Age and surgical outcome of low-grade glioma in Sweden.

BACKGROUND: Low-grade gliomas (LGG) are slow-growing primary brain tumors that typically affect young adults. Advanced age is widely recognized as a poor prognostic factor in LGG. The impact of age on postoperative outcome in this patient group has not been systemically studied. METHODS: We performed a nationwide register-based study with data from the Swedish Brain Tumor Registry (SBTR) for all adults diagnosed with a supratentorial LGG (WHO grade II astrocytoma, oligoastrocytoma, or oligodendroglioma) during 2005-2015. Patient- and tumor-related characteristics, postoperative complications, and survival were compared between three different age groups (18-39 years, 40-59 years, and ≥60 years). RESULTS: We identified 548 patients; 204 patients (37.2%) aged 18-39 years, 227 patients (41.4%) aged 40-59 years, and 117 patients (21.4%) ≥60 years of age. Unfavorable preoperative prognostic factors (eg, functional status and neurological deficit) were more common with increased age (P < .001). In addition, overall survival was significantly impaired in those 60 years and above (P < .001). We observed a clear dose-response for age with separation of survival curves at 50 years. Biopsy was more common in patients ≥60 years (P < .001). Subgroup analysis of patients with resection revealed a higher amount of postoperative neurological deficits in older patients (P = .029). CONCLUSION: In general, older patients with LGG have several unfavorable prognostic factors compared with younger patients but seem to tolerate surgery in a comparable fashion. However, more neurological deficits were observed following resections in elderly. Our data further support a cutoff at 50 years rather than 40 years for selection of high-risk patients.

Value of microarray allergen assay in the management of eosinophilic oesophagitis.

BACKGROUND: Eosinophilic oesophagitis (EoE) is a disorder characterised by oesophageal dysfunction and, histologically, by eosinophilic inflammation. Although treatment, which includes dilatations, oral corticosteroids and restrictive diets, is often effective, choosing the foods to be eliminated from the diet is difficult. OBJECTIVE: Component resolved diagnostic by microarray allergen assay may be useful in detecting allergens that might be involved in the inflammatory process. METHODS: We studied 67 patients with EoE, diagnosed clinically and histologically by endoscopic biopsy. CRD analysis with microarray technology was carried out in the 67 EoE patients, 50 patients with pollen allergy without digestive symptoms, and 50 healthy controls. RESULTS: Allergies were not detected by microarray in only seven of the 67 patients with EoE. Controls with pollen allergy showed sensitisation to different groups of pollen proteins without significant differences. In EoE patients with response to some allergens, the predominant allergens were grasses group 1 and, in particular, nCyn d 1 (Cynodon dactylon) or Bermuda grass pollen in 59.5%, followed by lipid transfer proteins (LTP) of peach (19.40%), hazelnut (17.91%) and Artemisia (19.40%). CONCLUSIONS: In patients with EoE, sensitisation to plant foods and pollen is important. The proteins most frequently involved are nCyn d 1 and lipid transfer proteins, hazelnuts and walnuts. After one year of an array-guided exclusion diet and pollen-specific immunotherapy in the case of high levels of response, patients with EoE showed preliminary significant improvements.

Topographical distribution and characterization of epithelial cells and intraepithelial lymphocytes in the human ocular mucosa.

The conjunctiva plays a key role in the protection of the ocular surface by initiating and regulating immune responses. In this study, we analyze the relative proportion of intraepithelial lymphocytes (IELs), apoptotic cells, and proliferative state in three different topographical regions of the normal human conjunctiva. Superior tarsal, superior bulbar, and inferior tarsal-bulbar-fornical conjunctival cells were collected by brush cytology from 63 healthy donors. Flow cytometry analysis showed higher levels of CD3⁺ and CD8⁺ IELs in both upper tarsal and bulbar conjunctiva than in the inferior tarsal-bulbar-fornix, where the CD19⁺ B cells were increased. For all zones two different cell populations (by cell size and complexity) were present in the apoptosis assay. The more complex cells were reduced within the inferior tarsal-bulbar-fornix when compared with the superior bulbar and tarsal areas. Less complex cells were more predominant in the inferior conjunctiva and were mainly alive. The mean proliferation index of the conjunctival epithelium was significantly lower in the superior bulbar conjunctiva than in superior tarsal and inferior fornical conjunctivas. These findings suggest that each topographical zone from normal human conjunctiva has a unique profile of immunophenotype, viability, and proliferative state that could be related to a differentiated regional functionality.

Role of Nijmegen breakage syndrome protein in specific T-lymphocyte activation pathways.

