A new family with Papillon-Lefèvre syndrome: effectiveness of etretinate treatment.

Papillon-Lefèvre syndrome is characterized by the association of palmoplantar hyperkeratosis, severe periodontitis, and early loss of deciduous and permanent teeth. We report two patients from the same family, aged 21 and 30 years, who were unaware of their pathology; one was successfully treated with etretinate.

Opioid-immune interactions in autism: behavioural and immunological assessment during a double-blind treatment with naltrexone.

The emerging concept of opioid peptides as a new class of chemical messengers of the neuroimmune axis and the presence of a number of immunological abnormalities in infantile autism prompted us to correlate biological (hormonal and immunological) determinations and behavioural performances during treatment with the potent opiate antagonist, naltrexone (NAL). Twelve autistic patients ranging from 7 to 15 years, diagnosed according to DSM-III-R, entered a double-blind crossover study with NAL at the doses of 0.5, 1.0 and 1.5 mg/kg every 48 hours. The behavioural evaluation was conducted using the specific BSE and CARS rating scales NAL treatment produced a significant reduction of the autistic symptomatology in seven ("responders") out of 12 children. The behavioural improvement was accompanied by alterations in the distribution of the major lymphocyte subsets, with a significant increase of the T-helper-inducers (CD4+CD8-) and a significant reduction of the T-cytotoxic-suppressor (CD4-CD8+) resulting in a normalization of the CD4/CD8 ratio. Changes in natural killer cells and activity were inversely related to plasma beta-endorphin levels. It is suggested that the mechanisms underlying opioid-immune interactions are altered in this population of autistic children and that an immunological screening may have prognostic value for the pharmacological therapy with opiate antagonists.

Disruption of hypothalamic-pituitary-adrenocortical system in transgenic mice expressing type II glucocorticoid receptor antisense ribonucleic acid permanently impairs T cell function: effects on T cell trafficking and T cell responsiveness during postnatal development.

We used transgenic mice with impaired corticosteroid receptor function, caused by expression of type II glucocorticoid receptor (GR) antisense RNA, to study the role of glucocorticoid feedback during the developmental maturation of hypothalamus-pituitary-adrenal-immune functions. These mice have increased plasma concentrations of ACTH and corticosterone as well as reduced GR binding capacity. In control mice, a strong sex dimorphism in the development of GR gene expression is apparent, and in males between postnatal days 9-36, the GR gene transcript concentration is approximately twice that in female mice. Endogenous GR messenger RNA levels were markedly reduced in transgenic mice, and the sex dimorphism was abolished. An abnormal developmental pattern of adrenal secretory activity accompanied the postnatal maturation of the hypothalamic-pituitary-adrenocortical system of the transgenic mice, and high plasma corticosterone levels were measured at early postnatal ages through adulthood. Inefficient glucocorticoid inhibitory action on the immune axis was supported by both the inability of high circulating levels of corticosterone to reduce thymus weight and the failure of dexamethasone to influence in vitro thymocyte and splenocyte cell proliferation. Alterations in thymocyte trafficking/migration in transgenic mice was supported by flow cytometric analysis of the distribution of phenotypically distinct lymphocyte subsets accompanying the postnatal maturation of the thymus. A marked increase in CD4+CD8+ double positive cells and a 2-fold increase in the CD4/CD8 (helper/suppressor) ratio caused by a 40-60% increase in the CD4+CD8- (T helper) subset and a decrease in the CD4-CD8+ (T suppressor) subset, was seen. Moreover, in transgenic mice, an absence of sexual dimorphism and a significantly increased immune reactivity were observed. The present study shows that disruption of the hypothalamic-pituitary-adrenocortical system has both developmental and permanent effects on T cell function characterized by a shifting of the T cell balance toward the CD4+CD8- helper-inducer phenotype coupled with hyperresponsiveness of the T (helper) cell compartment. These findings point to the GR as a major factor in the counterregulatory feedback loop controlling autoaggressive immune responses and underline the potential modulatory role of sex steroids in this feedback regulation and in the pathogenesis of autoimmune diseases.

Neuroendocrineimmunology (NEI) at the turn of the century: towards a molecular understanding of basic mechanisms and implications for reproductive physiopathology.

The interactions between the nervous, endocrine and immune systems require a complex communication network. The central nervous system (CNS) affects the immune system through endocrine, paracrine and neuronal mechanisms. Evidence that this bidirectional communication plays a vital role in the regulation of physiological homeostatic mechanisms while a disfunction of the neuroendocrineimmune balance favors the susceptibility to a number of diseases is derived largely by animal models but also by an increasing number of clinical studies in different fields, including endocrinology, reproductive physiology, pediatrics, oncology, neurology and psychiatry. An increasing number of endocrine hormones, neurotransmitters and neuropeptides are expressed in immune tissues and cells and are actively involved in the physiological regulation of immunity. Conversely, the endocrine and nervous systems harbor receptors for a wide variety of immunologically-derived substances, suggesting potential regulatory feedback loops between the three major integrative bodily systems. Major implications for the reproductive endocrinology field are that psychoneuroendocrine processes may alter fertility via immunomodulation, and that events that occur as part of immune responses influence the neuroendocrine axes, which in turn counter-regulate immune function. In the present article, some features of reproductive-immune interactions will be described, and the neuroendocrineimmune dialogue via the chief reproductive hormone, luteinizing hormone-releasing hormone (LHRH), will be summarized as prototype of intersystem crosstalk. A particular emphasis will be given to the cytokine-LHRH interrelationships both at central (i.e. especially with the astroglial compartment) and peripheral levels. The surprisingly similar communication network systems used by the gonads and the thymus will be summarized, and the sexually-driven dimorphisms dictating female versus male reproductive and immunological capacities reviewed. Evidence that neural, endocrine and immune systems work together as a single unit are emphasized in animal models and human pathologies where interruption of NEI feedback loops results in long lasting pathological consequences for the nervous, endocrine and immune functions.

