Disease relevance of H2-Aa

• 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) [1].
• Adoptive transfer of SP but not DP T cells from Aalpha(-/-) or Abeta(-/-) B6 mice into congenic RAG(-/-) hosts induces colitis [2].
• The other B cell lymphoma showed A beta, E alpha, and E beta mRNA expression but only minimal A alpha mRNA expression [3].
• These mutant cDNAs were individually cotransfected with wild-type A alpha cDNA into the class II-negative M12.C3 B lymphoma and Sal sarcoma cell lines [4].
• Pit assays performed with TAT-calcineurin Aalpha-positive osteoclasts revealed a concentration-dependent (10-200 nM) attenuation of bone resorption in the absence of cell cytotoxicity or changes in cell number [5].

Psychiatry related information on H2-Aa

• The role of A alpha chain is also implied by the permissiveness of E kappa alpha Aq beta but not Aq alpha Aq beta molecules in the deletion of V beta 6+ T cells [6].
• Hyperphosphorylated tau, the major component of the paired helical filaments of Alzheimer's disease, was found to accumulate in the brains of mice in which the calcineurin A alpha gene was disrupted [calcineurin A alpha knockout (CNA alpha -/-)] [7].

High impact information on H2-Aa

• 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 [8].
• Two independent experimental strategies are employed: the ability of 12 monoclonal antibodies to recognize L cell transfectants bearing chimeric and mutant A alpha chains is assessed, and the amino acid sequences of A alpha chains expressed by immunoselected B lymphoma mutants are deduced [9].
• We have now isolated and sequenced A alpha cDNA clones from five other mouse haplotypes: d, b, f, u, and q [10].
• Regions of allelic hypervariability in the murine A alpha immune response gene [10].
• The structure of one of these class II major histocompatibility complex molecules, A alpha, was recently deduced from sequence analysis of a cDNA clone produced from k haplotype mice [10].

Chemical compound and disease context of H2-Aa

• Chloramphenicol acetyltransferase gene expression was cis-activated by a region of the Ia A alpha k gene in a B lymphoma line, but not in a myeloma line [11].
• To further substantiate the importance of fibrin removal as the mechanism by which PAI-1 deficiency limited bleomycin-induced fibrosis, bleomycin was administered to mice deficient in the gene for the Aalpha-chain of fibrinogen (fib) [12].

Biological context of H2-Aa

• 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 [13].
• The dimorphic allelic lineages are in marginally detectable linkage disequilibrium with the exon 2 sequences, particularly in H2Aa, thus lending further support to the coevolution hypothesis [14].
• We report nucleotide sequences for the A alpha chain cDNAs of the k, r, and s haplotypes, which, when compared to previously published A alpha sequences, demonstrate the existence of one k-specific amino acid residue and of another present only in the k and r haplotypes [15].
• The murine Ia alpha chains, E alpha and A alpha, show a surprising degree of sequence homology [16].
• To account for these observations, it is proposed that during evolution of the mouse H-2 complex, in addition to gene duplication of ancestral gene(s) to yield the genes encoding E alpha A alpha, A beta, and E beta polypeptide chains, further gene duplication occurred, forming multiple copies of genes encoding each Ia polypeptide chain [17].

Anatomical context of H2-Aa

• Significant proliferative responses of F-MuLV envelope-specific, H-2a/b T cells were observed when the T cells were stimulated with antigen-pulsed peritoneal exudate cells (PEC) having the b allele at the K, A beta, A alpha, and E beta loci of the H-2 [18].
• These mice feature immune system perturbations like those of Aalpha and Abeta knockout animals, notably a dearth of CD4(+) lymphocytes in the thymus and spleen [19].
• Analysis of the mutant cell lines has allowed us to assign the reactivity of each mAb to either the A alpha- or the A beta-polypeptide [20].
• We have compared the presentation of five different epitopes derived from hen egg white lysozyme (HEL) to Ak-restricted T hybridomas by rat-2 fibroblasts transfected with A alpha k and A beta k (RKK) and RKK cells supertransfected with the mouse invariant chain (RKKI) [21].
• By contrast, although C57BL/6 gave a good response, the mutant strain was unable to generate cytotoxic T lymphocytes to the male-specific H-Y antigen--a response under I-A subregion Ir gene control, which now must be considered to be the Ia-1 gene [22].