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.

Cathepsin C gene: First compound heterozygous patient with Papillon-Lefèvre syndrome and a novel symptomless mutation.

Papillon-Lefèvre syndrome (PLS) has recently been shown to be caused by mutations in the cathepsin C gene resulting in periodontal disease and palmoplantar keratosis. Thirteen different homozygous mutations have been characterised in PLS patients of different ethnic origin. In the present paper, a PLS patient is described who carries two novel mutations (706G>T and 872G>A) in the paternal and maternal chromosomes, respectively. This is the first compound patient described so far. In addition, a novel symptomless mutation (458C>T) in the cathepsin C gene is described in three homozygous individuals. Thus, not all mutations should be considered as a cause of disease, whether case studies or general population screening is performed. Another already described mutation that provoked the Haim-Munk syndrome (HMS) in Indian Jews has also been found to give rise to PLS in a Spanish family from Madrid. On the other hand, PLS patients are ameliorated by retinoids, which indicates that retinoids may be used as therapeutic agents in this immune system deficiency.

A point mutation in a domain of gamma interferon receptor 1 provokes severe immunodeficiency.

Gamma interferon (IFN-gamma) and the cellular responses induced by it are essential for controlling mycobacterial infections. Most patients bearing an IFN-gamma receptor ligand-binding chain (IFN-gammaR1) 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-gammaR1 ligand-binding 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-gamma (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-gamma receptor expression. Future research on these nontruncating mutations will make it possible to develop new therapeutical alternatives in this group of patients.

Reference strand mediated conformation analysis resolves HLA-DRB1 typing ambiguities when matching for unrelated bone marrow transplantation.

We show here the use of reference strand mediated conformation analysis (RSCA) to unambiguously resolve the HLA-DRB1 typing of two individuals which were selected as potential unrelated donors for bone marrow transplantation (BMT). In the first case, both sequence-specific primer (SSP) amplification and sequence-specific oligonucleotide probing (SSO), routinely used in different tissue typing laboratories gave, for the two unrelated donors, the same ambiguous typing of HLA-DRB1*04011+*0403 or DRB1*0407+*0413. In this case sequence-based typing (SBT) was not the method of choice to resolve the situation, due to the sequence ambiguities of these two given combinations. RSCA of both samples, using homozygous typing cells (HTCs) for DRB1*04011, *0403 and *0407 as internal controls, gave the unambiguous result that both donors were HLA-DRB1*04011+*0403. In the second case, a donor was typed as DRB1*1102+1103 by SSP, while SSO excluded the DRB1*1102 allele. The patient was unambiguously typed as DRB1*1101+1103 by both techniques. RSCA, using DNA from reference cell lines as internal controls, gave the unambiguous typing that the donor was DRB1*1103 homozygous.

Higher incidence of autoantibodies in X-linked chronic granulomatous disease carriers: random X-chromosome inactivation may be related to autoimmunity.

The presence of autoantibodies and autoimmune diseases was tested in all available members of five families with at least one member affected with X-linked chronic granulomatous disease. Patients and carriers relatives possess autoantibodies more frequently than non-carriers relatives (95% vs 10%, p < 1.0 x 10(-5), Fisher test). Further, a survey of the literature revealed that in X-linked immunodeficiencies with X-chromosome random inactivation, clear features of autoimmunity are observed, not found in those with non-random inactivation. It appears then as if random inactivation of the X-chromosome in these pathologies, may favor the expression of an autoimmune phenotype in patients and carriers.

Immunodeficiency associated with anorexia nervosa is secondary and improves after refeeding.

Several studies have addressed the question of starvation effects on immune function by means of changes in lymphocyte subsets, cytokine induction or lymphocyte activation. Anorexia nervosa (AN) patients are severely malnourished and contradictory results have been obtained regarding the accompanying immunodeficiency, including its assignation as a part of the primary nervous disorder. In the present work, an extensive immunological function examination was carried out on 40 AN patients who were compared with a control group of 14 healthy girls. The AN patients were also classified according to their nutritional status (by the Body Mass Index: BMI), this being critical for a better understanding of these secondary immunodeficiency bases. Moreover, another immune system study was performed on five patients after refeeding. Lymphocyte subsets and function, cytokine induction and peripheral blood concentrations, and innate as well as humoral immunity were evaluated. Deregulation in the cytokine network, owing to the interaction of the central nervous (CNS) and immune systems, seems to be the initial immune alteration in AN immunodeficiency but it has not been disproved that the immunodeficiency is a direct consequence of the original psychiatric perturbation. Spontaneous high levels of circulating interleukin-1beta (IL-1beta) and tumour necrosis factor-alpha (TNF-alpha) have been observed; this is probably one of the causes of the anomalies found in the T-cell subpopulations (mainly the naive CD4+CD45RA+ reduction and the cytotoxic CD8+ increase) and T-cell activation status (mainly the down-regulation of the CD2 and CD69 activation pathways). This finally leads to an impairment, not only in T-cell function but also in T-cell to B-cell co-operation. The AN specificity of these results is confirmed by the fact that these immune alterations improve after refeeding and when nutritional status becomes less critical, which also suggests that AN immunodeficiency is indeed secondary to malnutrition.

