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Association of blood IgG with tumor necrosis factor-alpha and clinical course of chronic lymphocytic leukemia.

ABSTRACT: The intrinsic humoral immunodeficiency of chronic lymphocytic leukemia (CLL) is often managed with immunoglobulin replacement therapy (IgRT) to maintain IgG levels in the low-normal range (6-8?g/L) but optimal targets for IgG and timing to commence IgRT are unclear. IgG levels fell near 6?g/L at rates of -0.85±0.14?g/L/year in 51 patients who required treatment for CLL within 4.5±0.4?years from initial diagnosis and?-?0.27±0.04?g/L/year in 40 patients with progressive disease who remained untreated after 8.5±0.5?years. In contrast, endogenous IgG levels remained above 8?g/L in patients with highly indolent disease (n?=?25) and TNF? and beta-2-microglobulin (?2M) in blood decreased when IgRT was used to increase IgG levels over 9?g/L. At 15?g/L but not 5?g/L, the IgRT product Hizentra® inhibited B cell receptor (BCR)-activation, TNF? production, and survival in vitro, particularly of CLL cells that spontaneously made little TNF?. These findings suggest deterioration of the humoral immune system is associated with progressive CLL and altering the dosing of IgRT to achieve higher than conventional IgG target levels may have therapeutic activity.

SUBMITTER: Spaner DE

PROVIDER: S-EPMC6156707 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Association of blood IgG with tumor necrosis factor-alpha and clinical course of chronic lymphocytic leukemia.

Spaner David E DE Venema Robertson R Huang Justin J Norris Peter P Lazarus Alan A Wang Guizhi G Shi Yonghong Y

EBioMedicine 20180830

The intrinsic humoral immunodeficiency of chronic lymphocytic leukemia (CLL) is often managed with immunoglobulin replacement therapy (IgRT) to maintain IgG levels in the low-normal range (6-8 g/L) but optimal targets for IgG and timing to commence IgRT are unclear. IgG levels fell near 6 g/L at rates of -0.85±0.14 g/L/year in 51 patients who required treatment for CLL within 4.5±0.4 years from initial diagnosis and - 0.27±0.04 g/L/year in 40 patients with progressive disease who remained untrea ...[more]

PMID: 30174282

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Project description:The immunoglobulin (Ig) variable region (V) genes expressed by IgM chronic lymphocytic leukemia (CLL) B cells display little or no somatic mutations. However, preliminary findings have shown that Ig V genes of IgA and IgG CLLs may be somatically mutated, suggesting that isotype-switched CLLs may represent a "subtype" of the disease. To investigate the degree and nature of somatic mutations and the role of antigen (Ag) in the clonal selection and expansion of isotype-switched CLLs, and to determine whether specific oncogene or tumor suppressor gene mutations are associated with isotype-switched CLLs, we analyzed the expressed Ig VH gene, bcl-1 and bcl-2 proto-oncogene, and p53 tumor suppressor gene configurations of 3 IgA-, 1 IgG-, and 1 IgA/ IgG-expressing CLLs. These isotype-switched CLL B cells expressed surface HLA-DR, CD19, CD23, and CD5, and displayed no alterations of the bcl-1 and bcl-2 oncogenes and the p53 tumor-suppressor gene. The cDNA VH-D-JH gene sequence was joined with that of the C alpha gene in the B cells of the three IgA CLLs, and with that of the C gamma gene in the IgG CLL B cells. In the IgA/IgG-coexpressing CLL B cells, identical VH-D-JH cDNA sequences were spliced to either C alpha or C gamma genes. In all five CLLs, the pattern of C mu DNA probe hybridization to the digested genomic DNAs was consistent with deletion of the C mu exon from the rearranged Ig gene locus, suggesting that these CLL B cells had undergone DNA switch recombination. In one IgA CLL, the expressed VH gene was unmutated. In all other class-switched CLLs, the Ig VH segment gene was mutated, but the point mutations were not associated with intraclonal diversification. In one IgA and in the IgA/IgG-coexpressing CLL, the nature and distribution of the mutations were consistent with Ag selection. These findings suggest that IgA- and/or IgG-expressing CLLs represent, in their VH gene structure, transformants of B cells at different stages of ontogeny. They also suggest that Ag may play a role in the clonal selection of some of these isotype-switched leukemic cells, but bcl-1 and bcl-2 oncogene rearrangements and p53 tumor suppressor gene mutation are not associated with the pathogenesis of isotype-switched CLLs.

Dataset Information

Association of blood IgG with tumor necrosis factor-alpha and clinical course of chronic lymphocytic leukemia.

Publications

Association of blood IgG with tumor necrosis factor-alpha and clinical course of chronic lymphocytic leukemia.

Similar Datasets

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