Oligomerization of CD4 is required for stable binding to class II major histocompatibility complex proteins but not for interaction with human immunodeficiency virus gp120.

Previous studies have failed to detect an interaction between monomeric soluble CD4 (sCD4) and class II major histocompatibility complex (MHC) proteins, suggesting that oligomerization of CD4 on the cell surface may be required to form a stable class II MHC binding site. To test this possibility, we transfected the F43I CD4 mutant, which is incapable of binding to class II MHC or human immunodeficiency virus (HIV) gp120, into COS-7 cells together with wild-type CD4 (wtCD4). Expression of F43I results in a dominant negative effect: no class II MHC binding is observed even though wtCD4 expression is preserved. Apparently, F43I associates with wtCD4 oligomers and interferes with the formation of functional class II MHC binding structures. In contrast, F43I does not affect the binding of gp120 to wtCD4, implying that gp120 binds to a CD4 monomer. By production and characterization of chimeric CD4 molecules, we show that domains 3 and/or 4 appear to be involved in oligomerization. Several models of the CD4-class II MHC interaction are offered, including the possibility that one or two CD4 molecules initially interact with class II MHC dimers and further associate to create larger complexes important for facilitating T-cell receptor crosslinking.

Low major histocompatibility complex class II diversity in European and North American moose.

Major histocompatibility complex (MHC) genes encode cell surface proteins whose function is to bind and present intracellularly processed peptides to T lymphocytes of the immune system. Extensive MHC diversity has been documented in many species and is maintained by some form of balancing selection. We report here that both European and North American populations of moose (Alces alces) exhibit very low levels of genetic diversity at an expressed MHC class II DRB locus. The observed polymorphism was restricted to six amino acid substitutions, all in the peptide binding site, and four of these were shared between continents. The data imply that the moose have lost MHC diversity in a population bottleneck, prior to the divergence of the Old and New World subspecies. Sequence analysis of mtDNA showed that the two subspecies diverged at least 100,000 years ago. Thus, viable moose populations with very restricted MHC diversity have been maintained for a long period of time. Both positive selection for polymorphism and intraexonic recombination have contributed to the generation of MHC diversity after the putative bottleneck.

Class II injection wells and your drinking water.

Mode of access: Internet.

The crystal structure of a bacterial Class II ketol-acid reductolsomerase: Domain conservation and evolution

Ketol-acid reductoisomerase (KARI; EC 1.1.1.86) catalyzes two steps in the biosynthesis of branched-chain amino acids. Amino acid sequence comparisons across species reveal that there are two types of this enzyme: a short form (Class 1) found in fungi and most bacteria, and a long form (Class 11) typical of plants. Crystal structures of each have been reported previously. However, some bacteria such as Escherichia coli possess a long form, where the amino acid sequence differs appreciably from that found in plants. Here, we report the crystal structure of the E. coli enzyme at 2.6 A resolution, the first three-dimensional structure of any bacterial Class 11 KARI. The enzyme consists of two domains, one with mixed alpha/beta structure, which is similar to that found in other pyridine nucleotide-dependent dehydrogenases. The second domain is mainly alpha-helical and shows strong evidence of internal duplication. Comparison of the active sites between KARI of E. coli, Pseudomonas aeruginosa, and spinach shows that most residues occupy conserved positions in the active site. E. coli KARI was crystallized as a tetramer, the likely biologically active unit. This contrasts with P. aeruginosa KARI, which forms a dodecamer, and spinach KARI, a dimer. In the E. coli KARI tetramer, a novel subunit-to-subunit interacting surface is formed by a symmetrical pair of bulbous protrusions.

Prediction of HLA-DQ3.2 beta ligands: evidence of multiple registers in class II binding peptides

Motivation: While processing of MHC class II antigens for presentation to helper T-cells is essential for normal immune response, it is also implicated in the pathogenesis of autoimmune disorders and hypersensitivity reactions. Sequence-based computational techniques for predicting HLA-DQ binding peptides have encountered limited success, with few prediction techniques developed using three-dimensional models. Methods: We describe a structure-based prediction model for modeling peptide-DQ3.2 beta complexes. We have developed a rapid and accurate protocol for docking candidate peptides into the DQ3.2 beta receptor and a scoring function to discriminate binders from the background. The scoring function was rigorously trained, tested and validated using experimentally verified DQ3.2 beta binding and non-binding peptides obtained from biochemical and functional studies. Results: Our model predicts DQ3.2 beta binding peptides with high accuracy [area under the receiver operating characteristic (ROC) curve A(ROC) > 0.90], compared with experimental data. We investigated the binding patterns of DQ3.2 beta peptides and illustrate that several registers exist within a candidate binding peptide. Further analysis reveals that peptides with multiple registers occur predominantly for high-affinity binders.

