Somatic mutation of human immunoglobulin V genes in the X-linked HyperIgM syndrome.

Chu, Yu‐Waye; Marin, Elides; Fuleihan, Ramsay; Ramesh, Narayanaswamy; Rosen, Fred S.; Geha, Raif S.; Insel, Richard A.

doi:10.1172/jci117791

Cited by 51 publications

(30 citation statements)

References 40 publications

(36 reference statements)

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“…It should be noted that an alternative way to acquire somatic V H gene mutations has been described in the hyper-IgM syndrome because of a nonfunctional CD40 -CD154 interaction leading to no development of germinal centres (Durandy and Honjo, 2001). However, the mutation frequency in the hyper-IgM syndrome (usually o2%) (Chu et al, 1995;Monson et al, 2001;Weller et al, 2001) is below the cutoff level used to distinguish between mutated and unmutated CLL cases. Hence, it seems unlikely that the mutated CLL cases had acquired V H gene mutations by the alternative CD40-independent pathway.…”

Section: Discussionmentioning

confidence: 99%

Association between telomere length and VH gene mutation status in chronic lymphocytic leukaemia: clinical and biological implications

et al. 2003

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The immunoglobulin V H gene mutation status can divide B-cell chronic lymphocytic leukaemia (CLL) into two entities with a different clinical course. Cases with unmutated V H genes, considered to evolve from pregerminal centre (GC) cells, have a worse outcome compared to cases showing mutated V H genes, that is, post-GC derived. Also, telomere length has been reported to be of prognostic significance in CLL. Interestingly, telomerase becomes activated during the GC reaction and an elongation of the telomeres occurs in GC B cells. We performed telomere length and V H gene analysis in a series of 61 CLL cases, in order to investigate if the unique telomere lengthening shown in GC B cells could reflect the telomere status in the two subsets of mutated and unmutated CLL. A novel association was found between V H gene mutation status and telomere length, since significantly shorter telomeres were demonstrated in the unmutated group compared to the mutated group (mean length 4.3 vs 6.3 kbp). Shorter telomeres also constituted a subgroup with a worse prognosis than cases with longer telomeres (median survival 59 vs 159 months). Furthermore, the Ig gene sequence data revealed that samples with high mutations frequency (46%) had long telomeres (B8 kbp). Thus, both the telomere and V H gene mutation status in CLL appear linked, which may reflect the proliferative history of the clonal cells with regard to the GC reaction.

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Section: Discussionmentioning

confidence: 99%

Association between telomere length and VH gene mutation status in chronic lymphocytic leukaemia: clinical and biological implications

et al. 2003

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“…and X-linked lymphoproliferative disorder, who lack functional germinal centers, but do show some SHM. 43,44 Multiple other studies have also shown germinal centerindependent SHM. 45,46 Very recently, Warsame and associates showed evidence of ongoing mutations in microdissected monocytoid B cells.…”

Section: Cell Of Originmentioning

confidence: 90%

Recognizing nodal marginal zone lymphoma: recent advances and pitfalls. A systematic review

