RESUMO
Increased IgE is a typical feature of allergic rhinitis. Local class-switch recombination has been intimated but B cell precursors and mechanisms remain elusive. Here we describe the dynamics underlying the generation of IgE-antibody secreting cells (ASC) in human nasal polyps (NP), mucosal tissues rich in ASC without germinal centers (GC). Using VH next generation sequencing, we identified an extrafollicular (EF) mucosal IgD+ naïve-like intermediate B cell population with high connectivity to the mucosal IgE ASC. Mucosal IgD+ B cells, express germline epsilon transcripts and predominantly co-express IgM. However, a small but significant fraction co-express IgG or IgA instead which also show connectivity to ASC IgE. Phenotypically, NP IgD+ B cells display an activated profile and molecular evidence of BCR engagement. Transcriptionally, mucosal IgD+ B cells reveal an intermediate profile between naïve B cells and ASC. Single cell IgE ASC analysis demonstrates lower mutational frequencies relative to IgG, IgA, and IgD ASC consistent with IgE ASC derivation from mucosal IgD+ B cell with low mutational load. In conclusion, we describe a novel mechanism of GC-independent, extrafollicular IgE ASC formation at the nasal mucosa whereby activated IgD+ naïve B cells locally undergo direct and indirect (through IgG and IgA), IgE class switch.
Assuntos
Formação de Anticorpos/imunologia , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Imunoglobulina D/imunologia , Imunoglobulina E/imunologia , Mucosa Nasal/imunologia , Mucosa Nasal/metabolismo , Adulto , Formação de Anticorpos/genética , Células Produtoras de Anticorpos/imunologia , Células Produtoras de Anticorpos/metabolismo , Biologia Computacional , Perfilação da Expressão Gênica , Centro Germinativo/imunologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hipersensibilidade/etiologia , Hipersensibilidade/metabolismo , Switching de Imunoglobulina/genética , Switching de Imunoglobulina/imunologia , Isotipos de Imunoglobulinas/genética , Isotipos de Imunoglobulinas/imunologia , Imunofenotipagem , Pólipos Nasais/etiologia , Pólipos Nasais/metabolismo , Pólipos Nasais/patologia , Pólen/imunologia , Estações do Ano , Hipermutação Somática de ImunoglobulinaRESUMO
The use of B-cell targeted therapies for the treatment of systemic lupus erythematosus (SLE) has generated great interest owing to the multiple pathogenic roles carried out by B cells in this disease. Strong support for targeting B cells is provided by genetic, immunological and clinical observations that place these cells at the center of SLE pathogenesis, as initiating, amplifying and effector cells. Interest in targeting B cells has also been fostered by the successful use of similar interventions to treat other autoimmune diseases such as rheumatoid arthritis, and by the initial promise shown by B-cell depletion to treat SLE in early studies. Although the initial high enthusiasm has been tempered by negative results from phase III trials of the B-cell-depleting agent rituximab in SLE, renewed vigor should be instilled in the field by the convergence of the latest results using agents that inhibit B-cell-activating factor (BAFF, also known as BLyS and tumor necrosis factor ligand superfamily, member 13b), further analysis of data from trials using rituximab and greatly improved understanding of B-cell biology. Combined, the available information identifies several new avenues for the therapeutic targeting of B cells in SLE.