ANÁLISE COMPARATIVA DO NÚMERO DE CONTATOS OCLUSAIS AO FINAL DA FASE DE CONTENÇÃO, E APÓS UM PERÍODO DE 5 ANOS, EM PACIENTES COM MÁ-OCLUSÃO DE CLASSE II, TRATADOS COM EXTRAÇÕES DE 4 PRÉ- MOLARES.

Realizou-se um estudo comparativo do número de pontos de contato oclusais na posição de máxima intercuspidação habitual em uma amostra composta por 14 pacientes leucodermas, sendo 9 do sexo feminino e 5 do sexo masculino, com máoclusão de Classe II, divisão 1a de Angle, tratados ortodonticamente pela técnica de Edgewise, com extrações dos 4 primeiros pré-molares. Estes pontos foram registrados em dois tempos: T1 - ao final da fase de contenção superior e T2 - após um período médio de 5,2 anos. A contagem dos contatos oclusais foram realizadas nos arcos superior e inferior, separadamente, para as regiões anterior e posteriores. Depois da análise estatística, pôde-se concluir que não houve diferença estatisticamente significante entre o número médio de contatos oclusais nos diferentes períodos estudados.(AU)

AVALIAÇÃO DAS ALTERAÇÕES DENTOESQUELÉTICAS DECORRENTES DO TRATAMENTO DA MALOCLUSÃO DE CLASSE II COM O APARELHO FORSUS POR MEIO DE TOMOGRAFIA COMPUTADORIZADA

Este estudo teve como objetivo avaliar cefalometricamente as alterações dentoesqueléticas decorrentes do tratamento da maloclusão de Classe II, divisão 1, com o aparelho Forsus®, por meio de Tomografia Computadorizada de Feixe Cônico (TCFC). O grupo avaliado foi composto por 10 pacientes, sendo 7 do sexo masculino e 3 do sexo feminino, com idade média de 16,1 anos, maloclusão com severidade mínima de 1/2 Classe II, trespasse horizontal mínimo de 5 mm, padrão facial meso ou braquifacial. Estes jovens se encontravam no estágio IV ou V de maturação óssea, verificada pelas vértebras cervicais. O tempo de uso do aparelho Forsus foi de 7,16 meses (média), período de avaliação compreendido entre a aquisição da primeira teleradiografia gerada através da TCFC (T1 - pré-Forsus) e da segunda teleradiografia (T2 - pós-Forsus). Para análise estatística foi utilizado o teste-t pareado. Os resultados mostraram um pequeno crescimento mandibular que, juntamente com uma diminuição do SNA levaram a uma melhora da relação maxilomandibular. Houve uma rotação no sentido anti-horário da mandíbula e do plano oclusal no sentido horário. Os incisivos superiores foram retruídos, verticalizados e extruídos e os molares superiores distalizaram por inclinação. Houve vestibularização, protrusão e intrusão dos incisivos inferiores, além de mesialização e extrusão dos molares inferiores. Desta maneira, conclui-se que o aparelho Forsus foi efetivo na correção da maloclusão de Classe II, propiciando maiores alterações dentoalveolares do que esqueléticas.(AU)

BENEFÍCIOS DO TRATAMENTO TARDIO DA MÁ OCLUSÃO DE CLASSE II COM OS APARELHOS FORSUS E TWIN FORCE

O objtivo deste estudo pros

AVALIAÇÃO TOMOGRÁFICA DA INCLINAÇÃO E DAS TÁBUAS ÓSSEAS VESTIBULAR E LINGUAL DE INCISIVOS NO TRATAMENTO DA CLASSE II DIVISÃO 1 COM O APARELHO FORSUS®

