Lack of deleterious somatic mutations in the CD95 gene of plasmablasts from systemic lupus erythematosus patients and autoantibody-producing cell lines

Kurth, Julia; Perniok, Andreas; Schmitz, Roland; Iking‐Konert, Christof; Chiorazzi, Nicholas; Thompson, Keith M.; Winkler, Thomas; Rajewsky, Klaus; Küppers, Ralf

doi:10.1002/1521-4141(200212)32:12<3785::aid-immu3785>3.0.co;2-e

Cited by 7 publications

(8 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Based on a Taq DNA polymerase error rate of 10 Ϫ5 /bp and cycle, 14,15 we expected 1 error/2857 bp and 1 error/3333 bp for PAX5 (35 cycles) and RhoH/TTF (30 cycles), respectively. Considering the number of base pairs of the individual sequences and the number of sequences analyzed (18,20, and 20 for PAX5, patients 2 and 10, and for RhoH/TTF, patient 10, respectively), one would have expected the introduction of 6, 6, and 5 mutations because of Taq DNA polymerase errors for PAX5, patients 2 and 10, and for RhoH/TTF, patient 10, respectively. With 18, 27, and 7 point mutations in patient 2 and patient 10 for the PAX5 gene and in patient 10 for the RhoH/TTF gene (Table 2), respectively, the number of point mutations is clearly above this threshold.…”

Section: Resultsmentioning

confidence: 99%

“…19 Furthermore, the observation of autoreactive diseases suggested a link between CD95 mutation, lymphomagenesis, and autoimmunity, although this is still controversially discussed because CD95 gene mutations appeared to play little, if any, role in the generation of the pool of plasmablasts in patients with systemic lupus erythematosus. 13,20 However, although CD95 mutations alone are unlikely to commit a GC B cell to malignant transformation, they may represent an early event in lymphomagenesis by favoring the persistence of mutant GC B cells, which may acquire additional transforming modifications, ultimately resulting in malignant lymphoma formation. In this context it is interesting that PCNSLs preferentially rearranged the V4-34 gene segment, which has been implicated in autoimmune disorders, including cold agglutinin disease.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Primary diffuse large B-cell lymphomas of the central nervous system are targeted by aberrant somatic hypermutation

Montesinos‐Rongen

Roost

Schaller

et al. 2004

Blood

160

114

View full text Add to dashboard Cite

We have addressed whether aberrant ongoing hypermutation can be detected in the proto-oncogenes PIM1, c-MYC, RhoH/TTF, PAX5, and the tumor-suppressor gene CD95 in primary central nervous system lymphomas (PCNSLs) derived from immunocompetent HIV-negative patients. Nine of 10 PCNSLs analyzed harbored somatic mutations in the PIM1, c-MYC, RhoH/TTF, and PAX5 genes, but not in the CD95 gene, with 8 tumors carrying alterations in at least 2 of these genes. Furthermore, ongoing aberrant mutation was evidenced in a subset of PCNSLs (2 of 3). Although most of the mutations corresponded to base pair substitutions, deletions were also present. The mean mutation frequency was approximately 60-fold lower for these genes compared with the values obtained for immunoglobulin genes in PCNSL. They were increased 2- to 5-fold compared with extracerebral diffuse large B-cell lymphoma (DLBCL). In summary, our data demonstrate aberrant somatic hypermutations at high frequency in the PIM1, PAX5, RhoH/TTF, and c-MYC genes in most PCNSLs. These findings may indicate a pathogenic role for aberrant somatic hypermutation in PCNSL development. In contrast, although mutations were detected in exon 9 of the CD95 gene, the lack of mutations in the 5' region provides no evidence for the CD95 gene as a target for aberrant somatic mutation.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Primary diffuse large B-cell lymphomas of the central nervous system are targeted by aberrant somatic hypermutation

Montesinos‐Rongen

Roost

Schaller

et al. 2004

Blood

160

114

View full text Add to dashboard Cite

show abstract

“…Recent immunohistochemical studies have identified directly infected memory and germinal center cells which express EBNA2 and appear to have undergone EBV-driven clonal expansion (27,28) in the tonsils of AIM patients. The infection of all B-cell subsets in the tonsils of healthy carriers has also been seen (4); however, in this case, each subset uses a discrete transcription program and EBNA2 was not detected in the memory or germinal center cells.…”

Section: Discussionmentioning

confidence: 99%

Acute Infection with Epstein-Barr Virus Targets and Overwhelms the Peripheral Memory B-Cell Compartment with Resting, Latently Infected Cells