Retinol (vitamin A) is a cofactor in CD3-induced human T-lymphocyte activation.

Immunomodulatory 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) M) 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-gamma) 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.

Cell surface phenotype and ultramicroscopic analysis of purified human enterocytes: a possible antigen-presenting cell in the intestine.

Epithelial cells of the intestine seem to act as antigen-presenting cells to surrounding lymphoid tissue and may be crucial to maintain the pool of peripheral T lymphocytes. The scope of this study was to carry out an immunophenotypic and ultramicroscopic analysis of purified human enterocytes to elucidate their role as antigen-presenting cells, in the immune responses in the gut-associated lymphoid tissue. A method has been developed to obtain purified and viable human enterocyte populations, later labeled with relevant monoclonal antibodies directed to leukocyte antigens and subjected to cytofluorometric analysis. Phenotypic analysis revealed the presence of markers common to "classical" antigen-presenting cells (CD14, CD35, CD39, CD43, CD63 and CD64), reinforcing the idea that enterocytes may act as such. Moreover, several integrins (CD11b, CD11c, CD18, CD41a, CD61 and CD29) were also found. CD25 (IL-2 receptor alpha chain) and CD28, characteristic of T cells, were detected on the surface of these cells; this latter finding rises the possibility that enterocytes could be activated by IL-2 and/or via CD28 through binding to its ligands CD80 or CD86. Finally, the presence of CD21, CD32, CD35 and CD64 that may bind immune complexes via Fc or C3, suggests their participation in the metabolism of immune complexes. Furthermore, the finding of a Birbeck's-like granule in the cytoplasm of the cells, shows that enterocytes contain an ultramicroscopic feature previously thought to be characteristic of Langerhans' cells, an antigen-presenting cell. The phenotype detected on the surface of enterocytes, along with their ultramicroscopic characteristics, suggests that they may play an important role in the immune responses elicited in the gut, presenting antigens to surrounding lymphoid cells, and establishing cognate interactions with them.

Herpes virus saimiri transformation of T cells in CD3 gamma immunodeficiency: phenotypic and functional characterization.

The characterization of T cell immunodeficiencies could in part be supported by using stable cell lines in which biochemical and molecular studies of the defect could be carried out thereby omitting frequent bleeding of patients. First attempts to obtain such cell lines included HTLV-I transformation and exogenous IL-2 administration, but both models have important disadvantages. Recently, a virus isolated from the squirrel monkey, Herpes virus saimiri (HVS), has been reported to have the ability to transform T cells. A stable IL-2-dependent HVS-transformed T cell line from a CD3 gamma deficient patient has been obtained; and this cell line displays both the phenotypic and the functional characteristics of the patient's lymphocytes. Moreover, the line down-modulates TCR/CD3 surface expression upon CD3 engagement, as do the patient's lymphocytes, showing that CD3 gamma and its phosphorylation are not necessary for TCR/CD3 internalization. In addition, the abnormal staining pattern of different anti-TCR/CD3 monoclonal antibodies is preserved in the HVS-patient line. Since HVS is capable of transforming CD3 gamma- T cells, the CD3 gamma chain does not seem to be involved in the HVS receptor process. The fact that it is not possible to obtain a CD8+ HVS line from the CD3 gamma- patient supports the existence of a functional anomaly in his scanty CD8+ peripheral lymphocytes. Thus, HVS transformation is a suitable model for T cell immunodeficiency studies and characterization. It may also be used in the future in cellular models for in vitro gene therapy trials.

Frequencies of HLA-A24 and HLA-DR4-DQ8 are increased and that of HLA-B blank is decreased in chronic toxic oil syndrome.

