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Objective. Systemic lupus erythematosus (SLE) is an autoimmune disease reported to be associated with several alleles in the HLA complex. The purpose of this study was to systematically examine the extended HLA complex (xMHC) in order to get an overview of the primary predisposing genetic factors.Materials and methods. One hundred and sixty-four SLE patients and 254 healthy, unrelated controls were genotyped for HLA-DRB1, -B and -A alleles, as well as 13 microsatellites markers covering the xMHC. Moreover, we selected 335 additional controls matched with the patients for the HLA haplotypes showing the strongest associations, in order to look for additional predisposing loci.Results. Two regions of the xMHC showed associations: the region covering DRB1 to B, and the extended class I region. Explicitly, DRB1*03 and B*08 displayed strong associations with SLE, which seem to be independent of each other. Furthermore, associations were seen with alleles at microsatellites D6S2225 and D6S2223, located about 3.6 Mb telomeric of HLA-B, and these were not secondary to the associations found with DRB1*03 and B*08.Conclusion. Both the DRB1*03 and the B*08 alleles display disease association, either implicating involvement of both alleles or caused by another yet unidentified gene(s) in linkage disequilibrium. The associations found in the extended class I region could be markers for a ‘novel’ predisposing locus (loci) in SLE, adding to the risk conferred by DRB1*03 and B*08. Interestingly, this region has been shown to also be associated with other autoimmune diseases, hence the gene(s) might confer a general propensity for autoimmunity.

214 consecutive recipients of renal grafts from HLA‐haploidentical family members were treated with cyclosporine and prednisolone. No donor‐specific transfusions were given. The overall graft survival rate was 91.6% and 90.5% at 1 and 2 years, respectively, while the patient survival was 98.6% at 2 yr. Graft survival tended to be lower, and frequency of rejection episodes significantly higher, in recipients of HLA‐DR or MLC‐mismatched grafts, but satisfactory results were also observed in the HLA‐mismatched group. No beneficial effect on graft survival of pretransplant blood transfusions was seen. However, in the sub‐group of patients with antibodies reactive with allogenic panel T cells, significantly lower graft survival was seen, in spite of a negative cross‐match.

CD34+ cells isolated from bone marrow or umbilical cord blood from healthy donors were studied for proliferation and differentiation in liquid cultures in the presence of recombinant human granulocyte- monocyte colony-stimulating factor (GM-CSF), granulocyte CSF (G-CSF), monocyte CSF (M-CSF), and interleukin-3 (IL-3), followed by immunophenotyping for myeloid and myeloid-associated cell surface markers. IL-3, either alone or together with GM-CSF, G-CSF, or M-CSF, induced, on average, 50-fold cell multiplication, GM-CSF five fold to 10-fold, and G-CSF and M-CSF less than fivefold. Cells from cultures stimulated with GM-CSF, G-CSF, or M-CSF alone contained cells with a “broad” myeloid profile, “broader” than observed in cultures with IL-3. However, since IL-3 induced rapid cell multiplication, high numbers of cells expressing early (CD13, CD33) and late myeloid markers (CD14, CD15) were recovered. The presence of other CSFs together with IL-3 did not alter the IL-3-induced effect on the cells. When 5,000 CD34+ cells were cultured with IL-3 alone, the cultures still contained 2,000 to 5,000 CD34+ cells after 14 days of culture, while cells cultured with GM-CSF, G-CSF, or M-CSF contained less than 1,000 CD34+ cells. Furthermore, 1,000 to 3,000 cells were positive for the megakaryocytic lineage marker CD41b after cultures with GM-CSF or IL-3, while cultures with G-CSF or M-CSF did not contain detectable numbers of CD41b+ cells. Finally, erythroid cells could also be generated from purified CD34+ cells. The results show that IL-3 and GM-CSF can induce rapid proliferation of purified CD34+ cells in vitro with differentiation to multiple myeloid lineages, while certain subsets maintain expression of CD34.

