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A patient is described in whom an acute human immunodeficiency virus seroconversion illness occurred following a trip to southern Africa. The presentation was strikingly similar to that of African tick typhus and could only be distinguished by serological testing.
Shared histocompatibility antigens between spouses may affect reproductive outcome adversely as a result of prenatal selection against compatible fetuses. Evidence from both animal and human studies suggest that histocompatible fetuses may not initiate a maternal immunologic response that prevents rejection of the embryo. Therefore, parents sharing HLA antigens may produce compatible fetuses and consequently experience a greater frequency of early fetal losses and show poorer reproductive outcome than couples not sharing antigens. In the Hutterites, an inbred human isolate that proscribes contraception, we tested the hypothesis that couples sharing HLA antigens have poorer reproductive outcomes than couples who do not. The Hutterites are characterized by high fertility and large family sizes. Couples that share zero (no. = 21), one (no. = 15), and more than one (no. = 10) HLA-A or HLA-B antigens were compared for reproductive performance. Median intervals between births were larger among couples that share more than one antigen in eight of 11 intervals examined. In addition, the median intervals from marriage to first, fifth, and tenth birth were consistently larger among couples that share more than one antigen. Differences among the groups appear to become larger with increasing parity, suggesting that the effect of histocompatibility on reproductive performance becomes more evident in later pregnancies. These differences in reproductive performance between couples that share zero, one, or more than one HLA-A or HLA-B antigens may have significant evolutionary consequences. However, our results demonstrate that sharing HLA antigens does not preclude normal pregnancy and caution should be exercised before concluding that shared HLA antigens are solely responsible for repeated fetal losses.
The secretion of the rabbit seminal vesicle has been investigated by morphological and biochemical means. Apical regions of seminal vesicle epithelial cells show highly active protein synthesizing and releasing organells. The secretory proteins released are analysed by disc-electrophoresis and three different immunological procedures. There is evidence for the presence of an uteroglobin-like antigen in seminal vesicle secretion. Comparison with seminal plasma indicated that the uteroglobin-like protein is also present in this fluid. The immunological and electrophoretical identity of rabbit uteroglobin, obtained from the uterus, with "male uteroglobin" is obvious, but molecular-biochemical and biological identity awaits further clarification. The demonstration of uteroglobin-like antigen in the male as in the female points towards new aspects in reproductive and contraceptive research.
The sedative thalidomide was withdrawn from the market 30 years ago because of its teratogenic and neurotoxic adverse effects. The compound was later discovered to be extremely effective in the treatment of erythema nodosum leprosum, a complication of lepromatous leprosy. This effect is probably due to a direct influence on the immune system, because thalidomide possesses no antibacterial activity. The compound is presently used as an experimental drug in the treatment of a variety of diseases with an autoimmune character, including recurrent aphthosis of nonviral and nonfungal origin in human immunodeficiency virus (HIV) patients. This article reviews the most important chemical and pharmacokinetic properties of thalidomide. The possible mechanisms of the nonsedative effects of thalidomide with respect to the safety of its use in HIV patients are discussed. Because the mechanism of the immunomodulatory effect of thalidomide is unknown, the possibility that the administration of this compound will accelerate the deterioration of the immunological status of HIV patients cannot be excluded. Clinical evidence suggests that thalidomide may aggravate the condition of patients with preexisting peripheral neuropathy. Hypersensitivity reactions to thalidomide may occur more frequently in HIV patients than in other patient groups. Because of the teratogenic activity of thalidomide, reliable contraception must be provided to female patients of childbearing age. Before the introduction of thalidomide therapy to an HIV patient presenting with oral ulcers, a fungal or viral origin of the lesions should be excluded. Thalidomide should not be used in patients with preexisting HIV-related peripheral polyneuropathy, polyradiculopathy or encephalopathy. In patients experiencing a complete remission, the discontinuation of thalidomide treatment and its reintroduction in the case of a relapse are preferable to maintenance therapy.
