Major histocompatibility locus in the Arabian horse.

Combined immunodeficiency disease (CID) is a genetic disorder of T and B lymphocyte production which results in a nonfunctional immune system. It is inherited as an autosomal recessive trait and has been reported in humans and in horses of the Arabian breed. Arabian horses known to have the CID gene and horses of unknown carrier status were tested using a microlymphocytotoxicity technique. Computer chi 2 analysis distinguished six serologically defined specificities. The study of unrelated horses and a limited number of families showed that the specificities behave as codominant alleles segregating at one locus. No differences in antigen frequency was detected between the CID carriers and the random horse population.

Correction of equine severe combined immunodeficiency by bone marrow transplantation.

A 32-day-old horse with severe combined immunodeficiency was transplanted with equine bone marrow cells in an attempt to establish immunologic responsiveness. A histocompatible, mixed-leukocyte-culture-nonreactive, sex-matched, full sibling was used as the donor. Recipient total lymphocyte count, T and B lymphocyte numbers, and response of peripheral blood mononuclear cells to phytolectin stimulation increased by 14 days following transplantation. Circulating lymphocytes exceeded 1000 cells/microliter blood by 40 days posttransplantation, and by 170 days following transplantation, T and B lymphocyte numbers had reached normal values. The foal demonstrated significant primary and secondary antibody responses when immunized with bacteriophage phi X 174 at 100 and 142 days posttransplantation. Concentrations of IgG and IgM remained within the normal range following cessation of i.v. plasma therapy 156 days after transplantation. More than 300 days following transplantation, the foal remains healthy and is growing normally. At no time during the posttransplant period was there detectable evidence of graft-versus-host disease.

Immunologic reconstitution of foals with combined immunodeficiency.

Thirty-eight foals with combined immunodeficiency (CID) received transplanted fetal liver cells, fetal liver and thymus cells, histocompatible bone marrow cells, or equine lymphocyte antigen (ELA) haploidentical bone marrow cells in an attempt to reconstitute their deficient immune systems. Engraftment was infrequent, partial, and unpredictable when fetal cells were employed. Three of five CID foals receiving ELA haploidentical bone marrow cells demonstrated partial reconstitution, but engraftment was only temporary. Administration of histocompatible bone marrow cells resulted in rapid, full and sustained engraftment.

Equine lymphocyte antigens in a Welsh pony family.

Lymphocytes from an extended family of Welsh ponies were tested in a microcytotoxicity test against Thoroughbred and Arabian horse-derived antisera, which defined 4 and 6 equine lymphocyte antigen (ELA) specificities, respectively. Mixed leukocyte culture (MLC) tests were also performed. Welsh pony lymphocytes reacted to the Thoroughbred antisera. Most of the ponies' lymphocytes showed reactivity to 2 of the Thoroughbred ELA specificities, the offspring inheriting 1 antigen from each parent. Antigenic determinants were only partially demonstrated with Arabian antisera, although results indicated serologic identities among the ponies, which may reflect the historical background of the Welsh pony. There was no MLC reactivity between cells from most pairs of ponies that were ELA-identical, as typed with the Thoroughbred antisera, but cells from 2 ELA-identical pairs did react in MLC, indicating that MLC and ELA determinants may be on separate loci, as in other species.

HLA and survival in lung cancer.

HLA A and B antigens were determined in a study of 125 patients with lung cancer. Differences between antigen frequencies in cancer and control populations were determined by chi 2 analysis or Fisher's exact test. Survival data were analyzed using the Cox model for censored data. Cancer patients had an increased frequency of the antigen Aw33 (relative risk = 10.5, P less than 0.016). The Cox model (D. R. Cox, J. R. Stat. Soc. B, 34, 187, 1972) indicated that four covariates had a significant effect on mean survival time independently: the presence of A3 (P less than 0.005) and of Aw33 (P less than 0.05) increased mean survival time of the cancer population; patients with anaplastic carcinoma and stage three of any histological type of cancer had a decreased mean survival time. The determination of HLA phenotypes, cancer type, and the stage of the disease can provide the expected mean survival time of any particular patient. This could be of importance for evaluating prognosis. The effect of Aw33 and A3 on survival time may be related to HLA closely linked genes, possibly coding for resistance to the disease.

