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Defective T cell activation has been recognized in a number of patients with primary immunodeficiencies (ID). A distal defect resulting in abnormal production of IL2, IL3, IL4 and IFN gamma was found to be associated with reduced binding of the NF-AT transcription factor to the promoters of the genes coding for these lymphokines. Defect in early steps of T cell activation have been described in primary IDs, consisting in defective calcium flux and phosphoinositides turnover following TCR/CD3 ligation. We herein report a primary ID found in a 13 year old girl. It consists in a partially defective T cell proliferation which could be related to a defective Tyrosine phosphorylation.

A technique not involving surgery is described for obtaining axenic (germ-free) newborn animals and human infants by decontamination immediately after birth. Three steps are involved: cleansing the perineal region of the mother with an iodinated bactericidal solution, washing the newborn with the same solution, and after the newborn has been placed in a sterile isolator, administering a single oral dose of an antibiotic mixture previously determined to be active against the fecal and vaginal flora of the mother. All of the newborn obtained by means of this technique, including 13 piglets, 2 lambs, and 4 human infants, were found to be axenic throughout their stay in the isolators. Four piglets obtained by the same technique, but without administration of antibiotic mixture, were found not to be axenic.This technique, as compared with methods of surgical delivery of axenic young, embodies a number of advantages. It is harmless to the mother and to the newborn, it is relatively inexpensive, and it obviates the risk of prematurity involved in elective surgical delivery before term.

Although an excess of human adult blood adherent cells inhibits the pokeweed mitogen- (PWM) induced normal adult lymphocyte proliferation and B cell maturation into immunoglobulin-containing cells (ICC), adherent cells collected from newborn infants or pregnant women at time of delivery were unable to exert a similar suppressor activity. After activation by Concanavalin A (Con A), newborns' and pregnant women's adherent cells acquired a suppressor activity comparable to that of control adult adherent cells. The adherent suppressor cell was shown to be radioresistant (3000 rad), indicating its probable monocytic origin. Both monocyte-suppressor activities (MSA) observed in adulthood (spontaneously) and in the neonatal period (after activation) were dependent on prostaglandin E2 (PGE2) secretion, because they were abolished by indomethacin or a specific anti-PGE2 antiserum. Expression of MSA appeared to be under a negative regulation exerted by naturally occurring T suppressor lymphocytes present in the blood of newborns or pregnant women, because incubation of adult monocytes or Con A-activated newborn monocytes with newborns' or pregnant women's T lymphocytes resulted in a dramatic decrease of their MSA. These results strongly suggest that the lack of MSA in the neonatal period and in late pregnancy is a consequence of activation of T suppressor lymphocytes.

Severe combined immunodeficiency was diagnosed soon after birth in an infant with a well documented familial history of recessive autosomal inheritance. No thymic shadow was detectable and the number of circulating lymphocytes was decreased. Both humoral and cell-mediated immunity were severely impaired. Despite the absence of in vitro response to stimulation by phytohaemagglutinin, the circulating lymphocytes responded normally to allogeneic cells in the mixed leucocyte culture reaction. In addition, the vast majority of the blood lymphocytes were B lymphocytes bearing membrane-bound immunoglobulins which were shown to be actual cell products. A foetal thymus graft was performed at the age of 1 month and was not followed by any improvement of the immunological parameters. The transplantation of unfractionated bone marrow cells from an HLA identical brother with negative reactions in mixed lymphocyte culture was performed 1 month later and resulted in a gradual restoration of immunological competence for both B-cell and T-cell functions. High numbers of circulating B lymphocytes persisted for several months after immunological reconstitution. These unusual findings argue against the hypothesis of a stem cell defect in the presently described variant and suggest that severe combined immunodeficiencies may represent a heterogeneous group of diseases with regard to the level of the basic defect.

Epstein-Barr (EB) virus serology was correlated with the results of immunological investigations of three inherited immunodeficiency diseases, in an attempt to understand the immune mechanisms controlling EB virus infection. In nine patients with Wiskott-Aldrich syndrome (WAS), the constant lack of anti-EB virus associated nuclear antigen (EBNA) was accompanied by a consistent impairment of allogeneic cytotoxicity. We confirmed a frequent absence of anti-EBNA antibody in ataxia telangiectasia (AT), and we showed a correlation between the level of anti-EBNA response and the mixed leucocyte response (MLR), i.e., an absence of anti-EBNA antibody correlated with a decreased MLR. In two of three untreated patients with Chediak-Higashi syndrome (CHS), high persistent titres of anti-EA antibodies were observed, which were possibly related to a defective natural killer (NK) cell activity. In spite of previous infection with EB virus, none of the 41 patients exhibited clinical signs attributable to the virus, suggesting that residual or compensatory mechanisms must have limited activation of the virus. In patients with AT and WAS these mechanisms may include NK cell activity, which is not depressed in these syndromes, whereas in patients with CHS, they may involve T cell cytotoxicity.

