NNAlign: a platform to construct and evaluate artificial neural network models of receptor-ligand interactions.

Peptides are extensively used to characterize functional or (linear) structural aspects of receptor-ligand interactions in biological systems, e.g. SH2, SH3, PDZ peptide-recognition domains, the MHC membrane receptors and enzymes such as kinases and phosphatases. NNAlign is a method for the identification of such linear motifs in biological sequences. The algorithm aligns the amino acid or nucleotide sequences provided as training set, and generates a model of the sequence motif detected in the data. The webserver allows setting up cross-validation experiments to estimate the performance of the model, as well as evaluations on independent data. Many features of the training sequences can be encoded as input, and the network architecture is highly customizable. The results returned by the server include a graphical representation of the motif identified by the method, performance values and a downloadable model that can be applied to scan protein sequences for occurrence of the motif. While its performance for the characterization of peptide-MHC interactions is widely documented, we extended NNAlign to be applicable to other receptor-ligand systems as well. Version 2.0 supports alignments with insertions and deletions, encoding of receptor pseudo-sequences, and custom alphabets for the training sequences. The server is available at http://www.cbs.dtu.dk/services/NNAlign-2.0.

HLA-A, -B, -DRB1 allele and haplotype frequencies of 920 cord blood units from Central Chile.

We present human leukocyte antigen (HLA) haplotype and allele/antigenic group frequencies derived from a data set of 920 umbilical cord blood units collected in Central Chile. HLA-A and -B genotypes were typed using sequence specific oligonucleotide probe methods while HLA-DRB1 genotypes were obtained from sequencing-based typing. The most frequent haplotype is A*29~B*44~DRB1*07:01 with an estimated frequency of 2.1%.

Promiscuous Recognition of a Trypanosoma cruzi CD8+ T Cell Epitope among HLA-A2, HLA-A24 and HLA-A1 Supertypes in Chagasic Patients.

BACKGROUND: TcTLE is a nonamer peptide from Trypanosoma cruzi KMP-11 protein that is conserved among different parasite strains and that is presented by different HLA-A molecules from the A2 supertype. Because peptides presented by several major histocompatibility complex (MHC) supertypes are potential targets for immunotherapy, the aim of this study was to determine whether MHC molecules other than the A2 supertype present the TcTLE peptide. METHODOLOGY/PRINCIPAL FINDINGS: From 36 HLA-A2-negative chagasic patients, the HLA-A genotypes of twenty-eight patients with CD8+ T cells that recognized the TcTLE peptide using tetramer (twenty) or functional (eight) assays, were determined. SSP-PCR was used to identify the A locus and the allelic variants. Flow cytometry was used to analyze the frequency of TcTLE-specific CD8+ T cells, and their functional activity (IFN-γ, TNFα, IL-2, perforin, granzyme and CD107a/b production) was induced by exposure to the TcTLE peptide. All patients tested had TcTLE-specific CD8+ T cells with frequencies ranging from 0.07-0.37%. Interestingly, seven of the twenty-eight patients had HLA-A homozygous alleles: A*24 (5 patients), A*23 (1 patient) and A*01 (1 patient), which belong to the A24 and A1 supertypes. In the remaining 21 patients with HLA-A heterozygous alleles, the most prominent alleles were A24 and A68. The most common allele sub-type was A*2402 (sixteen patients), which belongs to the A24 supertype, followed by A*6802 (six patients) from the A2 supertype. Additionally, the A*3002/A*3201 alleles from the A1 supertype were detected in one patient. All patients presented CD8+ T cells producing at least one cytokine after TcTLE peptide stimulation. CONCLUSION/SIGNIFICANCE: These results show that TcTLE is a promiscuous peptide that is presented by the A24 and A1 supertypes, in addition to the A2 supertype, suggesting its potential as a target for immunotherapy.

HLA-A*01 allele: a risk factor for dengue haemorrhagic fever in Brazil's population.

Severe forms of dengue, such as dengue haemorrhagic fever (DHF) and dengue shock syndrome, are examples of a complex pathogenic mechanism in which the virus, environment and host immune response interact. The influence of the host's genetic predisposition to susceptibility or resistance to infectious diseases has been evidenced in several studies. The association of the human leukocyte antigen gene (HLA) class I alleles with DHF susceptibility or resistance has been reported in ethnically and geographically distinct populations. Due to these ethnic and viral strain differences, associations occur in each population, independently with a specific allele, which most likely explains the associations of several alleles with DHF. As the potential role of HLA alleles in the progression of DHF in Brazilian patients remains unknown, we then identified HLA-A alleles in 67 patients with dengue fever and 42 with DHF from Rio de Janeiro, Brazil, selected from 2002-2008 by the sequence-based typing technique. Statistical analysis revealed an association between the HLA-A*01 allele and DHF [odds ratio (OR) = 2.7, p = 0.01], while analysis of the HLA-A*31 allele (OR = 0.5, p = 0.11) suggested a potential protective role in DHF that should be further investigated. This study provides evidence that HLA class I alleles might be important risk factors for DHF in Brazilian patients.

