Question 3: What is the problem with B cell tolerance?

@Xia Jiang and Nastya Kharlamova
Great posts.
Some might refer to me as a "T cell person" but I think one of the problems with B cell tolerance - which you briefly mentioned - is that it relies on T cell tolerance. Without proper help from CD4+ in germinal centers, there cannot be good maturation of antibodies. In normal condition, self-specific B cells will not receive such helps from T cells. However, if there is a break in T cells tolerance, somatic hypermutation will occur and maturation of those B cells will give rise to high affinity antibodies which could be pathogenic (whereas low affinity self-specific antibodies might not be)

To Xia Jiang: thanks for your comment. Yes, you are right, environmental factors such as infectious agents could also generate the breakdown of B cell tolerance for instance by molecular mimicry of the of the immunodominant epitope. Despite amino acid sequence of infectictious ag

@Nastya Kharlamova. Thank you for your answer, I agree with your on the two reasons why B cell tolerance are more difficult to achieve compared with T cell tolerance. Do you think environmental factors such as infectious agents or tissue damage due to some other reasons could also generate the breakdown of B cell tolerance?

From my point of view B cell tolerance is more difficult to achieve as T cell tolerance first of all because of the multiple overlapping mechanisms at several checkpoints in B cell differentiation. The B cell repertoire is generated in two stages: there is V(D)J recombination occurs in the first stage within the Bone marrow and during this stage the “pre-immune repertoire” is created. The second stage occurs in the germinal centres following antigen stimulation and co-stimulatory signals from T-cells. This stage involves somatic hypermutation of immunoglobulin variable region genes.
One of the question/challenge that makes B cell tolerance so complicated is bone marrow microenvironment by the meaning of the presence of specific niche (with different cytokines and chemoattractants) for self antigen presentation to newly generated B cells.
Another mechanism which is also appear during the central B cell tolerance and is under the investigation is what factors regulate the proper BCR signaling in immature B cells and what defines the threshold for signaling that separate negative and positive selection.
Regarding breaking B cell tolerance there are several evidences suggesting that one of the main cause of the development of autoreactive B cells is gene mutations and polymorphisms. For instance, risk alleles encoding variants altering BCR signaling, such as PTPN22 alleles associated with the development of Rheumatoid Arthritis, SLE, and type 1 diabetes, interfere with the removal of developing autoreactive B cells. It´s also known that BCR signaling in immature B cells plays an essential role in sensing self antigen bound to autoreactive BCRs. Alterations in B cell receptor and Toll-like receptor signaling pathways results in a defective central checkpoint and developing autoreactive B cells in the bone marrow. Interestingly, that decreased numbers of regulatory T cells and increased concentration of B cell activating factor may interfere with the peripheral removal of autoreactive B cells. This supported by the fact that CD40L- and MHC class II-deficient patients only have defects in peripheral B cell tolerance.