The cause of toxic oil syndrome (TOS) has not yet been definitively determined, but some genetic susceptibility factors (certain HLA antigens and female sex) have been identified in 236 patients. Similarities with genetic factors for scleroderma and hydralazine-induced lupus (i.e. in TOS female sex and HLA-A24, Pcorrected = 0.00001 and DR4, Pcorrected = 0.04, respectively) may provide a clue to the responsible xenobiotic and its pathogenesis, and may also help in understanding the basis of the related eosinophilia-myalgia syndrome associated with tryptophan ingestion. In this paper it is also established that a human class I antigen (HLA-A24) and, independently, an HLA class II haplotype (DR4-DQ8, Pcorrected = 0.04) and arginine 52 in the alpha-DQ chains (Pcorrected = 0.03) are associated with TOS susceptibility, similarly to insulin-dependent diabetes. This further supports the classification of TOS as an autoimmune disease. Also, the increased frequency of a particular set of low-frequency HLA class I antigens in chronic TOS patients (i.e. B27, B37, B38 and B49) and the probable decrease in the frequency of HLA-B homozygotes in surviving patients (Pcorrected = 0.008) may provide an objective model to explain the maintenance of the HLA polymorphism: less frequent HLA alleles may be more advantageous in the event of unexpected human contact with unusual xenobiotics (not only microbes); however, other mechanisms working together to preserve and generate HLA polymorphism may coexist.

Primate DRB6 gene expression and evolution: a study in Macaca mulatta and Cercopithecus aethiops.

DRB6 has been found to be transcribed in human and apes. Promoter region and exon 1 come from a 5' LTR from a mammary tumour retrovirus. However, the putative protein structure would be very different to other DR molecules and it is doubtful that it may function as an antigen presenting molecule. Primate DRB6 alleles previously published together with the two new macaque sequences reported here support the existence of a strong selective pressure working on exon 2 to generate stop codons at the end of the exon (between codons 74 and 94) during at least 23 million years. The topology of dendrograms constructed with different primate DRB6 alleles supports the "trans-species" evolution proposed for MHC class I, class II and possibly C4 genes. Finally, DRB6, which is one of the oldest DRB genes, has been lost in the HLA-DRB3 (or DR52) group of haplotypes (DR3, DR5, DR6 and DR8) and a small DRB6 sequence is present at the exon 2 first hypervariable region of DRB4 (or DR53) gene, which is present in DR4, DR7 and DR9 haplotypes.

Peripheral blood reduction of memory (CD29+, CD45RO+, and "bright" CD2+ and LFA-1+) T lymphocytes in Papillon-Lefèvre syndrome.

A Papillon-Lefèvre patient with characteristic chronic periodontal disease and palmoplantar keratoderma was studied over a 4-year period. An abnormal T-cell phenotype was steadily observed in peripheral blood; both low numbers of CD29+ and CD45RO+ cells and a low density surface expression of CD2 and LFA-1 molecules were found. T-cell activation through CD3, CD2 and ConA, PWM and IL-2 receptors was normal; however, there was impairment in the activation via CD28. CD2, LFA-1 and CD45 molecules were normal in charge and molecular weight. There was no tissue sequestering of T lymphocytes in periodontal lesions, but rather a relative T-cell reduction. It is suggested that an important decrease of the so-called "memory/hyperreactive" (CD45RO-positive) T cells does exist; therefore, hyperreactive T cells would not be available in sufficient numbers to leave the bloodstream through blood vessel endothelium, and the periodontium would be left without these important defenses and thus exposed to chronic infections. A disregulated factor affecting the transition from "naive" to "memory" T cells and the increase in certain surface molecules expression (i.e., CD2, LFA-1, CD29, and CD45RO) or the reversion from memory to naive T cells may be responsible for the disease pathogenesis. CD2 and LFA-1 molecule synthesis might be conjointly regulated on T lymphocytes.

Human T-cell activation deficiencies.

The increasing understanding of T-cell activation is paralleled by the recognition of a growing range of 'experiments of nature' that cause T-cell activation deficiencies. Analysis of these deficiencies is, in turn, contributing to the understanding of T-cell function in vivo. Here, José Regueiro, Antonio Arnaiz-Villena and colleagues review current knowledge of structural and functional T-cell defects and the implications of these for T-cell biology.

The HLA-DRB6 locus defines an evolutionary supratypic group within the DRB family of genes.

A novel DRB gene member has recently been identified (DRB6). It defines a new supratypic group of HLA-DR alleles comprising the DR1-, DR2-, and DRw10-carrying haplotypes. The comparison of this gene either at the nucleotide or at the protein level with other HLA-DRB genes supports its inclusion in the DRB gene family and not in DPB or DQB gene families. Moreover, the construction of an evolutionary gene-tree shows that this gene is probably the eldest member of the DRB gene family. Contradictory expression results do not clarify whether or not DRB6 is a pseudogene.