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Abundance and unique repertoire of plasma cells secreting IgA autoantibodies to transglutaminase 2 in the intestinal lesion of celiac disease
Celiac disease (CD) is an immune mediated disorder in which mucosal autoantibodies to the enzyme transglutaminase 2 (TG2)(1) are generated in response to the exogenous antigen gluten(2) in individuals who are HLA-DQ2 or HLA-DQ8(3). We assessed in a comprehensive and non-biased manner the IgA anti-TG...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4533878/ https://www.ncbi.nlm.nih.gov/pubmed/22366952 http://dx.doi.org/10.1038/nm.2656 |
Sumario: | Celiac disease (CD) is an immune mediated disorder in which mucosal autoantibodies to the enzyme transglutaminase 2 (TG2)(1) are generated in response to the exogenous antigen gluten(2) in individuals who are HLA-DQ2 or HLA-DQ8(3). We assessed in a comprehensive and non-biased manner the IgA anti-TG2 response by expression cloning of the antibody repertoire on ex vivo isolated intestinal antibody-secreting cells (ASCs). We found that TG2-specific plasma cells are hugely expanded in patients with active CD, representing on average 10% of ASCs within the duodenal mucosa. Surprisingly, anti-TG2 antibodies were of high affinity and yet showed little adaptation by somatic mutations. Unlike infection-induced peripheral blood plasmablasts(4), the TG2-specific ASCs had neither recently proliferated nor were they short-lived ex vivo. Altogether these observations demonstrate that there is a germline repertoire with high affinity for TG2 that may favour massive generation of autoreactive B cells. Anti-TG2 antibodies did not block enzymatic activity and served as substrates for TG2-mediated crosslinking when expressed as IgD or IgM, but not as IgA1 or IgG1. This could result in preferential recruitment of plasma cells from naïve IgD/IgM-expressing B cells, thus possibly explaining why the anti-TG2 response bears signs of a primary immune response despite the disease chronicity. |
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