Absence of demonstrable suppressor cell activity in a severe combined immunodeficiency patient with a sustained engraftment of DR-positive maternal T cells.
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Biomedical subjects
Publications and source records attributed to B Dupont.
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Classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21-OH-def) has been established to be an HLA-linked, recessive monogenetic disease. However, two nonclassical forms of 21-OH-def have also been described: "cryptic" 21-OH-def, which has been shown to be HLA-linked, and "late onset" 21-OH-def, for which the status of linkage to HLA has been less certain. We now describe studies of eight additional unrelated probands with symptomatic, "late onset" 21-OH-def, and conclude that this form is also HLA-linked. Both "late onset" and "cryptic" 21-OH-def are highly associated with the same HLA antigens and markers (HLA-B14, HLA-DR1, and Bf type S) in individuals from different ethnic and geographical backgrounds. Since both "late onset" and "cryptic" 21-OH-def appear to occur in individuals with one classical 21-OH-def (21-OHCAH) allele who in addition have another 21-OH-def allele, as well as in individuals who appear to be homozygous for variant 21-PH-def alleles, and since both late onset and cryptic 21-OH-def appear to occur in the same families, our data suggest that these syndromes may represent different clinical expressions of similar or identical nonclassical 21-OH-def alleles.
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Human lymphocytes precultured for 24--48 hr form more T-lymphoid colonies (LT-CFU) in agar than do fresh cells. It appears that during the preculture period lymphocytes proceed from G0 to the next S phase, a process that is dependent upon active cellular metabolism. Thus, lymphoproliferation as assayed by LT-CFU growth appears to be controlled by short-lived suppressor cells (SLSC) which may be similar to those described for blastogenesis evaluated by thymidine incorporation assay. The activity of SLSC operating in LT-CFU system may be controlled by prostaglandins.
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Two large groups of bone and joint mycoses should be recognised: fungal osteoarthritis due to blood spread and osteoarthritis due to traumatic inoculation. The authors report data in the literature and the experience of the Mycology unit of the Pasteur Institute. In the first group, one may recognise a category of cosmopolitan, opportunist fungi (Candida, cryptococcus) becoming grafted on a background of iatrogenic factors, in particular, Candida albicans arthritis of the newborn (2 new cases have been added to 12 already described in the literature) and osteoarthritis (17 cases) and candida spondylodiscitis (1 recent case out of 8 described in the literature). Out of 39 cases of cryptococcosis at various levels, in 7 cases we observed bony localisations in recent years. Another category consisted of mycoses due to dimorphic exotic fungi in the first place, african histoplasmosis due to H. Duboisii (73 cases of osteitis out of 179). The group of osteoarthritis by traumatic inoculation consists mainly of fungal mycetomas and actinomycoses, occasionally sporotrichosis; recently we have observed for the first time in the literature an arthritis due to a black fungus similar to Beauveria sp. The immunological reactions (immunoelectrophoresis) may be useful for the diagnosis and assessment of the efficacy of treatment. Present treatment is based on the routine use of antifungal agents: e.g. amphotericin B, 5-fluorocytosine, imidazole derivatives (Ketoconazole) according to the sensitivity of the fungi.
In two patients suffering from chronic neurobrucellosis with negative Wright's reaction the diagnosis could be made by other serological methods: complement fixation, demonstration of blocking antibodies by indirect immunofluorescence or Coombs'test. The therapeutic problems raised by chronic neurobrucellosis are discussed.