Brand

Krieken

2013

Haematologica

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The diagnosis of nodal marginal zone lymphoma is one of the remaining problem areas in hematopathology. Because no established positive markers exist for this lymphoma, it is frequently a diagnosis of exclusion, making distinction from other low-grade B-cell lymphomas difficult or even impossible. This systematic review summarizes and discusses the current knowledge on nodal marginal zone lymphoma, including clinical features, epidemiology and etiology, histology, and cytogenetic and molecular features. In particular, recent advances in diagnostics and pathogenesis are discussed. New immunohistochemical markers have become available that could be used as positive markers for nodal marginal zone lymphoma. These markers could be used to ensure more homogeneous study groups in future research. Also, recent gene expression studies and studies describing specific gene mutations have provided clues to the pathogenesis of nodal marginal zone lymphoma, suggesting deregulation of the nuclear factor kappa B pathway. Nevertheless, nodal marginal zone lymphoma remains an enigmatic entity, requiring further study to define its pathogenesis to allow an accurate diagnosis and tailored treatment. However, recent data indicate that it is not related to splenic or extranodal lymphoma, and that it is also not related to lymphoplasmacytic lymphoma. Thus, even though the diagnosis is not always easy, it is clearly a separate entity. ABSTRACT© F e r r a t a S t o r t i F o u n d a t i o n . Epidemiology and etiology NMZL is a rare lymphoma, accounting for 1.5-1.8% of lymphoid neoplasms. 9,10 The incidence of NMZL appears to be increasing, which is most likely due to a 'real' increase, rather than better recognition.11 Most studies report a median age around 60 years with a wide age distribution ranging from adolescence to patients over 90 years old. [9][10][11][12][13][14][15][16][17][18][19][20] Both sexes are affected with approximately equal frequency.Morphologically, NMZL resembles EMZL. EMZL is well known for its association with conditions that provide a chronic stimulation to the immune system, including chronic infections (e.g. Helicobacter pylori infection in gastric EMZL) and autoimmune conditions (e.g. salivary gland EMZL in Sjögren's syndrome). From this, one could hypothesize that NMZL, or a subset of NMZLs, might also be caused by specific chronic inflammatory conditions. Indeed, infections and autoimmune disorders have been reported in association with NMZL, but this evidence remains far from sufficient to establish a definitive role for these stimuli in lymphomagenesis. Recently, we encountered a case of what we had referred to as NMZL lymphoma in an axillary lymph node. However, we detected H. pylori by PCR analysis and a gastric biopsy revealed EMZL. This case implies that without extensive workup, including gastric biopsies, one cannot be sure that a case of NMZL really represents this entity.Hepatitis C virus (HCV) has been reported in a subset of NMZL patients. In an early but small study, monocytoid B-cell lymph...

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“…CD40 knockout mice have impaired immune responses and cannot develop germinal centers (41,42). In humans, the X-linked HIGM syndrome which results from the absence of functional CD40L leads to a defect in germinal center formation, the lack of isotype switch recombination, and the accumulation of IgM with no or very few somatic mutations (46,52). Indeed, in our previous study, the presence of somatic mutations in V H 6 genes from a peculiar HIGM patient was associated with the transient expression of CD40L at the surface of his activated T cells (32).…”

Section: Discussionmentioning

confidence: 99%

T Cells Can Induce Somatic Mutation in B Cell Receptor-Engaged BL2 Burkitt’s Lymphoma Cells Independently of CD40-CD40 Ligand Interactions

Denépoux¹,

Fournier²,

Péronne³

et al. 2000

The Journal of Immunology

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The B cell surface trigger(s) and the molecular mechanism(s) of somatic hypermutation remain unknown, partly because of the lack of amendable in vitro models. Recently, however, we reported that upon B cell receptor cross-linking and coculture with activated T cells, the Burkitt’s lymphoma cell line BL2 introduces mutations in its IgVH gene in vitro. We now confirm the relevance of our culture model by establishing that the entire spectrum of somatic mutations observed in vivo, including insertions and deletions, could be found in the DNA of BL2 cells. Additionally, we show that among four human B cell lines, only two with a centroblast-like phenotype can be induced to mutate. Triggering of somatic mutations in BL2 cells requires intimate T-B cell contacts and is independent of CD40-CD40-ligand (CD40L) interactions as shown by 1) the lack of effect of anti-CD40 and/or anti-CD40L blocking Abs on somatic mutation and 2) the ability of a CD40L-deficient T cell clone (isolated from an X-linked hyper-IgM syndrome patient) to induce somatic mutation in B cell receptor-engaged BL2 cells. Thus, our in vitro model reveals that T-B cell membrane interactions through surface molecules different from CD40-CD40L can trigger somatic hypermutation.

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Somatic mutation of human immunoglobulin V genes in the X-linked HyperIgM syndrome.

Cited by 51 publications

References 40 publications

Association between telomere length and VH gene mutation status in chronic lymphocytic leukaemia: clinical and biological implications

Association between telomere length and VH gene mutation status in chronic lymphocytic leukaemia: clinical and biological implications

Recognizing nodal marginal zone lymphoma: recent advances and pitfalls. A systematic review

T Cells Can Induce Somatic Mutation in B Cell Receptor-Engaged BL2 Burkitt’s Lymphoma Cells Independently of CD40-CD40 Ligand Interactions

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