Genetics of immunoglobulins: Ontogenic, biological, and clinical implications
Gabriel Virella in Medical Immunology, 2019
During ontogeny and functional differentiation, the H chain genes may undergo further gene rearrangements that result in immunoglobulin class switching. As the B lymphocytes differentiate into plasma cells, one heavy-chain C gene segment can be substituted for another without alteration of the VDJ combination (Figure 7.3). In other words, a given variable region gene can be expressed in association with more than one heavy-chain class or subclass, so that at the cellular level, the same antibody specificity can be associated with the synthesis of an IgM immunoglobulin (characteristic of the early stages of ontogeny and of the primary response) or with an IgG immunoglobulin (characteristic of the mature individual and of the secondary response). Immunoglobulin class switching is the result of an intrachromosomic recombination between the switch region of Cμ and one of the downstream switch regions. This recombination event leads to looping-out deletion of the intervening DNA segment and joins the rearranged V region to a different C region (Cγ, Cε, Cα).
Molecular Mechanisms Controlling Immunoglobulin E Responses
Thomas F. Kresina in Immune Modulating Agents, 2020
The second type of signal responsible for Ig class switching involves cytokine-induced expression of particular germline CH transcripts via cytokine activation of the corresponding germline promoter. Immunoglobulin class switching has been shown to be preceded by the expression of germline transcripts in the area surrounding the switch region. Also, certain cytokines have been shown to regulate specific Ig class switching differentially through the induction of particular germline transcripts. For example, it has been demonstrated that the addition of IL-4 to lipopolysaccharide (LPS) cultures of B cells induces high levels of germline ∈ and γI transcripts that correlate with the amount of IgE and IgG1 induction, respectively [76,78]. More recently, IL-13 has been shown to induce germline IgE heavy-chain gene transcription in purified B cells, even in the presence of neutralizing anti-IL-4 antibody, confirming its independent role in IgE production [25]. In contrast, IFN-γ has been shown to suppress the IL-4-induced germline e transcription. Furthermore, regulation of IgE switching seems to occur through these cytokines’ antagonistic effects on the germline ∈ promoter [79]. These observations seem to support a model in which specific heavy-chain germline transcription always precedes switch recombination and in which type 1 versus type 2 cytokines differentially regulate the switching process to C∈.
Immune Reconstitution after Hematopoietic Stem Cell Transplantation
Richard K. Burt, Alberto M. Marmont in Stem Cell Therapy for Autoimmune Disease, 2019
Immunoglobulins, similar to TCR genes, are generated by somatic recombination of V(D)J genes.65 Similar to development of the thymus, immunogobulins are found only in vertebrates and first arise in the evolutionarily more primitive jawless vertebrates (hagfish and lamprey).3 Immunoglobulin class switching (e.g., IgM to IgG) appears later in amphibians, and somatic hypermutation occurs even later with development of germinal centers that first arise in warm-blooded vertebrates (birds and mammals). For all vertebrates, TCRab repertoire diversity occurs in the thymus. In contrast, B cell receptor (BCR) diversity occurs in different lymphoid tissues for different vertebrate species. For birds, immunoglobulin diversification occurs in the bursa of Fabricius, a cloacal gut associated lymphoid tissue.3 For humans, B cell development begins in the bone marrow and is completed in the germinal center of lymph nodes (Figs. 3-4). Within the bone marrow, stem cell differentiation into B lymphocyte lineage has two major developmental checkpoints, a pre-B cell that expresses the pre-B cell receptor (pBCR) and an immature B cell that expresses the mature BCR. At both B cell selection checkpoints, signaling through either the pBCR or BCR causes either apoptosis or proliferation.66
Immunophenotype involved in IgG4-related disease
Published in Modern Rheumatology, 2019
Satoshi Kubo, Shingo Nakayamada, Yoshiya Tanaka
Since these results were based on comprehensive analysis, plasmablast and Tfh cells, the importance of which had already been shown in previous reports, were indicated to be more important than other immunocompetent cells. However, abnormal differentiation of B cells has been seen in other autoimmune diseases such as systemic lupus erythematosus and Sjögren syndrome as well, and could also be central pathological role in these diseases. Is the characteristic of IgG4-RD in comparison with these diseases is B cell immunoglobulin class switching to IgG4? Meanwhile, the mechanism of this class switching to IgG4 is not well known. Although cytokines such as IL-4, IL-10, and IL-21 has been considered as the factor which can induce immunoglobulin class switching to IgG4, these factors cannot be said to be specific only to class switching to IgG4, while promoting the B cell differentiation and class switching to other subtypes as well. Not only interactions through cytokines but also cell–cell contact between T cells and B cells may be also important, and investigation of the mechanism how to promote immunoglobulin class switching to IgG4 is likely to lead elucidation of the pathological processes of IgG4-RD.