One hundred ninety-one consecutive living related transplants performed from 1969 to the end of 1978 have been analyzed for the effect of pretransplant blood transfusions. Superior graft survival was observed in transfused patients transplanted with a one HLA haplotype-disparate kidney, whereas no effect of blood transfusions could be observed on the survival of HLA-identical transplants. The frequency of first rejection episodes was significantly reduced in transfused compared to nontransfused one haplotype-mismatched transplants, while no influence of blood transfusions was seen in patients with HLA-identical transplants. The survival of patients was, however, not influenced by previous transfusions. Pretransplant hemodialysis improved graft survival and patient survival; the difference was, however, only significant at 2 years in the one haplotype-mismatched group. When analyzed separately, both blood transfusions and hemodialysis had a beneficial effect on graft survival in one haplotype-mismatched transplants.

Primed peripheral blood hematopoietic stem cells (PBSC) generate and sustain lymphohematopoiesis in myeloablated animals, and recent reports indicate that allogeneic transplantation using PBSC grafts may be feasible in humans. A major concern with the use of PBSC transplants is that permanent engraftment may be limited because of lack of sufficient numbers of primitive progenitor cells in the graft. In the present study, in vitro colony formation and immunophenotype of CD34+ cells in PB of healthy adults during short-term granulocyte colony-stimulating factor (G-CSF) administration were compared with that of CD34+ cells in normal bone marrow (BM). The number of CD34+ cells mobilized to PB peaked at day 4 or 5 of G-CSF administration. The phenotypic profile of CD34+ PB cells showed a substantial increase in the percentage of CD34+CD13+ and CD34+CD33+ cells (myeloid progenitors) and a corresponding decrease in the percentage of CD34+CD10+ and CD34+CD19+ cells (B lymphoid progenitors) compared with CD34+ BM cells. The other subsets studied, including CD34+CD38- and CD34+HLA-DR- cells, were present in both compartments in similar proportions. Furthermore, primed CD34+ PB cells were enriched for colony-forming cells (CFC) and displayed an increased clonogenicity when compared with their counterparts in BM. A comparison between a postulated PBSC graft and an average BM graft is presented, showing that such PBSC grafts will be enriched for CD34+ cells as a whole, CD34+CD33+ cells, and colony- forming cells (CFC), factors which have been shown to correlate to acceleration of hematologic reconstitution and reduction in requirements for supportive care in autografting. Hence, we predict that allogeneic transplantation using G-CSF-primed PBSC grafts will result in a more rapid hematologic reconstitution after myeloablative conditioning than BM grafting. The question of whether PBSC allografting will result in permanent engraftment and clinical benefits as observed in autografting has to be determined in prospective clinical studies.

Background & Aims: The gut is the largest immunologic organ in the human body, but little is known about the antigen specificity of mucosal T cells. This study sought to determine whether T cells resident in the duodenal mucosa could recognize astrovirus, a common and clinically important gastroenteritis virus. Serum antibodies against astrovirus are prevalent, indicating frequent viral exposure and postinfectious induction of systemic immune responses. Mucosal immune responses may conceivably mediate protection on astroviral reinfections. Methods: Small intestinal biopsy specimens with normal histology were obtained from 8 adults and challenged in an organ culture system with inactivated human astrovirus. T cells activated by the viral challenge were isolated either by immunomagnetic positive selection of mucosal resident cells or by collecting cells emigrating into the culture supernatant. Results: Astrovirus-specific, mucosal T-cell lines were isolated from all 8 subjects. Analysis of 29 CD4^+ T-cell clones from 3 subjects showed predominant HLA-DR restriction of astrovirus responses. Most of the T-cell clones showed a Th1-like cytokine profile when restimulated with astrovirus. Conclusions: Helper T cells residing in normal, duodenal mucosa of adult subjects recognize a common enteropathogenic virus. These mucosal CD4^+ T cells are presumably important in mucosal defense against recurrent astroviral infections. GASTROENTEROLOGY 1998;114:115-122