HLA-A*01 allele: a risk factor for dengue haemorrhagic fever in Brazil's population

Severe forms of dengue, such as dengue haemorrhagic fever (DHF) and dengue shock syndrome, are examples of a complex pathogenic mechanism in which the virus, environment and host immune response interact. The influence of the host's genetic predisposition to susceptibility or resistance to infectious diseases has been evidenced in several studies. The association of the human leukocyte antigen gene (HLA) class I alleles with DHF susceptibility or resistance has been reported in ethnically and geographically distinct populations. Due to these ethnic and viral strain differences, associations occur in each population, independently with a specific allele, which most likely explains the associations of several alleles with DHF. As the potential role of HLA alleles in the progression of DHF in Brazilian patients remains unknown, we then identified HLA-A alleles in 67 patients with dengue fever and 42 with DHF from Rio de Janeiro, Brazil, selected from 2002-2008 by the sequence-based typing technique. Statistical analysis revealed an association between the HLA-A*01 allele and DHF [odds ratio (OR) = 2.7, p = 0.01], while analysis of the HLA-A*31 allele (OR = 0.5, p = 0.11) suggested a potential protective role in DHF that should be further investigated. This study provides evidence that HLA class I alleles might be important risk factors for DHF in Brazilian patients.

A deletion in exon 3 results in a new HLA-A*01 null allele (A*0115N) in a Martinican woman.

We report the identification of a new HLA-A null allele, HLA-A*0115N. This null allele has been identified within the A*01 group by a combination of serological and molecular typing [Polymerase chain reaction (PCR) sequence-specific primers, PCR sequence-specific oligoprobes and sequence-based typing (SBT)] in a potential intrafamilial bone marrow donor from Martinique (French West Indies). To characterize this A*01 null allele, we performed DNA typing by PCR-SBT on genomic DNA from the beginning of exon 2 (position 84) through the end of the exon 4 (position 895) and revealed a nucleotide deletion at the end of the exon 3. This sole difference between the new allele and the HLA-A*0101 generates a premature stop codon (TGA) in the beginning of exon 4. This deletion most likely explains the lack of cell surface expression of the encoded protein despite the presence of A*01 allele. The absence of correct expression of the antigen on the cell surface was confirmed by one-dimensional isoelectric focusing (1D-IEF). To date, this is the fourth null allele described within the A*01 group.

Doenca de Jorge Lobo e sua relacao com os antigenos do sistema HLA / Disease Jorge Lobo and his relationship with the antigens of the HLA system

A doenca de Jorge Lobo e uma micose causada pelo fungo Lacazia loboi (L.loboi), o qual se assemelha filogenetica e antigeneticamente ao Paracoccidioides brasiliensis (P.brasiliensis). Devido as caracteristicas epidemiologicas e aos poucos estudos relacionados aos apectos imunologicos dessa doenca, o objetivo desse trabalho foi pesquisar a frequencia dos antigenos HLA de classe I e classe II em 21 pacientes portadores da doenca de Jorge Lobo e comparar com populacao controle. As tipagens HLA de classe I foram realizadas pela tecnica de microlinfocitotoxicidade e as de classe II pelo metodo de PCR-SSP. Como controles, utilizaram-se duas populacoes: uma do Estado do Acre e outra da populacao brasileira, segundo os dados publicados no 11th IHW no Japao

Common Caucasoid HLA-A1B8DR3 linkage group and immune responsiveness in a hybrid Venezuelan population: preliminary data.

A study performed on Venezuelans reveals a correlation between the common Caucasoid linkage group HLA-A1 B8 (A*0101, B*0801, DR3-) and increased lymphoproliferative activity stimulated by several concentrations of phytohemagglutin and concanavalin A in comparison to the group of persons possessing either the HLA-A1 (A*0101) antigen or the HLA-B8,DR3 (B*0801,DRB1*03012) haplotype. The increased lymphoproliferative activity was simultaneously present with increased CD16 cell counts and decreased CD3 and total mononuclear counts. A further comparison of lymphocyte population and subpopulation counts in peripheral blood and serum Ig G,A,M levels in the HLA-A1+ B8+ versus the HLA-A1-B8-high-responder individuals revealed increased CD16 cell counts and IgM levels in persons with the common Caucasoid haplotype (HLA-A1 B8). The data may suggest that some of the genes responsible for these levels or genes controlling their expression could be localized in or along the length of the common Caucasoid haplotype HLA-A1 B8 between the A and B loci of the MHC.

HLA na dermatologia: o que existe de concreto / HLA in dermatology: what there are of real

A participaçäo genética nas doenças auto-imunes torna-se cada vez mais evidente. A imunogenética compreende a análise de genes e seus produtos, localizados na regiäo 6p21, no braço curto do cromossomo 6, que também é conhecida como complexo principal de histocompatibilidade (CPH). Antígenos HLA de classe I, II e III säo altamente polimórficos. Um grande número de doenças dermatológicas está associado ao HLA. Essas associaçöes variam em diferentes populaçöes e grupos étnicos. A determinaçäo do HLA pode estar associada ao curso da doença, predileçäo anatômica podendo ser utilizado como subsídio para o diagnóstico. Entretanto, o papel patogênico do HLA na suscetibilidade ou resistência a determinadas doenças cutâneas permanece incerto. Nesta revisäo, discutem-se alguns aspectos do sistema HLA, o papel patogênico dos antígenos HLA e sua associaçäo com doenças dermatológicas.