Two situations that result in the conversion of human mid-cycle cervical mucus from a sperm-receptive to a sperm-hostile form are described here: firstly, the addition of mucospissic agents, and secondly, the presence of antisperm antibodies. Two mucospissic biguanides were studied, chlorhexidine and Vantocil; both were totally spermicidal in the range 1-10 mg ml-1. Treatment of mucus with 1.5 microM to 1.65 mM Vantocil caused a dose-dependent increase in the dynamic storage modulus. The compatibility of the two biguanides with mucus was examined by measuring the rate of entry of diffusion of the [14C]biguanides into mucus. Chlorhexidine entered the mucus up to 0.53 mM, i.e. the highest concentration used, whilst Vantocil only entered at concentrations below 0.53 mM. This limited entry may be caused by the precipitation of mucus at the interface, producing a barrier of reduced permeability. The behaviour of purified mucin on ultracentrifugation was also altered after treatment with chlorhexidine. The s20 (at 2 mg ml-1 purified mucin) increased from 11.2 S to 19.3 S upon addition of 200 microM chlorhexidine. Further indication of structural alteration of biguanide-treated mucin was given by its loss of solubility in 0.22 M-sodium thiocyanate. The application of these biguanides to vaginal contraception is suggested. When antisperm antibodies are present in either the semen or cervical mucus, we suggest that an interaction can occur between galactose residues on the spermatozoa and galactose recognition sites on the antisperm antibody; in addition, binding can also occur between the Fc region of the antibody and cervical mucus. This process could therefore contribute to the binding of spermatozoa to the antibody and the immobilisation of this complex by the cervical mucus that is seen in immunological infertility. It was shown, by Immunobead binding, that immediate exposure of spermatozoa to D-galactose in the presence of chymotrypsin resulted in a considerable decrease or total loss of bound antisperm antibodies in males who had previously had a high titre of antibody. This reduction in the antibody level on the spermatozoa was accompanied by the appearance of the antibody level on the spermatozoa was accompanied by the appearance of the ability of the spermatozoa to penetrate cervical mucus in those couples examined. This pretreatment regimen for the ejaculate is suggested as a form of therapy for infertility related to the presence of antisperm antibodies.
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Epidemiological and immunological evidence has suggested that female sex hormones may play a role in the etiology and course of autoimmune diseases such as rheumatoid arthritis (RA). In this review the present clinical data with regard to estrogens and RA are discussed, with emphasis on the possible preventive effect of oral contraceptives on the incidence of RA and on the possibility of using estrogens as adjuvant therapy in RA. It is concluded that oral contraceptives may mitigate or postpone the onset of RA slightly, but that estrogens are not able to alleviate the symptoms of RA. Presently there is no evidence to promote the use of estrogens in preventing or treating RA in females.
The beta-subunit of hCG (hCG beta) displays immunological cross-reactivity with human LH (hLH). A detailed study was undertaken to investigate the effect of chemical and enzymatic modifications on the immunological behavior of hCG beta, particularly on its cross-reactivity with hLH, with a view to obtaining a highly hCG-specific antigen. hCG beta was modified in both the carbohydrate and protein parts of the molecule. The carbohydrate part was modified enzymatically by sequential cleavage of monosaccharides by specific glycosidases, and the protein portion was modified chemically in the amino and carboxyl groups and in the cystinyl, tyrosyl, histidyl, and arginyl residues. These derivatives were immunologically evaluated by RIAs; their hCG beta activities were measured in the [125I]hCG beta-anti-hCG beta system, and the hLH cross-reactivity in the [125I]hLH-anti-hLH system. The present studies have led to the following conclusions. 1) The carbohydrate does not play a significant role in the immunological activity of hCG beta. 2) The antigenic determinants of hCG beta reside primarily in the polypeptide chain and are conformational rather than sequential in nature. 3) hCG beta has two types of antigenic determinants, those which are unique to hCG and those which are common to both hCG and hLH. 4) Finally, it is possible to destroy preferentially one or the other type of determinants. The controlled reduction and alkylation of hCG beta yielded derivatives which retain significant immunological activity in the hCG beta system, but have no or reduced cross-reactivity in the hLH system. These derivatives are much more specific antigens than hCG beta and, therefore, are of potential importance for the development of a specific RIA for hCG and possibly for use as contraceptive agents.
