Multiple paths to loss of anergy and gain of autoimmunity

Conrad, F.J.; Rice, Jeffrey S.; Cambier, John C.

doi:10.1080/08916930701464723

Cited by 19 publications

(15 citation statements)

References 67 publications

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“…Nonetheless, it is unsettling to consider that autoantibodies traditionally have been viewed as a loss or aberration of self-tolerance. 29,30 Thus, finding that we all have the potential to produce autoantibodies as a consequence of physiological redox reactions gives pause to reconsider the immunological basis of tolerance, which is discussed by Prof. Davies 30 . Although this is the first report of redox-induced autoantibody activity from FDA approved therapeutic monoclonal antibodies, other investigators have used various procedures to reveal polyreactivity of monoclonal antibodies, and some of these reports have contained data on mechanisms that might account for such promiscuous activity.…”

Section: Resultsmentioning

confidence: 99%

Autoantibody potential of cancer therapeutic monoclonal antibodies

McIntyre

Faulk

2010

Intl Journal of Cancer

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We and others have reported that multiple autoantibodies are unmasked in human polyclonal antibody preparations after exposure to physiological oxidizing agents (hemin) or electromotive force. We now have asked if oxidation unmasks autoantibody reactivities in monoclonal antibodies (mAb). To do this, we have studied 9 FDA approved mAb used therapeutically, including 4 chimeric, 4 humanized and 1 chemically modified chimeric Fab that were exposed to the physiological oxidizing agent hemin at 36°C for 20 hr. These mAb were studied for autoantibody activity to phospholipids and DNA before and after oxidation with hemin and found to develop autoantibody activities after oxidation, while retaining their original specificity as measured by mAb anti-glycophorin A binding of erythrocytes, CD 19 binding to B lymphocytes and anti-HLA-A29 binding to A29-positive lymphocytes. The finding that certain mAb have the potential to unmask autoantibody activities as a consequence of exposure to physiological redox reactions in vitro gives pause to our present understanding of the immunological basis of tolerance and concern for potential autoimmune side effects in patients receiving mAb for diagnosis or treatment.Genetic engineering is a growth strategy in the design and development of monoclonal antibodies (mAb) for clinical therapeutics, such as drug targeting in cancer chemotherapy.1,2 However, the clinical use of mAb has been associated with serious side effects, 3 presumably due to collateral damage from reactions with antigens of unintended targets. 4 Inasmuch as a tenant of the scientific basis for the clinical use of mAb is that they react only with one or a small number of closely related epitopes, 5 we asked if their specificities might be altered by exposure to physiological concentrations of physiological oxidants known to participate in physiological redox reactions. We posed this query due to our earlier reports of the unmasking of autoantibody activities in human blood as well as in purified IgG that had been exposed to such physiological redox reactions. 6 One might then ask why such redox-reactive antibodies exist. We have proposed that redox-reactive antibodies represent elements of the body's immune defense and surveillance network. 7 Recently, a similar explanation has been put forward by others. 8 In the following paragraphs, we present data indicating that autoimmune activities can be unmasked in solutions of FDA approved mAb of several different specificities and immunochemistries. Material and MethodsThe experimental design and techniques used in this study are the same as those used in our earlier report of the unmasking of autoantibody activity in human IgG following oxidation with physiological oxidants such as hemin 6 or by using electromotive force (EMF).9 It was shown that hemin was responsible for oxidation of the antibody because (i) none of the antibody changes occurred in the absence of hemin, (ii) none of the antibody changes occurred in the presence of hemopexin, which is a biological inhibitor ...

