![]() ![]() Transgenic mice overexpressing FcγRIIb on B cells display a reverse phenotype, with reduced immune responses and resistance to autoimmune disease 40. Thus, FcγRIIb-deficient mice present an exacerbated immune response 32, 33, are prone to inducible and spontaneous autoimmunity 34, 35, 36, 37, 38 with more autoreactive GC B-cell clones 39, and are protected from malaria 26. FcγRIIb appears to play a remarkably similar role in mouse and human biology. Naturally occurring variations have also been described in the promoter of human FCGR2 B, and it has been suggested these too may predispose to SLE 30, 31. Humanised mice reconstituted with cord blood cells bearing the 232T polymorphism display defective B-cell development and produce autoantibodies 29. In humans, a single-nucleotide polymorphism in FCGR2B leading to the replacement of an isoleucine by a threonine at position 232 (T232I) results in reduced inhibitory function 21, 22, and has been associated with susceptibility to SLE 23, 24, 25, 26, 27, but protection against malaria 26, 28. This question is important, as reduced FcγRIIB expression or function has been associated with autoimmune disease in both humans and mice. The inhibitory receptor FcγRIIb negatively regulates signalling induced by the BCR 19, 20 and is involved in the control of autoimmunity however, its role in the regulation of specific B-cell tolerance checkpoints has not been determined. ![]() The strength of BCR signalling is thought to be important in all of these mechanisms, suggesting that inhibitory receptors regulating the BCR threshold of activation may be central actors in B-cell tolerance. It has been suggested that autoantigens need to be present within the germinal center to properly control autoreactive clones, either by apoptosis 15, 16 or by redemption of their B-cell receptor (BCR) via corrective somatic hypermutation 7, 17, 18. Germinal center (GC) tolerance mechanisms are still only partially characterised. The nature and location of specific autoantigens seem to determine which tolerance mechanism is used, with deletion being preferentially induced by high-avidity antigens while low-avidity interactions tend to drive receptor editing and anergy 9, 10, 11. Autoreactive B cells can also be excluded from the B-cell follicles, with a lack of T cell help precipitating their subsequent apoptosis 13, 14. Receptor editing has also been shown to play a key role in central tolerance in the BM 4, 11, 12. Clonal deletion and anergy were first proposed as major mechanisms regulating B-cell tolerance 2, 3, 5, 8, 9, 10. The last two checkpoints, taking place outside the BM, contribute to peripheral tolerance 1, 6, 7.Īt a cellular and molecular level, several mechanisms of B-cell tolerance have been described. Finally, following B-cell activation, autoreactive B cells may also be eliminated from the germinal center or corrected by somatic hypermutation, further reducing the chance of generating potentially harmful autoreactive memory B cells and autoantibody-producing plasma cells. Autoreactive B cells that manage to leave the BM are subjected to a second checkpoint as they transit from immature to mature B cells in the blood and spleen, leading to a further decrease in the frequency of autoreactive clones among mature B cells 5, 6. First, the self-reactivity of immature B cells in the bone marrow (BM) is tested, with a large fraction of autoreactive clones being eliminated (a process called central tolerance) 2, 3, 4. The first two checkpoints shape the pre-immune repertoire, while the third occurs following antigen-mediated activation 1. Particularly, we discuss several aspects of challenges in this field and highlight the efforts to develop potential solutions, in the era of high-throughput sequencing of the immune repertoire.īCR High-throughput sequencing Immune repertoire TCR.Three major tolerance checkpoints during B-cell development control the generation of autoreactive B-cell clones. In this article, we review the history of immune repertoire studies, in terms of technologies and research applications. The massive paralleled sequencing technology suits perfectly the researches on immune repertoire. Before the emergence of high-throughput sequencing, the studies on immune repertoire were limited by the underdeveloped methodologies, since it was impossible to capture the whole picture by the low-throughput tools. Immune repertoire is defined as the sum of T cell receptors and B cell receptors (also named immunoglobulin) that makes the organism's adaptive immune system. ![]() The diversity of T and B cells in terms of their receptor sequences is huge in the vertebrate's immune system and provides broad protection against the vast diversity of pathogens. ![]()
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