Treatment of alloimmune neonatal neutropenia with granulocyte colony-stimulating factor.

Despite numerous attempts to increase the neutrophil count of infants with alloimmune neonatal neutropenia, no therapy has been consistently effective. We describe two infants with alloimmune neutropenia who had a rapid and prolonged increase in neutrophil number after treatment with granulocyte colony-stimulating factor (G-CSF). Patient 1 had antibody directed against the neutrophil antigen NA2. He received three daily doses of G-CSF, and within 2 days his neutrophil count increased from 0.350 x 10(9) to 3.584 x 10(9)/L (350 to 3584/mm3). Despite cessation of treatment the neutrophil count remained in the normal range. Patient 2 had antibody to the neutrophil antigen NA1, and received six daily doses of G-CSF. Within 4 days his neutrophil count increased from 0.477 x 10(9) to 4.320 x 10(9)/L (477 to 4320/mm3) and remained in the normal range for 11 days after the last dose of G-CSF. We recommend that treatment with G-CSF be considered for selected infants with alloimmune neutropenia.

Lack of association between paracoccidioidomycosis and HLA histocompatibility antigens

Foi realizado um estudo de associaçäo HLA e doença, onde 40 pacientes com diagnóstico clínico e laboratorial de Paracoccidioidomicose (PCM) e, 80 indivíduos brancos, clinicamente saudáveis, usados como controles, foram tipados para os antígenos HLA-A, -B, -Cw, -DR e - DQ. Os resultados obtidos mostraram uma associaçäo positiva dos antígenos HLA-A1 (P = 0.050), -A3 (P = 0.014), -B8 (P = 0.014), -Cw7 (P = 0.020), - DQw2 (P = 0.014) e DQw3 (P = 0.019) nos pacientes e uma associaçäo negativa dos antígenos HLA-Cw3 (P = 0.032), -DR1 (P = 0.019) e -DQw1 (P = 0.003) no mesmo grupo, comparados aos controles e, sem correçäo pelo número de antígenos testados (50). Os resultados sugerem uma fraca associaçäo destes antígenos HLA com a doença, uma vez que outros fatores podem também estar influenciando na susceptibilidade genética à PCM. Se corrigido o valor de P, segundo Svejgaard e Ryder (HLA and disease, J, Dausset and A. Svejgaard, eds., 1977), nenhuma associaçäo é demonstrada neste estudo

On the association between HLA-A1 and B5 and clinical forms of schistosomiasis mansoni

The association between both HLA-A1 and B5 antigens and chronic forms of human schistosomiasis was studied in 64 patients and 26 normal controls from a southern Brazilian hospital. No apparent correlation between the chronic forms of the disease and the expression of those antigens was detected. However, the analysis of these date together with those observed on an Egyptian sample suggests that the presence of either of the antigens and the hepatomegalic forms of schistosomiasis is significant, without heterogeneity. Converseley, the association of histocompatibility antigens with splenogegaly is consistent and significant only for HLA-B5, but not HLA-A1

On the association between HLA-A1 and B5 and clinical forms of schistosomiasis mansoni.

The association between both HLA-A1 and B5 antigens and chronic forms of human schistosomiasis was studied in 64 patients and 26 normal controls from a southern Brazilian hospital. No apparent correlation between the chronic forms of the disease and the expression of those antigens was detected. However, the analysis of these data together with those observed on an Egyptian sample suggests that the presence of either of the antigens and the hepatomegalic forms of schistosomiasis is significant, without heterogeneity. Conversely, the association of histocompatibility antigens with splenomegaly is consistent and significant only for HLA-B5, but not HLA-A1.

Association of dengue hemorrhagic fever with the HLA system.

The frequency of HLA antigens was determined in 82 unrelated patients who had been hospitalized with the most severe form of dengue hemorrhagic fever: shock, dehydration and severe hemorrhages (DHF/DSS). The HLA-A1, HLA-B plank, HLA Cw1 and HLA-A29 antigens showed a significant difference when their values were compared with the normal control group.

Hepatitis B epidemiology and its relation to immunogenetic traits in South American Indians.

Serologic tests for hepatitis B prevalence and immunogenetic characterizations were carried out on a sample of 800 persons from several isolated tribes of the lower Amazon basin and the southern Andes. The prevalence of hepatitis B antigen carriers and of antibody to the surface antigen varied from one tribe to another, but were high in all the forest tribes. The serologic evidence indicated high infection rates early in life, but also an increasing proportion showing evidence of infection with increasing age. The frequency of past infections was not differentially associated with the antigen status of the mother or father. A higher proportion of infected males than females had antigenemia. Contrary to published reports, no association of antigenemia was found with any HLA-A, B or C antigen or immunoglobulin allotype, individually or interactively. Antibody prevalence, however, did differ in persons with different HLA haplotypes.