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Section: Resultsmentioning

confidence: 99%

Autoantibody potential of cancer therapeutic monoclonal antibodies

McIntyre

Faulk

2010

Intl Journal of Cancer

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“…Anergy in T cells can be induced using several distinct methods including costimulation blockade, calcium flux, anti-CD3, APLs, and MHC variant peptides (35)(36)(37)(38)(39). Although all of these methods induce decreased levels of T cell division and IL-2 production, they may mediate the observed anergic properties through distinct molecular mechanisms (37,40).…”

Section: Discussionmentioning

confidence: 99%

MHC Variant Peptide-Mediated Anergy of Encephalitogenic T Cells Requires SHP-1

Wasserman

Beal

Zhang

et al. 2008

The Journal of Immunology

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Our lab has demonstrated that encephalitogenic T cells can be effectively anergized by treatment with MHC variant peptides, which are analogues of immunogenic peptides containing an amino acid substitution at an MHC anchor residue. The MHC variant peptide of myelin oligodendrocyte glycoprotein (MOG)35–55 proves an effective treatment as it does not induce symptoms of experimental autoimmune encephalomyelitis and fails to recruit macrophages or MOG35–55-specific T cells to the CNS. In this study, we sought to characterize the signaling pathways required for the induction of anergy by building upon the observations identifying the tyrosine phosphatase SHP-1 as a critical regulator of T cell responsiveness. Motheaten viable heterozygous mice, which contain a mutation in the SHP-1 gene resulting in a reduction in functional SHP-1, were challenged with MOG35–55 or the MOG35–55 MHC variant 45D. These mice display symptoms of experimental autoimmune encephalomyelitis upon immunization with MHC variant peptide and have significant CNS infiltration of tetramer-positive CD4+ cells and macrophages, unlike B6 mice challenged with the variant peptide. The effects of SHP-1 are directly on the T cell as Motheaten viable heterozygous mice autoreactive T cells are not anergized in vitro. Lastly, we demonstrate no distinguishable difference in the initial interaction between the TCR and agonist or MHC variant. Rather, an unstable interaction between peptide and MHC attenuates the T cell response, seen in a decreased half-life relative to MOG35–55. These results identify SHP-1 as a mediator of T cell anergy induced by destabilized peptide:MHC complexes.

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“…Of these, B cell anergy is a particularly attractive target for therapeutic immune intervention in vivo , as suggested in preclinical models of lupus in which restoration of B cell expression of inhibitory FcγRIIB ameliorates nephritis (McGaha et al 2005). Anergy is a final safeguard against autoreactivity when editing or deletion fails, and in autoimmune individuals is itself a major site of failed tolerance (Cambier et al 2007; Conrad et al 2007). The murine lupus-associated Ly108 susceptibility allele at the Sle1z/Sle1bz locus, for which there is an orthologous human locus, impairs B cell anergy as well as editing and deletion (Kumar et al 2006).…”

Section: Introductionmentioning

confidence: 99%

Tracking Differential Gene Expression in MRL/MpJ versus C57BL/6 Anergic B Cells: Molecular Markers of Autoimmunity

2008

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Background: Anergy is a key mechanism controlling expression of autoreactive B cells and a major site for failed regulation in autoimmune diseases. Yet the molecular basis for this differentiated cell state remains poorly understood. The current lack of well-characterized surface or molecular markers hinders the isolation of anergic cells for further study. Global gene profi ling recently identifi ed transcripts whose expression differentiates anergic from naïve B cells in model mouse systems. The objective of the current study was to evaluate the molecular and cellular processes that differentiate anergic cells that develop in the healthy C57BL/6 (B6) milieu from those that develop in the autoimmune-prone MRL/MpJ (MRL) background. This approach takes advantage of B6 and MRL mice bearing an anti-laminin Ig transgene with a well characterized anergic B cell phenotype.

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Multiple paths to loss of anergy and gain of autoimmunity

Cited by 19 publications

References 67 publications

Autoantibody potential of cancer therapeutic monoclonal antibodies

Autoantibody potential of cancer therapeutic monoclonal antibodies

MHC Variant Peptide-Mediated Anergy of Encephalitogenic T Cells Requires SHP-1

Tracking Differential Gene Expression in MRL/MpJ versus C57BL/6 Anergic B Cells: Molecular Markers of Autoimmunity

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