HLA compatibility and susceptibility to habitual abortion. Results of histocompatibility testing of couples with frequent miscarriages

We have performed class I HLA antigen testing in 42 women with recurrent habitual abortions and in their husbands. The main criterion for inclusion in this group was a frequency of more than two abortions without the known reasons for abortion and without a living child. 29 couples with a least two healthy children and no abortion in the clinical history served as a control group. The data were evaluated in respect to the association of HLA and disease as well as to the level of histocompatibility within the couples. In our results we did not find any significant association between HLA-A, B, C phenotypes and the habitual abortion. On the other hand, we observed a significantly higher level of histocompatibility in the couples with habitual abortions in comparison to the control couples. The frequency of identity in one and more histocompatibility antigens was in the patient group significantly higher than in the control group and as it could be expected by chance, calculated on the basis of antigen distribution within the loci A, B, C in the population in the southern part of the GDR. In no case we have revealed lymphocytotoxic antibodies as a possible cause for miscarriage. Our results are in favour of the hypothesis that a higher level of histocompatibility could be an immunological explanation for the habitual abortions. In addition, this hypothesis was supported by the successful immunotherapy with leukocytes derived from the husband or nonrelative donors.     

Intracytoplasmic sperm injection

Intracytoplasmic sperm injection (ICSI) with ejaculated, epididymal or testicular spermatozoa was first successful in 1992 and has since become the widely accepted treatment for couples with severe male-factor infertility. The outcome of several thousands of ICSI cycles in terms of fertilization, embryo cleavage and implantation is similar to that for conventional in-vitro fertilization in couples with tubal or idiopathic infertility. To evaluate the important issue of safety of the new technique of ICSI, a prospective follow-up study of children born after ICSI was carried out. The aim was to compile data on karyotypes, congenital malformations, growth parameters and developmental milestones. Parents' agreement to genetic counseling was obtained, as well as prenatal diagnosis, followed by a physical examination of the children at 2 months, 1 and 2 years. Important outcome data to be examined comprise information on major and minor congenital malformations obtained prenatally or after birth, as well as on the further development of the children.     

Distribution of transplantation HLA antigens in children and adolescents with meningitis of various etiology]

An interaction between HLA antigens and predisposition to meningitis of specific and nonspecific etiology was studied in children and adolescents from an Azerbaijan population. The distribution of HLA antigens was found to be heterogeneous in the patients with meningitis of various etiology. Tuberculous meningitis was characterized by a significant rise in the detection rate of HLA-DR3 antigen, by a considerable frequency of B14 and DR2 antigens; patients with purulent meningitis much more significantly showed HLA-B12 antigen; in terms of locus A, there was an increase in the detection rates of HLA-A19 antigen in serous meningitis.     

Trichosporon antibodies (corrected of antigen) and HLA-antigen in summer-type hypersensitivity pneumonitis in a family]

We encountered a family in which all of the three members (the parents, a 45-year-old woman and 51-year-old man, and their 15-year-old daughter) had Trichosporon cutaneum antibodies (corrected of antigen), and two (the parents) suffered from summer-type hypersensitivity pneumonitis in the late summer. The husband complained of dry cough, fever and dyspnea on exertion from July after severe interstitial pneumonitis and was treated with steroid pulse in September 2004. His wife visited our hospital and complained of a common cold-like symptom which progressed in August 2005. The couple were given diagnoses of summer-type hypersensitivity pneumonitis because they were positive for serum anti-Trichosporon mucoides antigen and asahii antigen. Their asymptomatic daughter was positive for these antigens. Both wife and daughter had HLA-DQ 8 (3) and 9 (3) that are suggested to be important HLA antigens related to the occurrence of summer-type hypersensitivity pneumonitis.     

