Disease relevance of HMHA1

• It is suggested that HA-1 may be one of the immunodominant antigens inducing not only graft-versus-host disease but also graft-versus-malignancy effects [1].
• Our results suggest that the HA-1 168His variant is associated with reduced susceptibility to primary Sjögren's syndrome [2].
• RESULTS: We found that mRNA of HA-1 is expressed in all leukemia/lymphoma cell lines and PBMNC [1].
• Quantification of the HA-1 gene product at the RNA level; relevance for immunotherapy of hematological malignancies [3].
• We chemically synthesized 20 peptides corresponding to 75% of the HA1 molecule of the influenza virus [4].

High impact information on HMHA1

• Cytotoxic T lymphocytes (CTLs) specific for mHags of the recipients can be isolated from the blood of recipients with severe GvHD (ref. 3). A retrospective study demonstrated an association between mismatch for mHags HA-1, -2, -4 and -5 and the occurrence of GvHD in adult recipients of bone marrow from HLA genotypically identical donors [5].
• The minor histocompatibility antigen HA-1: a diallelic gene with a single amino acid polymorphism [6].
• Family analysis with HA-1 allele-specific polymerase chain reaction showed an exact correlation between this allelic polymorphism and the HA-1 phenotype [6].
• The regions of antigenic variation in influenza hemagglutinin (HA) are located on surface-accessible regions in the three-dimensional structure of the HA1 monomer [7].
• A conserved region of the hemagglutinin molecule around amino acid position 115 in the heavy chain (HA1) was implicated as being important in this recognition by the lack of stimulatory activity associated with a glutamic acid to lysine substitution at position 115 in the laboratory mutant RV6, derived from wild-type PR8 [8].

Chemical compound and disease context of HMHA1

• At calcium-specific ionophore A23187 concentrations of approximately 0.25 microM [which still allow assembly and release of fowl plague virus (FPV) particles] post-translational proteolytic cleavage of the viral hemagglutinin precursor HA into the fragments HA1 and HA2 is inhibited [9].
• The influenza virus hemagglutinin polypeptides, HA1 and HA2, have been purified by gel filtration in the presence of sodium dodecyl sulfate from a vaccine preparation of the recombinant strain Heq1N2 [10].
• Low-molecular-weight inhibitors of serine proteases, aprotinin and leupeptin, when added to influenza virus-infected HAEC suppressed HA0 cleavage and reduced the amount of cleaved HA1/HA2 both in cells and in progeny virions and thus diminished the infectivity of the virus [11].
• The haemagglutinin from the Hong Kong influenza virus A/Memphis/102/72 contains seven oligosaccharide units attached to asparagine residues 8, 22, 38, 81, 165 and 285 in the heavy chain (HA1) and to residue 154 in the light chain (HA2) [12].
• Furthermore, extracellular reaction of GSH with cisplatin prior to treating HA1 cells reduced the toxicity of the compound, indicating that this reaction is capable of participating in the detoxification of cisplatin [13].

Biological context of HMHA1

• We investigated the feasibility of this strategy using the hematopoietic system-specific minor histocompatibility antigen HA-1, which is known to induce HLA-A2-restricted CTLs [14].
• Genotypes of ABCA7 and HA-1 SNP were determined in three distinct Caucasian populations of patients with primary Sjögren's syndrome and ethnically matched controls [2].
• However, the tissue distribution of HA-1 has been described as restricted to the cells of the hematopoietic lineage [1].
• METHODS: We examined the HA-1 expression in peripheral blood mononuclear cells (PBMNC), leukemia/lymphoma cell lines, solid tumor cell lines, and paired samples of tumor and normal tissues from individual cancer patients by quantitative reverse-transcription polymerase chain reaction [1].
• Comparison of allele frequencies between these groups revealed that the incidence of the HA-1 168His allele is significantly lower in Sjögren's syndrome patients than in controls (p<0.003) [2].

Anatomical context of HMHA1

• The cord blood-derived HA-1-specific cytotoxic T cells are from child origin [15].
• Moreover, we observed pre-existing HA-1-specific T cells in cord blood samples [15].
• Generation of minor histocompatibility antigen HA-1-specific cytotoxic T cells restricted by nonself HLA molecules: a potential strategy to treat relapsed leukemia after HLA-mismatched stem cell transplantation [14].
• Both the circulating and the ex vivo-generated HA-1-specific T cells show specific and hematopoietic restricted lysis of human leukocyte antigen-A2(pos)/HA-1(pos) (HLA-A2(pos)/HA-1(pos)) target cells, including leukemic cells [15].
• HLA-A2(-) peripheral blood mononuclear cells were stimulated with HLA-A2(+) T2 cells pulsed with synthetic HA-1 peptide or with dendritic cells transduced with the HA-1 cDNA [14].

Associations of HMHA1 with chemical compounds

• Vir-2 cells recognized the reduced and alkylated purified HA1 of PR8 virus, and this reactivity was retained after cleavage at methionine and tryptophan residues [8].
• Our results show that the only difference in glycosylation between the HA1s of the virulent and avirulent strains is the lack of an asparagine-linked carbohydrate on the virulent HA1 polypeptide at residue 11 [16].
• Their HA1 amino acid sequences differ at 10 positions, one of which (N154) introduces a potential glycosylation site in A/Vietnam/1203/04 (H5N1) [17].
• These include a hydrophobic signal peptide, hydrophobic NH2 and COOH termini of the HA2 subunit, and a HA1/HA2 cleavage site involving an arginine residue [18].
• (1) as the intact hemagglutinin after disruption of the virus in sodium dodecyl sulfate, giving 2 subunits of 58,000 daltons (HA1) and 26,000 daltons (HA2), and (2) after treatment of the virus with bromelain, giving 2 subunits of 58,000 daltons (BHA1) and 21,000 daltons (BHA2) [19].

Physical interactions of HMHA1

• We identified a total of 31 exonic single-nucleotide polymorphisms (SNP) in the ABCA7/HA-1 gene complex, nine of which represent non-synonymous nucleotide alterations [2].

Other interactions of HMHA1

• In contrast, the frequencies of all ABCA7 allelic variants and additional HA-1 polymorphisms were similar in patients and controls [2].
• Since maternal cells traffic into the fetus during pregnancy, we questioned whether cord blood has the potential to generate cytotoxic T cells specific for the hematopoietic minor histocompatibility (H) antigen HA-1 that would support the graft-versus-leukemia effect [15].

Analytical, diagnostic and therapeutic context of HMHA1

• In the alloreactive cultures, HA-1-specific CTLs were enriched up to 7% by 3 rounds of antigen-specific stimulations and up to 87% by fluorescence-activated cell sorting of tetramer-positive T cells [14].
• Genomic identification of the minor histocompatibility antigen HA-1 locus by allele-specific PCR [20].
• The sequence analysis of HA-1 cDNA identified two alleles, termed HA-1H and HA-1R, which differ in only two nucleotides at 3' end of exon A, at positions 500 and 504 [21].
• Prospective genomic typing for the HA-1 alleles will improve donor selection and identify HLA-A*0201-positive recipients with a high risk for HA-1-induced GvHD [20].
• CONCLUSION: Our results demonstrate that HLA class I-minor histocompatibility antigen tetramers are useful tools for monitoring and selection of high avidity HA-1- and HA-2-specific cytotoxic T cells for adoptive immunotherapy [22].

References