Grand-paternal age and the development of autism-like symptoms in mice progeny.

Advanced paternal age (APA) contributes to the risk of autism spectrum disorders (ASDs) in children. In this study, we used a mouse model to investigate the effects of APA on behavioral features related to autistic syndromes (that is, social deficits, communication impairments and stereotypic/repetitive behaviors). We also examined whether such effects are transmitted across generations. To do this, males aged 15 months (APA) and 4 months (control) were bred with 4-month-old females, and the resulting offspring (F1) and their progeny (F2; conceived by 4-month-old parents) were tested for the presence and severity of ASD-like behaviors. Our results indicate that APA resulted in offspring that displayed distinctive symptoms of ASD. We found that both F1 conceived from old fathers and F2 derived from old grandfathers displayed increased ultrasound vocalization (USV) activity, decreased sociability, increased grooming activity and increased anxiety-like responses. Moreover, such abnormalities were partially transmitted to the second generation of mice, having APA grandfathers. In conclusion, our study suggests that the risk of ASD could develop over generations, consistent with heritable mutations and/or epigenetic alterations associated with APA.

Two new alleles of the RHCE gene in Black individuals: the RHce allele ceMO and the RHcE allele cEMI.

Six unrelated individuals of Afro-Caribbean origin, whose red cells have a marked reduction of the Rhe antigen expression, have been identified. All exhibited the same serological profile with anti-e monoclonal antibodies and lacked expression of the high frequency e-related antigen hrS. Transcripts and genomic analysis showed that these phenotypes resulted from the presence of two new RHCE alleles, ceMO and cEMI. The ceMO allele corresponded to a RHce gene carrying a G667T mutation (exon 5) and was detected at the homozygous state in sample 1 and at the heterozygous state in samples 2-6. The G667T mutation resulted in a Val223Phe substitution on the Rhce polypeptide, in close proximity to Ala226 (e-antigen polymorphism), which might account for the altered expression of e. The ceMO allele is also associated with the lack of expression of the hrS antigen. The absence of the hrS antigen expression may have implications in transfusion as hrS-negative individuals may develop clinically significant antibodies. The cEMI allele corresponded to a silent RHE allele carrying a nine nucleotide deletion within exon 3 and was detected at the heterozygous state in sample 2. This deletion resulted in a shortened polypeptide of 414 residues (instead of 417) that was absent (or severely reduced) at the red cell surface, as the E antigen was undetectable using serology and Western blot analysis with anti-E reagents. In DNA-based polymerase chain reaction genotyping for RHE determination, the cEMI allele provided a false positive result as the cells carrying this allele are serologically phenotyped as E-negative. The incidence of this allele in the Black population is unknown but, as shown already for D genotyping, one must exercise caution when genotyping is performed to detect the e/E polymorphism.

A recombinant human scFv anti-Rh(D) antibody with multiple valences using a C-terminal fragment of C4-binding protein.

Monomeric recombinant molecules prove generally unsatisfactory for in vivo use. Most biological systems are indeed multivalent either structurally, associating different chains, or functionally, when cross-linked by their ligands. Mimicking natural molecules for immune intervention implies the need for multimerizing systems to create multivalent molecules capable of interfering with physiological processing. A multivalent anti-Rh(D) recombinant protein has been designed by reconstructing the antibody binding site of a human monoclonal anti-Rh(D) antibody as a single chain Fv mini antibody, then multimerizing it by inserting at its C-terminal end the C-terminal part of the C4 binding protein (C4bp) alpha chain, which is responsible for the octamer multimerization of that molecule. This soluble multivalent recombinant molecule was functional, bound red blood cells (RBCs), agglutinated them, and did not activate complement. This demonstration model opens the way for future in vivo use of multivalent molecules associating antibody valences and other functional molecules for cell targeting, imaging, or removal of cells such as Rh(D)-positive RBCs for preventing Rh alloimmunization.

Murine monoclonal antibodies against Gerbich antigens.

Two murine monoclonal antibodies (E11-1 and MR4-130) agglutinated all samples of human red cells except those of the Ge (-1, -2, -3) phenotype. It was possible to demonstrate that these antibodies recognize two different epitopes of the Gerbich antigen.

