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The Aging Immune System
Published in Constantin A. Bona, Francisco A. Bonilla, Textbook of Immunology, 2019
Constantin A. Bona, Francisco A. Bonilla
Concurrent with the decline in specific anti-microbial humoral immunity, the amount of self-specific antibodies increases. These are commonly of the “natural autoantibody” type (see Chapters 5 and 12), i.e., low-affinity polyspecific IgM. The majority of these arise from CD5+ B cells, whose specificity repertoire is heavily skewed toward natural autoantibodies. The percentage of CD5+ B cells increases with age. Chronic lymphocytic leukemia is almost exclusively a disease of the aged. Malignant clones are predominantly CD5+ and autoantibody-producing. The amount of autoantibodies with higher affinity and more restricted binding, both organ-specific (e.g., thyroglobulin), and non-specific (e.g., DNA) also increase with aging. In one study, two-thirds of people over age 60 had either anti-nuclear antibodies, thyroglobulin antibody, or circulating rheumatoid factors. The amount of non-organ-specific autoantibody is highest in the elderly with chronic illness.
Lymphocyte and plasma cell malignancies
Published in Gabriel Virella, Medical Immunology, 2019
Juan Carlos Varela, Gabriel Virella
A large proportion of patients with CLL is asymptomatic and does not require any treatment but rather close surveillance. Patients are monitored for the development of findings that indicate the need for treatment. These include the following: (1) symptoms such as fever, night sweats, chills, weakness, and weight loss; (2) rapid lymphocytosis (doubling within 6 months); (3) extranodal involvement; (4) evidence of bone marrow failure secondary to involvement by CLL; and (5) repeated infections. Treatment consists of combination chemotherapy; the most common regimens include bendamustine/rituximab (monoclonal antibody to CD20), fludarabine/cyclophosphamide/Rituximab, and single-agent treatment with ibrutinib (a Bruton's tyrosine kinase inhibitor). Cure is not achieved with the aforementioned regimens, but prolonged disease control is possible. To date, the only known curative treatment for CLL is allogeneic stem cell transplantation. However, this approach can be highly toxic and is reserved for younger, fitter patients.
Practical Approach to Molecular Biology in Hematopathology
Published in Harold R. Schumacher, William A. Rock, Sanford A. Stass, Handbook of Hematologic Pathology, 2019
Anwar Mikhael, Harold R. Schumacher
a. Chronic Lymphocytic Leukemia. The diagnosis of chronic lymphocytic leukemia (CLL) can be easily rendered based on clinical and morphologic criteria. The lymphocytes of CLL are mature B cells, and virtually all CLL lymphocytes rearrange their Ig heavy and Ig light chains. TCR β-chain rearrangement is present in about 10% of cases.
Protein kinase 2 (CK2): a potential regulator of immune cell development and function in cancer
Published in Immunological Medicine, 2021
Kazim Husain, Tanika T. Williamson, Nadine Nelson, Tomar Ghansah
Consistent with studies in solid tumors, the overexpression of CK2 and its regulation of apoptosis also occurs in blood malignancies. Increased CK2 activity and protein expression have been detected in plasma cells of multiple myeloma patients compared to control subjects. In vitro inhibition of CK2 activity had a cytotoxic effect on multiple myeloma plasma cells and increased their sensitivity to the chemotherapeutic agent, melphalan [38]. In fact, CX-4945, a small molecule inhibitor of CK2 [39] has been tested in a Phase I clinical trial in patients that have relapsed, experienced refractory multiple myeloma or have advanced solid tumors. In human T cell acute lymphoblastic leukemia (T-ALL), activation of the PI3K/AKT pathway is attributed to reduced phosphatase activity of PTEN. This occurs when CK2 becomes overexpressed, which causes the Bcr-Abl to activate AKT via the phosphorylation of PIP2 and PIP3 (Figure 1(A)) [40–42] This chain of events then increases cell proliferation, survival, growth, and angiogenesis. Contrastingly, the inhibition of CK2 promotes death within the cell (Figure 1(B)). Overexpression of CK2α contributed to the development of T cell leukemia and lymphoma [40,42]. Kim et al. [43] studied elevated CK2α expressions in patients with acute myeloid leukemia and found it to be an unfavorable prognostic marker and therapeutic target for inducing cell death. Martins and colleagues [44] found similar results with chronic lymphocytic leukemia patients.
What role for AHR activation in IL4I1-mediated immunosuppression ?
Published in OncoImmunology, 2021
Flavia Castellano, Armelle Prevost-Blondel, José L. Cohen, Valérie Molinier-Frenkel
The role of IL4I1 has been characterized in mouse models of transplanted and spontaneous melanoma, both in WT and IL4I1 deficient backgrounds, clearly showing that it facilitates tumor growth by inhibiting the antitumor cytotoxic T-cell response and remodeling the tumor immune microenvironment.9,10 These observations have been recently extended to a model of chronic lymphocytic leukemia.11 In line with this, clinical correlations have been reported between IL4I1 expression by stromal cells and invasion of the sentinel lymph nodes, a higher melanoma stage, and rapid relapse in human primary cutaneous melanomas, in which IL4I1 expression was analyzed by immunohistochemistry.12 Most interestingly, zones in which IL4I1 expression was concentrated were depleted of cytotoxic CD8+ T cells and enriched with regulatory FoxP3+ T cells. Moreover, IL4I1 was overexpressed in melanoma patients with progressive disease under treatment with the anti-PD-1 antibody nivolumab, suggesting a relation between IL4I1 expression and resistance to immune-checkpoint blockade.11
Case Series and Review of Hematological and Non-Hematological Malignancies in Aging Patients with Sickle Cell Disease in the Hydroxyurea Era
Published in Hemoglobin, 2020
Sanaa Rizk, David J. Axelrod, Rasaq Olaosebikan, Samir K. Ballas
A more recent analysis released by Brunson et al. [14] in 2017, compared cancer incidences in sickle cell disease patients to the general population. Six thousand, four hundred and twenty-three sickle cell disease patients were identified using the California database from the Office of Statewide Health Planning and Development. Compared to the California population, sickle cell disease patients had a 72.0% increased risk of hematological malignancies and 38.0% reduced risk of solid tumors. There was a 2-fold increased risk of leukemia, specifically acute myeloid leukemia and chronic lymphocytic leukemia. This risk was increased by 4-fold in more severe sickle cell disease. There was a 38.0% reduced risk of solid tumors, specifically, there was a lower risk of breast cancer and male genital cancers. The cancer incidence was different from the English study [13], most likely due to different recruitment practices (hospital coding) rather than using the highly validated registry data in the California study [14]. Brunson et al. [14] also commented on the effect of HU on cancer incidence and mentioned no difference in cancer incidence before and after HU in 1998.