Associations of H2-Aa with chemical compounds

• Here we report that the expression of I-Ak (A alpha kA beta k) in transgenic NOD mice can also prevent insulitis, and that this protection is seen not only when the I-A beta-chain has aspartic acid as residue 57, but also when this residue is serine [23].
• Constructs containing 5' deletion mutations of the A alpha promoter attached to the bacterial chloramphenicol acetyl transferase gene were used to delineate the minimum 5' flanking sequences required for promoter activity, and for inducibility by IFN-gamma and TNF-alpha [24].
• 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 [25].
• Induction of A alpha-specific mRNA was sensitive to the protein synthesis inhibitor cycloheximide [26].
• To test whether this residue actually was important physiologically, a lysine codon was created in a recombinant A beta gene possessing the amino-terminal sequence of the kappa haplotype, and the ability of this mutant chain to be expressed with various mouse A alpha-chains was examined [27].

Physical interactions of H2-Aa

• 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 [28].
• Additional studies showed that A alpha mRNA was stabilized by IL-4 treatment of 70Z/3 cells, and that changes in gene transcription accounted for little of the increase in mRNA levels [29].
• These proteins are indistinguishable in binding assays from proteins previously shown to bind an enhancer region of the class II major histocompatibility complex gene A alpha [30].

Regulatory relationships of H2-Aa

• Decorin enhances the IFN-gamma-induced expression of the IAalpha and IAbeta MHC class II genes [31].
• In one line, 70Z/3, A alpha mRNA was induced greater than 10 fold by 65 hr of IL-4 stimulation [29].

Other interactions of H2-Aa

• Incubation of T cells with the A alpha (g7)63-82YC peptide resulted in up-regulation of IL-2R alpha chain expression and induction of IFN-gamma secretion [32].
• C3H.Q lacks functional H2-E molecules and share H2-Aalpha with C3H.NB [33].
• The results obtained demonstrate that the regions between residues 69 to 76 of the A alpha k chain and the regions between residues 63 to 67 and 75 to 78 of the A beta k-chain exert a dominant effect on the presentation of lysozyme peptides by I-Ak to the T cell hybridomas in our panel [34].
• We show that embryonic day (E)9.5 A alpha/A gamma embryos display severe malformations, similar to those already described in retinaldehyde dehydrogenase 2 null mutants [35].
• The hindbrain of E8.5 A alpha/A gamma embryos shows a posterior expansion of rhombomere 3 and 4 (R3 and R4) markers, but fails to express kreisler, a normal marker of R5 and R6 [35].

Analytical, diagnostic and therapeutic context of H2-Aa

• Northern blot analyses indicated that one I-A-, I-E+ tumor strongly expressed A alpha, E alpha, and E beta mRNAs but possessed only a weak expression of A beta mRNA [3].
• By immunoprecipitation and two-dimensional analysis of Ia molecules from F1 spleen cells, we could independently map the reactivities of the mAb as being determined by the A alpha or A beta chain [36].
• Further, we have used our high-pressure liquid chromatography tryptic peptide map technique to formally map the genes encoding Aalpha, Abeta, and Ebeta to the I-A subregion using recombinant and F1 hybrid mice [37].
• HPLC peptide map comparisons of A alpha d, A beta d and the 22Kd polypeptides demonstrated that the 22Kd polypeptide has extensive homology with A alpha d [38].
• We have compared the tryptic peptide fingerprints of the A alpha, A beta, E alpha, and E beta subunits encoded by four wild-derived H-2 complexes expressing A molecules closely related to Ak [39].

References