O objetivo deste estudo prospectivo foi avaliar os efeitos do aparelho Forsus® nos incisivos centrais superiores e inferiores. A amostra constituiu-se de 22 tomografias computadorizadas de 11 pacientes (sexo masculino e feminino) idade média de 15,8 anos com má oclusão de Classe II que foram tratados com o aparelho Forsus® na clínica do programa de pós-graduação em Odontologia, área de concentração Ortodontia, da Universidade Metodista de São Paulo. As tomografias foram obtidas em dois momentos T1 (final de nivelamento e antes da instalação do Forsus® e T2 (remoção do Forsus®). Para avaliar a distância do ápice até a tábua óssea, as imagens a serem examinadas foram obtidas com o auxílio do viewer do próprio i-CAT® , o iCATVision® e examinadas com o CorelDRAW X5® já para as medidas cefalométricas IMPA e 1.PP as imagens cefalométricas ortogonais foram obtidas em proporção 1:1 com auxílio do software Dolphin 3D® (Dolphin Imaging and Management Solutions, Chatsworth, EUA) e em seguida examinadas com o software Radiocef Studio 2 (Radio Memory, Belo Horizonte, Brasil). Para a obtenção do erro intra-examinador foi feito o teste t de Student pareado para o erro sistemático e a fórmula de DAHLBERG para estimar a ordem de grandeza dos erros casuais e na análise estatística dos resultados utilizou-se: o teste t para a determinação das diferenças entres as fases de observação e o teste de correlação de Pearson para avaliar a correlação entres as alterações. Observou-se: um aumento significativo (p<0,05) tanto no IMPA quanto no 1.PP, aproximação do ápice dos incisivos inferiores da tábua óssea lingual, aproximação do ápice dos incisivos superiores da tábua óssea vestibular, uma correlação negativa muito forte entre o IMPA e a distância do ápice do incisivo até a tábua óssea lingual e uma correlação negativa moderada entre 1.PP e a distância do ápice do incisivo até a tábua óssea vestibular. Sendo assim o aparelho Forsus® no tratamento da Classe II teve como efeito: vestibularização significativa dos incisivos centrais inferiores, uma verticalização significativa dos incisivos centrais superiores, aproximação do ápice dos incisivos inferiores da cortical óssea lingual e aproximação do ápice dos incisivos superiores da cortical óssea vestibular.

MHC class II binding prediction:a little help from a friend

Vaccines are the greatest single instrument of prophylaxis against infectious diseases, with immeasurable benefits to human wellbeing. The accurate and reliable prediction of peptide-MHC binding is fundamental to the robust identification of T-cell epitopes and thus the successful design of peptide- and protein-based vaccines. The prediction of MHC class II peptide binding has hitherto proved recalcitrant and refractory. Here we illustrate the utility of existing computational tools for in silico prediction of peptides binding to class II MHCs. Most of the methods, tested in the present study, detect more than the half of the true binders in the top 5% of all possible nonamers generated from one protein. This number increases in the top 10% and 15% and then does not change significantly. For the top 15% the identified binders approach 86%. In terms of lab work this means 85% less expenditure on materials, labour and time. We show that while existing caveats are well founded, nonetheless use of computational models of class II binding can still offer viable help to the work of the immunologist and vaccinologist.

Peptide binding prediction for the human class II MHC allele HLA-DP2:a molecular docking approach

MHC class II proteins bind oligopeptide fragments derived from proteolysis of pathogen antigens, presenting them at the cell surface for recognition by CD4+ T cells. Human MHC class II alleles are grouped into three loci: HLA-DP, HLA-DQ and HLA-DR. In contrast to HLA-DR and HLA-DQ, HLA-DP proteins have not been studied extensively, as they have been viewed as less important in immune responses than DRs and DQs. However, it is now known that HLA-DP alleles are associated with many autoimmune diseases. Quite recently, the X-ray structure of the HLA-DP2 molecule (DPA*0103, DPB1*0201) in complex with a self-peptide derived from the HLA-DR a-chain has been determined. In the present study, we applied a validated molecular docking protocol to a library of 247 modelled peptide-DP2 complexes, seeking to assess the contribution made by each of the 20 naturally occurred amino acids at each of the nine binding core peptide positions and the four flanking residues (two on both sides).

Peptide length significantly influences in vitro affinity for MHC class II molecules

Class II Major Histocompatibility Complex (MHC) molecules have an open-ended binding groove which can accommodate peptides of varying lengths. Several studies have demonstrated that peptide flanking residues (PFRs) which lie outside the core binding groove can influence peptide binding and T cell recognition. By using data from the AntiJen database we were able to characterise systematically the influence of PFRs on peptide affinity for MHC class II molecules.

Static energy analysis of MHC class I and class II peptide-binding affinity

Antigenic peptide is presented to a T-cell receptor (TCR) through the formation of a stable complex with a major histocompatibility complex (MHC) molecule. Various predictive algorithms have been developed to estimate a peptide's capacity to form a stable complex with a given MHC class II allele, a technique integral to the strategy of vaccine design. These have previously incorporated such computational techniques as quantitative matrices and neural networks. A novel predictive technique is described, which uses molecular modeling of predetermined crystal structures to estimate the stability of an MHC class II-peptide complex. The structures are remodeled, energy minimized, and annealed before the energetic interaction is calculated.