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Molecular mimics can induce a nonautoaggressive repertoire that preempts induction of autoimmunity.

ABSTRACT: To determine the role that competition plays in a molecular mimic's capacity to induce autoimmunity, we studied the ability of naïve encephalitogenic T cells to expand in response to agonist altered peptide ligands (APLs), some capable of stimulating both self-directed and exclusively APL-specific T cells. Our results show that although the APLs capable of stimulating exclusively APL-specific T cells are able to expand encephalitogenic T cells in vitro, the encephalitogenic repertoire is effectively outcompeted in vivo when the APL is used as the priming immunogen. Competition as a mechanism was supported by: (i) the demonstration of a population of exclusively APL-specific T cells, (ii) an experiment in which an encephalitogenic T cell population was successfully outcompeted by adoptively transferred naïve T cells, and (iii) demonstrating that the elimination of competing T cells bestowed an APL with the ability to expand naïve encephalitogenic T cells in vivo. In total, these experiments support the existence of a reasonably broad T cell repertoire responsive to a molecular mimic (e.g., a microbial agent), of which the exclusively mimic-specific component tends to focus the immune response on the invading pathogen, whereas the rare cross-reactive, potentially autoreactive T cells are often preempted from becoming involved.

SUBMITTER: Maverakis E

PROVIDER: S-EPMC2823870 | biostudies-other | 2010 Feb

REPOSITORIES: biostudies-other

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Molecular mimics can induce a nonautoaggressive repertoire that preempts induction of autoimmunity.

Maverakis Emanual E Menezes Juscilene S JS Ametani Akio A Han Mei M Stevens David B DB He Yong Y Wang Yan Y Ono Yoko Y Miyamura Yoshinori Y Lam Kit S KS Ward E Sally ES Sercarz Eli E EE

Proceedings of the National Academy of Sciences of the United States of America 20100120 6

To determine the role that competition plays in a molecular mimic's capacity to induce autoimmunity, we studied the ability of naïve encephalitogenic T cells to expand in response to agonist altered peptide ligands (APLs), some capable of stimulating both self-directed and exclusively APL-specific T cells. Our results show that although the APLs capable of stimulating exclusively APL-specific T cells are able to expand encephalitogenic T cells in vitro, the encephalitogenic repertoire is effecti ...[more]

PMID: 20133742

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Project description:Alemtuzumab is a monoclonal antibody that causes rapid depletion of CD52-expressing immune cells. It has proven to be highly efficacious in active relapsing-remitting multiple sclerosis; however, the high risk of secondary autoimmune disorders has greatly complicated its use. Thus, deeper insight into the pathophysiology of secondary autoimmunity and potential biomarkers is urgently needed. The most critical time points in the decision-making process for alemtuzumab therapy are before or at Month 12, where the ability to identify secondary autoimmunity risk would be instrumental. Therefore, we investigated components of blood and CSF of up to 106 multiple sclerosis patients before and after alemtuzumab treatment focusing on those critical time points. Consistent with previous reports, deep flow cytometric immune-cell profiling (n = 30) demonstrated major effects on adaptive rather than innate immunity, which favoured regulatory immune cell subsets within the repopulation. The longitudinally studied CSF compartment (n = 18) mainly mirrored the immunological effects observed in the periphery. Alemtuzumab-induced changes including increased numbers of naïve CD4+ T cells and B cells as well as a clonal renewal of CD4+ T- and B-cell repertoires were partly reminiscent of haematopoietic stem cell transplantation; in contrast, thymopoiesis was reduced and clonal renewal of T-cell repertoires after alemtuzumab was incomplete. Stratification for secondary autoimmunity did not show clear immununological cellular or proteomic traits or signatures associated with secondary autoimmunity. However, a restricted T-cell repertoire with hyperexpanded T-cell clones at baseline, which persisted and demonstrated further expansion at Month 12 by homeostatic proliferation, identified patients developing secondary autoimmune disorders (n = 7 without secondary autoimmunity versus n = 5 with secondary autoimmunity). Those processes were followed by an expansion of memory B-cell clones irrespective of persistence, which we detected shortly after the diagnosis of secondary autoimmune disease. In conclusion, our data demonstrate that (i) peripheral immunological alterations following alemtuzumab are mirrored by longitudinal changes in the CSF; (ii) incomplete T-cell repertoire renewal and reduced thymopoiesis contribute to a proautoimmune state after alemtuzumab; (iii) proteomics and surface immunological phenotyping do not identify patients at risk for secondary autoimmune disorders; (iv) homeostatic proliferation with disparate dynamics of clonal T- and B-cell expansions are associated with secondary autoimmunity; and (v) hyperexpanded T-cell clones at baseline and Month 12 may be used as a biomarker for the risk of alemtuzumab-induced autoimmunity.

Dataset Information

Molecular mimics can induce a nonautoaggressive repertoire that preempts induction of autoimmunity.

Publications

Molecular mimics can induce a nonautoaggressive repertoire that preempts induction of autoimmunity.

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