Multiple tolerance defects contribute to the breach of B cell tolerance in New Zealand Black chromosome 1 congenic mice

• Published in: PloS one Vol. 12; no. 6; p. e0179506
• Main Authors: Chang, Nan-Hua, Manion, Kieran P, Loh, Christina, Pau, Evelyn, Baglaenko, Yuriy, Wither, Joan E
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 19.06.2017; Public Library of Science (PLoS)
• Subjects: Albumen; Anergy; Animals; Antibodies; Antigens; Apoptosis; Arthritis; Autoimmune diseases; B cells; B-Lymphocytes - cytology; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; B7-2 Antigen - metabolism; Biology and Life Sciences; Bone marrow; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - metabolism; CD86 antigen; Cell Differentiation; Cell survival; Chickens; Chromosome 1; Chromosomes; Chromosomes - genetics; Chromosomes - metabolism; Defects; Differentiation; Genes; Genetically modified mice; Genetics; Germinal centers; Health care networks; Helper cells; Immune Tolerance; Immunoglobulin G; Immunoglobulin M; Immunoglobulins - genetics; Immunoglobulins - metabolism; Immunological tolerance; Immunology; Laboratories; Lupus; Lymphocytes; Lymphocytes B; Lymphocytes T; Lysozyme; Medicine and Health Sciences; Mice; Mice, Congenic; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Fluorescence; Muramidase - genetics; Muramidase - metabolism; New Zealand; Phosphatidylinositol 3-Kinases - metabolism; Plasma cells; Research and Analysis Methods; Rodents; Spleen; Spleen - metabolism; Spleen - pathology; Survival; Toleration; Transgenes; Transgenic mice; Up-Regulation; New Zealand
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0179506

Lupus is characterized by a loss of B cell tolerance leading to autoantibody production. In this study, we explored the mechanisms underlying this loss of tolerance using B6 congenic mice with an interval from New Zealand Black chromosome 1 (denoted c1(96-100)) sufficient for anti-nuclear antibody production. Transgenes for soluble hen egg white lysozyme (sHEL) and anti-HEL immunoglobulin were crossed onto this background and various tolerance mechanisms examined. We found that c1(96-100) mice produced increased levels of IgM and IgG anti-HEL antibodies compared to B6 mice and had higher proportions of germinal center B cells and long-lived plasma cells, suggesting a germinal center-dependent breach of B cell anergy. Consistent with impaired anergy induction, c1(96-100) double transgenic B cells showed enhanced survival and CD86 upregulation. Hematopoietic chimeric sHEL mice with a mixture of B6 and c1(96-100) HEL transgenic B cells recapitulated these results, suggesting the presence of a B cell autonomous defect. Surprisingly, however, there was equivalent recruitment of B6 and c1(96-100) B cells into germinal centers and differentiation to splenic plasmablasts in these mice. In contrast, there were increased proportions of c1(96-100) T follicular helper cells and long-lived plasma cells as compared to their B6 counterparts, suggesting that both B and T cell defects are required to breach germinal center tolerance in this model. This possibility was further supported by experiments showing an enhanced breach of anergy in double transgenic mice with a longer chromosome 1 interval with additional T cell defects.