Sections of ethanol-fixed, paraffin-embedded tissue specimens from human vagina and exocervix were stained by an indirect immunofluorescence method with a rabbit antiserum to HLA-DR antigens. A specific staining of cells having a dendritic appearance were seen. The cells were randomly distributed, mainly in the parabasal cell-layer of the stratified squamous epithelium. The number of dendritic cells was 1-3% of all cells in the cervical epithelium and 1-5% of the cells in the vaginal epithelium. Most probably these cells are Langerhans' cells.

C6 typing was performed in a family material by two different techniques: serum or plasma samples were subjected either to high-voltage agarose gel electrophoresis or to isoelectric focusing in polyacrylamide gel slabs. Proteins with C6 activity were then visualized by a specific, hemolytic assay.

Bf allele frequencies in a material of 172 unrelated Norwegians are given. Bf/HLA linkage relations in 49 informative matings with 178 children, and Bf/HLA association data of a material of 212 Bf-HLA haplotypes are presented. Of 171 informative meioses, there were no Bf-HLA-B recombinations, while 3 out of 158 Bf-HLA-A informative meioses showed recombination. There is significant association between the BfF and the HLA-BW 35 allele.

Data on the linkage relation between the GLO locus and the HLA, Bf, and PGM3 loci are presented. The family material includes 49 GLO/HLA-B (and/or Bf) segregating matings with 134 children informative on 199 parental meioses. Of phase-known meioses, 3 are recombinants and 75 nonrecombinants; linkage is therefore proven. From the total material a distance of 2.5 cM between GLO and HLA-B/Bf is calculated; and from the segregation in some informative family groups it is shown that GLO is situated between PGM3 and HLA-B/Bf.

Summary In 9 families of which at least two members were affected by rheumatoid arthritis (RA), no specific combination of HLA genes, i.e., HLA haplotype was found to be associated with transmission of disease susceptibility. The results suggested an important role of HLA-DR4 in the etiology of RA, irrespective of other HLA markers. In addition, it may be concluded that genetic markers other than DR4 may act together with this HLA antigen in determining which individuals are at risk of developing this rheumatic disorder.

Typing of DNA from 94 unrelated children with celiac disease (CD) with HLA-DQA1 and -DQB1 allele-specific oligonucleotide probes revealed that all but one (i.e., 98.9%) may share a particular combination of a DQA1 and a DQB1 gene. These genes are arranged in cis position on the DR3DQw2 haplotype and in trans position in DR5DQw7/DR7DQw2 heterozygous individuals. Thus, most CD patients may share the same cis- or trans-encoded HLA-DQ alpha/beta heterodimer.

A high proportion of Staphylococcus aureus strains of human origin produce one or more exotoxins. In vivo, these toxins may give rise to a variety of clinical syndromes. In vitro, staphylococcal exotoxins have been shown to bind both to human leukocyte antigen (HLA) class II molecules on antigen-presenting cells and to the T-cell receptors on large fractions of T cells. The result of this interaction may be proliferation of the T cells, T-cell anergy, or apoptosis, depending on several factors, including the state of the responding cells and the presence of accessory molecules. Using naturally infected peripheral blood mononuclear cells depleted of CD8+ T cells, we have shown that staphylococcal exotoxins are powerful inducers of human immunodeficiency virus type 1 expression and that they induce expression at low concentrations and with greater efficiency than other T-cell mitogens. Human immunodeficiency virus type 1 was produced entirely by CD4+ T cells in this model; monocytes were expendable both as a source of virus and as a source of HLA class II molecules as long as other cells expressing HLA class II molecules were present. The results suggest that infection by S. aureus may be a cofactor in the immunopathogenesis of AIDS.