Longitudinal studies on human growth have revealed seasonal patterns in the gain of height in 1/3 of the population. Seasonal sensitivity of growth velocity is apparently linked with a lean body structure. This being so, a subgroup with specific biological features could be isolated, including specific endocrine mechanisms (e.g. shorter interval between menarche and menopause, higher incidence of irregular early postmenstrual cycles, and higher concentration of growth hormone secretion) and specific metabolic pathways (more frequent drinking, smoking, and use of the contraceptive pill). This biological specificity may be responsible for behavioral heterogeneity in cancer in general and in breast malignancies in particular. One third of the breast cancer patient population is hormone responsive. The response to all the methods of cancer adjuvant therapy (including ablation of hormone producing organs, chemotherapy, and immunologic manipulation) used up till now does not surpass 33% in the long run. Breast cancer risk reduction by 1/3 due to full-term teenage pregnancies suggests that this may be a consequence of the interruption of a premalignant process initiated in women of the aforementioned subgroup. Simulation of early pregnancy might therefore lead to prevention of breast cancer in women who had seasonal growth patterns as children.
Both genetic and environmental factors contribute to the development of rheumatoid arthritis (RA). A long-term latent process often precedes the onset of arthritis. Hence, the ultimate causes of RA cannot be clarified by studying only the inflamed joints. Longitudinal studies focusing on risk factors are crucial in approaching the true aetiology. At present, most information gained from epidemiological studies is contradictory or vague. For instance, there is no consensus concerning the long-term effects of pregnancy or the putative protective role of oral contraceptives. There is no doubt that diet plays a role, but no specific nutrient has proved to be either protective or deleterious. Smoking is the only environmental risk factor that has been firmly verified epidemiologically for RA. It can be reasonably regarded as a contributory cause of RA. Studying the immunological effects of exposure to cigarette smoke may offer an opportunity to combine information from basic and epidemiological research to clarify the causal chains leading to RA.
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Glycodelin-A is a human amniotic fluid-derived glycoprotein with contraceptive and immunosuppressive activities. An immunoreactive form of glycodelin was detected in seminal plasma over a decade ago, but definitive characterization of this glycoprotein was not pursued. We considered it unlikely that the seminal plasma of fertile men would contain an appreciable amount of contraceptive glycodelin-A. To address this issue we purified seminal plasma glycodelin (glycodelin-S) and performed comparative studies with glycodelin-A. Glycodelin-S behaved differently when compared with glycodelin-A during sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and isoelectric focusing but identically after enzymatic deglycosylation. N-terminal sequencing of glycodelin-A and glycodelin-S gave identical results, and digestion with trypsin gave identical peptide fragments. The glycoproteins were also found to be indistinguishable from each other based upon immunological analyses. These results indicate that glycodelin-S and glycodelin-A have similar overall protein structure, suggesting the likelihood that these glycoproteins are differentially glycosylated forms of very similar proteins. This latter possibility is supported by lectin binding studies indicating that, unlike glycodelin-A, glycodelin-S does not manifest any affinity for lectins from Wisteria floribunda or Sambucus nigra. The results of sugar analysis and neuraminidase digestion also lead us to conclude that glycodelin-S and glycodelin-A are differentially glycosylated forms of similar proteins. Our evidence indicates that glycodelin-A mediated its biological activities via its unusual oligosaccharide sequences that are not associated with glycodelin-S. In lectin-immunoassay no appreciable amount of contraceptive glycodelin-A was found in the 22 seminal plasma samples studied.
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We have recently demonstrated that a human amniotic fluid-derived glycoprotein, glycodelin-A (GdA; previously known as PP14 or PAEP), potently inhibits gamete binding in an established sperm-egg binding system and expresses immunosuppressive activities directed against a variety of different immune cell types. GdA has high mannose-, hybrid-, and complex-type biantennary oligosaccharides including structures with fucosylated or sialylated N, N'-diacetyllactosediamine (GalNAcbeta1-4GlcNAc) sequences, which are rare in other human glycoproteins. We now report the characterization of glycodelin-S (GdS). This is a human seminal plasma glycoprotein that is immunologically indistinguishable from GdA, but unlike the latter, does not inhibit human sperm-zona pellucida binding under hemizona assay conditions. Analysis of the N-glycans of GdS by mass spectrometry revealed that all glycoforms of GdS are different from those of GdA. GdS glycans are unusually fucose-rich, and the major complex-type structures are biantennary glycans with Lewisx (Galbeta1-4(Fucalpha1-3)GlcNAc) and Lewisy (Fucalpha1-2Galbeta1-4(Fucalpha1-3)GlcNAc) antennae. It is probable that these highly fucosylated epitopes contribute to the immunosuppressive activity of human seminal plasma and to the low immunogenicity of sperm. This study provides the first evidence for gender-specific glycosylation that may serve to regulate key processes involved in human reproduction.
