Central tolerance

Central tolerance is not perfect, so peripheral tolerance exists as a secondary mechanism to ensure that T and B cells are not self-reactive once they leave primary lymphoid organs. Peripheral tolerance is distinct from central tolerance in that it occurs once developing immune cells exit primary lymphoid organs (the thymus and bone-marrow), prior to their export into the periphery. Central tolerance is essential to proper immune cell functioning because it helps ensure that mature B cells and T cells do not recognize self antigens as foreign microbes. More specifically, central tolerance is necessary because T cell receptors (TCRs) and B cell receptors (BCRs) are made by cells through random somatic rearrangement. This process, known as V(D)J recombination, is important because it increases the receptor diversity which increases the likelihood that B cells and T cells will have receptors for novel antigens. Junctional diversity occurs during recombination and serves to further increase the diversity of BCRs and TCRs. The production of random TCRs and BCRs is an important method of defense against microbes due to their high mutation rate. This process also plays an important role in promoting the survival of a species because there will be a variety of receptor rearrangement within a species meaning that there is a very high chance of at least one member of the species having receptors for a novel antigen. While the process of somatic recombination is essential to a successful immune defense, it can lead to autoreactivity. For example, lack of functional RAG1/2, enzymes necessary for somatic recombination, has been linked to development of immune cytopenias in which antibodies are produced against the patient’s blood cells. Due to the nature of a random receptor recombination, there will be some BCRs and TCRs produced that recognize self antigens as foreign. This is problematic since these B and T cells would, if activated, mount an immune system attack against self if not killed or inactivated by central tolerance mechanisms. Therefore, without central tolerance, the immune system could attack self, which is not sustainable and could result in an autoimmune disorder. The end result of tolerance is a population of lymphocytes that are not reactive to self-antigens, but may be able to recognize foreign, non-self antigens depending on the randomly arranged receptor. Importantly, lymphocytes can only develop tolerance towards antigens that are present in the bone marrow (for B cells) and thymus (for T cells). Immature B cells in the bone marrow undergo negative selection when they bind self peptides. Properly functioning B cell receptors recognize non-self antigen or pathogen associated molecular proteins (PAMPs). Main outcomes of autoreactivity of BCRs T cell central tolerance occurs in the thymus. T cells undergo positive and negative selection.