Ectopic B-cell clusters that infiltrate transplanted human kidneys are clonal

Cheng, Julong; Torkamani, Ali; Grover, Rajesh K.; Jones, Teresa M.; Ruiz, Diana I.; Schork, Nicholas J.; Quigley, Michael; Hall, Frank W.; Salomon, Daniel R.; Lerner, Richard A.

doi:10.1073/pnas.1101148108

Cited by 50 publications

(48 citation statements)

References 51 publications

(53 reference statements)

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“…These reactions were first identified in patients with autoimmune diseases, including multiple sclerosis (15), Sjögren's syndrome (57), RA (54), and Hashimoto's thyroiditis (5), and they have recently been identified in allografts (13) and cancer (14). They have been associated with the production of autoantibodies (39), and therefore, we speculate that they are also present in chronic HCV infection.…”

Section: Discussionmentioning

confidence: 99%

Chronic Hepatitis C Virus Infection Breaks Tolerance and Drives Polyclonal Expansion of Autoreactive B Cells

Roughan¹,

Reardon²,

Cogburn³

et al. 2012

Clin. Vaccine Immunol.

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b Chronic Hepatitis C virus (HCV) infection has been linked with B cell lymphoproliferative disorders and several autoimmune-related diseases. The mechanisms of how chronic viral infection affects B cell development and predisposes the patients to autoimmune manifestations are poorly understood. In this study, we established an experimental system to probe the B cell responses and characterize the antibodies from chronic-HCV-infected individuals. We identified an unusual polyclonal expansion of the IgM memory B cell subset in some patients. This B cell subset is known to be tightly regulated, and autoreactive cells are eliminated by tolerance mechanisms. Genetic analysis of the immunoglobulin (Ig) heavy chain variable gene (V H ) sequences of the expanded cell population showed that the levels of somatic hypermutation (SHM) correlate with the extent of cell expansion in the patients and that the V H genes exhibit signs of antigen-mediated selection. Functional analysis of the cloned B cell receptors demonstrated autoreactivity in some of the expanded IgM memory B cells in the patients which is not found in healthy donors. In summary, this study demonstrated that, in some patients, chronic HCV infection disrupts the tolerance mechanism that normally deletes autoreactive B cells, therefore increasing the risk of developing autoimmune antibodies. Long-term follow-up of this expanded B cell subset within the infected individuals will help determine whether these cells are predictors of more-serious clinical manifestations. Hepatitis C virus (HCV) is a single-stranded RNA virus that is transmitted predominantly through direct blood contact, such as accidental needle sticks in the health care workplace, blood transfusions, and needle sharing among intravenous drug users (reviewed in reference 33). About 70% of those infected cannot clear the virus and succumb to persistent infection (reviewed in reference 22). Of those, more than half will develop some form of liver disease and ϳ2 to 3% will develop liver cancer over a course of 20 to 40 years (4, 17). HCV has also been associated with B cell and antibody abnormalities (non-Hodgkin's lymphoma [NHL] [40]) and a number of autoimmune diseases (mixed cryoglobulinemia [MC] [2], celiac disease [56], Sjögren's syndrome [68], and systemic autoimmune diseases [53]). The contribution of the virus to these diseases is unclear. One hypothesis is that E2, a glycoprotein found on the surface of HCV, binds to CD81 instead of B cell receptors (BCRs) on B cells, stimulating cell proliferation (55) and hypermutation of immunoglobulin (Ig) genes (38). Prolonged stimulation by E2 during chronic infection can eventually lead to some form of B cell lymphoproliferative disorder. It is also thought that HCV itself may provide a chronic antigen stimulus that drives clonal expansion of B cells. In support of this, it was shown that Ig cloned from NHL biopsy specimens bound E2 (50). In addition, Charles et al. demonstrated an antigen-driven expansion of peripheral blood (PB) IgM ϩ CD27 ϩ B c...

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Section: Discussionmentioning

confidence: 99%

Chronic Hepatitis C Virus Infection Breaks Tolerance and Drives Polyclonal Expansion of Autoreactive B Cells

Roughan¹,

Reardon²,

Cogburn³

et al. 2012

Clin. Vaccine Immunol.

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“…Recently, one group suggested a connection between the microbiome and chronic injury. 47 Finally, although its importance was recognized early, recent studies have re-emphasized the importance of nonadherence as either a causative or contributing factor for some cases of late failure.…”

Section: Contributing Factorsmentioning

confidence: 99%

Through a Glass Darkly

Stegall

Gaston

Cosio

et al. 2015

Journal of the American Society of Nephrology

115

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A common lament is that long-term kidney transplant outcomes remain the same despite improvements in early graft survival. To be fair, progress has been made -in both our understanding of chronic injury and modestly, graft survival. However, we are still a long way from actually solving this important and difficult problem. In this review, we outline recent data supporting the existence of several causes of renal allograft loss, the incidences of which peak at different time points after transplantation. On the basis of this broadened concept of chronic renal allograft injury, we examine the challenges of clinical trial design in longterm studies, including the use of surrogate end points and biomarkers. Finally, we suggest a path forward that, ultimately, may improve long-term renal allograft survival.

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“…While the mechanism of chronic kidney rejection is far from certain, recent studies have suggested that a large set of genes that encode proteins of the innate and adaptive immune system are expressed in the host during rejection (2). Another interesting immunological feature of transplanted kidneys is the appearance of highly organized ectopic B-cell clusters in the transplant (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14).…”

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confidence: 99%

The costimulatory immunogen LPS induces the B-Cell clones that infiltrate transplanted human kidneys

Grover

Cheng²,

Peng³

et al. 2012

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

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The mechanism of chronic rejection of transplanted human kidneys is unknown. An understanding of this process is important because, chronic rejection ultimately leads to loss of the kidney allograft in most transplants. One feature of chronic rejection is the infiltration of ectopic B-cell clusters that are clonal into the transplanted kidney. We now show that the antibodies produced by these B-cells react strongly with the core carbohydrate region of LPS. Since LPS is a costimulatory immunogen that can react with both the B-cell receptor (BCR) and the Toll-like receptor 4 (TLR4), these results suggest a mechanism for the selective pressure that leads to clonality of these B-cell clusters and opens the possibility that infection and the attendant exposure to LPS plays a role in the chronic rejection of human kidney transplants. If confirmed by clinical studies, these results suggest that treating patients with signs of chronic rejection with antibiotics may improve kidney allograft survival.

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Ectopic B-cell clusters that infiltrate transplanted human kidneys are clonal

Cited by 50 publications

References 51 publications

Chronic Hepatitis C Virus Infection Breaks Tolerance and Drives Polyclonal Expansion of Autoreactive B Cells

Chronic Hepatitis C Virus Infection Breaks Tolerance and Drives Polyclonal Expansion of Autoreactive B Cells

Through a Glass Darkly

The costimulatory immunogen LPS induces the B-Cell clones that infiltrate transplanted human kidneys

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