To understand the rules determining peptide binding to the celiac disease and type 1 diabetes mellitus associated HLA-DQ2 molecule, we have studies in detail the binding of a peptide OVA 258-276Y (IINFEKLTEWTSSNVMEERY) which exhibits strong binding to DQ2. First we tested a set of N- and C-terminal truncated variants, and found the core binding region to comprise residues 267-276Y. Single alanine substitution analysis of the OVA 267-276Y peptide revealed that replacements of V272, E275 and the C-terminal Y had negative effects whereas the substitution of N271 had a positive effect. A polyalanine analogue of the OVA 267-276Y peptide with V272, E275 and a C-terminal Y bound at least as well as the original peptide. A variant peptide with a deletion of R276 displayed decreased binding, suggesting that the anchor residues were out of frame in this analogue. To further characterize the residues playing a role in the binding of the OVA 267-276Y peptide to DQ2 we tested the binding of several analogues with substitutions for V272, E275 and the C-terminal Y residue. Our results indicate that peptides binding to DQ2 have anchor residues in relative positions 4, 7 and (P4, P7 and P9). Residues with negatively charged or hydrophobic aliphatic but not positively charged side chains are preferred in P4 and P7, whereas residues with bulky hydrophobic side chains are preferred in P9.

Genes in the HLA complex are by far the most important in determining genetic predisposition or resistance to Type 1 (insulin-dependent) diabetes mellitus. In this review evidence is presented that the HLA genes mainly involved are those encoding some particular HLA-DQ molecules. Both among Black, Caucasian and Japanese subjects particular cis or trans encoded DQ molecules are significantly associated with susceptibility, while others are associated with resistance. A varying degree of susceptibility or resistance seems to be conferred by these DQ molecules, where those determining resistance are dominant over those determining susceptibility. The degree of genetic predisposition to develop Type 1 diabetes carried by an individual would therefore be the result of his or her particular combination of DQ molecules. A primary association to particular DQ molecules explains previously found associations to other HLA complex genes by linkage disequilibrium. Some mechanisms by which particular DQ molecules may determine susceptibility or resistance are also discussed. Potential islet beta-cell reactive CD4+T-cells may escape negative selection (deletion) in the thymus, but normally become anergized or remain ignorant extra-thymically. However, under particular circumstances they may be triggered. The DQ molecules associated with Type 1 diabetes susceptibility may preferentially bind and present triggering and/or beta-cell derived peptides to such T cells, causing beta-cell destruction. The finding that particular DQ molecules determine susceptibility may lead to new methods of preventing development of Type 1 diabetes in susceptible individuals.

Previous studies have suggested an association between polymorphisms in the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Most of the studies so far have been performed in Caucasoid populations. We have investigated 418 random IDDM patients and 422 healthy control subjects from three different ethnic groups; Tanzanian blacks, Norwegian Caucasians and Japanese orientals. Our data suggest that polymorphisms in the insulin gene region confer susceptibility to IDDM in Caucasians, and that a similar tendency though not statistically significant is observed among Tanzanian blacks, while no significant contribution is seen among Japanese orientals. We further demonstrate that the disease-associated genotype INS +/+ confers susceptibility independently of HLA class II alleles associated with IDDM. Compared to the contribution of particular HLA-DQ alleles in IDDM susceptibility, the additional risk conferred by the insulin gene region polymorphism is, however, small. Genotyping of the insulin gene region will therefore most probably not be a useful tool in the prediction of IDDM.

Eight patients underwent orthotopic heart transplantation in Norway during 1984, with retransplantation in one case. The age range of the 5 men and 3 women was 19-53 years. The preoperative diagnosis was cardiomy-opathy in 6 patients, ischaemic heart disease in one, and a combination of the two disorders in one patient. The immunosuppressive regimen, with cyclosporin A and low-dose prednisolone, and the treatment of graft rejection, followed the Stanford University protocol. There was no operative mortality. Three patients died shortly after the transplantation, 2 of them after about a week from acute rejection; in one of these 2 cases a second transplant was made, but was followed by pulmonary and renal complications. The third death occurred about 10 weeks postop-eratively, from donor heart failure due to Toxoplasma myocarditis. The 5 survivors are clinically in good condition.

