title: The molecular basis of lymphoid architecture and B cell responses: implications for immunodeficiency and immunopathology.
abstract: Immune responses usually take place in secondary lymphoid organs such as spleen and lymph nodes. Most lymphocytes within these organs are in transit, yet lymphoid organ structure is highly organized; T and B cells segregate into separate regions. B cell compartments include naïve cells within follicles, marginal zones and B-1 cells. Interactions between TNF family molecules on hematopoietic cells and their receptors on mesenchymal cells guide the initial phase of lymphoid organogenesis, and regulate chemokine secretion that mediates subsequent T-B cell segregation. Recruitment of B cells into different compartments depends on both the milieu established during organogenesis, and the threshold for B cell receptor signaling, which is modulated by numerous coreceptors. Novel intrafollicular (germinal center) and extrafollicular (plasma cell) compartments are established when B cells respond to antigen. These divergent B cell responses are mediated by different patterns of gene expression, and influenced again by BCR signaling threshold and cellular interactions that depend on normal lymphoid architecture. Aberrant B cell responses are reviewed in the light of these principles taking into account the molecular and architectural aspects of immunopathology. Histological features of immunodeficiency reflect defects of B cell recruitment or differentiation. B cell hyper-reactivity may arise from altered BCR signaling thresholds (autoimmunity), defects in stimuli that guide differentiation in response to antigen (follicular hyperplasia vs plasmacytosis), or defective B cell gene expression. Interestingly, in diseases such as rheumatoid arthritis, Sjogren's syndrome and Hashimoto's thyroiditis lymphoid organogenesis may be recapitulated in non-lymphoid parenchyma, under the influence of molecular interactions similar to those that operate during embryogenesis.
authors.affiliation: Medical Genome Center, John Curtin School of Medical Research, Australian National University, Canberra, ACT. carola.vinuesa@anu.edu.au
authors.forename: C G
authors.initials: CG
authors.lastname: Vinuesa
authors.forename: M C
authors.initials: MC
authors.lastname: Cook
mesh_terms: D000818:Animals; D000941:Antigens; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000502:physiology; D002465:Cell Movement; D018925:Chemokines / Q000502:physiology; D018858:Germinal Center / Q000166:cytology / Q000276:immunology; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000473:pathology / Q000502:physiology; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D008221:Lymphoid Tissue / Q000033:anatomy & histology* / Q000254:growth & development / Q000276:immunology* / Q000473:pathology; D053259:Lymphotoxin beta Receptor; D008954:Models, Biological; D010950:Plasma Cells / Q000166:cytology / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D015398:Signal Transduction
chemical_list: D000941:Antigens; D018925:Chemokines; C505697:LTBR protein, human; D053259:Lymphotoxin beta Receptor; D011947:Receptors, Antigen, B-Cell; D018124:Receptors, Tumor Necrosis Factor