Genetic control of autoimmune encephalomyelitis and recognition of the critical nonapeptide moiety of myelin basic protein in guinea pigs are exerted through interaction of lymphocytes and macrophages

Abstract

Genetic control has been studied of the response to the encephalitogenic nonapeptide (NP) determinant of myelin basic protein (BP) in inbred guinea pigs of strains resistant or susceptible to induction of experimental autoimmune encephalomyelitis (EAE). By studying bone marrow-reconstituted animals, we found that susceptibility to induction of EAE was a function of the genotype of the cells of the lymphohematopoietic system and not of the physiological environment or target organ. Analysis of the T cell response showed that susceptible strains 13 or (2 X 13)F1 hybrid guinea pigs recognized the NP determinant when injected with whole BP in adjuvant. Resistant strain 2 guinea pigs responded to undefined determinants on BP, but not to the NP moiety. We investigated the cells involved in regulating the response to the NP determinant by injecting susceptible F1 hybrids with BP-pulse macrophages of either parental strain. Susceptible strain 13 macrophages triggered a response to the NP determinant and induced clinical EAE. In contrast, F1 animals injected with resistant strain 2 macrophages failed to respond to the NP determinant, although the macrophages were capable of presenting other undefined determinants present on whole BP. Therefore, genetic control of the immune response to the NP determinant appears to be exerted at the level of antigen presentation by macrophages to T lymphocytes.

Immunodominance of a low-affinity major histocompatibility complex-binding myelin basic protein epitope (residues 111-129) in HLA-DR4 (B1*0401) subjects is associated with a restricted T cell receptor repertoire.

“…These observations are compatible with the view that differences in frequency between patients and controls should not be overrated in the implication of MBPspecific T cells in the pathogenesis of MS (48). More importantly, and for the first time to our knowledge, we show that the MBP region (111-129), encompassing the encephalitogenic epitopes for guinea pig strain 13 (41,58,59) and Lou/M rats (60), is largely immunodominant in human HLA-DRB1*0401-positive individuals. MBP(111-129)-specific, mostly DRB1* 0401-restricted TCL were detectable with no exception, and contributed Ͼ 50% of all MBP-specific TCL in the majority (9/12) of subjects (Table II).…”

“…First, putative immune disorders in humans are found in association with HLA genes, in particular HLA-DR (38). Second, in animal models for autoimmunity such as EAE, disease susceptibility of various rodent strains is under the control of MHC-class II genes (39)(40)(41)(42). On these grounds, it is currently believed that disease-related MHC molecules may contribute to the pathogenesis by presenting specific autoantigenic peptides to T cells.…”

In vivo effects of antibodies to immune response gene products: prevention of experimental allergic encephalitis.

“…I-A and I-J (17,18) determinants are present on activated T lymphocytes and on some antigen-presenting cells (19). An I region product present on macrophages is critical for the effective presentation of the encephalitogenic determinant of myelin basic protein to T cells in the guinea pig (6,7). In the mouse, humoral responses to myelin basic protein are controlled by genes in the I-A subregion (20).…”

Genetic control of experimental autoimmune encephalomyelitis at the level of cytotoxic lymphocytes in guinea pigs

“…In a recent study of genetic factors involved in the induction of EAE [3], we found that strain 2 M@ were incapable of inducing EAE or a T cell proliferative response against the NP determinant in (2 x 13)F1 guinea pigs. Therefore, it seems that strain 2 MQ can present the NP determinant for cytotoxicity but not for induction of disease or for proliferation.…”

“…Antigen-specific proliferating T lymphocytes and helper or delayed hypersensitivity T lymphocytes have been found to recognize their antigens in association with syngeneic I region gene products [ll-131. We have found that MQ, originating from strains 2 or 13 differed in their ability to present the encephalitogenic NP determinant to proliferating T lymphocytes [3]. Therefore, it was of interest to study the ability of strain 13 and 2 target MQ, to present BP to cytotoxic cells of either genotype since strains 2 and 13 appear to be similar at the IUD region of the MHC and different at the I region [14].…”