A male uremic patient was first transplanted with a kidney from a female cadaveric donor. The kidney was rejected after two weeks. He was retransplanted approximately one year later with a kidney from his HLA-identical sister. This graft was also irreversibly rejected after one week. No serum antibodies could be detected against the sibling donor before or after transplantation, but the recipient had formed donor-specific cytotoxic T lymphocytes (CTLs). The CTLs were cloned, and clones with two different specificities were obtained. One clone lysed target cells from the donor, from some other family members, and from 50 of a panel sharing HLA-B15 with the recipient. It may recognize a minor transplantation antigen, that is restricted by HLA-B15. The other clone lysed target cells from the donor, from all HLA-B8-positive family members (except the recipient), and from third-party cell donors sharing HLA-B8 with the recipient. When CTLs from third-party individuals were induced toward HLA-B8, target cells from all HLA-B8-positive family members were lysed, except those from the recipient. This indicates that the recipient may have inherited a variant of HLA-B8 that is not detectable by antibodies but by CTLs. These donor-specific CTLs may have contributed to the rejection of the HLA-identical sibling transplant.

Patients with well-functioning kidney allografts from one-HLA-haplotype—mismatched related donors have strongly reduced donor-specific cell-mediated cytotoxicity 2–10 years after having received their grafts. This could also be demonstrated in secondary in vitro cellmediated lympholysis (CML). Even though secondary donor-specific CML did not exceed 10 at an effector-to-target cell ratio of 50:1, specific lysis of donor target cells increased significantly with increasing effector cell concentrations. The weak cytotoxicity toward the donor could be enhanced neither through pool-cell stimulation nor by adding exogenous Interleukin 2 (IL-2) during the induction phase. Furthermore, growth factors were produced in the cultures during the induction of cytotoxic cells in concentrations comparable to those of the sibling control. Thus no evidence could be obtained that lack of IL-2 was causing the decreased cytotoxicity in these patients.

Proteins were separated by prolonged isoelectric focusing in polyacrylamide gels, whereupon C2 bands were detected by a specific hemolytic assay. This was performed by treating the gel with iodine to increase C2 activity, and then developing C2 bands with an agarose gel overlay containing sensitized sheep cells and diluted human serum as a complement source deficient in functional C2. The gene frequencies observed in a material of 122 unrelated adults were: C21:0.97 and C22:0.03.

Two T4 cell clones (TLC) specific for antigenic epitopes on Chlamydia trachomatis were studied. Using a panel of allogeneic antigen-presenting cells (APC), both TLC were found to be restricted by HLA class II elements closely associated with, but not identical to the DRw5S specificity, as determined by highly selected alloantisera, a monoclonal antibody (mAb), 109d6, and confirmed on the DNA level by determination of restriction fragment length polymorphisms (RFLP) with a DR beta probe. Furthermore, HLA-DR-specific mAb, including 109d6, but not other HLA class II- or class I-specific antibodies inhibited the two TLC, strongly suggesting that the restriction element is expressed by a DR molecule. Using digestion with Hind III restriction enzyme and a DR beta probe, we found a complete concordance between the appearance of a 9.3 kilobase band and the ability of allogeneic APC to restimulate the T cell clones. Thus, the restriction element for these T cell clones appear to be expressed by DR molecules, but can, at present, only be detected at the genomic level.

The C4 polymorphism in man has been studied by immunofixation electrophoresis, crossed immunoelectrophoresis, and functional detection after agarose gel electrophoresis. It has so far not been possible to reveal this polymorphism by isoelectric focusing and functional detection of C4 bands. Three common alleles and one less frequently occuring allele have been identified. In a small population sample studied by all the different techniques and verified by family segregation, the following gene frequencies have been found: C4F: 0.46, C4S: 0.32, C4F1: 0.20, and C4M: 0.02. By linkage and association studies in a family material it has been shown that a structural C4 locus is situated in the HLA region of chromosome 6 very close to the HLA-B and Bf loci.

