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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
The structure of GALT is similar throughout the gastrointestinal tract with prominent B-cell follicles with intervening T-cell zones. CD4+ T cells in the outermost zone intermingle and interact with antigen-exposed B cells. GALT contains a marginal zone that resembles the splenic marginal zone and is surrounded by and merged with the memory B-cell population (Figure 10.1). Splenic and GALT marginal zone B cells are similar morphologically and are medium-sized cells with cleaved nuclei. These B cells are CD27+IgM+ and do not express high levels of IgD. Splenic marginal zone B cells have mutations in their IgHV genes that are acquired in the germinal centers of GALT. The GALT marginal zone also contains B cells with mutations in IgHV. Internal to and overlapping with the marginal zone is the mantle zone of IgD high naive B cells. The broadest aspect of the often narrow, crescent-shaped mantle zone faces the antigen-exposed FAE. Memory B cells expressing predominantly IgA or IgM (but not IgD) are located on the periphery of the B-cell area of GALT. At the center of the follicle is the germinal center. B cells proliferate and mutate in the cell-dense dark zone of the germinal center and are selected for further antigen-driven mutation and maturation by T-follicular-helper (TFH) cells in the light zone.
Leukaemias of Mature B- and T/NK-Cells
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
Chlorambucil has now been largely replaced by fludarabine, which induces CR in about 40% when used as a monotherapy. Fludarabine (9-α-d-arabinofuranosyl 2-fluroadenine monophosphate) is a purine analogue, which is generally considered as the standard-of-care for previously untreated patients with CLL, either as a single agent or in combination with rituximab with or without the addition of cyclophosphamide (FCR). The incidence of CR is about 70%, many of which are MRD-negative and the LFS and overall survival appears to be longer with the addition of rituximab and/or cyclophosphamide, particularly in the cohort without poor-risk features. Indeed, FCR should probably be considered the treatment of choice for patients with mutated IgHV and no poor-risk features. Additional support for FCR’s efficacy for such patients have been garnered from the MD Anderson and the German CLL study groups, which collectively suggest that about 20% of all patients achieve long-term remission, and possible cure. The combination is also remarkably effective in patients with relapsed disease. A dose-modified FCR trial (FCR-Lite), with reduced doses of fludarabine and cyclophosphamide, was conducted in older patients and found to yield 77% CRs with only 13% grade 3/4 neutropenias.
The Immunoglobulin Variable-Region Gene Repertoire and Its Analysis
Published in Cliburn Chan, Michael G. Hudgens, Shein-Chung Chow, Quantitative Methods for HIV/AIDS Research, 2017
Thomas B. Kepler, Kaitlin Sawatzki
Each heavy chain gene is constructed from the recombination of one each of variable (IGHV), diversity (IGHD), and joining (IGHJ) genes. In humans and mice, these germline genes are arrayed along a single locus. In humans there are 46–54 IGHV genes (there is copy number polymorphism among individuals), followed by 23 IGHD genes, and then by 6 IGHJ genes. The light chain genes come in two types on two distinct genomic loci, kappa and lambda, and are recombined using two components rather than three (variable and joining). The stochastic selection of these germline genes constitutes antibody combinatorial diversity.
Refractory and relapsed hairy-cell leukemia (HCL): casting light on promising experimental drugs in clinical trials
Published in Expert Opinion on Investigational Drugs, 2023
BRAF is a key kinase in the mitogen-activated protein kinase (MAPK) pathway. Its mutation results in continuous BRAF activation and signaling to the RAS–RAF–MEK-ERK pathway. The immunoglobulin heavy chain variable region (IGHV) gene is also mutated in 90% of HCL patients [15]. In most patients, HCL is asymptomatic and diagnosed on a routine blood cell count examination for pancytopenia [16,17]. However, other patients present symptoms related to pancytopenia splenomegaly and recurrent infections. In addition, polyarteritis nodosa, cutaneous leukocytoclastic vasculitis, bone involvement or central PB and BM [18–22]. Trephine biopsy and immunophenotyping are recommended for establishing a diagnosis of HCL. HCL cells are strongly positive for pan-B cell antigens including CD19, CD20, and CD22 and the hairy-specific antigens CD11c, CD25, CD103, CD123 (bright). In addition, intense expression of CD200 is observed [21]. Most of the patients with HCL demonstrate an enlarged spleen. However, the lymph nodes are rarely enlarged [22].
Immunotherapy combinations for chronic lymphocytic leukemia: advantages and disadvantages
Published in Expert Opinion on Biological Therapy, 2023
Chronic lymphocytic leukemia (CLL) is a disorder of mature malignant B cells, characterized by a progressive accumulation of functionally incompetent lymphocytes [1]. It is the most common form of leukemia found in adults in Western countries. In the United States, an estimated 20,160 new cases and 4,410 deaths were reported for 2022 [2]. A diagnosis of CLL requires the detection of at least 5000 B-lymphocytes exhibiting the CD5 +/CD19 + and CD5 +/CD23 + immunophenotype per microliter of peripheral blood. In addition, the World Health Organization (WHO) recognizes small lymphocytic lymphoma (SLL) as the same disease entity as CLL; it demonstrates the same morphology and immunophenotype as CLL, but does not primarily involve the bone marrow (BM) and peripheral blood (PB) (SLL/CLL) [3]. Courses of CLL are heterogenous, ranging from indolent and requiring no treatment, to symptomatic and rapidly progressing disease. In the course of disease, the immunoglobulin heavy chain variable (IGHV) region mutational status in CLL cells has significant prognostic and predictive value. Patients with unmutated IGHV have shorter response duration to the treatment with immunochemotherapy [4,5]. Patients with 17p deletion (del (17p)), and/or TP53 mutation have the most unfavorable outcome as they are refractory to chemo- and chemoimmunotherapy with anti-CD20 monoclonal antibodies (Mabs), rituximab, or obinutuzumab (Obi) [6]. Treatment of CLL should be initiated only in symptomatic, progressive disease [7].
Ravaging SARS-CoV-2: rudimentary diagnosis and puzzling immunological responses
Published in Current Medical Research and Opinion, 2021
Tapan Kumar Mukherjee, Parth Malik, Radhashree Maitra, John R. Hoidal
This assay determines the efficacy of patient Abs to prevent viral infection in a laboratory setting and can be performed even when the infection has been cleared. Input samples comprise whole blood, serum or plasma. This assay is conducted in cell culture under conditions allowing SARS-CoV-2 growth (like Vero E6 cells). Concerns with this assay include the 3 to 5 days requirement besides detecting the non-ARS-CoV-2 Abs. When virus and healthy cells are grown with serially diluted patient Abs, the antibody titer can be computed for inhibiting viral replication. Neutralizing antibodies may be used to treat a SARS-CoV-2 infected person. The immunoglobulin heavy chain gene (IGHV) mutation status correlates with the clinical outcome of patients presenting with certain diseases54. A treatment option for SARS-COV-2 patients in past 6 months has been convalescent plasma therapy. Convalescent plasma is a ready source of antibody and may help patients recover. The low somatic hypermutation of BCR genes should provide a greater opportunity for success of the convalescent plasma therapy, as it can be more widely used in patients with different degrees (mild to severe) of infection. There are reports of the presence of antibodies to IGHV3 in patients recovering from SARS-COV-2, inferring that antibodies with low somatic mutation of IGHV are sufficient to neutralize viral antigens and may possibly be successfully used as therapy55.