Leukocytes from newborns and pregnant women were shown to be unable to mature into plasma cells in cultures stimulated by pokeweed mitogen (PWM). This is in contrast with the generation of IgM, IgG, and IgA-containing cells constantly observed in adult leukocytes. This defective B cell maturation was due to an active suppression mediated by T lymphocytes. T lymphocytes bearing receptors for IgG (Tγ) and Tγ-depleted populations were both able to exert this effect. Tγ lymphocytes inhibited B cell maturation without significantly affecting T and B cell proliferation, and their effect persisted after an incubation of 18 hr at 37°C. Tγ-depleted lymphocytes suppressed lymphocyte proliferation and, subsequently, B cell maturation into plasma cells. The suppressor activity of this second cell type was markedly diminished after incubation. Co-culture experiments showed that PWM-induced newborn suppressor T lymphocytes suppressed maturation of adult B cells only when T lymphocytes were present, suggesting that suppressor cells acted upon a target T cell population rather than directly upon B cells. Indirect inhibition of B cell maturation resulted in a lack of appearance of membrane IgG and IgA expression, although proliferation and loss of membrane IgD were observed. Although similar suppressor effects can be induced in vitro in adult leukocytes by fixation of immune complexes on Tγ populations or after concanavalin A activation of Tγ-depleted populations, the peculiarity of the perinatal period appears to be the spontaneous activation of the two types of T suppressor lymphocytes.

An excess of adult blood adherent cells (monocytes) inhibits mitogen, antigen and allogeneic cell-induced lymphocyte proliferations. This inhibition is dependent on the number of the adherent monocytes in the cultures and is substantially reduced (by 60%) by indomethacin or anti-PGE2 antiserum. Newborn monocytes exert only a weak inhibitory effect and produce about eight times less PGE2 than adult monocytes. The production of PGE2 and the suppression can be induced by incubating newborn monocytes with mixed leucocyte culture supernatants. Both monocytes from mothers at the time of delivery and from newborn infants, usually exert a poor suppressive activity related to a low production of PGE2. We strongly suggest that the expression of the PGE2-mediated suppression by monocytes is under the control of activated short-lived suppressor lymphocytes.

We report 8 cases of familial lymphohistiocytosis collected in 6 families. Several data argue for an hyperactivation of the reticuloendothelial system (RES). An abnormal visualization of all organs was observed in a scintigraphic study after 99technetium labelled red blood cells injection. Blood monocytes contained very low peroxidase activity as detected by cytoenzymology and secreted large quantities of prostaglandin E2 (PGE2). Adherent cells isolated from blood exercised a strong suppressor effect on the proliferation of normal lymphocytes induced by phytohemaglutinin. This effect was reduced by indomethacin and therefore appears PGE2-dependent. One patient's serum exerced an inhibitory activity on antigen-induced proliferation of normal lymphocytes and on mixed leucocyte reaction. In contrast, cellular and humoral functions were not deeply impaired. The hyperactivation of the RES remains unexplained and not related to a graft versus host reaction, which could be excluded in 3 of our patients. Therapeutic attempts were not efficient, all patients dying despite steroid, vincaleucoblastin and indomethacin therapy.

We herein report five new cases of severe combined immunodeficiency with hypereosinophilia, the so-called familial reticuloendotheliosis first described by Omenn. It is characterized by erythroderma, polyadenopathy, hepatosplenomegaly, severe and repeated infections, protracted diarrhoea with failure to thrive. There is marked eosinophilia as well as a profound immunodeficiency. The immunologic abnormalities consist of an increase in T cell number, a B cell lymphopenia and a complete lack of humoral and cellular immune responses to antigens. A deficiency of lymphocytes 5'-nucleotidase has been inconstantly found. Histologic findings are characteristic, consisting of severe T and B lymphocyte depletion in lymphoid organs with infiltration by histiocytes and, to a lesser extent, eosinophils. The outcome was uniformly fatal within the first year of life. Treatment by a combination of parenteral nutrition, steroids and epipodophyllotoxin was effective in obtaining the complete remission of clinical manifestations due to the histiocytic and eosinophilic infiltration in two patients. However, the treatment failed to correct the immunologic defect. These results indicate that the histiocytic infiltration is possibly not responsible for the immunologic detect observed in this condition.