Association of human leucocyte-DR and DQ antigens in coeliac disease: a family study

BACKGROUND AND AIMS: No family studies regarding the association of coeliac disease with the human leucocyte antigen (HLA)-DQ locus are available. Moreover, no HLA studies have been carried out in coeliac disease patients from India. The aim of this study was to study the HLA class II (DR and DQ) antigens in children with coeliac disease and in their first-degree relatives. METHODS: Fifteen children with coeliac disease and their first-degree relatives (birth parents of all the coeliac disease patients and fifteen siblings) were studied. A group of 123 healthy unrelated and ethnically matched subjects were used as controls. The HLA-DR and -DQ typing was carried out by a complement-dependent microlymphocytotoxicity assay. The transmission disequilibrium test was used for analysis of results. RESULTS: There was no association of coeliac disease with DR phenotypes. Ninety-three per cent of patients (14/15) carried the DQ2 allele. DQ2 was transmitted in 15 of 19 informative cases (transmission probability of 79%, chi2 6.368 with 1 df, nominal P=0.012 and P value corrected for multiple test=0.035). The haplotype relative risk associated with DQ2 was 5.71 (95% confidence interval 1.71-16.28). CONCLUSION: Coeliac disease in Indian children is predominantly associated with HLA-DQ2.     

Role of HLA in congenital heart block: susceptibility alleles in mothers

In congenital heart block (CHB), abnormal maternal immunisation leads to autoantibody production against SS-A/Ro and SS-B/La antigens. These maternal antibodies are transferred across the placenta to the unborn child and are believed to transmit irreversible immunological injury in developing foetal heart tissue, thus causing 3rd-degree atrioventricular block. The mothers may suffer from systemic lupus erythematosus (SLE) or primary Sj?gren's syndrome (SS), but they may be asymptomatic. Women with primary SS show a typical autoimmune HLA antigen pattern, namely higher frequency of HLA B8 and DR3 than in the normal population. The HLA pattern may affect individual ability to resist infecting bacteria and viruses and to response in various ways to autoantigens. It is probable that other factors such as genetic regulation of immune response are involved in CHB. We compared the HLA class I and class II alleles of mothers having CHB children with those of women suffering from primary SS and having healthy children, and with those of healthy Finns. Antibodies against 52-kD and 60-kD SS-A/Ro and 48-kD SS-B/La antigens were compared between the two groups of mothers. Our results show that anti-SS-A/Ro antibody-positive mothers all show a strong association with known autoimmune-predisposing HLA alleles, however, the mothers of CHB children differ in some HLA class I alleles, and especially in HLA haplotypes, from mothers of healthy children. Mothers with HLA A1, Cw7, B8 and without B15 are at particularly high-risk of having CHB children.     

Immunogenetic study of the response to streptococcal carbohydrate antigen of the cell wall in rheumatic fever.

An immunogenetic study of the response to streptococcal carbohydrate antigen of the cell wall was carried out on members of 15 multiplex families each having more than one sib affected with rheumatic heart disease. They comprised 30 parents and 61 sibs (32 with rheumatic disease and 29 without). Fifty healthy unrelated subjects served as controls. A history was taken and clinical examination carried out. Rheumatic activity was determined and HLA typing was carried out for nine A antigens, 15 B antigens, and six DR antigens. The immune response of lymphocytes to streptococcal polysaccharide antigen of the cell wall of group A beta haemolytic streptococci in vitro was studied by tritiated thymidine uptake. The results were statistically and genetically analysed. It was found that (a) all subjects with rheumatic disease were highly responsive to the streptococcal polysaccharide antigen of the cell wall, the sib pairs being mostly HLA identical; (b) all low responders had no rheumatic disease and their phenotypes were mostly different from those of the rheumatic member of their sib pair; (c) correlation of immune responsiveness (high or low) between HLA-identical sibs was significant, but insignificant between haplotype identical and non-identical sibs; (d) the gene responsible for high responsiveness to the streptococcal polysaccharide antigen of the cell wall is recessive and closely linked to HLA. In conclusion, it was found that exposure to pharyngeal infection with group A beta haemolytic streptococci may lead to acute rheumatic fever in those with an inherited recessive gene responsible for high responsiveness to the streptococcal polysaccharide antigen of the cell wall.     

Increased frequency of DR2 in patients with aplastic anaemia and increased DR sharing in their parents

68 patients with aplastic anaemia, their parents and healthy siblings were typed for HLA-A, B and DR antigens. Among the patients there is an overrepresentation of DR2. The parents of affected children show an increased compatibility at the DR locus. This situation could favour the expression of recessive gene(s) involved in haematopoiesis and located in the HLA locus.     