The potential for utilization as a contraceptive vaccine of a 60,000 Mr glycoprotein component, purified porcine zona antigen (PPZA), isolated from porcine zonae, was investigated in the squirrel monkey. Immunization resulted in production and maintenance of high antibody titers for at least 1 year. Comparable immune profiles were obtained using either monkey or pig zonae in assay systems, but dose-dependent variations in immune response were not observed. In situ antibody binding to monkey zonae was detected, but significantly fewer ovulated eggs were obtained from immunized monkeys than from controls. Exposure of antibody-pretreated pig, monkey, and human zonae to homologous sperm resulted in total inhibition of sperm attachment for the respective species. Thus, the contraceptive potential of PPZA antibodies in these species is demonstrated.
The immunological properties of a panel of synthetic peptides that represent the most accessible and mobile segments of the lactate dehydrogenase (LDH)-C4 molecule were characterized. Peptides corresponding to mouse LDH-C4 amino acid sequences: 1-14b, 5-15, 49-58, 97-110, 211-220, 231-243, 274-286, 304-316, and 318-330 were synthesized and compared in terms of binding antibodies raised in rabbits against the intact protein. Six of these sequences were covalently coupled to diphtheria toxoid and used to immunize groups of rabbits. LDH-C4-specific antibodies were detectable in immune sera by enzyme-linked immunosorbent assay, Western blotting, and immunoprecipitation assays. The immunogenicity of the mouse LDH-C4 peptides in rabbits could be ranked in the following order: 5-15, 304-316 greater than 211-220, 274-286 greater than 49-58, 97-110. The immunological properties of these short synthetic peptides did not correlate with features of the mouse LDH-C4 structure except that the most active sequences appeared to be those that differed from the somatic isozymes to the greatest extent. These results have direct bearing on the selection of immunogenic LDH-C4 peptides for contraceptive vaccine studies in humans and non-human model systems.
The synthesis of prothrombin in hepatic microsomes is augmented in intact estrogen-treated rats and in hypophysectomized rats treated with purified prolactin. We investigated the influence of these gonadal and pituitary hormones on the titer of Hageman factor (factor XII), reportedly elevated in women using oral contraceptives. Rats were ovariectomized to minimize the influence of endogenous estrogen and progesterone on the Hageman factor titer. The administration of progesterone did not alter the plasma concentration of Hageman factor. In contrast, the infusion of 17 beta-estradiol induced a marked elevation of the plasma Hageman factor titer, as measured functionally and immunologically. The titer of Hageman factor was directly related to both plasma estradiol and prolactin concentrations, indicating that prolactin may play a role in the regulation of plasma Hageman factor titers. In agreement with this, hypophysectomy induced a marked decrease in the Hageman factor level. In hypophysectomized ovariectomized animals, the administration of estradiol restored the Hageman factor titer to normal levels, whereas the infusion of prolactin induced a dramatic rise in the Hageman factor titer to the degree observed in nonhypophysectomized estrogen-treated rats. No further increase in the Hageman factor titer was observed in rats treated with both estradiol and prolactin. These data indicate that estrogens increase the plasma Hageman factor titer both directly and through its release of prolactin and that prolactin may also increase the titer of Hageman factor through estrogen-independent mechanisms.
Physiologic regulation of fibrinolysis plays an important role in the control of hypercoagulable states and thrombogenesis. Both the hereditary and acquired conditions leading to fibrinolytic deficit result in thrombotic complications leading to arterial and venous occlusive disorders. Several changes in physiologic states such as pregnancy, old age, stress, obesity, and temperature alterations lead to the modulation of the fibrinolytic system. Various disease states, surgery, radiation, and diet can also trigger mechanisms leading to impaired fibrinolytic states. Several drugs, including anticancer agents, oral contraceptives, cytokines, and blood components can also produce transitory fibrinolytic deficit which can predispose patients to thrombotic complications. The identification of the patient populations with an impaired fibrinolytic state is an important step toward the prevention of thrombotic complications which may lead to such catastrophic events as myocardial infarction and thrombotic strokes. Both functional and immunologic methods have currently become available for the rapid diagnosis of fibrinolytic deficit. Thus, it is important to evaluate patients who are at risk of thrombotic complications due to fibrinolytic deficit. Currently, specific guidelines are developed to identify high risk groups and propose methods to manage these groups of patients.