Primary cutaneous indolent B-cell lymphomas – a retrospective multicenter analysis and a review of literature
Published in Acta Oncologica, 2021
Magdalena Olszewska-Szopa, Marta Sobas, Kamel Laribi, Laura Bao Perez, Joanna Drozd-Sokołowska, Edyta Subocz, Monika Joks, Krzysztof Zduniak, Małgorzata Gajewska, Anna Kulikowska de Nalecz, Joanna Romejko-Jarosińska, Beata Kumiega, Anna Waszczuk-Gajda, Tomasz Wróbel, Anna Czyz
Indolent PCBCLs affect primarily adults at the age of 40–60 years. The pathogenesis of these lymphomas remains unclear. The potential role of infections in PCMZL etiopathology was suggested by some authors but has not been clearly confirmed yet [3]. The disease localizes preferably within the trunk, head and arms, with lesions that are heterogeneous in their appearance. Large wedge-shaped biopsy and excision biopsy, which enable histological analysis are the golden standard in the diagnostic process. CT scans are the recommended imaging studies although they are not reliable in cutaneous lesions assessment [4]. Bone marrow examination is not a part of the routine diagnostic workup in indolent PCBCLs. Histologically indolent PCBCLs usually differ from their systemic equivalents [2,5]. Only a small subset of PCMZLs shows diffuse proliferation of B cells while a vast majority of cases show evidence of immunoglobulin class switching. There is some evidence that t(14;18) and Bcl-2 expression may be useful for differentiation between PCFCL and systemic FL [6]. Both TNM and Ann Arbor classification does not appear as useful and reliable in the PCBCLs staging process, as in systemic lymphomas. In 2011 International Extranodal Lymphoma Study Group proposed a new tool for risk stratification, the Cutaneous Lymphoma International Prognostic Index – CLIPI (Supplementary file). However generally, indolent PCBCLs are characterized by a very good prognosis, since 5-year disease-specific survival is as high as 99% for PCMZL and 95% for PCFCL [1].
Th1, Th2, and Th17 cytokines in systemic lupus erythematosus
Published in Autoimmunity, 2020
Farhana Muhammad Yusoff, Kah Keng Wong, Norhanani Mohd Redzwan
IFN-γ is a type II IFN produced by CD4+ and CD8+ lymphocytes, NK cells as well as B cells [21,68]. Pathogenic mechanism of IFN-γ leading to autoimmunity remains unclear. However, the importance of IFN-γ to T cell differentiation and B cells immunoglobulin class switching has been a substantial contribution to adaptive immunity in autoimmunity [69]. The ability of IFN-γ to promote B cell class switching to more pathogenic autoantibodies in mice and activation of IgG Fc receptors and complement might also contribute to the severity of autoimmune disease [70]. Mutation of Roquinsan/san mice, a lupus model, leads to the reduction of IFN-γ mRNA decay, resulting in increased IFN-γ signalling and follicular helper T cells accumulation that increased autoantibodies production [71]. In addition, growing number of studies has reported the association of gene polymorphisms affecting IFN-γ and its production with SLE susceptibility. Single nucleotide polymorphism (SNP) affecting the locus that encodes IFN-γ showed significant association with SLE susceptibility [72]. Moreover, T cells of SLE patients that carried STAT4 risk allele increased the production of IFN-γ in response to IL-12, implying the association between strong genetic SLE risk variant in STAT4 and high IFN-γ production [73]. Furthermore, untreated SLE patients showed significantly higher IFN-γ response genes compared to healthy controls [74].
Related Knowledge Centers
- Antibody
- B Cell
- Immunoglobulin Heavy Chain
- Immunoglobulin M
- Isotype
- Ligand
- Epitope
- Immunoglobulin G
- B-Cell Receptor
- V(D)J Recombination