SUMMARYImmunomodulatory effects of different retinoids have been demonstrated, both in vivo and in vitro, in different cellular lineages including human and murine thymocytes, human lung fibroblasts, Langerhans' cells, tumoral cells and natural killer (NK ) cells; however, any attempt to demonstrate the effect of retinoids on human peripheral blood mononuclear cells (PBMC ) resulted in negative results. In the present work, it is shown that retinol and retinoic acid induce a marked increase of proliferation on human PBMC from 32 unrelated healthy individuals, which had previously been stimulated with anti-CD3 antibodies 48 hr before. Serum-free medium, specific retinoid concentration (10−7 ) and a particular timing of retinol addition to the cultures (48 hr after CD3 stimulation) was necessary clearly to detect this retinol-enhancing effect. The increased proliferative response is specifically mediated via the clonotipic T-cell receptor-CD3 complex and correlates with the up-regulation of certain adhesion/activation markers on the T-lymphocyte surface: CD18, CD45RO and CD25; also Th1-type of cytokines (interleukin-2 and interferon-c) are found concordantly increased after retinoid costimulation, both measured by a direct protein measurement and by a specific mRNA increase. In addition, it is shown that the in vitro retinol costimulation is only present in immunodeficient patients who have no defect on CD3 molecules and activation pathway. The fact that retinol costimulate lymphocytes only via CD3 (and not via CD2 or CD28) and the lack of response enhancement in immunodeficients with impaired CD3 activation pathway indicates that retinoids may be used as therapeutic agents in immune system deficiencies that do not affect the clonotypic T-cell receptor.

Gamma interferon (IFN-␥) and the cellular responses induced by it are essential for controlling mycobacterial infections. Most patients bearing an IFN-␥ receptor ligand-binding chain (IFN-␥R1) deficiency present gross mutations that truncate the protein and prevent its expression, giving rise to severe mycobacterial infections and, frequently, a fatal outcome. In this report a new mutation that affects the IFN-␥R1 ligandbinding domain in a Spanish patient with mycobacterial disseminated infection and multifocal osteomyelitis is characterized. The mutation generates an amino acid change that does not abrogate protein expression on the cellular surface but that severely impairs responses after the binding of IFN-␥ (CD64 and HLA class II induction and tumor necrosis factor alpha and interleukin-12 production). A patient's younger brother, who was also probably homozygous for the mutation, died from meningitis due to Mycobacterium bovis. These findings suggest that a point mutation may be fatal when it affects functionally important domains of the receptor and that the severity is not directly related to a lack of IFN-␥ receptor expression. Future research on these nontruncating mutations will make it possible to develop new therapeutical alternatives in this group of patients.Gamma interferon (IFN-␥) is a widely studied cytokine and one of the most promising biological agents, with great therapeutic potential for several pathologies. This is mainly due to its immunomodulatory and antiproliferative effects and, probably, to its antiviral capacity (13). IFN-␥, after binding to its highaffinity receptor, regulates over 200 genes (7). IFN-␥ upregulates major histocompatibility complex (MHC) class I protein expression and induces MHC class II proteins on a variety of leucocytes and epithelial cells. IFN-␥ is also the major cytokine responsible for activating or regulating the phagocytic function of mononuclear cells. It also regulates the production of several immunomodulatory or proinflammatory cytokines such as interleukin-12 (IL-12) and tumor necrosis factor alpha (TNF-␣) (7).The IFN-␥ high-affinity receptor is composed of at least two subunits. IFN-␥R1 (alpha chain or CD119) is the IFN-␥ binding chain. It is encoded by a 30-kb gene located on the long arm of chromosome 6 (23), and it is expressed at moderate levels on the surfaces of nearly all cells. IFN-␥R2 (beta chain or accessory factor 1) is the signaling chain (27), and it is encoded by a gene located on chromosome 21q22.1 (8).The relationship between IFN-␥, IL-12, and TNF-␣ makes up a particularly important system, since it controls mycobacterial infections in humans (14). Recently, several mutations in some components of this system (ligands or receptors) have been described (4,11,12,(17)(18)(19)21). Patients with these mutations have similar susceptibilities to infections by atypical and nontuberculous mycobacteria (5). MATERIALS AND METHODS Subjects.A 5-year-old Spanish girl from consanguineous parents was referred to our hospital with disseminated infecti...

Nijmegen breakage syndrome (NBS) is a genetic disorder characterized by immunodeficiency, microcephaly, and "bird-like" facies. NBS shares some clinical features with ataxia telangiectasia (AT), including increased sensitivity to ionizing radiation, increased spontaneous and induced chromosome fragility, and strong predisposition to lymphoid cancers. The mutated gene that results in NBS codes for a novel double-stranded DNA break repair protein, named nibrin. In the present work, a Spanish NBS patient was extensively characterized at the immunological and the molecular DNA levels. He showed low CD3 ؉ -cell numbers and an abnormal low CD4؉ naive cell/CD4 ؉ memory cell ratio, previously described in AT patients and also described in the present report in the NBS patient. The proliferative response of peripheral blood lymphocytes in vitro to mitogens is deficient in NBS patients, but the possible link among NBS mutations and the abnormal immune response is still unknown.Nijmegen breakage syndrome (NBS) is a rare, autosomal recessive disorder characterized by microcephaly, immunodeficiency, and a predisposition to cancer (27). It shares some striking clinical and cellular similarities to the genetic disease ataxia telangiectasia (AT), and for this reason, NBS has been classified as a variant of AT (12). However, NBS patients have neither ataxia nor telangiectasia, and microcephaly is absent from AT patients (25, 27). The serum ␣-fetoprotein concentration is within the normal range in NBS patients, in contrast to AT patients, about 90% of whom are found to have elevated serum ␣-fetoprotein concentrations (31). In addition, different defective genes in patients with AT and NBS have been identified (3,23,28) and have been mapped in chromosomes 11q23 (8) and 8q21-24, respectively (22), which demonstrates that NBS is a genetic entity distinct from AT.Patients with both NBS and AT display chromosome instability, hypersensitivity to ionizing radiation, and a lack of DNA replication delay in response to radiation, which is governed, in normal cells, by the protein kinase C (PKC)-mediated upregulation of tumor suppresor protein p53 (9,13,14,15,18). These similarities suggest that ATM and nibrin, the proteins responsible for AT and NBS, respectively, may play a role in common functions, which appear to be defective in both diseases.Both ATM and nibrin participate in the processing of double-stranded breaks in DNA (3, 25). It has recently been shown that nibrin, in particular, forms a trimolecular complex, together with Rad50 (a protein similar to those required for the structural maintenance of chromosomes) and Mre11 (with both structural and catalytic activities, including single-stranded DNA endonuclease and double-stranded DNA exonuclease activities). The complex participates in the repair of doublestranded DNA breaks induced by radiation, and the Mre11 hyperphosphorylation observed after DNA damage is dependent on the presence of intact nibrin (6, 7). Recently, it has been shown that the phosphorylation of nibrin induced ...

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