Differences in expression of lupus nephritis in New Zealand mixed H-2z homozygous inbred strains of mice derived from New Zealand black and New Zealand white mice. Origins and initial characterization.

BACKGROUND: F1 hybrids of New Zealand Black (NZB) and New Zealand White (NZW) mice develop autoimmune glomerulonephritis resembling human lupus nephritis. Susceptibility to this complex autoimmune syndrome in humans and mice has been linked to genes mapping in or near the major histocompatibility complex that govern immune responses and levels of certain complement components. Previous studies showed that both parental strains contribute major histocompatibility complex-linked genes that are important for disease of the F1 hybrid. EXPERIMENTAL DESIGN: New inbred strains of New Zealand Mixed (NZM) mice were derived by selective inbreeding of progeny of a cross between NZB and NZW mice. Twelve of the 27 new NZM strains were selected for analysis. Mice were observed for up to 10 months of age to document the occurrence of nephritis and strain-specific differences in disease expression. H-2, Hc, and coat color loci were determined for each strain to establish homozygosity of NZB and NZW polymorphic markers. Strains were screened for the presence of anti-dsDNA autoantibodies. RESULTS: In some NZM strains early onset of lupus nephritis in females resembled the (NZB x NZW)F1 model, whereas in other strains early disease also occurred in males. Age at death and severity of nephritis vary among the lines; a few strains remain relatively free of glomerular lesions. Histocompatibility (H-2) typing showed that all strains are homozygous for the NZW haplotype (Ku, Au, Sz, Dz). Coat color analysis for four loci on chromosomes 2, 4, and 7 was consistent with specific reassortments and recombinations to explain the grey, tan, and white mice with red/pink eyes and the presence or absence of the fifth component of serum complement (C5) (Hc, chromosome 2). Anti-dsDNA autoantibodies were found in all but one of the NZM strains reported here. CONCLUSIONS: The NZM strains of mice are a unique set of inbred strains that have inherited various genomic segments of the two parental strains that lead to phenotypic differences in disease expression. These results indicate that the previously proposed strict requirement for H-2 heterozygosity for the development of nephritis in the (NZB x NZW)F1 hybrid mice may not be valid. It is assumed that both the Lpn-1 locus of NZB and the Lpn-2 locus of NZW and a sufficient number of other disease-associated genes of both ancestral strains have been recombined in these new strains to produce the various patterns of renal disease.

Decreased HLA heterogeneity in parents of children with Down syndrome.

HLA-A and B antigens were determined in a study of 37 couples and their children with trisomy 21 Down syndrome (DS), using a standard microlymphocytotoxicity test. The comparison groups included 76 couples and their healthy children. All individuals were Caucasians from the same geographical area, and there was no history of consanguinity. The parents of children with DS did not show an association with a specific HLA antigen or haplotype. Sixteen of the 37 couples (43.24%) having children with DS share two or more antigens at the A and/or B locus. This was significantly higher than the proportion in the control group (6/76, or 7.88%). Of the 16 couples having children with DS and sharing two or more antigens, eight had a haplotype in common, in contrast with only two couples in the control group. The data suggest that sharing of parental HLA-A and B antigens may be related either to the occurrence of trisomy 21 zygotes or to prenatal survival of affected embryos and fetuses.

Joint report of the Third International Workshop on Lymphocyte Alloantigens of the Horse, Kennett Square, Pennsylvania, 25-27 April 1984.

The Third International Workshop on Lymphocyte Alloantigens of the Horse was held on 25-27 April 1984 in Kennett Square, Pennsylvania. Twelve laboratories from five countries participated. The principal purpose of this Workshop was to determine the phenotypic and gene frequencies of the 10 equine lymphocyte antigens (ELA) and a non-ELA lymphocyte antigen, ELY-2.1, in several breeds of horse. A total of 86 alloantisera characterized in previous workshops were tested against lymphocytes from 1179 horses. In addition, several experimental antisera were also tested against the same panel of lymphocytes. As a result of analysis of these data, the Workshop recognized two new equine lymphocyte alloantigens: W11 of the ELA system, and ELY-1.1, an antigen not linked to the ELA system.