The immune response evokes up- and down-modulation of beta 2-adrenergic receptor messenger RNA concentration in the male rat thymus.

Important alterations of noradrenergic activity are known to occur in specific brain regions and in different lymphoid tissues during the course of an immune response. Our recent characterization of the beta 2-adrenergic receptor (beta 2AR)-cAMP system of the rat thymus gland, the identification of a thymic beta 2AR gene expression, and the marked modulation of receptor mRNA concentration after castration and replacement with estrogen prompted us to study the ability of products of immune axis activation to modulate beta 2AR number, distribution, and expression in the male rat thymus. Moreover, the effect of adrenergic stimulation of adenylyl cyclase activity on thymus gland membrane preparations was measured. The beta 2AR present in the rat thymus undergoes marked changes in both number and distribution during the course of an immune response. At 3 days after antigenic challenge (injection of BSA in complete Freund's adjuvant), a sharp decrease of receptor number coupled with a significant loss of the autoradiographic reaction in the medullary compartment of the rat thymus gland were observed. These effects were followed by a significant increase in receptor density and number without changes in receptor affinity at 7 and 15 days post immunization, corresponding to the pick of the immune response. Parallel alterations in adenylyl cyclase activity were measured. Northern blot analysis, using a human beta 2AR cDNA as a probe, revealed dramatic alterations of the beta 2AR mRNA in the thymus, characterized by an approximately 75% decrease of mRNA level 3 days after immunization, and by a progressive increase at 7 and 15 days, with beta 2AR mRNA concentration rising to levels even higher than those found in control animals. These results suggest that the immune response evokes marked alterations of the thymic beta 2AR-cAMP signaling pathway. Moreover, antigenic stimulation triggers a down- and up-modulation of beta 2AR gene expression. Although it is presently unknown whether factor(s) released by immune axis activation act at the level of gene transcription to modulate adrenergic receptor function in the rat thymus, such down- and up-regulation of beta 2AR mRNA may play a role in the dynamic regulation of the immune response.

Upregulation of lymphocyte beta-adrenergic receptor in Down's syndrome: a biological marker of a neuroimmune deficit.

To test the hypothesis of an altered central nervous system influence upon the immune system of Down's syndrome (DS) patients and in order to establish a peripheral biological marker of neuroimmune deficit, we have studied the characteristics of the beta 2-adrenergic receptor (B2AR) system in peripheral blood monocytes (PBMC) of 12 pre-pubertal (six boys and six girls) individuals and correlated alterations in binding with changes in distribution of lymphocyte subsets. Using the very potent beta-adrenergic antagonist, iodocyanopindolol ([125I]CYP), as a ligand, the present study shows that a typical BAR population of the beta 2-subtype is present in PBMC from DS children, with binding kinetics and structural specificity similar to those measured in PBMC from patients with other (non-genetic) forms of mental retardation, or in PBMC from age-matched healthy subjects. On the other hand, this study revealed a significant increase in B2AR binding capacity of PBMC from DS subjects (Bmax = 5258 +/- 470 sites/cell) compared to the values measured in the control population of retarded children (Bmax = 1965 +/- 280 sites/cell), characterized by an approximately three-fold increase in the Bmax, without changes in binding affinity (KD = 40.5 +/- 2.0 and 36.6 +/- 2.5 pM in DS and retarded patients, respectively). The flowcytometric analysis of lymphocyte subsets using a panel of monoclonal antibodies against a series of lymphocyte markers revealed a profound alteration in the distribution of lymphocyte subtypes with an almost 50% decrease in B cell and T-helper populations, a three-fold increase in T-cytotoxic suppressor, a seven-fold increase in lymphocyte-activated killer cells (LAK) and 30% increase in natural killer (NK) subpopulations. When fluorescence-labelled lymphocytes were visualized in the cytofluorograph and sorted for their use in the radioreceptor assay, B cells had approximately twice the number of B2AR when compared to T cells; and cytotoxic/suppressor showed a higher binding capacity compared to T-helper cells. On the other hand, labelled lymphocytes from DS patients showed a specific increase in receptor number in B cells, T-cytotoxic suppressor and NK subpopulations. It is concluded that a profound catecholaminergic dysfunction not previously appreciated in DS is reflected by a significant alteration in lymphocyte subset distribution and by a specific up-regulation of lymphocyte B2AR in phenotypically and functionally distinct T and B cells as well NK subpopulations, suggesting a possible denervation supersensitivity phenomenon.(ABSTRACT TRUNCATED AT 400 WORDS)

Luteinizing hormone-releasing hormone signaling at the lymphocyte involves stimulation of interleukin-2 receptor expression.