Objective. Disseminated bacillus Calmette Guérin (BCG) infection after inoculation of live vaccine is considered to result from impaired immunity of the child. However, in half of the cases, regarded as idiopathic, no well-defined immunodeficiency condition can account for the infection. The objective of the present study is to report the prevalence, clinical features, associated infections, and outcomes of children with idiopathic disseminated BCG infection. Design. National retrospective survey during the period from 1974 through 1994 in France. Setting. All neonatology and pediatrics units in primary care and referral centers throughout France. Patients. Data were collected from 595 (82%) of 721 units, 377 (93%) of 407 centers, and 320 (93%) of 345 cities. Selection criteria included BCG infection, dissemination to at least two areas beyond the inoculation site, and no well-defined immunodeficiency condition. Sixteen children (8 girls and 8 boys), born to families unrelated to each other but often consanguinous (5 of 16), satisfied the criteria; children were born in France (11 of 16) or abroad (5 of 16). Results. The minimal prevalence rate was estimated at 0.59 cases per 1 million vaccinated children born in France. Clinical features included fever and cachexia, disseminated BCG infection to lymph nodes (15 of 16), skin (13 of 16), soft tissues (11 of 16), lungs (11 of 16), spleen (11 of 16), liver (11 of 16), and bones (9 of 16). Eight children had associated or subsequent severe opportunistic infection (50%), with either nontyphi Salmonella enterica serotypes (7 of 16) or Mycobacterium abscessus (1 of 16). The outcome was poor: 8 children (50%) died; the cause of death was BCG infection for most children (7 of 8); 8 survived until the last follow-up (50%). Conclusions. Idiopathic disseminated BCG infection is a rare but severe complication of BCG vaccination. The infection probably results from an as yet unknown genetically determined immunodeficiency condition that affects the killing of intracellular bacteria such as BCG and Salmonella.

The Wiskott-Aldrich syndrome (IMD2) is an X-linked recessive immunodeficiency. Initial linkage studies mapped the disease locus on the proximal short arm of the X chromosome, a localization which was further refined to the interval framed by DXS7 and DXS14. We have recently shown that a novel hypervariable locus, DXS255, is very closely linked to the disease gene and is likely to be, at present, the marker closest to the disease gene. The analysis of one family, however, displayed conflicting linkage results, as all of the informative markers situated in the Xp11-q22 region appeared to recombine with the disease locus in two "phase-known" meioses. We have shown by X-inactivation studies that the segregation of the disease through three obligate carrier females in this family originates from a grandpaternal mosaicism, which accounts for the apparent recombinations. This shows that germ-line mosaicism can simulate genetic heterogeneity in linkage studies.

Antenatal diagnosis is now available for most severe inherited immune deficiencies. Several techniques are used: the development of methods for sampling fetal tissue as soon as the tenth week of gestation has made possible the antenatal diagnosis of immune deficiencies associated with detectable enzyme defects, and, in combination with recent molecular biology techniques, can be expected to allow early identification of severe combined immune deficiencies due to the absence of T lymphocyte precursors, agammaglobulinemia, and some instances of X-linked chronic granulomatous disease. A great number of immune deficiencies can be identified by direct studies of fetal lymphocytes or polymorphonuclear leukocytes in fetal blood sampled by fetoscopy at the twentieth week of gestation. Fetal blood studies combined with skin biopsy examination allows the diagnosis of immune defects associated with partial albinism such as Chediak-Higashi disease. No reliable antenatal diagnostic method is as yet available for two severe diseases: Wiskott-Aldrich syndrome, that can be expected to become detectable in utero using molecular biology techniques, and ataxia-telangiectasia. Antenatal diagnosis of a severe immune deficiency does not necessarily indicate termination of the pregnancy as in some cases, such as severe combined immune deficiencies, HLA-identical bone marrow transplantation at birth or in utero is permanently successful in over 90% of cases.

The effects of bone marrow or fetal lymphoid organ transplants in 15 patients with severe combined immunodeficiency disease are reported. The benefits and dangers inherent to the various transplantation strategies are discussed. Our studies indicate that, even in the group of patients with B cells, bone marrow transplantation may be the best procedure to obtain the reconstitution of cellular and humoral functions.