The [3H]thymidine suicide technique was used to test the hypothesis that the response of immune human T cells from HLA-D/DR heterozygous donors to the soluble protein antigen purified protein derivative (PPD) is clonally expressed and consists of the concurrent proliferation of at least two separable subpopulations of lymphocytes. The results showed that each of the two subpopulations react to one or the other of the HLA-D/DR antigens presented together with PPD by allogeneic monocytes. In addition, using in vitro priming techniques of in vivo sensitized lymphocytes from heterozygous donors, it was possible to generate specific memory cells capable of recognizing the priming soluble protein antigen together with the HLA-D/DR determinant present in the initial sensitizing culture.

Celiac disease (CD) is most probably an immunological disease, precipitated in susceptible individuals by ingestion of wheat gliadin and related proteins from other cereals. The disease shows a strong human HLA association predominantly to the cis or trans encoded HLA-DQ(alpha 1*0501,beta 1*0201) (DQ2) heterodimer. T cell recognition of gliadin presented by this DQ heterodimer may thus be of immunopathogenic importance in CD. We therefore challenged small intestinal biopsies from adult CD patients on a gluten-free diet in vitro with gluten (containing both gliadin and other wheat proteins), and isolated activated CD25+ T cells. Polyclonal T cell lines and a panel of T cell clones recognizing gluten were established. They recognized the gliadin moiety of gluten, but not proteins from other cereals. Inhibition studies with anti-HLA antibodies demonstrated predominant antigen presentation by HLA-DQ molecules. The main antigen-presenting molecule was established to be the CD-associated DQ(alpha 1*0501, beta 1*0201) heterodimer. The gluten-reactive T cell clones were CD4+, CD8-, and carried diverse combinations of T cell receptor (TCR) V alpha and V beta chains. The findings suggest preferential mucosal presentation of gluten-derived peptides by HLA-DQ(alpha 1*0501, beta 1*0201) in CD, which may explain the HLA association.

Matching for HLA haplotypes as well as for HLA-A and B antigens improved graft survival in 112 living related first transplants. In cadaveric first transplants, matching for HLA-A and B antigens had a beneficial effect on the fate of 373 grafts, while matching for HLA-C antigens had no predictive value. One hundred seventeen cadaveric transplants and their recipients were prospectively typed for the HLA-DR antigens. Compatibility for HLA-DR was found to be prognostically beneficial irrespective of matching for HLA-A and B antigens, and with no difference between transfused and nontransfused patients. Matching both for HLA-A, B and D/DR was thus found to influence the outcome of renal transplantation.

A 22-year-old previously nonsensitized female patient (HLA-A2,28; B7,14; DR1,2) received a kidney from her HLA-identical brother. She irreversibly rejected the graft 21/2weeks later. In vitro tests performed 6 weeks after the graft loss, using reipient responding and donor-stimulating and target cells, revealed a weak mixed lymphocyte culture (MLC) response and negative direct cell-mediated lympholysis (CML), but strong cytotoxicity against donor target cells after priming in MLC. Both MLC and CML tests using donor-responding cells and recipient-stimulating and target cells were negative. When the patient's cytotoxic cells were tested on a panel of target cells from nonrelated donors, a significant CML was only found against target cells from male donors sharing HLA-A2 and/or B7 with the patient, not with male target cells sharing A28 or B14. By using cold target inhibition tests, two separate populations of male-specific cytotoxic cells could be demonstrated. The one was restricted by HLA-A2, the other by B7. These findings indicate that a self-HLA-restricted cytotoxicity against a male-specific minor histocompatibility antigen was a major cause of the rejection in this case.

