An Innate Path to Human B Cell Tolerance

Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
Immunity (Impact Factor: 21.56). 12/2008; 29(5):667-9. DOI: 10.1016/j.immuni.2008.10.001
Source: PubMed


The random nature of antibody diversification processes guarantees that a large number of newly generated antibodies will recognize self-antigens. These potentially harmful antibodies with self-specificities are eliminated in large numbers at various steps of B cell development so that the mature B cell repertoire of a healthy individual is largely devoid of self-reactive antibodies. Knowledge of this process has greatly advanced ever since the Nussenzweig group developed a combination of single-cell polymerase chain reaction (PCR) and antibody-cloning techniques to investigate single B cell specificities in humans (Wardemann and Nussenzweig, 2007). This technique is now utilized by Isnardi et al. to characterize alterations in the naive B cell repertoire of patients with deficiencies in innate immune pathways (Isnardi et al., 2008).

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    ABSTRACT: Establishing long-term allograft acceptance without the requirement for continuous immunosuppression, a condition known as allograft tolerance, is a highly desirable therapeutic goal in solid organ transplantation. Determining which recipients would benefit from withdrawal or minimization of immunosuppression would be greatly facilitated by biomarkers predictive of tolerance. In this study, we identified the largest reported cohort to our knowledge of tolerant renal transplant recipients, as defined by stable graft function and receiving no immunosuppression for more than 1 year, and compared their gene expression profiles and peripheral blood lymphocyte subsets with those of subjects with stable graft function who are receiving immunosuppressive drugs as well as healthy controls. In addition to being associated with clinical and phenotypic parameters, renal allograft tolerance was strongly associated with a B cell signature using several assays. Tolerant subjects showed increased expression of multiple B cell differentiation genes, and a set of just 3 of these genes distinguished tolerant from nontolerant recipients in a unique test set of samples. This B cell signature was associated with upregulation of CD20 mRNA in urine sediment cells and elevated numbers of peripheral blood naive and transitional B cells in tolerant participants compared with those receiving immunosuppression. These results point to a critical role for B cells in regulating alloimmunity and provide a candidate set of genes for wider-scale screening of renal transplant recipients.
    Full-text · Article · Jun 2010 · The Journal of clinical investigation