A novel serogenetic approach determines the community prevalence of celiac disease and informs improved diagnostic pathways

Background
Changing perspectives on the natural history of celiac disease (CD), new serology and genetic tests, and amended histological criteria for diagnosis cast doubt on past prevalence estimates for CD. We set out to establish a more accurate prevalence estimate for CD using a novel serogenetic approach.

Methods
The human leukocyte antigen (HLA)-DQ genotype was determined in 356 patients with ‘biopsy-confirmed’ CD, and in two age-stratified, randomly selected community cohorts of 1,390 women and 1,158 men. Sera were screened for CD-specific serology.

Results
Only five ‘biopsy-confirmed’ patients with CD did not possess the susceptibility alleles HLA-DQ2.5, DQ8, or DQ2.2, and four of these were misdiagnoses. HLA-DQ2.5, DQ8, or DQ2.2 was present in 56% of all women and men in the community cohorts. Transglutaminase (TG)-2 IgA and composite TG2/deamidated gliadin peptide (DGP) IgA/IgG were abnormal in 4.6% and 5.6%, respectively, of the community women and 6.9% and 6.9%, respectively, of the community men, but in the screen-positive group, only 71% and 75%, respectively, of women and 65% and 63%, respectively, of men possessed HLA-DQ2.5, DQ8, or DQ2.2. Medical review was possible for 41% of seropositive women and 50% of seropositive men, and led to biopsy-confirmed CD in 10 women (0.7%) and 6 men (0.5%), but based on relative risk for HLA-DQ2.5, DQ8, or DQ2.2 in all TG2 IgA or TG2/DGP IgA/IgG screen-positive subjects, CD affected 1.3% or 1.9%, respectively, of females and 1.3% or 1.2%, respectively, of men. Serogenetic data from these community cohorts indicated that testing screen positives for HLA-DQ, or carrying out HLA-DQ and further serology, could have reduced unnecessary gastroscopies due to false-positive serology by at least 40% and by over 70%, respectively.

Conclusions
Screening with TG2 IgA serology and requiring biopsy confirmation caused the community prevalence of CD to be substantially underestimated. Testing for HLA-DQ genes and confirmatory serology could reduce the numbers of unnecessary gastroscopies.

The effect of plant tissue and vaccine formulation on the oral immunogenicity of a model plant-made antigen in sheep

Antigen-specific antibody responses against a model antigen (the B subunit of the heat labile toxin of enterotoxigenic Escherichia coli, LTB) were studied in sheep following oral immunisation with plant-made and delivered vaccines. Delivery from a root-based vehicle resulted in antigen-specific immune responses in mucosal secretions of the abomasum and small intestine and mesenteric lymph nodes. Immune responses from the corresponding leaf-based vaccine were more robust and included stimulation of antigen-specific antibodies in mucosal secretions of the abomasum. These findings suggest that oral delivery of a plant bioencapsulated antigen can survive passage through the rumen to elicit mucosal and systemic immune responses in sheep. Moreover, the plant tissue used as the vaccine delivery vehicle affects the magnitude of these responses.

The release and induced immune responses of a plant-made and delivered antigen in the mouse gut

This study investigated the site of release of a model vaccine antigen from plant cells and the corresponding induced immune response. Three plant tissues (leaf, fruit and hairy root) and two formulations (aqueous and lipid) were compared in two mouse trials. A developed technique that enabled detection of antigen release by plant cells determined that antigen release occurred at early sites of the gastrointestinal tract when delivered in leaf material and at later sites when delivered in hairy roots. Lipid formulations delayed antigen release from all plant materials tested. While encapsulation in the plant cell provided some protection of the antigen in the gastrointestinal tract and influenced antigen release, formulation medium was also an important consideration with regard to vaccine delivery and immunogenicity. Systemic immune responses induced from the orally delivered vaccine benefited from late release of antigen in the mouse gastrointestinal tract. The influences to the mucosal immune response induced by these vaccines were too complex to be determined by studies performed here with no clear trend regarding plant tissue site of release or formulation medium. Expression and delivery of the model antigen in plant material prepared in an aqueous formulation provided the optimal systemic and mucosal, antigen-specific immune responses.

