Christadoss, Premkumar

Abstract MHC class I and CD8+ cell deficiency have either prevented systemic lupus erythematosus-like disease in mice or enhanced type I diabetes in nonobese diabetic mice. To study the involvement of MHC class I and class I-restricted CD8+ T cells in the induction of a classical Ab-mediated disease, experimental autoimmune myasthenia gravis (EAMG), we immunized beta 2 microglobulin (beta 2-m) gene-disrupted (beta 2 m-/-) C57BL10 (B10) mice, deficient in class I gene expression and CD8+ cells, and heterozygous (beta 2-m+/-) B10 mice with normal expression of class I molecules and sufficient CD8+ cells with Torpedo acetylcholine receptor in CFA, and assessed them for clinical and immunopathologic manifestations of EAMG. Despite MHC class I and CD8+ cell deficiency, beta 2-m-/- mice developed EAMG. Moreover, the incidence of EAMG in the beta 2-m-/- mice was higher than that of beta 2-m+/- heterozygous mice with normal class I expression and frequency of CD8+ cells. The finding provided direct genetic evidence against a pathogenic effector role in C57BL10 mice for MHC class I molecule and class I-restricted CD8+ T cells in EAMG pathogenesis.

Abstract When MHC congenic and recombinant mice are inoculated with Torpedo acetylcholine receptors (AChR) with adjuvants, the magnitude of autoantibody responses to muscle AChR and the defect of neuromuscular transmission closely parallel in vitro lymphocyte proliferative responses to Torpedo AChR. All of these responses are controlled by gene(s) at the I-A subregion of the H-2 complex. Data presented in this report confirm in back-cross mice that T lymphocyte proliferative responses to AChR are controlled by a Mendelian dominant gene linked to H-2, at the I-A subregion. Lymphocyte responses were eliminated by blocking Ia antigens on lymph node cell surfaces with appropriate anti-I-A alloantisera and by removal of adherent cells. A spontaneous mutation at the I-A subregion in the B6 strain, which resulted in structural alteration of the A beta chain of Ia, converted high responsiveness to AChR to a state of low responsiveness. These data implicate a macrophage-associated Ia molecule in induction of autoimmune responses to AchR, probably in the presentation of AChR to helper T lymphocytes that thereby help B lymphocytes to differentiate into anti-AChR antibody-forming cells.

Abstract The proliferative response of regional lymph node lymphocytes to Torpedo acetylcholine receptor (TAR) is under H-2 linked Ir gene control. In high responder B6 (H-2b) congenic mice, lymphocytes that proliferate in vitro in response to TAR are dependent on T cells of a subpopulation expressing the phenotype associated with helper functions, Lyt-1+23-.

Abstract Studies on the genetic control of immune response to sperm whale myoglobin were initiated. As demonstrated in this paper, the T lymphocyte proliferative response to whale myoglobin is under H-2-linked Ir gene control. Mice of H-2d, H-2f, and H-2s haplotypes were high responders to the myoglobin, whereas haplotypes H-2b, H-2k, H-2p, H-2q, and H-2r were low responders. The Ir gene(s) was localized between H-2K and H2D regions, since the recombinant strain A.TL (KsIkSkDd) was a low responder and A.TH (KsIsSsDd) was a high responder. Further studies with recombinant strains revealed that the expression of the high-responder I-Ad or I-As alleles was sufficient to give a good response, since strains D2.GD (d d b b b b b b) and B10.HTT (s s s s k k k d) were high responders. The expression of the I-Cd allele in strains B10.A (k k k k k d d d) and B10.A(5R) (b b b k k d d d) also gave high response, and thus suggested a second Ir gene, derived from the H-2d haplotype. The finding that expression of the I-Cs allele in B10.S(8R) (k k ? ? s s s s) did not result in high response suggests the lack of the second Ir gene in the high-responder H-2s haplotype.

Abstract As a first step in determining the genetic control of experimental autoimmune myasthenia gravis in mice, we tested the proliferative responses of lymph node cells to torpedo acetylcholine receptors (TAR). Studies with congenic and recombinant inbred strains of mice revealed that T-cell responses to TAR are controlled by an H-2-linked Ir gene, mapping in the I-A subregion of mouse major histocompatibility complex.