The marked modulation of lymphocyte function exerted by the hypothalamic decapetide LHRH prompted us to study the possible involvement of the neuropeptide in one of the major steps of lymphocyte proliferation, namely the expression of interleukin-2 (IL-2) receptor during in vitro treatment of rat lymphocytes with LHRH agonists (LHRH-A) or antagonists (LHRH-ANTA). The basal proliferative activity of splenocytes and thymocytes from proestrous female rats was significantly stimulated after incubation with LHRH and LHRH-A, but not LHRH fragments [LHRH-(1-3), LHRH-(1-5), and LHRH-(2-6)]. Similarly, in the absence of the mitogenic stimulus, IL-2 receptor expression was significantly stimulated in thymocyte and splenocyte cultures incubated with increasing doses of LHRH or its agonists. The amplification of Concanavalin-A-induced increase in blastogenic transformation of lymphocytes by LHRH was paralleled by a significant stimulation of IL-2 receptor expression. The specificity of such effect was demonstrated by 1) the failure of LHRH fragments [LHRH-(1-6)] to mimick the LHRH stimulatory effect; and 2) the complete reversal produced by simultaneous addition of a potent LHRH-ANTA on IL-2 receptor expression induced by LHRH. Moreover, basal and lectin stimulation of IL-2 receptor-positive cells were significantly inhibited by treatment with the LHRH-ANTA. These data clearly demonstrate that 1) LHRH induction of lymphocyte activation in vitro is accompanied by a specific increase in IL-2 receptor-positive cells; 2) endogenous lymphocyte LHRH may participate in stimulation of IL-2 receptor expression under both basal and stimulated conditions, suggesting that LHRH signaling at the lymphocyte may interact synergistically with intracellular mechanisms responsible for lymphocyte activation.

Blockade of central and peripheral luteinizing hormone-releasing hormone (LHRH) receptors in neonatal rats with a potent LHRH-antagonist inhibits the morphofunctional development of the thymus and maturation of the cell-mediated and humoral immune responses.

The development of the thymus and the hypothalamic-pituitary-gonadal axis are linked by bidirectional hormonally mediated relationships. In the present study, the direct involvement of the neuropeptide LHRH in the maturation of the thymus and development of the cell-mediated and humoral immune responses were assessed after treatment of neonatal (from post-natal day 1-day 5) female rats with a potent LHRH-antagonist (LHRH-anta, p-Glu-D-Phe 2.6,Pro3-LHRH, 50 micrograms/rat), and the effects compared to those resulting from neonatal castration. Whereas in control animals the maturation of mitogenic potential in thymocyte cultures showed a progressive and age-dependent increase, reaching a maximal activity at 30 days of age and then decreasing after puberty onset, in LHRH-anta-treated rats, the thymocyte's proliferative response was completely blocked at 7 days of age and remained very low at each time interval studied, until 3 months of age. A similar effect of the LHRH-anta treatment on splenocyte cultures was measured. Moreover, a reduced percentage of the T-helper lymphocyte subpopulation followed LHRH-anta administration. By contrast, in neonatally castrated rats, blastogenic activity was significantly higher, compared to control cultures, at each stage studied. Treatment with LHRH-anta produced a significant decrease in thymus wt, an alteration of the maturational pattern characterized by a cellular monomorphism, reduced thymocyte volume, reduction of the cortical area, and depauperation of the epithelial microenvironment. Moreover, a morphometric analysis revealed a selective decrease in the large lymphoid cell population of the subcapsular cortex at 7 and 15 days. On the other hand, neonatal castration produced an opposite effect, leading to a marked hypertrophy of the cortical area, and counteracted the post-puberal thymus atrophy. When LHRH-anta-treated adult (3-month-old) rats were challenged with an antigenic stimulus (multiple sc injections of complete Freund adjuvant and BSA) and antibody (anti-BSA antibodies of the immunoglobulin G class) production measured in the serum after 15 days, a marked and significant decrease in immunoglobulin G levels was observed, compared to the values measured in untreated control. The described immune deficiencies in LHRH-anta-treated rats were associated with a clear inhibition of sexual maturation. This study clearly indicates that the blockade of central and peripheral LHRH receptors during a critical period for maturation of both hypothalamus-hypophyseal-gonadal axis and brain-thymus-lymphoid axis dramatically impairs immune system development, suggesting a potential role of the neuropeptide LHRH in the bidirectional programming of both neuroendocrine and immune functions.

Subchromosomal localization of two human cytokeratin genes (KRT4 and KRT15) by in situ hybridization.

The genes for human cytokeratins 4 and 15 (KRT4 and 15) are assigned to the p11.2----q12 region of chromosome 12 (cytokeratin 4) and to the q21----q23 region of chromosome 17 (cytokeratin 15), respectively.