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The Importance of Immune Cells in the Pathogenesis Of NEC
Published in David J. Hackam, Necrotizing Enterocolitis, 2021
Andres Gonzalez Salazar, David J. Hackam
ILC1s and ILC3s have been the subject of several studies showing their contribution to inflammatory disease of the gut. ILC1s accumulate in the inflamed intestinal epithelium, particularly in murine colitis models and in patients with inflammatory bowel disease (IBD) (12–14). ILC3s have been associated with a proinflammatory response involving IL-17 and INF-γ release. This response was seen in recombination activating gene 2–deficient (Rag2-/-) mice that fail to generate T and B lymphocytes (13, 14). Although there is still no direct link between ILCs and NEC, their involvement in IBD raises the possibility of NEC involvement (2).
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
Generation of Antigen-specific Receptors: The growth of B and T cells from pluripotent stem cells requires successive differentiation through a series of stages that starts in the bone marrow and ends in the thymus (T cells) or peripheral lymphoid tissue (B cells) (Marrack et al. 2000, Carding et al. 2002, Calame 2001). During differentiation lymphocytes are able to recognize self and non-self antigens through the expression of antigen-specific receptors known as T Cell Receptors (TCR) and B Cell Receptors (BCR) (Nemazee 2000). TCRs are comprised of ab or gd subunits whereas BCRs are composed of membrane-bound immunoglobulins (Fig. 1.1). Approximately 90% of peripheral blood T cells are ab+ and the remainder cells are gd+, although the proportion of the latter reaches 25–30% in the gastrointestinal mucosa and skin.2 The generation of TCRs and BCRs creates an impressive repertoire in the order of > 1014 through combinatorial joining of V, D and J (b and d chains) or V and J (Fig. 1.2). Recombination is triggered by IL-7 and involves recombination-activating gene-1 and -2 (RAG-1 & -2) and a DNA repair enzyme (metallo-b-lactamase) encoded by the gene Artemis (Hesslein and Schatz 2001). The deficiency of the RAG enzymes, IL-7 receptor- and the Artemis gene product causes Severe Combined Immunodeficiency (SCID). A partial deficiency of RAG-1 & -2 causes Omenn syndrome. The BCR is capable of recognizing small and large peptides, in contrast, the TCR recognizes small stretches of linear peptides of 10–12 amino-acids in length.
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 junctional sequences between the V, D, and J regions created in the CDR3 region of IgH genes by RAG-mediated recombination during B-cell development are unique to an individual B-cell or B-cell clone. This unique “clonal signature” can therefore be used to track the distribution and migratory potential of B cells and their plasma cell progeny. This methodology demonstrated that B cells in the germinal centers of human Peyer's patches and lamina propria plasma cells can be developmentally linked and that clones of plasma cells can be widely distributed along the gut, consistent with dissemination of GALT-derived plasma cell precursors via the blood. The identification of clonally related cells in the intestinal lamina propria at multiple sites also is consistent with the idea that GALT produces large numbers of progeny from a single founder B cell. Whether chronic exposure to an excess of an antigen in the gut affects this process is not known. The iterative processes of B cells competing for interactions with follicular dendritic cell ligands then cognate, and soluble TFH interactions result in selection of optimized B-cell clones for maturation into memory and plasma cells that exit the germinal centers for recirculation and tissue homing (see Figure 10.4).
Tryptophan metabolites modulate inflammatory bowel disease and colorectal cancer by affecting immune system
Published in International Reviews of Immunology, 2022
RAG1 (recombination activating gene 1) is a molecule which conducts the recombination process during production of antibodies and T cell receptors (TCR) and is a critical factor for competent performance of adaptive immunity [159]. AOM/DSS mice model of colitis-associated colorectal cancer indicated that RAG1/IDO1 double-knockout mice had significantly decreased number of tumors, compared with RAG1−/− mice [151]. Lu et al. showed that 1-methyl-L-tryptophan (L-1MT), an IDO inhibitor, leads to apoptotic cell death of colon cancer cells in vitro and reduces tumors number and size in-vivo. Interestingly, they observed that L-1MT did not bring further therapeutic effects in IDO−/− mice but could help in RAG1−/− mice [125]. These findings reveals that participation of kynurenine pathway in carcinogenesis is more complex than our present knowledge and other mechanisms except the immune mechanisms can be involved in its effects.
Unfolding the Role of Splicing Factors and RNA Debranching in AID Mediated Antibody Diversification
Published in International Reviews of Immunology, 2021
Ankit Jaiswal, Amit Kumar Singh, Anubhav Tamrakar, Prashant Kodgire
Humans are surrounded by millions of pathogens that have the potential to cause various types of disease. To combat against these pathogens or antigens our immune cells produce a diverse range of antibodies. Antibody diversity is an exceptional feature of B-cells that produced millions of different antibodies from just a handful number of immunoglobulin genes [1]. B-cells diversify its antibody archive even before it had encountered an antigen via the process of V(D)J recombination. V(D)J recombination increases antibody repository by rearrangements of the variable (V), diversity (D) and joining (J) gene segments mediated by RAG recombinase [2]. In contrast to V(D)J recombination, Somatic Hypermutation (SHM) and Class Switch Recombination (CSR) further diversify antibody upon antigenic stimulation of B-cell. SHM and CSR are mediated by a key genome mutator enzyme widely known as activation-induced cytidine deaminase (AID) encoded by the AICDA locus [3–5]. SHM is confined to the variable regions of light and heavy chain, where AID induced point mutations are unfaithfully repaired giving rise to antibody, having either higher or lower affinity against an antigen, and subsequently, the higher affinity antibodies are selected in the process of clonal selection. CSR is a DNA deletion event taking place in the constant region of IgH. AID mediated SHM and CSR required the transcription of the target genes and AID is found to be localized with splicing factors. This review unfolds the potential role of splicing factors in AID mediated antibody diversification.
Clinical value of RAG1 expression and IKZF1 deletions in Philadelphia negative pediatric B cell precursor acute lymphoblastic leukemia
Published in Pediatric Hematology and Oncology, 2020
Salah Aref, Nada Khaled, Nadia El Menshawy, Mohamed Sabry, Mohamed Al Agder
The recombination-activating gene 1 (RAG1) is the member of a recombination-activating gene family which plays an important role in the rearrangement and recombination of the genes of immunoglobulin and T-cell receptor molecules and is critical for the generation of T- and B-cells. However, the abnormalities in RAG family members are observed quite commonly in lymphoid malignancies.13,14 In B-cell progenitors, IKZF1 is required to induce RAG1 and RAG2 expression, many reports suggested that RAG1 high expression works together with IKAROS dysfunction (product of IKZF1) to drive oncogenesis of B-ALL, which have significance in an integrated prognostic model for adult ALL.15,16 Moreover, the interrelation between RAG1 and IKZF1 genes has been studied by Han et al16 who concluded that RAG1 is a direct target of tumor suppressor gene IKZF1. And that IKZF1 deletion is significantly correlated with high RAG1 expression.