Human innate B cells: a link between host defense and autoimmunity?

Milner, Eric C. B.; Anolik, Jennifer H.; Cappione, Amedeo; Sanz, Iñaki

doi:10.1007/s00281-004-0188-9

Cited by 74 publications

(46 citation statements)

References 126 publications

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“…3-5 Indeed, it has been proposed that the IGHV4-34 gene may have been selected during evolution for its ability to encode protective antibodies, as indicated by the fact that the immune response to pathogens carrying NAL epitopes selectively targets IGHV4-34 B cells. 11,40,41 In this study, we investigated whether patients with CLL-expressing IGHV4-34 BCRs might somehow be linked with Abbreviations: CD38, cluster of differentiation 38; CLL, chronic lymphocytic leukemia; IgG, immunoglobulin G. It should be noted that seven of nine group C cases belonged to a subset with stereotyped IGHV4-34/IGKV2-30 BCRs (subset 4, following the numbering from two previous studies from our group 22,24,36 chronic activation by common herpesviruses, in particular EBV and CMV. The ideal approach would be that of testing directly the CLL cell capacity of being stimulated by viral antigens in vitro.…”

Section: Discussionmentioning

confidence: 99%

Molecular evidence for EBV and CMV persistence in a subset of patients with chronic lymphocytic leukemia expressing stereotyped IGHV4-34 B-cell receptors

et al. 2009

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The chronic lymphocytic leukemia (CLL) immunoglobulin repertoire is uniquely characterized by the presence of stereotyped B-cell receptors (BCRs). A major BCR stereotype in CLL is shared by immunoglobulin G-switched cases utilizing the immunoglobulin heavy-chain variable 4-34 (IGHV4-34) gene. Increased titers of IGHV4-34 antibodies are detected in selective clinical conditions, including infection by B-cell lymphotropic viruses, particularly Epstein-Barr virus (EBV) and cytomegalovirus (CMV). In this context, we sought evidence for persistent activation by EBV and CMV in CLL cases expressing the IGHV4-34 gene. The study group included 93 CLL cases with an intentional bias for the IGHV4-34 gene. On the basis of real-time PCR results for CMV/EBV DNA, cases were assigned to three groups: (1) double-negative (59/93); (2) single-positive (CMV-or EBV-positive; 25/93); (3) double-positive (9/93). The doublenegative group was characterized by heterogeneous IGHV gene repertoire. In contrast, a bias for the IGHV4-34 gene was observed in the single-positive group (9/25 cases; 36%). Remarkably, all nine double-positive cases utilized the IGHV4-34 gene; seven of nine cases expressed the major BCR stereotype as described above. In conclusion, our findings indicate that the interactions of CLL progenitor cells expressing distinctive IGHV4-34 BCRs with viral antigens/superantigens might facilitate clonal expansion and, eventually, leukemic transformation. The exact type, timing and location of these interactions remain to be determined.

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Section: Discussionmentioning

confidence: 99%

Molecular evidence for EBV and CMV persistence in a subset of patients with chronic lymphocytic leukemia expressing stereotyped IGHV4-34 B-cell receptors

et al. 2009

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“…Our initial recognition of 9G4 APCB in SLE (9,27,28) has been recently consolidated by extensive serological analysis in our laboratory showing that such autoreactivity is present in 60% of unselected SLE patients, is present in the vast majority of patients with elevated serum 9G4 Ab titers (80% of 9G4 + ), and correlates with disease activity and active lupus nephritis (29). A summary of these data are provided in Supplemental Fig.…”

Section: Autoreactivity Of Sle 9g4 Absmentioning

confidence: 99%

“…In vivo, 9G4 BCB is prominent in active SLE and correlates with naive B cell lymphopenia possibly due to a direct lytic activity of these Abs (9,23). Yet, 9G4 Abs may also react with ssDNA, dsDNA (11,(24)(25)(26), as well as apoptotic cells as shown own by our studies of SLE sera (27)(28)(29) and by chronic lymphocytic leukemia studies (30). The latter reactivity is of great interest because apoptotic cells accumulate in SLE GC (31) and may induce antiapoptotic cell Abs (APCA) with pathogenic functions (32)(33)(34)(35)(36)(37)(38)(39)(40).…”