H-deficient blood groups of Reunion island. II. Differences between Indians (Bombay Phenotype) and whites (Reunion phenotype).

Two variants of recessive, H-deficient nonsecretor individuals (h/h, se/se) were identified on Reunion Island: (1) H-negative individuals corresponding to the classical Bombay phenotypes (OhO, OhA, OhB, OhAB) who lack completely the H antigen on their red cells; all of them were Indian and had strong anti-H antibodies reacting with normal O and Oh red cells from whites; and (2) H-weak individuals (Oh, Ah, Bh, ABh). This phenotype represented the majority (85%) of the H-deficient phenotypes on Reunion Island, and all of them were white. They had only a weak expression of the H antigen and showed small but detectable amounts of ABH antigens on their red cells. Their anti-H antibodies reacted with normal O erythrocytes, but failed to react with Oh red cells, regardless of the ethnic origin of the donor. They were all from the same geographical area on the Island (Cilaos) and showed homogeneous titers of anti-H antibodies in sera. We propose to call this particular variant of weak H phenotype, belonging to the so-called para-Bombay series, Reunion.

alpha-2-L-fucosyltransferase activity in sera of individuals with H-deficient red cells and normal H antigen in secretions.

alpha-2-L-fucosyltransferase activity was found in the sera of 4 H-deficient secretor individuals (Hz). This activity represented about 5-10% of the activity present in the serum of normal H phenotypes.

Relationship between I and H antigens. I. A study of the plasma and saliva of a normal population.

The H and I antigens were studied in the plasma and saliva of 52 group O subjects, by hemagglutination inhibition at continuous flow. H plasma substance was detected with one anti-H antibody from a Bh donor. Secretors have more H plasma substance than do non-secretors, but there was no relationship between the amounts of I and H substances in the plasma. On the contrary, the amounts of I substance in the saliva detected by anti-I (Sti) is a function of secretor status. Nonsecretors had a much greater amount of I in saliva than did secretors. These results support the hypothesis that I antigen (detected by anti-I (Sti)) is a part of the substrate of H antigen.

Different H deficient phenotypes present in one kindred.

Two different H deficient phenotypes are observed in one kindred. Three of them in two generations of a same family appear as Bombay like. In the other branch of the kindred, an Hz phenotype (as described in the editorial of this issue) is observed. The most simple explanation is that the three Bombay like phenotypes correspond to Hz ABH non secretor (Hz sese) individuals, this being indistinguishable from a true Bombay. The high level of I antigen in the plasma of the three Bombay like (as observed in Hz in contrast to true Bombay) could favour such an hypothesis. According to ORIOL'S new hypothesis [5], III2, III3 and IV2 would genetically be hh sese, III8 would be hh Se and the h Se would therefore be a recombining haplotype (the original haplotype being h se).

Relationship between I and H antigens. II. Study of the H and I deficient phenotypes.

H and I substances are present in the plasma and the saliva. In the plasma there is no quantitative relationship between H and I substances, whereas in the saliva only non-secretors produce I substance [shown by anti-Is serum, (Sti.)]. The study of I and H substances in the plasma and the saliva of H and I deficient subjects gives a better understanding and enables the completion of the classification of these rare phenotypes. The results also allow the proposal of a synthetic scheme of Is and H substances in the saliva.

[A family with an "Hm" phenotype transmitted over 3 generations]. / Une famille où un phénotype "Hm" est transmis à travers trois générations.

Hm phenotype represents a dissociation between a normal salivary expression of H substance and a very weakened expression of the antigen on red blood cells. Genetic analysis of the reported family reveals a dominant inheritance: Some members (Marie K..., Francette, Carmen) present a phenotype marked by a normal H enzyme but a deficient H antigen in erythrocyte membrane. Others Alice, Mathilde) have no expression of A1 antigen due to H substrate deficiency. H substance in salivary secretion is normal. In the other branch of this pedigree without consanguinity, Herbert presents an H substance deficiency, though quite different, as A1 antigen is expressed. In this family, Hm phenotype can be explained, without resorting to a Zm allele, by the expression of an exceptional allele at the H locus (like Am is an ABO allele). This hypothesis supports the possible polymorphism of H locus.