Hochberg

Souza

Catalina

et al. 2004

J Virol

149

150

View full text Add to dashboard Cite

In this paper we demonstrate that during acute infection with Epstein-Barr virus (EBV), the peripheral blood fills up with latently infected, resting memory B cells to the point where up to 50% of all the memory cells may carry EBV. Despite this massive invasion of the memory compartment, the virus remains tightly restricted to memory cells, such that, in one donor, fewer than 1 in 10 4 infected cells were found in the naive compartment. We conclude that, even during acute infection, EBV persistence is tightly regulated. This result confirms the prediction that during the early phase of infection, before cellular immunity is effective, there is nothing to prevent amplification of the viral cycle of infection, differentiation, and reactivation, causing the peripheral memory compartment to fill up with latently infected cells. Subsequently, there is a rapid decline in infected cells for the first few weeks that approximates the decay in the cytotoxic-T-cell responses to viral replicative antigens. This phase is followed by a slower decline that, even by 1 year, had not reached a steady state. Therefore, EBV may approach but never reach a stable equilibrium.The B-lymphotropic herpesvirus Epstein-Barr virus (EBV) is a ubiquitous human virus (reviewed in references 23 and 45) that establishes a lifelong persistent infection in memory B lymphocytes (3). It is an important pathogen because of its association with several human neoplasias (reviewed in references 38 and 45). However, no good animal model exists for the study of EBV. The murine gammaherpesvirus 68 (MHV68) is a related virus which has tropism for B lymphocytes (44) and also persists in memory B cells (12, 50). However, it appears to lack the specific latency transcription programs of EBV and persistence is not dependent on B lymphocytes (49). Primate homologues of EBV are known (7,11,42), but these are not useful because of financial constraints and the lack of virological and immunological reagents for these systems. Despite this limitation, EBV has emerged as an excellent system for studying persistent infection in humans. There are two primary reasons for this. First, EBV infects resting B cells in culture and transforms them into continuously proliferating, latently infected lymphoblasts (35,36). This provides a readily manipulable in vitro system for studying the functions of the latency-associated proteins. Second, the major sites of viral persistence, the peripheral blood and Waldeyer's ring (29), are relatively accessible for study. Taking together information from both in vitro and in vivo studies we have developed a unified model of how EBV establishes and maintains a persistent infection (46) (Fig. 1). The key underlying theme of the model is that EBV uses its latent proteins to provide signals to the infected B cell that cause it to become activated and then differentiate, through a mechanism analogous to the germinal center reaction (30, 31), into a resting memory cell. We have provided evidence that these events occur in the lymphoid tissue o...

show abstract

“…These ideas in turn imply that the EBV-driven lymphomas associated with immunosuppression occur because of inappropriate infection of B cells, i.e., in a form or location where they cannot differentiate out of the proliferative state, an event we refer to as bystander infection. Such events are seen in acute AIM patients' tonsils, which contain infected memory and germinal center cells clonally expanding under the influence of EBNA2 (30,31). These types of cells are not present in healthy carriers (10,11) and, therefore, do not relate to the biology of persistence.…”

Section: ) the Exception Is That When The Cells Divide They Expresmentioning

confidence: 99%

Demonstration of the Burkitt's lymphoma Epstein-Barr virus phenotype in dividing latently infected memory cellsin vivo

Hochberg

Middeldorp

Catalina

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

245

236

View full text Add to dashboard Cite

Epstein-Barr virus (EBV) is a herpesvirus that establishes a lifelong, persistent infection.It was first discovered in the tumor Burkitt's lymphoma (BL). Despite intensive study, the role of EBV in BL remains enigmatic. One striking feature of the tumor is the unique pattern of viral latent protein expression, which is restricted to EBV-encoded nuclear antigen (EBNA) 1. EBNA1 is required to maintain the viral genome but is not recognized by cytotoxic T cells. Consequently, it was proposed that this expression pattern was used by latently infected B cells in vivo. This would be the site of long-term, persistent infection by the virus and, by implication, the progenitor of BL. We now know that EBV persists in memory B cells in the peripheral blood and that BL is a tumor of memory cells. However, a normal B cell expressing EBNA1 alone has been elusive. Here we show that most infected cells in the blood express no detectable latent mRNA or proteins. The exception is that when infected cells divide they express EBNA1 only. This is the first detection of the BL viral phenotype in a normal, infected B cell in vivo. It suggests that BL may be a tumor of a latently infected memory B cell that is stuck proliferating because it is a tumor and, therefore, constitutively expressing only EBNA1.

show abstract

Lack of deleterious somatic mutations in the CD95 gene of plasmablasts from systemic lupus erythematosus patients and autoantibody-producing cell lines

Cited by 7 publications

References 30 publications

Primary diffuse large B-cell lymphomas of the central nervous system are targeted by aberrant somatic hypermutation

Primary diffuse large B-cell lymphomas of the central nervous system are targeted by aberrant somatic hypermutation

Acute Infection with Epstein-Barr Virus Targets and Overwhelms the Peripheral Memory B-Cell Compartment with Resting, Latently Infected Cells

Demonstration of the Burkitt's lymphoma Epstein-Barr virus phenotype in dividing latently infected memory cellsin vivo

Contact Info

Product

Resources

About