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Basics of Allergy
Published in Pudupakkam K Vedanthan, Harold S Nelson, Shripad N Agashe, PA Mahesh, Rohit Katial, Textbook of Allergy for the Clinician, 2021
Rafeul Alam, Dipa K Sheth, Magdalena M Gorska
B cell precursors are not subjected to extensive deletions; self-reactive B cells undergo another round of receptor gene rearrangement (receptor editing) to replace an auto-reactive BCR with a normal BCR. In the early phase of differentiation, immature T cells express both CD4 and CD8 co-receptors (double-positive cells) (Sebzda et al. 1999, Germain 2002) CD4 T cells are selected through interaction with class II MHC molecules and CD8 T cells through interaction with class I MHC molecules.
Mucosal B cells and their function
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Jo Spencer, Edward N. Janoff, Per Brandtzaeg
Somatic hypermutation changes on average over 5% of the variable region sequence of human mucosal immunoglobulins. Mutation frequencies in plasma cells in the lamina propria of the gut, salivary gland, and other mucosal tissues exceed those from plasma cells from the systemic compartment, including the splenic red pulp, independent of isotype. Mutation frequencies in the 250–350 nucleotide IgV sequence also provide an estimate of the number of cell divisions with approximately one mutation per two cell divisions. A plasma cell with the average number of 15 IgHV mutations is likely to have undergone approximately 30 divisions, with the resulting greater than 109 potential progeny from a single cell, providing tremendous capacity for generating plasma cell precursors. That the estimated progeny (up to 1018 cells) may exceed the number of cells in the human body by a million-fold predicts that intestinal plasma cells show diverse antigen reactivity, are turning over rapidly, and undergo extensive cell death. Like plasma cells in bone marrow, a subset of intestinal plasma cells is very long-lived. Antibody diversity may also be facilitated by receptor editing in which the initial κ light chain is replaced by a λ chain, a process that also limits initially autoreactive B cells.
The Etiopathogenesis of Autoimmunity
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Howard Amital, Yehuda Shoenfeld
Tolerance is the process that neutralizes autoreactive cells; therefore, whenever this process is disrupted, autoimmune manifestations might develop. Several mechanisms are engaged in the maintenance of this fragile equilibrium. Clonal deletion of immature B cells takes place in the bone marrow, and of autoreactive B cells within the T-cell zones of the spleen and lymph nodes.45,46 Tolerance of B cells can be obtained via the lack of T cell assistance and by “receptor editing”, a mechanism that changes the specificity of the B-cell receptor when an autoantigen is encountered.47
How do nuclear factor kappa B (NF-κB)1 and NF-κB2 defects lead to the incidence of clinical and immunological manifestations of inborn errors of immunity?
Published in Expert Review of Clinical Immunology, 2023
Nazanin Fathi, Hanieh Mojtahedi, Marzieh Nasiri, Hassan Abolhassani, Mahsa Yousefpour Marzbali, Marzie Esmaeili, Fereshte Salami, Furozan Biglari, Nima Rezaei
NF-κB in hematopoietic cells indirectly controls B cell lymphopoiesis by maintaining an appropriate amount of TNF production. Pro-B cells are driven by the development of common lymphoid progenitor (CLP) which gives rise to hematopoietic stem cells (HSC). Pro-B cells undergo a sequential genetic rearrangement of heavy chain and surrogate light chains along with the signaling molecules, Igα and Igβ, resulting in the expression of the pre-B-cell receptor (pre-BCR). Pre-B cells successfully undergo light-chain gene rearrangements and become immature B cells with the expression of BCR (IgM) on their surface. Then, immature B cells are tested for autoreactivity (receptor editing), marked by enhanced NF-κB-mediated induction of Bcl-2. It is indicated that the critical function of NF-κB in this process is the inhibition of apoptosis [41].
Chronic immune thrombocytopenia in a child with X-linked agammaglobulinemia-an uncommon phenotype
Published in Platelets, 2022
Jing Yin, Jijun Ma, Xiaoxue Liu, Jingyue Xia, Qi Ai, Chongwei Li
During the early B-cell development, Ig gene recombination produces many autoreactive B cells that are effectively removed by immune tolerance mechanisms such as apoptosis, clonal anergy, and receptor editing. However, the elimination of these autoreactive B cells fails when BCR signaling is impaired. A study by Eric Meffre et al. concluded that central B-cell tolerance checkpoints are abrogated in the absence of BTK, and the antibodies expressed by XLA B cells are self-reactive and highly polyreactive [11]. Robbins et al., (1969) reported autoimmune hemolytic anemia in a 6-year-old boy with congenital sex-linked hypogammaglobulinemia [12]. Further, this child developed a positive Coombs test for two years and responded well to corticosteroids, although he relapsed when corticosteroids were discontinued [12], which is similar to our patient.
Burning controversies in NETs and autoimmunity: The mysteries of cell death and autoimmune disease
Published in Autoimmunity, 2018
Self-antigen recognition by B cells and production of autoantibodies is a complex process that depends on self-reactive B and T cells but that is counteracted by central and peripheral tolerance mechanisms. Most self-reactive B and T cells are deleted from the mature repertoire during development, but this mechanism is not failsafe, as lymphocytes that reach the periphery have a broad antigen recognition capacity, including the ability to recognize self-antigens. It is estimated that about 75% of B cells at the immature B cell stage may react to nuclear autoantigens, yet only 40% of newly emigrated B cells have this specificity [78]. The reduction in autoreactive capacity is achieved by central tolerance mechanisms including clonal deletion, anergy and receptor editing. The remaining, potentially autoreactive B cells in the periphery are kept in a quiescent state by peripheral tolerance mechanisms. Research has identified multiple checkpoints for tolerance induction and enforcement. It stands to reason that any condition that increases the risk of autoreactivity, such as the release of “modified self” in the form of NETs, may be balanced by specialized tolerogenic mechanisms. Evidently, intense NET release during a variety of infections does not (usually) elicit the production of autoantibodies. Plausibly, multiple defects in NET clearance may predispose to autoimmunity, although a specific NET clearance pathway that leads to enhanced tolerance has not yet been identified.