Evidence for the association of unexplained pulmonary hypertension in children with the major histocompatibility complex.

BACKGROUND. A link between primary pulmonary hypertension (PPH) and autoimmune disorders has been postulated. To investigate this relation, we performed immunofluorescent antinuclear antibody tests (ANA) and serological human leukocyte antigen (HLA)-A, B, C, DR, and DQ typing on two groups of Caucasian children with unexplained pulmonary hypertension (PHT) and their parents. METHODS AND RESULTS. Group 1 consisted of 17 children with PPH including two patients with familial PPH and three patients with trivial congenital pulmonary to systemic communications. Group 2 consisted of 13 children with advanced PHT and anatomically large congenital pulmonary to systemic communications (PHT + shunt). Both groups had comparably severe pulmonary vascular disease documented by cardiac catheterization. The following statistically significant data (p less than 0.05) were obtained when the study groups were compared with those published for normal controls. Although positive ANAs and varying titers of autoantibodies were found in both groups of children and mothers (not fathers), +ANAs were only significant for the maternal groups. The PPH (group 1) children had increased frequencies of HLA-DR3, DRw52, and DQw2 and decreased DR5, whereas the group 2 (PHT + shunt) children (also their parents) had no statistically significant alterations in any of the DR or DQ alleles. The PPH mothers had decreased DQw3, an allele in linkage disequilibrium with DR5. CONCLUSIONS. These immunogenetic data suggest that childhood PPH appears to be associated with the major histocompatibility complex alleles HLA-DR3, DRw52, and DQw2. This newly found correlation of juvenile PPH with these alleles adds this disease to the DR3+ group of autoimmune diseases. Further studies are needed to determine whether there is also an immunological or autoimmune component in some children with PHT + shunt lesions because this group lacked an HLA association.     

The outcome of pregnancy in the wives of men with familial mediterranean fever treated with colchicine

OBJECTIVE: To evaluate the outcome of pregnancies of normal women married to men with familial Mediterranean fever (FMF), some of whom took colchicine during the conception with their wives. PATIENTS AND METHODS: We followed the outcome of pregnancies and deliveries of 60 wives of FMF patients; 53 of the husbands were taking colchicine during that time. As a control group we screened the outcome of pregnancy and delivery from 230 healthy women married to healthy men. RESULTS: The 60 FMF patients- wives had 222 pregnancies, of which 206 ended in term delivery with 209 live births. Sixteen pregnancies ended in spontaneous abortions (7%). Three of the newborns in the study group were born with congenital malformations. In the control group, of 788 pregnancies, 127 ended in abortions (16%). Six of the newborns were born with congenital malformations. The rate of the late abortions (second trimester) in both groups was comparable. CONCLUSIONS: The results of our study indicates that neither FMF nor colchicine increases the rate of abortions or congenital malformations. Therefore we believe that there is no need to discontinue colchicine treatment in men with FMF before the conception with their wives.     

Parental HIV serodiscordance: implications for the care of the HIV seropositive child in a resource-poor setting

This prospective study compared the care and support provided for symptomatic HIV seropositive children of HIV serodiscordant parents (only the mother of the child is HIV infected) with children of seroconcordant parents (both parents are HIV infected) during admission and after discharge from a tertiary health institution in southwestern Nigeria. Information was collected from parents of eligible children by semi-structured questionnaires and observation of the children and their parents while on admission and at home. Of the 51 couples who met the study criteria, there were 27 seroconcordant couples and 24 serodiscordant couples. The children from serodiscordant couples were more frequently discharged against medical advice, abandoned, lost to follow-up, cared for by their mothers alone and were not up-to-date with their immunization schedule when compared with children from seroconcordant parents. These were statistically significant (p < 0.05). There was a higher mortality among these children and their mothers (p < 0.05). Paternal reasons for not providing adequate care for the children from serodiscordant parents included fear of being infected, doubt of child's paternity and waste of family resources on a 'child who is dying'. None of the children from both groups received support from governmental and non-governmental agencies. It is concluded that the care of sick HIV seropositive children of serodiscordant parents poses special challenges for clinicians working in Nigeria where there is no social support system.     