Patients with well functioning kidney grafts from one HLA haplotype-mismatched related donors were studied 2 to 10 years after transplantation. No direct cell-mediated lympholysis (CML) toward donor cells was found. After in vitro sensitization in mixed lymphocyte culture, the recipient effector cells were not able to significantly kill donor target cells at an effector to target cell ratio of 50:1, while the HLA-A,B,D/DR-identical sibling of the recipient could generate strong cytotoxicity toward the donor at similar effector to target cell ratios. Nevertheless, the patient developed strong cytotoxicity toward third-party targets. Our findings indicate in vivo depletion of cytotoxic cells with specificity for donor antigens. No correlation between the mixed lymphocyte culture (MLC) response and the ability to generate cytotoxic cells could be found in recipient-donor combinations. In looking for in vivo generated suppressor cells toward the donor, a moderate suppression was found in three of six patients studied.

BACKGROUND & AIMS: T-cell immune reactions toward wheat gliadins seem important in the pathogenesis of celiac disease. We have previously shown that gliadin-specific T-cell clones (TCCs) from the small intestinal mucosa of patients with celiac disease are predominantly restricted by the celiac disease-associated HLA-DQ2 and HLA-DQ8 molecules, suggesting a link between the HLA association and immunopathogenesis. The aim of the present study was to investigate the nature of the stimulating gliadin antigens.

This is a study of immune responses generated by mutant ras peptide vaccination of patients with pancreatic adenocarcinoma. Responding T cells from one patient were cloned and two CD4+ T-lymphocyte clones (TLC) specific for the 12 Val peptide and restricted by HLA-DR6 or DQ2 were obtained. These class II molecules have not previously been found to bind or present mutant ras peptides to T cells. The DR6-restricted TLC showed marked cytotoxicity against autologous target cells pulsed with the 12 Val peptide. Target cells pulsed with the control peptide were not killed. Responding T cells from another patient showed cross-reactivity towards the homologous ras peptides. Investigation by limiting dilution analysis (LDA) revealed different T-cell precursor frequencies for the immunising, mutant ras peptide (1:28000), compared with the normal ras peptide (1:110000).

The frequency of HLA A. -B. and -C antigens, of -DRw3 and the associated B-lymphocyte alloantigen -DRw3 has been studied in 68 children with coeliac disease (CD). CD was found to be primarily associated with the B-lymphocyte alloantigen, the relative risk being calculated to 54. The possible relation between the B-lymphocyte alloantigen DRw3 and -Dw3 is discussed. The high relative risk and the fact that 95 of the patients with probable or definite CD had the B-lymphocyte alloantigen DRw3, underline the diagnostic value of B-lymphocyte typing in coeliac disease.

Serologic HLA typing was carried out in 20 patients with ulcerative colitis (UC) combined with hepatobiliary disease, in 34 UC patients without hepatobiliary disease, and in control subjects. Association with HLA-B8 and -DR3 was found in both groups of patients. HLA-B8 was found in 80 of patients with combined disease (p < 0.0005 vs. controls; relative risk (RR), 12.0), whereas 32 of the patients with UC without hepatobiliary disease were HLA-B8-positive (not significant vs. controls). Concomitantly, HLA-DR3 was found in 70 of patients with combined UC and hepatobiliary disease (p < 0.0005 vs. controls; RR, 9.95) and in 35 of UC patients without hepatobiliary disease (p < 0.05 vs. controls; RR, 2.33). HLA-B8 was found more frequently in UC patients with than without hepatobiliary disease (p < 0.001; RR, 8.36), as was the case with HLA-DR3 (p < 0.025; RR, 4.28). No indications of defects in immunoregulatory lymphocytes (Tγ and Tμ cells) which could explain hyperactivity in the immune system were observed in the patients with combined UCand hepatobiliary disease. The present study gives support to the theory that UC and, particularly. UC combined with hepatobiliary lesion may be autoimmune diseases with a genetic predisposition.

