C. M. Steel

HLA HAPLOTYPE A1 B8 DR3 AS A RISK FACTOR FOR HIV-RELATED DISEASE

Of 32 patients exposed to a single batch of factor VIII contaminated with human immunodeficiency virus (HIV), 18 became antibody positive. Serial T cell subset analyses over the succeeding four years have shown a progressive decline in circulating T4 cells in those 18 but no change in the 14 who remain seronegative. 2 of the seroconverters have died and a further 7 have symptoms attributable to HIV infection. In the group as a whole, the HLA haplotype A1 B8 DR3 was weakly associated with an increased risk of seroconversion on exposure to the virus while, in those who seroconverted, it was strongly associated with a rapid decline in T4 cells and development of HIV-related symptoms within four years of infection.

Evidence implicating at least two genes on chromosome 17p in breast carcinogenesis.

The DNA of paired tumour and blood leucocyte samples from a large series of breast cancer patients was analysed to map regions of loss of heterozygosity on chromosome 17. The high frequency of loss of heterozygosity on 17p was confirmed, and a third of informative tumours had also lost an allele at the long arm locus THH59. On the short arm two distinct regions of loss of heterozygosity were identified, in bands p13-3 and p13-1. The latter probably involves the structural gene p53, which has been implicated as an oncogene or as a tumour suppressor in various human cancers. 17p 13-3, however, showed a significantly higher frequency of loss of heterozygosity, and there was no correlation between allele losses at the two sites. Nevertheless, loss of heterozygosity at 17p 13-3 is associated with overexpression of p53 mRNA, suggesting the existence of a gene some 20 megabases telomeric of p53 that regulates its expression. Lesions of this regulatory gene seem to be involved in the majority of breast cancers.

Determinants of HIV disease progression: six-year longitudinal study in the Edinburgh haemophilia/HIV cohort

Markers of immune function present before infection may determine the subsequent course of disease in HIV-infected individuals. In 1983, we measured immune function in a group of haemophiliacs in Edinburgh. In 1984, 18 of these patients became infected with HIV-1 from contaminated factor VIII. We have followed-up these patients since their seroconversion. The rate of disease progression, as assessed by the appearance or not of AIDS symptoms or signs within five years of seroconversion, was related both to the concentration of total plasma IgM before exposure to infection and to the pattern of specific IgM and IgA anti-HIV response around the time of IgG seroconversion. Disease progression also correlated with concentrations of plasma interleukin-2 receptor (a marker of lymphocyte activation) and with the number and percentage of circulating DR + ve (activated) T cells. Our findings show that the extent of host immune reactivity, which may be genetically determined, is a powerful factor in the pathogenesis of HIV-associated disease.

AGE-RELATED VARIATION IN PROPORTION OF CIRCULATING T CELLS

Abstract The proportion of mononuclear cells spontaneously forming rosettes with sheep erythrocytes (T cells) was estimated in peripheral-blood samples from healthy infants (cord blood), healthy adults aged 18-41 years, and ambulant elderly patients (70-87 years). There was no difference between the values in healthy adult males and females. Samples of cord-blood and blood-samples from elderly patients contained significantly lower mean percentages of circulating T cells than those from young adults. In newborn infants this can be accounted for by an increase in overall lymphocyte numbers, especially of non-T cells, but there is evidence of a reduction in the absolute number of circulating T cells in the elderly.

HIV antigen and antibody detection: variable responses to infection in the Edinburgh haemophiliac cohort

Sequential serum samples from 18 haemophiliac patients exposed simultaneously to human immunodeficiency virus type 1 (HIV 1) in early 1984 were tested retrospectively for serological markers of infection. Assay for total antibodies to HIV established that the time to seroconversion might be as long as 110 days after exposure to contaminated factor VIII; serum samples were also tested by Western blotting, by enzyme linked immunosorbent assay (ELISA) for specific antibodies to envelope and core proteins, and for p24 antigen by two assay systems during the two years after infection. The studies showed that five of the 12 patients for whom serum samples obtained between exposure and seroconversion were available had transient p24 antigenaemia. Although amounts of total antibody to HIV and of antibodies to envelope proteins rose continuously during the two years of the study, amounts of antibody to the core protein were variable and tended to decline in patients who became symptomatic. Two patients had persistent p24 antigenaemia that began four months after seroconversion; these patients remained asymptomatic. One patient who developed the acquired immune deficiency syndrome (AIDS) had transient antigenaemia at the time of seroconversion but failed to show any antigen for the rest of the study; progression to AIDS was accompanied by an increase in antibodies to envelope proteins. Much of the variability in the course of infection with HIV must represent the differences in the susceptibility of the patients to infection.

