Disease relevance of H2-Ab1

• Mutant mice with a defined genetic defect in the beta 2-microglobulin (beta 2m) or the H2-I-A beta chain, which are virtually devoid of functional CD8 or CD4 alpha beta T cells, respectively, were employed for analyzing immune mechanisms involved in acquired resistance against Listeria monocytogenes [1].
• CD4(+) alpha beta T cells from either normal C57BL/6 (B6) or MHC-II-deficient (A alpha(-/-) or A beta(-/-)) B6 donor mice engrafted into congenic immunodeficient RAG1(-/-) B6 hosts induced an aggressive inflammatory bowel disease (IBD) [2].
• BACKGROUND: Sporadic inclusion body myositis (IBM) is characterized by the presence of rimmed vacuoles and fibrillary inclusions of Abeta in muscle fibers, and often inflammatory cells [3].
• In contrast, the MHC class II-deficient A beta-/- mice, which are virtually devoid of functional CD4 T cells, succumbed to M. bovis BCG infection [4].
• Our data indicate that alpha-MSH peptides might be used to modulate the local response of the brain to Abeta deposition in this neurodegenerative disease [5].

Psychiatry related information on H2-Ab1

• It has been demonstrated that immunization of transgenic mouse models of Alzheimer's disease (AD) with amyloid-beta(1-42) peptide (Abeta(1-42)) results in prevention of Abeta plaque formation and amelioration of established plaques in the brain [6].
• We now report that administration of m266 to PDAPP mice can rapidly reverse memory deficits in both an object recognition task and a holeboard learning and memory task, but without altering brain Abeta burden [7].
• We hypothesize that impaired synaptic plasticity and associated memory dysfunction during early stage Alzheimer's disease and severe cellular degeneration and dementia during end stage could be caused by the biphasic impact of Abeta-derived diffusible ligands acting upon particular neural signal transduction pathways [8].
• Finally, mcip1/2-null mice displayed a neurologic phenotype that was similar to calcineurin Abeta-null mice, such as increased locomotor activity and impaired working memory [9].
• The serologic lesion of the I-A mutant mouse strain, bm12, was investigated with the use of monoclonal anti-Iab antibodies and anti-idiotypic (Id) reagents produced against these antibodies [10].

High impact information on H2-Ab1

• Mixed isotype (E alpha A beta and A alpha E beta) dimers are not found on Ia+ hematopoietic cells, although some pairs (e.g., E alpha A beta d) reach the membrane of transfected cells expressing only the two relevant class II genes [11].
• Transgenic mice expressing both chains of the I-A gene showed progressive atrophy of the islets of Langerhans, whereas mice expressing interferon-gamma suffered an inflammatory destruction of the islets [12].
• RNA analysis revealed a requirement for greater A beta, and particularly A alpha transcript levels in haplotype-mismatched vs. haplotype-matched transfectants with similar levels of membrane Ia [13].
• In this report we present evidence that A beta 2 is transcribed in spleen and in a cultured B cell hybridoma [14].
• The class II genes in the I region of the murine major histocompatibility complex encode the alpha and beta chains of the two known la antigens, I-A and I-E [14].

Chemical compound and disease context of H2-Ab1

• Alzheimer's disease (AD) pathology is characterized by senile plaques containing amyloid-beta (A beta) peptide, a protein with neurotoxic and glial immune activating potential [15].
• Here we show that nasal vaccination with a proteosome-based adjuvant that is well tolerated in humans plus glatiramer acetate, an FDA-approved synthetic copolymer used to treat multiple sclerosis, potently decreases Abeta plaques in an AD mouse model [16].
• These data suggest that TNFs protect hippocampal neurons against A beta toxicity by suppressing accumulation of ROS and Ca2+ and that kappa B-dependent transcription is sufficient to mediate these effects [17].
• The alpha- and beta-chains of the I-A kappa antigen from the AKTB-1b B cell lymphoma were separated by ion-exchange chromatography on CM-Sephadex in the presence of propionic acid and urea [18].
• Transplantation of bone marrow cells from nonobese diabetic (NOD) mice, a model for type 1 diabetes mellitus, to C3H/HeN mice, which express I-E alpha molecules and have aspartic acid at residue 57 of the I-A beta chain, induced insulitis followed by overt diabetes in the recipient C3H/HeN mice more than 40 weeks after bone marrow transplantation [19].

Biological context of H2-Ab1

• However, the E beta chain encoded by the I-A subregion of this strain, one of the two components of the plasma membrane located I-E antigens produced in D2.GD X A.TFR5)F1 animals, has been demonstrated to be the product of an intragenic recombinational event between E beta genes from the d and b haplotypes [20].
• Indeed, the A alpha and A beta chains of the I-A antigens appear to exhibit normal behavior by the criteria of serology and two dimensional gel analysis [20].
• At least two different class II histocompatibility antigens, I-A and I-E, are encoded by the murine major histocompatibility complex [21].
• We have determined the DNA sequence of the murine I-E beta b immune response gene of the major histocompatibility complex (MHC) of the C57BL/10 mouse and compared it with the sequence of allelic I-E and non-allelic I-A genes from the d and k haplotypes [22].
• The A beta bm12, a mutant I-A beta b gene from the C57BL/6 mouse, has been shown to result from three nucleotide changes clustered in a short region of the beta 1 domain, which suggests that a micro gene conversion event caused this mutation [22].

