphocytes to nucleosides conjugated to keyhole limpet hemocyanin (KLH) (A,G,C,T-KLH) was investigated. The nucleosides were chosen not only because they are a part of nucleic acid antigen and involved in autoimmunity, but also because nucleoside covalently bound to either soluble IgG or cells had been shown to induce unresponsiveness in mice. A significant proliferation index was induced in SLE lymphocytes, as compared with normal or rheumatoid arthritis (RA) lymphocytes in vitro [in (A,G,C,T)-KLH, 1 microgram/ml; stimulation index = M +/- SE, SLE 2.10 +/- 0.26, RA 1.06 +/- 0.14, normal 1.12 +/- 0.12 P less than 0.05]. Lymphocytes from SLE patients responded specifically to low doses of (A,G,C,T)-KLH and not to the protein carrier KLH alone. A solid-phase radioimmunoassay was developed to detect nucleoside-specific antibody. SLE lymphocytes spontaneously produced high levels of anti-A,G,C,T antibody. This was further increased by antigenic stimulation, but not with pokeweed mitogen (PWM) stimulation. In contrast normal lymphocytes failed to produce anti-A,G,C,T antibody either spontaneously or in response to antigen. However, normal lymphocytes produced antibody after stimulation with PWM. More importantly, anti-A,G,C,T antibody production by SLE lymphocytes was suppressed by preincubation with A,G,C,T-IgG (A,G,C,T-HGG). The antigen-specific unresponsiveness caused by A,G,C,T-HGG was demonstrated by the observation that preincubation with A,G,C,T-HGG did not affect the production of anti-dinitrophenyl antibody response. The ability to manipulate the altered response of SLE lymphocytes to nucleic acid antigens may have therapeutic implications in these patients.

Isologous IgG‐Induced Immunologic Tolerance to Haptens: A Model of Self Versus Non‐Self Recognition

An important function of the immune system is to tolerate self. A sideline of this central role is the defense against foreign antigens. How the body discriminates self from non-self is perhaps one of the most significant biological mechanisms in the life cycle, since if it did not exist, we would be destroyed in utero by an immune response to our own antigens. Whatever this mechanism, it is intimately related to the phenomenon of immunologic tolerance. In this review, the problem of self versus non-self discrimination to simple haptens using the model of carrier-determined tolerance will be reviewed. The system is unique for two reasons: the hapten by itself is neither immunogenic nor tolerogenic; the carrier protein to which the hapten is covalently bound, as tolerance-inducing carrier, is a physiologic protein naturally tolerated by the host. Discussion will be limited to work from the authors laboratory or that done in direct collaboration with others. The main theme of this review is to show how the induction of tolerance to haptens is a simple but powerful tool to examine two fundamental problems: the cellular basis of tolerance and the potential clinical application of tolerance to the treatment of immune disease.

Conjugation of DNA fragments to protein carriers by glutaraldehyde: Immunogenicity of oligonucleotide-hemocyanin conjugates☆

The practical realization of the concept of specific immunotherapy for systemic lupus erythematosus (SLE) has been hampered, thus far, by an inability to link DNA fragments to carrier protein. In this paper, a novel technique is described, in which glutaraldehyde is the linking agent. A 2-stage method was used to link oligonucleotides to a soluble protein carrier, such as keyhole limpet hemocyanin (KLH) or human gamma globulin (HGG), whereas a 1-stage technique was sufficient to link oligonucleotides to sheep red cells. Both the ultraviolet absorbance spectrum and diphenylamine assay demonstrated that oligonucleotides were coupled to soluble protein. The conjugate of oligonucleotide to protein carrier appears to be recognized by anti-DNA antibody since oligonucleotide linked to either KLH or HGG inhibited the binding of anti-DNA antibody in vitro, and oligonucleotide-coupled sheep cells are agglutinating by seropositve sera from lupus patients. In addition, oligonucleotide-KLH raised hemagglutinating antibody to denatured DNA in C57BL/6, DBA/2 or NZB mice, as well as IgG antibody as detected by SPRIA in C57BL/6 and DBA/2 mice. The significance of this new method for the development of an antigen specific therapy of SLE is discussed.

Different effects of cortisone on the humoral immune response to T-dependent and T-independent antigens

Abstract The effect of the administration of cortisone on the murine humoral immune response to either thymus-dependent (TD) or -independent (TI) antigens was studied in vivo . Whereas the thymus-dependent immune response was markedly suppressed, the thymus-independent immune response was preserved. The opposing effect of steroids on these two types of immune responses appears to be due to the relative independence of thymus-independent antigens of a radioresistant cortisone-sensitive accessory cell.

Functional characteristics of human T-lymphocyte subsets identified by sera from patients with systemic lupus erythematosus.

Abstract The sera from some patients with SLE can be used to identify and isolate two distinct subsets of normal human T cells. These subsets are designated SLE+ (those which react with anti-T-cell antibodies from these sera) and SLE− (those unreactive with SLE sera). SLE+ T cells enhance the secretion of immunoglobulin by B cells, proliferate poorly to PHA, Con A, soluble antigens, and allogeneic cells. The SLE− subset, in contrast, responds as well as or better than the total T-cell population in proliferative assays but will not enhance the secretion of Ig by B cells. Furthermore, the subset of T cells identified by SLE sera (SLE+) is not identical to that identified with sera from patients with juvenile rheumatoid arthritis (JRA).