Inflammatory bowel disease in married couples: 10 cases in Nord Pas de Calais region of France and Liège county of Belgium.

Ten pairs of husband-wife couples are reported with inflammatory bowel disease who were seen in the same geographical area in Nord Pas de Calais region of France and in Liège county (Belgium). Among these 10 couples, four were concordant for Crohn's disease, two for ulcerative colitis, and four were discordant. In nine of 10 couples neither spouse had symptoms before marriage but inflammatory bowel disease subsequently developed in both. In one couple, one spouse had Crohn's disease before marriage and the other partner experienced symptoms afterwards. Eighteen children were born to eight of 10 couples. Five of them developed Crohn's disease but four belong to the same family. In all cases the affected children were born to parents who both developed Crohn's disease after they had married and were conceived at a time when parents did not yet have symptoms. It is proposed that this pattern of emergence of inflammatory bowel disease suggests a role for an infectious agent yet to be identified.     

Contribution to the pathogenesis of essential hypertension: a multivariate analysis of associated factors

This study attempts to develop a general aetiological concept of essential hypertension by multidimensional investigation of its various risk factors in childhood and adolescence. The investigation is based on married couples and their children (609 parents and their 639 children, a total of 1248 persons), all of them chosen under special aspects. Familial and environmental characteristics of children and young people with hypertension are compared with those of normotensive volunteers of the same age. The multi-dimensionally interacting factors found to be associated with hypertension in children are: hypertension, diabetes and early infarction in relatives of the first or second degree as well as overweight at birth, obesity, nutritional patterns in the earliest and later stages of life, social environment and physical activity of the children and adolescents. The familial factors most likely lead to a predisposition to hypertension while environmental factors may subsequently contribute to its manifestation.     

Study of genetic markers in families of patients with tuberculosis

The article deals with findings of the study of HLA-genotype influence on tuberculosis susceptibility in 26 families with tuberculosis patients. It was found that sensitivity to tuberculosis in the examined families is associated with HLA-DR2 antigen. Segregation analyses conducted in the families of patients with tuberculosis revealed a correlation between the sensitivity to tuberculosis and inheritance of certain HLA haplotypes from the affected parents to their children with tuberculosis.     

HLADR5 and C4BQO high frequency and antinuclear antibodies positivity in patients with 21 hydroxylase deficiency from Campania region.

HLA haplotypes, complement C4 factor and factor B immunochemical concentrations and autoantibodies titer have been studied in six patients with mild congenital adrenal hyperplasia (MC-AH), in two patients with classical congenital adrenal hyperplasia (CCAH) and in their parents. A high frequency of DR5 and C4BQO alleles have been found in MCAH patients. Moreover, C4BQO allele is carried out in three out of four cases associated with DR5. In the two CCAH patients we found a B51 and a B14 allele, the last one usually described in the non classical form of the disease in population of different ethnic origin. Signs of autoimmunity in some patients and parents have been found. C4 null alleles were several-fold more frequent among our patients with respect to the same ethnic control group and the autoantibody positivity could be the result of an altered immune regulation. The presence of a positive correlation between cortisol basal levels and C4 and Bf concentrations in the six MC-AH patients suggests an interrelationship between hormonal factors and immunological findings in this disease. Our finding about HLA antigens not previously described in this syndrome may stimulate more profound studies by genomic and cDNA probes.     

Antigen expression of frozen platelets.

Platelet antigens of platelet samples from 36 donors, frozen for different intervals, were evaluated by the platelet suspension immunofluorescence test (PSIFT). A, B, PLA1(HPA-1a) and various HLA antigens were tested by their corresponding antisera. The antigen could be detected in almost all the samples after one month of freezing. After 3 and 6 months, the platelet antigens could only be detected in 29.2% and 3.7% of the samples, respectively. There was no difference in decay of antigen expression among A, B, PLA1 and HLA antigens. When compared with the freshly prepared platelets, frozen platelets presented stronger antigen expression after 2 to 4 weeks of storage. This may suggest that the frozen platelets could be used for platelet crossmatching procedures without loss of their antigenicity within one month.     

