Peripheral Tolerance Checkpoints Imposed by Ubiquitous Antigen Expression Limit Antigen-Specific B Cell Responses under Strongly Immunogenic Conditions

Abstract

A series of layered peripheral checkpoints maintain self-reactive B cells in an unresponsive state. Autoantibody production occurs when these checkpoints are breached; however, when and how this occurs is largely unknown. In particular, how self-reactive B cells are restrained during bystander inflammation in otherwise healthy individuals is poorly understood. A weakness has been the unavailability of methods capable of dissecting physiologically relevant B cell responses without the use of an engineered BCR. Resolving this will provide insights that decipher how this process goes awry during autoimmunity or could be exploited for therapy. In this study, we use a strong adjuvant to provide bystander innate and adaptive signals that promote B cell responsiveness in conjunction with newly developed B cell detection tools to study in detail the ways that peripheral tolerance mechanisms limit the expansion and function of self-reactive B cells activated under these conditions. We show that although self-reactive B cells are recruited into the germinal center, their development does not proceed, possibly because of rapid counterselection. Consequently, differentiation of plasma cells is blunted, and Ab responses are transient and devoid of affinity maturation. We propose this approach, and these tools can be more widely applied to track Ag-specific B cell responses to more disease-relevant Ags, without the need for BCR transgenic mice, in settings where tolerance pathways are compromised or have been genetically manipulated to drive stronger insights into the biology underlying B cell-mediated autoimmunity.

Interleukins 4 and 21 Protect Anti-IgM Induced Cell Death in Ramos B Cells: Implication for Autoimmune Diseases

“…Numerous autoimmune diseases are B-cell mediated, characterized in the formation of autoantibodies, and/or survival of autoreactive B cells; B-cell targeted therapy such as the depletion of circulating B cells has demonstrated therapeutic success in treating these B-cell mediated diseases ( 11 , 75 ). B cell tolerance checkpoints happen in both central and peripheral systems ( 10 – 12 , 76 , 77 ). Central tolerance is mediated by clonal deletion, anergy and receptor editing in the bone marrow while peripheral tolerance happens when the immature B cells expressing BCRs with low affinity for self-antigens escape central tolerance ( 75 , 77 ).…”

“…B cell tolerance checkpoints happen in both central and peripheral systems ( 10 – 12 , 76 , 77 ). Central tolerance is mediated by clonal deletion, anergy and receptor editing in the bone marrow while peripheral tolerance happens when the immature B cells expressing BCRs with low affinity for self-antigens escape central tolerance ( 75 , 77 ). Those autoreactive B cells are further eliminated through anergy, clonal deletion and irresponsiveness to respective T helper cells during maturation in spleen and activation in the germinal centers within spleen and lymph nodes as a result of peripheral tolerance ( 75 ).…”

“…Those autoreactive B cells are further eliminated through anergy, clonal deletion and irresponsiveness to respective T helper cells during maturation in spleen and activation in the germinal centers within spleen and lymph nodes as a result of peripheral tolerance ( 75 ). Although there remain small fractions of autoreactive B cells present in the bloodstream of healthy individuals, they lack the abilities to enter the germinal centers and produce high affinity auto-antibodies to self-antigens ( 77 – 79 ), presenting minimal or no risks in the elicitation of autoimmune diseases.…”

Negative feedback by NUR77/Nr4a1 restrains B cell clonal dominance during early T-dependent immune responses

“…Serum was harvested from blood collected by lateral tail vein sampling or cardiac puncture postmortem. OVA-specific and NP-specific IgG1 ELISA was performed as described ( Brooks et al, 2020 ; Tan et al, 2020 ). Briefly, ELISA plates were coated with NP conjugates (NP1-RSA, NP25-BSA, NP10-BSA all from LGC Biosearch; NP3-OVA, NP7-OVA, NP9-OVA and NP19-OVA were conjugated in-house as described above), OVA (Sigma Aldrich), BSA (Research Products International) or HEL antigen (10μg/mL; Sigma Aldrich), samples were added, and HRP-labeled anti-IgG1 antibodies (Southern Biotech) were used to detect plate-bound IgG1.…”

Covid-19 a triggering factor of autoimmune and multi-inflammatory diseases

“…The main influence on an adequate B cell response is the presence of a T-cell that is specific for a certain antigen. The production of autoantibodies is precisely organized by the presence of T-cells [72] . Although many different mechanisms that are controlling self-reactive B cells are known, in the case of autoimmune diseases, central and peripheral mechanisms of tolerance fail [72] .…”