Determinant spreading during the course of experimental autoimmune encephalomyelitis
The term, determinant spreading, was first applied by Lehmann and colleagues to the phenomenon observed in experimental autoimmune encephalomyelitis (EAE), a model of human multiple sclerosis (MS). EAE is an inflammatory demyelinating disease of the central nervous system mediated by CD4" T cells specific for myelin autoantigens. liAF can be induced in susceptible mouse strains by immunization with myelin basic protein (MBP) or a peptide containing its dominant determinant, Ac 1 -1 I, or with proteolipid protein (PLP).
EAE in (B10.PL X SJL/J)F1 mice manifests as an acute disease phase followed by a chronic phase. Lehmann and coworkers induced EAE in (BIO.PL X SJL/J)F1 mice by injection of MBP-domi-nant determinant peptide, Acl-11, and observed that in the acute phase of the disease the T cell response was directed against Acl-11, whereas in the chronic phase the response spread to cryptic determinants of MBP (35-47, 81-100 and 121-140). McCarron and colleagues also observed T cell reactivity to the large 89-169 fragment of MBP in mice immunized with MBP 1-37. T cell reactivity to these two fragments was restricted by different major histocompatibility complex (MHC) class II elements. Perry and coworkers observed that following induction of EAE in (SJL/J X PL/J)F1 mice by MBP immunization, T cell responses spread to PLP. Raine's and Miller's laboratories have shown that in EAE initiated in the SJL/J mouse by adoptive transfer of T cells reactive with the dominant determinant of MBP, responses spread to the dominant determinant, 139-151, of PLP. Miller's group went on to demonstrate intermolecular spreading between PLP 139-151 and PLP 178-191. Moreover, both groups demonstrated that T cells specific for the new determinants were functionally capable of causing EAE in naive recipient mice by adoptive transfer. Tuohy's laboratory has reported that in EAE in (SWR X SJL/J)F1 mice, there is a predictable, orderly determinant spreading involving PLP, MBP and myelin oligodendrocyte glycoprotein (MOG).
Intramolecular and intermolecular spreading in a spontaneous disease: insulin-dependent diabetes mellitus (IDDM)
During the very early phase of disease in the non-obese diabetic (NOD) mouse, T cell proliferative responses arise first to certain determinants on glutamic acid decarboxylase (GAD). Subsequently, a spreading of T cell responsiveness occurs to other determinants of GAD as well as to other unrelated antigens present in the p cells of the pancreatic islets (65 kDa heat shock protein, carboxypeptidase H, insulin, etc.). It is still unclear whether GAD is the endogenous initiator molecule, or whether some other proinflammatory event precedes this induction, to ignite a multidimensional conflagration. Interestingly, induction of intravenous or inhalation tolerance to GAD was successful in preventing insulitis as well as clinical diabetes.
Diversification of T cell response can lead to engaging regulatory T cells: autoimmune arthritis
Adjuvant arthritis (AA) can be induced in the Lewis rat by injection of Mycobacterium tuberculosis, and it serves as an experimental model for human rheumatoid arthritis (RA). T cell responses to the 65 kDa mycobacterial heat shock protein (Bhsp65) have been implicated in the pathogenesis of AA as well as RA. Moudgil and colleagues observed that in the acute phase of AA, T cell responses arise to several dominant and subdominant determinants of Bhsp65. Interestingly, in the late phase of AA, there was evidence for 'diversification' (broadening of responses to new determinants within an antigen after priming with the whole multideterminant antigen) of the T cell responses to certain additional determinants located at the C-terminal end of Bhsp65. Moreover, arthritic rats in the late phase of AA also raised vigorous responses to the corresponding C-terminal determinants within self(rat) hsp65 (Rhsp65). These results suggest that the observed diversification is possibly triggered in vivo by induction of Rhsp65-reactive T cells, and that it is critical in regulating acute inflammatory arthritis in the Lewis rat.
Reciprocal T and B cell spreading: systemic lupus erythematosus
In the (NZB X NZW)F1 mouse model of systemic lupus erythematosus (SLE), Hahn's group has shown that three V-region peptides from a single prototype DNA-specific antibody, under the appropriate conditions, can either accelerate or delay disease significantly. The above effects were explained on the basis of activation of T cells by the peptide-presenting B cells, followed by a T cell induction of B cells displaying a cross-reactive peptide, continuing reciprocally in this manner. Interference with this reciprocal expansion and/or associated regulatory (Tnl/TM2) interactions could lead to protection. Similarly, both intramolecular and intermolecular immunoglobulin epitope spreading has been reported by Harley's group.
Breaking of self tolerance by raising a B cell response to a foreign homologous protein
Mamula and Janeway have shown that although mice are tolerant at the T cell level to self cytochrome c (cyt c), coimmunization with human and mouse cyt c breaks T cell tolerance to cryptic determinant region 1-80 of self cyt c. It was suggested that the foreign cyt c induces B cells that are cross-reactive with self cyt c; these B cells then bind, process, and present the self molecule to T cells.
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