Fetal HLA typing in beta thalassaemia: implications for haemopoietic stem-cell transplantation

Stem-cell transplantation can cure beta thalassaemia. We aimed to assess whether fetal HLA typing done early in the pregnancy of couples who were at risk of beta thalassaemia could provide an alternative to pregnancy termination if the prospect of a bone-marrow transplantation from a family member was available. In our clinic in Sardinia, we did fetal HLA typing for 49 couples at risk of having a baby with beta thalassaemia. Two affected children were born and successfully received a transplantation from a family donor. Five non-affected fetuses were HLA compatible with an affected sibling and their cord blood was harvested for a future transplantation.     

HLA antigens in North American patients with Takayasu arteritis.

OBJECTIVE. To determine the frequency of HLA class I and II antigens in Caucasian North American patients with Takayasu arteritis (TA). METHODS. Seventy-three class I antigens and 13 class II antigens were examined in 21 Caucasian North American patients with TA, and their frequencies were compared with findings in 243 healthy, untreated controls. HLA typing was performed by microlymphocytotoxicity assay. RESULTS. We found no statistically significant positive association of TA with DR2, DR4, DQw3, or any of the other class I or class II antigens studied. A negative association between TA and DR1 was noted. There was no significant association between any of the HLA antigens and the severity of the disease or the presence of complications. CONCLUSION. The negative association between TA and the DR1 antigen suggests that this antigen may be protective against the development of the disease.     

HLA class-I and class-II antigen expression by human leukemic K562 cells and by Burkitt-K562 hybrids: modulation by differentiation inducers and interferon

K562 cells, which could be regarded as pluripotent hematopoietic progenitors, are usually considered as HLA class-I and class-II-negative cells. We show here that differentiation induction (with either sodium butyrate, 12-O-tetradecanoyl-phorbol-13-acetate, or teleocidin) or recombinant alpha- or gamma-interferon (IFN) treatment resulted in the augmentation of HLA class-I antigen expression. This augmentation of HLA class-I antigens was also observed in the Burkitt X K562 hybrid cells PUTKO and DUTKO (the latter coming from two presumably HLA-A, B-negative parents). HLA class-I genes are thus functional in K562 cells. In this system, alpha- and gamma-IFN had no clear differentiating capacity, since they were not able to modulate the expression of various hematopoietic markers, as chemical differentiation inducers did. On the other hand, neither differentiation induction nor interferon treatment could induce HLA class-II antigen expression on K562 cells. These molecules could be very faintly induced in PUTKO and DUTKO hybrids, in contrast with strong HLA class-II expression on the B parental lines. Whether these results are due to "lineage infidelity" in K562 cells or whether K562 cells represent the proliferation of HLA class-I-positive class-II-negative hematopoietic cells, with active suppression of HLA class-II antigen expression, is discussed.     

Fetal IgG specificities against Trypanosoma cruzi antigens in infected newborns.

A panel of Trypanosoma cruzi antigens produced by recombinant DNA techniques was used to analyze the IgM and IgG specificities present in sera from 22 mothers with chronic Chagas disease and their newborn infants. Ten of the newborns were congenitally infected and the other 12 children were healthy. While in most cases IgG specificities in the newborns mirrored those of their mothers, congenitally infected newborns had, in addition, IgG specificities that were undetectable in their mothers. The new IgG specificities observed most frequently were against a shed acute-phase antigen (SAPA), and less frequently, against other nine different parasite antigens. Thus, SAPA is able to identify new fetal IgGs because antibodies against this antigen are generated during the acute phase of the infection and not in their chronically infected mothers. Sera from congenital cases also had IgMs against several parasite antigens, but again, SAPA was the most frequently detected. Neither IgMs nor new IgG specificities were detected in healthy children born to mothers with Chagas disease. We conclude that individual antigens can be used to detect new IgG specificities present in the cord blood from infected newborns. Furthermore, detection of IgMs and new fetal IgGs with recombinant antigens may be used to sort out congenitally infected infants from uninfected ones, a method that might be applied to other infectious diseases.