Associação da dose de células CD34 com recuperação hematopoética, infecções e outros desfechos após transplante alogênico de medula óssea de doador familiar HLA-idêntico

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Diversidade genética do sistema HLA em Portugal, Cabo Verde e Guiné-Bissau

O polimorfismo dos genes HLA-A, HLA-B e HLA-DRB1 foi estudado em três populações Portuguesas (Portugal continental, Madeira e Açores) e em duas Africanas (Guiné-Bissau e Cabo Verde). Os dados em alta resolução, obtidos por sequenciação (SBT), foram comparados com a caracterização efectuada pelo método SSOP revelando 4,6% de incongruências entre os resultados destes dois métodos. Os alelos mais frequentes em cada um dos loci foram: HLA-A*0201 em todas as populações (13,5-26%); HLA-B*5101 em Portugal continental (12%, o mesmo para o B*440301), Madeira (9,7%) e Açores (9,8%) e B*350101 na Guiné-Bissau (14,4%) e Cabo Verde (13,2%); HLADRB1*0701 em Portugal continental (15%), Madeira (15,7%) e Açores (18,3%), DRB1*1304 na Guiné-Bissau (19,6%) e DRB1*110101 em Cabo Verde (10,1%). Os haplotipos 3-loci mais predominantes em cada população foram: A*020101-B*440301-DRB1*070101 em Portugal continental (3,1%), A*020101-B*510101- DRB1*130101 na Madeira (2,7%), A*2902-B*4403-DRB1*0701 nos Açores (2,4%), A*2301-B*1503-DRB1*110101 na Guiné-Bissau (4,6%) e A*3002-B*350101-DRB1*1001 em Cabo Verde (2,8%). O presente trabalho revela que a população continental Portuguesa tem sido influenciada geneticamente por Europeus e Norte Africanos devido a várias imigrações históricas. O Norte de Portugal parece concentrar, provavelmente devido à pressão da expansão Árabe, um antigo pool genético originado pela influência milenar de Europeus e Norte Africanos. Os dados obtidos nos genes do sistema HLA corroboram as fontes históricas que confirmam que o povoamento dos Açores teve o contributo de outros Europeus, essencialmente Flamengos, para além dos Portugueses. As frequências alélicas e haplotípicas neste arquipélago não apresentam uma distribuição homogénea entre as ilhas do grupo Oriental e Central. O grupo Central revela uma influência clara daEuropa Central e uma muito menor afinidade a Portugal continental. As frequências alélicas e haplotípicas mostram que a ilha da Madeira foi povoada por Europeus, a maioria Portugueses, mas também por sub-Saharianos devido ao comércio de escravos. Cabo Verde não é uma população tipicamente sub-Sahariana pois revela uma importante influência genética Europeia, para além da base genética Africana. A análise dos haplotipos e dendrogramas mostram uma influência genética Caucasiana no actual pool genético Cabo-Verdiano. Os dendrogramas e a análise das coordenadas principais mostram que os Guineenses são mais semelhantes aos Norte Africanos do que qualquer outra população sub-Sahariana já estudada ao nível do sistema HLA, provavelmente devido a contactos históricos com outros povos, nomeadamente Árabes do Este Africano e Berberes.

Polimorfismo do alelo HLA-B27 no desenvolvimento das espondilartropatias

A associação da molécula HLA-B27 com a espondilite anquilosante (AS) e outras espondilartropatias (SpA), permanece como uma das mais fortes verificada entre moléculas HLA e doenças humanas. Desde que foi descrita, em 1973, tem sido alvo de intensa investigação na tentativa de compreender o mecanismo patogénico que lhe está subjacente. Este artigo tem como objectivo fazer uma revisão dos conhecimentos actuais relativos à estrutura e polimorfismo da molécula HLA-B27, bem como descrever os modelos propostos para explicar o seu papel no desenvolvimento das espondilartropatias.