Anatomical context of H2-Ab1

• CD40 expression was increased on cultured microglia treated with freshly solublized amyloid-beta (Abeta, 500 nanomolar) and on microglia from a transgenic murine model of AD (Tg APPsw) [23].
• Helper effect could be obtained only toward B cell sources that shared the H-2K and I-A antigens with the hybridoma cells [24].
• IFN-gamma increases the surface expression of class II molecules in a murine B cell line without inducing detectable changes in either I-A or I-A mRNA levels [25].
• Based on numbers of L. monocytogenes organisms in spleens, beta 2m -/- mutants suffered more dramatically from primary and secondary infection than A beta -/- mice [1].
• Here, we demonstrate that induction of the mouse MHC class II I-A heterodimer is normal in RB+/+ mouse embryonic fibroblasts (MEFs), but deficient in RB-/- MEFs [26].

Associations of H2-Ab1 with chemical compounds

• Three of the four chains, A alpha, A beta and E beta, are controlled by loci in the I-A subregion, whereas the locus controlling the E alpha chain is located in the I-E subregion of the H-2 complex [27].
• Class II antigens display extensive genetic polymorphism, the main part of which resides in the NH2-terminal domains of the A alpha, A beta and E beta chains [21].
• Third, lipopolysaccharide abolished the IFN-gamma-induced expression of I-A beta, but enhanced the expression of TNF [28].
• C3 gene expression followed an intermediate time course between that for TNF and I-A beta [28].
• Interestingly, the sensitivity to cycloheximide only lasted 30 min following the addition of IFN-gamma, after which cycloheximide had no effect on the expression of I-A beta [28].

Physical interactions of H2-Ab1

• Moreover, major histocompatibility complex class II-deficient I-A-beta-/- mice were capable of mounting a substantial response to secondary infection, manifest by a 95% reduction in oocyst output compared with primary infection [29].
• Studies on cell lines transfected with MHC class II genes have revealed important limitations on the assembly of haplotype-mismatched A alpha/A beta complexes [30].
• The DNA minigene-induced anti-Abeta antibodies bound to Abeta plaques in brain tissue from an Alzheimer's disease patient demonstrating functional activity of the antibodies and the potential for therapeutic efficacy [31].
• The molecular mass of the Abeta binding protein was estimated to be 49kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis [32].

Regulatory relationships of H2-Ab1

• Role of Na+/H+ exchange by interferon-gamma in enhanced expression of JE and I-A beta genes [33].
• Production of IL-6 by human myoblasts stimulated with Abeta: relevance in the pathogenesis of IBM [3].
• Macrophage colony-stimulating factor (M-CSF) inhibits the decrease in the amount of rRNA and IA beta mRNA in cultured epidermal Langerhans cells of the mouse [34].
• We conclude that I-A beta gene expression is repressed by PU.1 binding to the PU box domain [35].
• In particular, as shown in mice with the recombinant H-2 haplotype and in class II mutant bm12 mice, the I-A heterodimer controls the recognition of the immunodominant 40-kDa antigen [36].

Other interactions of H2-Ab1

• We show here that the E beta b gene is identical to the non-allelic A beta bm12 DNA sequence in the mutated region and suggest, therefore, that the E beta b gene was the donor sequence for this intergenic transfer of genetic information [22].
• The I region of the C57BL/10 mouse: characterization and physical linkage to H-2K of an SB beta-like class II pseudogene, psi A beta 3 [37].
• Surface expression of MHC class I (Kb, Db) and class II (I-Ab) molecules by B16 cells was low, but strikingly up-regulated by IFN-gamma [38].
• CONCLUSIONS: Cultured muscle cells increase the constitutive production of IL-6 in response to local deposition of Abeta in sporadic IBM [3].
• Genetic diversity of class II genes in wild mice: definition of five evolutionary groups by RFLP analysis of A alpha and A beta [39].

Analytical, diagnostic and therapeutic context of H2-Ab1

• Localization of a critical restriction site on the I-A beta chain that determines susceptibility to collagen-induced arthritis in mice [40].
• Northern blot analysis of Abeta-stimulated human myoblasts revealed an increase in IL-6 mRNA expression [3].
• RESULTS: Messenger RNA for interferon (INF)-gamma, interleukin (IL)-4, and tumor necrosis factor (TNF)-alpha, known inducers of MHC Class II expression in vitro, could be detected in allografts either 24 hours before or simultaneously with massive induction of graft specific I-Abeta mRNA [41].
• Comparative sequence analysis of cDNA clones encoding I-A molecules of the CH12 B cell lymphoma: nucleotide differences do not account for their "defective" function in B cell stimulation [42].
• Adoptive transfer experiments revealed that the increase in apoptosis is due to a lack of interactions with mutant MHC class II rather than to an intrinsic defect in the CD4+ T-cells selected on mutant Abeta-expressing thymic epithelial cells [43].

References