B Lymphocytes Producing Demyelinating Autoantibodies: Development and Function in Gene-targeted Transgenic Mice

Injection of autoantigens in IFA has been one of the most effective ways of preventing experimental, T cell-mediated, autoimmune disease in mice. The mechanism that underlies this protection has, however, remained controversial, with clonal deletion, induction of suppressor cells or of type 2 immunity being implicated at one time or another. Using high resolution enzyme-linked immunospot (ELISPOT) analysis, we have revisited this paradigm. As models of autoimmunity against sequestered and readily accessible autoantigens, we studied experimental allergic encephalomyelitis, induced by myelin oligodendrocyte glycoprotein, proteolipid protein, myelin basic protein, and renal tubular Ag-induced interstitial nephritis. We showed that the injection of each of these Ags in IFA was immunogenic and CD4 memory cells producing IL-2, IL-4, and IL-5, but essentially no IFN-γ. IgG1, but not IgG2a, autoantibodies were produced. The engaged T cells were not classic Th2 cells in that IL-4 and IL-5 were produced by different cells. The IFA-induced violation of self tolerance, including the deposition of specific autoantibodies in the respective target organs, occurred in the absence of detectable pathology. Exhaustion of the pool of naive precursor cells was shown to be one mechanism of the IFA-induced tolerance. In addition, while the IFA-primed T cells acted as suppressor cells, in that they adoptively transferred disease protection, they did not interfere with the emergence of a type 1 T cell response in the adoptive host. Both active and passive tolerance mechanisms, therefore, contribute to autoantigen:IFA-induced protection from autoimmune disease.

Section: Discussioncontrasting

confidence: 39%

Revisiting Tolerance Induced by Autoantigen in Incomplete Freund’s Adjuvant

Heeger

Forsthuber

Shive

et al. 2000

“…Autoantibodies may play a role in autoimmune encephalitis (42)(43)(44)(45)(46)(47), but the significance of the BSA-exon 2 Ab cross-reactivity in the pathogenesis of BSA 193 -induced EAE remains to be determined.…”

Section: Resultsmentioning

confidence: 99%

T Cells of Multiple Sclerosis Patients Target a Common Environmental Peptide that Causes Encephalitis in Mice

Winer

Astsaturov

Cheung

et al. 2001

Multiple sclerosis (MS) is a chronic autoimmune disease triggered by unknown environmental factors in genetically susceptible hosts. MS risk was linked to high rates of cow milk protein (CMP) consumption, reminiscent of a similar association in autoimmune diabetes. A recent rodent study showed that immune responses to the CMP, butyrophilin, can lead to encephalitis through antigenic mimicry with myelin oligodendrocyte glycoprotein. In this study, we show abnormal T cell immunity to several other CMPs in MS patients comparable to that in diabetics. Limited epitope mapping with the milk protein BSA identified one specific epitope, BSA193, which was targeted by most MS but not diabetes patients. BSA193 was encephalitogenic in SJL/J mice subjected to a standard protocol for the induction of experimental autoimmune encephalitis. These data extend the possible, immunological basis for the association of MS risk, CMP, and CNS autoimmunity. To pinpoint the same peptide, BSA193, in encephalitis-prone humans and rodents may imply a common endogenous ligand, targeted through antigenic mimicry.

“…First, increasing evidence suggests that MOG-specific T and B cells play a crucial role in inflammatory demyelinating disease of the CNS in both experimental and clinical situations (1)(2)(3)(4). Second, MOG has several properties setting it apart from other myelin proteins.…”

mentioning

confidence: 99%

“…We have recently generated an Ig H-chain "knock-in" transgenic mouse (denominated TH) to retrace the function and fate of MOG-reactive B cells in vivo (4). The Ig H-chain V region was derived from the MOG-specific mAb 8.18C5, an Ab, which induces strong demyelination and clinical exacerbation in experimental autoimmune encephalomyelitis experiments (1,6).…”

mentioning

confidence: 99%

Development of Myelin Oligodendrocyte Glycoprotein Autoreactive Transgenic B Lymphocytes: Receptor Editing In Vivo After Encounter of a Self-Antigen Distinct from Myelin Oligodendrocyte Glycoprotein

Litzenburger

Blüthmann

Morales

et al. 2000

Self Cite

We explored mechanisms involved in B cell self-tolerance against brain autoantigens in a double-transgenic mouse model carrying the Ig H-chain (introduced by gene replacement) and/or the L-chain κ (conventional transgenic) of the mAb 8.18C5, specific for the myelin oligodendrocyte glycoprotein (MOG). Previously, we demonstrated that B cells expressing solely the MOG-specific Ig H-chain differentiate without tolerogenic censure. We show now that double-transgenic (THκmog) B cells expressing transgenic Ig H- and L-chains are subjected to receptor editing. We show that in adult mice carrying both MOG-specific Ig H- and L-chains, the frequency of MOG-binding B cells is not higher than in mice expressing solely the transgenic Ig H-chain. In fact, in THκmog double-transgenic mice, the transgenic κmog L-chain was commonly replaced by endogenous L-chains, i.e., by receptor editing. In rearrangement-deficient RAG-2− mice, differentiation of THκmog B cells is blocked at an immature stage (defined by the B220lowIgMlowIgD− phenotype), reflecting interaction of the autoreactive B cells with a local self-determinant. The tolerogenic structure in the bone marrow is not classical MOG, because back-crossing THκmog mice into a MOG-deficient genetic background does not lead to an increase in the proportion of MOG-binding B cells. We propose that an as yet undefined self-Ag distinct from MOG cross-reacts with the THκmog B cell receptor and induces editing of the transgenic κmog L-chain in early immature B cells without affecting the pathogenic potential of the remaining MOG-specific B cells. This phenomenon represents a particular form of chain-specific split tolerance.