Linked DNA markers for presymptomatic diagnosis of familial adenomatous polyposis

41 symptom-free individuals aged 0-39 years who were at risk of familial adenomatous polyposis (FAP) were genotyped with six linked DNA probes. 28 individuals were informative for probes flanking the gene and 14 people assigned a probe-derived risk of over 0.93 were subsequently shown to be affected by clinical screening. 4 individuals who had been discharged from follow-up were designated high risk by this method. In those screened negative, risk was calculated from genotypic, colonic, and CHRPE findings and 89% of subjects had a risk below 0.003. An integrated risk analysis may have an important place in screening programmes for FAP.

EVIDENCE OF ALTERED ANTIGENICITY IN CULTURED LYMPHOID CELLS FROM PATIENTS WITH INFECTIOUS MONONUCLEOSIS

Abstract X-irradiated lymphoid cells of established cell lines derived from two patients with infectious mononucleosis were found to stimulate fresh lymphocytes from the same individuals several months after recovery from the illness. This is believed to reflect a degree of antigenic disparity between the cultured lymphoblasts and autologous fresh lymphocytes.

Five year prospective study of HIV infection in the Edinburgh haemophiliac cohort.

OBJECTIVE--To identify measures of immune state that reflect the course of HIV related disease in order to predict deterioration of symptoms and assess response to treatment. DESIGN--Five year longitudinal clinical and laboratory study. SETTING--Regional haemophilia centre, university virology laboratory, and Medical Research Council laboratory. PATIENTS--32 Patients with haemophilia A exposed to a single batch of HIV contaminated factor VIII concentrate from the Scottish National Blood Transfusion Service in 1984 who were followed up regularly in Edinburgh (31) or abroad (one). MAIN OUTCOME MEASURES--Counts of circulating T cell subsets (CD4 and CD8); plasma beta 2 microglobulin, neopterin, and IgA concentrations; and delayed type hypersensitivity to multiple skin test antigens. RESULTS--18 Patients who seroconverted after exposure had received significantly more contaminated factor VIII than the 14 who did not (mean 43 (range 9-109) v 15 (3-30) phials, p less than 0.01). The two groups were not distinguishable by other criteria before exposure. The group that seroconverted subsequently showed a progressive fall in mean circulating CD4 lymphocytes and an increase in plasma beta 2 microglobulin and neopterin concentrations. From 1987 patients in this group also showed an increase in mean circulating CD8 lymphocytes and in plasma IgA concentration, neither of which was seen in patients who did not seroconvert. Patients with HIV antibody who developed Centers for Disease Control category IV symptoms within five years after infection showed more extreme changes in all measures, except CD8 lymphocyte count, than those whose symptoms remained in categories II and III. Skin test reactivity declined to barely detectable levels in all patients positive for HIV antibody. CONCLUSIONS--Serial estimates of circulating CD4 lymphocytes and of plasma beta 2 microglobulin concentration are the most reliable measures of disease progression; of these, beta 2 microglobulin concentration seems to be the better predictor of impending serious symptoms. High IgA concentrations reflect rather than predict disease state. Individual variation in most measures is such that a wide range of measurements should be used in assessing the effects of trial treatment in HIV infected patients without symptoms.

Glutaraldehyde and human T cell rosettes

Blood mononuclear cells from ten healthy donors and cells from fifty cultured human lymphoblastoid lines were tested for the capacity to form rosettes with sheep erythrocytes. The effect of adding glutaralhehyde before scoring rosettes and the effect of substituting glutaraldehyde-fixed for fresh sheep cells were both examined. The results suggest that glutaraldehyde increases the apparent proportion of rosette-forming cells by altering the sheep erythrocytes in such a way that they will adhere to some B lymphocytes. Although a small number of cells carry both surface immunoglobulins and receptors for fresh sheep erythrocytes, the rosette test with fresh sheep cells identifies T lymphocytes more accurately in the absence of glutaraldehyde than in its presence.

Status of the APC Gene in Familial and Sporadic Colorectal Tumours as Determined by Closely Flanking Markers

Using polymorphic close-flanking markers, allele deletion in the vicinity of APC was detected in the majority of sporadic colorectal cancers in a large unselected series. Deletion was due to interstitial deletion or mitotic recombination, but seldom to whole chromosome loss. Mitotic recombination affecting APC was associated with smaller tumours than interstitial deletion. Sporadic adenomas showed a slightly lesser frequency of allele loss, but no such loss was observed in 28 adenomas from 4 cases of familial polyposis.