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confidence: 94%

Molecular Basis of 9G4 B Cell Autoreactivity in Human Systemic Lupus Erythematosus

Richardson

Chida

Adlowitz

et al. 2013

The Journal of Immunology

116

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9G4+ IgG Abs expand in systemic lupus erythematosus (SLE) in a disease-specific fashion and react with different lupus Ags including B cell Ags and apoptotic cells. Their shared use of VH4-34 represents a unique system to understand the molecular basis of lupus autoreactivity. In this study, a large panel of recombinant 9G4+ mAbs from single naive and memory cells was generated and tested against B cells, apoptotic cells, and other Ags. Mutagenesis eliminated the framework-1 hydrophobic patch (HP) responsible for the 9G4 idiotype. The expression of the HP in unselected VH4-34 cells was assessed by deep sequencing. We found that 9G4 Abs recognize several Ags following two distinct structural patterns. B cell binding is dependent on the HP, whereas anti-nuclear Abs, apoptotic cells, and dsDNA binding are HP independent and correlate with positively charged H chain third CDR. The majority of mutated VH4-34 memory cells retain the HP, thereby suggesting selection by Ags that require this germline structure. Our findings show that the germline-encoded HP is compulsory for the anti–B cell reactivity largely associated with 9G4 Abs in SLE but is not required for reactivity against apoptotic cells, dsDNA, chromatin, anti-nuclear Abs, or cardiolipin. Given that the lupus memory compartment contains a majority of HP+ VH4-34 cells but decreased B cell reactivity, additional HP-dependent Ags must participate in the selection of this compartment. This study represents the first analysis, to our knowledge, of VH-restricted autoreactive B cells specifically expanded in SLE and provides the foundation to understand the antigenic forces at play in this disease.

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“…3B). The CD23 Ϫ subset has been reported to contain mature naive B cells; however, early class-switched B cells (19,21) and transitional B cells (Ref. 18 and Fig.…”

Section: Increased Expression Of B Cell Activation Markers Cd80 and mentioning

confidence: 99%

Expanded Population of Activated Antigen-Engaged Cells within the Naive B Cell Compartment of Patients with Systemic Lupus Erythematosus

Chang

McKenzie

Bonventi

et al. 2008

The Journal of Immunology

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Polyclonal B cell activation is a well-described feature of systemic lupus erythematosus (SLE), but the immune mechanisms leading to this activation are unclear. To gain insight into these processes, we extensively characterized the activated peripheral blood B cell populations in SLE. PBMC from lupus patients and healthy controls were stained with various combinations of conjugated Ab to identify distinct peripheral B cell subsets, and activation was assessed by measurement of forward scatter and CD80 or CD86 expression using flow cytometry. SLE patients had altered proportions of several B cell subsets, many of which demonstrated increased activation as assessed by forward scatter. This activation occurred at an early developmental stage, as B cells in the transitional (T2) stage were already significantly larger than those seen in controls. Increased proportions of CD80- or CD86-expressing cells were also seen in multiple B cell subsets, with the most striking differences observed in the naive CD27−CD23+ population. Within the CD23+ subset, increased costimulatory molecule expression was most pronounced in an IgD+IgMlow population, suggesting that activation follows Ag engagement. Although controls also had IgD+IgMlowCD23+ cells, they were reduced in number and not activated. Thus, there is an altered response to Ig receptor engagement with self-Ags in lupus.

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Human innate B cells: a link between host defense and autoimmunity?

Cited by 74 publications

References 126 publications

Molecular evidence for EBV and CMV persistence in a subset of patients with chronic lymphocytic leukemia expressing stereotyped IGHV4-34 B-cell receptors

Molecular evidence for EBV and CMV persistence in a subset of patients with chronic lymphocytic leukemia expressing stereotyped IGHV4-34 B-cell receptors

Molecular Basis of 9G4 B Cell Autoreactivity in Human Systemic Lupus Erythematosus

Expanded Population of Activated Antigen-Engaged Cells within the Naive B Cell Compartment of Patients with Systemic Lupus Erythematosus

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