Human peripheral blood lymphocytes are activated to proliferate and form colonies in semisolid agarose after only brief exposure (24 h) to allogeneic lymphocytes in liquid culture. Colony development is independent of cell contact and exogenously supplied growth factors. The colonies are composed of T cells which form E rosettes with sheep erythrocytes and do not express surface immunoglobulin. Pooled colonies derived from 24-h allogeneic stimulation of HLA-D homozygous typing cells (HTC) express the appropriate HLA-D-associated DR antigens, as measured by complement-mediated cytotoxicity and by the reactivity of anti-DRw alloantisera after absorption with HLA-D homozygous B lymphoid cell lines. Some of the antisera give extra reactions with HTC colony cells that have not been previously detected on B lymphoid cell lines and purified peripheral B and T cell populations, suggesting that these sera may also contain antibodies against antigens expressed only on alloactivated T lymphocytes. Single colonies removed from agarose undergo extensive proliferation (20-30 generations) in liquid culture with the aid of T cell growth factor provided by conditioned medium. The majority of these T lymphocyte "clones" tested display specific cytolytic effector function, indicating that within 24 h of exposure to alloantigen, responder lymphocytes that subsequently form colonies in agarose are committed to antigen-specific cytotoxic activity; memory for the priming alloantigens is retained after months of culture with reexposure to antigen. This is the first demonstration that primary alloreactive clones of human T lymphocytes express HLA-DRw antigens and are capable of antigen-specific cytotoxic function.
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Clinical histocompatibility testing has now developed to a stage where it is possible to select related bone marrow donors for some patients, when HLA genotypically identical siblings are not available. The most common type of such donors are the HLA phenotypically or HLA-D phenotypically identical related donors. The HLA-D homozygous recipient offers special options, since these patients can potentially receive bone marrow transplants from any of the parents or from HLA-haploidentical siblings. The studies in SCID have demonstrated that HLA-D compatibility in spite of HLA-A or B incompatibilities can be tolerated and there is now accumulating evidence that even patients with aplastic anemia or acute leukemia can be successfully treated with such bone marrow grafts.
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The genetic polymorphism of the fourth component of human complement, C4, was studied in 945 unrelated Caucasian individuals. A third allele of the C4F (Rodgers) locus, termed C4F1 was demonstrated. This allele is characterized using immunofixation electrophoresis, by the presence of an additional fast-moving anodal band of C4 which distinguishes it clearly from the common C4F variant. The allelic frequencies fit the Hardy-Weinberg equilibrium assuming three alleles at the C4F locus: C4F, C4Fo, and C4F1. The functional activity of the C4F variants was investigated using a specific hemolytic overlay technique for C4. It was found that in almost all individuals (75 out of 78), the C4F1 allele codes for a functionally inactive C4 product only when it occurs on an HLA-B17 positive haplotype but that the same allele codes for a functionally active fast variant of C4 when it occurs on an HLS-B37 positive haplotype (18 out of 18). Very strong genetic linkage disequilibrium was observed for the C4F1 allele with HLA-B17 and B37. The active and inactive C4F1 variant also has marked nonrandom gametic association to different alleles of the Bf locus and to HLA-C locus determinants. No further variants of the C4S (Chido) locus have been identified so far. Rodgers (Rg) typing by the plasma inhibition test of anti-Rg antiserum has shown that plasma from individuals homozygous for the C4F1 allele is only able to partially inhibit anti-Rg whereas all C4F positive individuals totally inhibited the reaction.
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Two hundred and three sera obtained from multiparous women were screened to determine the frequency of the appearance of antibodies reactive with PHA-activated T lymphocytes, but not with resting B or T cells from the same donor. The panel of cells on which the sera were tested consisted of lymphocytes from 38 unrelated donors known to be homozygous at the HLA-D locus. Forty-two sera were shown to react uniquely with PHA-activated T cells. The reactivities of these sera could not be explained in terms of the defined HLA-A,-B,-C, or DR antigen specificities on the panel cells, nor on the basis of known cross-reactivities among these antigens. Most of the antisera showed strong cytotoxicity with the activated T cells. Such sera may define antigens presented to the maternal immune system during differentiation and development, which are not expressed on adult T cells unless they are activated.
The association between HLA and disease has a sound experimental foundation. Currently HLA has been implicated in the natural history of numerous diseases of varied pathogeneses. Efforts nor are being directed toward characterizations of the actual loci involved, but this is proving to be difficult because more than one and probably all the described mechanisms are playing a role. Nonetheless HLA appears to be a unique region for such analysis because it is highly polymorphic, which means that a gene and its linkage group may be traced not only through a family but also through a population and even a geographic region. In addition, the HLA region is a natural focus for the discovery of regulatory genes with one gene facilitating the discovery of the next. The identification of subsets and genetic antigenic polymorphisms expressed on these cells constitutes the best approach to the study of immune regulation and noseology today.
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