The frequencies of Gm allotypes a, x, f, b, g and n have been investigated in classical seropositive rheumatoid arthritis (RA), erosive definite seronegative RA, non-erosive definite RA and in healthy individuals with serum IgM-RF. No differences in the frequencies of these Gm allotypes were found between patients and healthy controls. It is concluded that any possible putative genes outside the HLA region involved in RA are most likely unrelated to the genes coding for the constant regions of IgG heavy (γ) chains.

A restriction fragment length polymorphism analysis using double digestion of DNA preparations with XbaI and BglII restriction enzymes and hybridization with C4 and HLA-DR probes is described. The typing conditions selected reveal extensive individual variation in both C4 and DR gene regions. In our panel of 46 unrelated individuals, 37 different phenotypic patterns were recognized when both probes were used, and preliminary discriminative power values of 0.865 and 0.914 were calculated for C4 and DRß, respectively. The probability of a chance match using both systems is probably about 1.5 · 10-2.

The inhibitory effect of HLA antisera on Fc receptors of human lymphoid cells was investigated. The ability of lymphoid cells to form rosettes (FcRFC) with antibody-coated sheep red blood cells and to function as effector cells (K cells) in antibody-dependent cell-mediated cytotoxicity were used as assay systems. We found that antisera recognizing determinants of the HLA-A, -B, and -C series had no effect on FcRFC, while a specific inhibitory effect was observed of antisera probably reacting with determinants identical to or closely associated with those of the HLA-D series. This inhibitory effect was retained in the F(ab')2 fragments. Specific inhibition of K cells was observed with all HLA antisera, but this effect was lost in the F(ab')2 fragments. We conclude that the Fc receptor of rosette-forming lymphocytes may be closely associated with products of the HLA-D region. This is analogous to the association between the Fc receptor and the Ia antigens on murine rosette-forming B lymphocytes.

Human endothelial cells were separated by collagenase digestion from the umbilical vein of newborns. The cytotoxic effect of antisera against HLA-DRw antigens was tested on monolayers of endothelial cells, using a 51Cr retention microcytotox-icity assay in the presence of rabbit complement. Of the endothelial monolayers tested, significant concordance between the typing results obtained using cord blood-derived B lymphocytes and endothelial cell monolayers was observed. A rabbit anti-human polyspecific B cell antiserum was also capable of completely lysing the endothelial monolayers tested. In addition, 5ICr-labelled dissociated endothelial cells were lysed by nonimmune peripheral blood mononuclear cells in the presence of DRw antisera having a specificity for the target endothelium.

To study the relationships between the responses to viral antigens and the HLA-DR3 and -DR4 associations in Type 1 (insulin-dependent) diabetes mellitus, the frequency of T-lymphocyte proliferating in response to mumps, Coxsackie B4 and varicella-zoster antigens was determined. A decreased frequency was found in T lymphocytes able to respond to mumps or Coxsackie B4 when presented together with DR3, as compared with the frequency of T lymphocytes able to respond to these viruses together with other DR determinants. This was not found for varicella-zoster or purified protein derivative of tuberculin. In contrast, an increased frequency was found in T lymphocytes responding to mumps or Coxsackie B4 together with DR4, compared with other DR determinants. The results were similar in Type 1 diabetic and healthy individuals. The results suggest that elements on the DR3 and DR4 molecules may control T-lymphocyte responses to mumps and Coxsackie B4 viruses.

According to the rules of selecting suitable recipients for cadaver kidney transplants a high degree of HL-A compatibility is usually sought. This may lead to an uneven distribution of transplantations in the pool of waiting patients, favouring those who have a more common HL-A phenotype.The probability for histocompatibility has been calculated for all of 5044 phenotypes (Högman et al., 1972). All patients who were registered in Scandiatrans-plant for kidney transplantation during a 6-month period were classified in retrospect according to this probability and followed up for at least 12 months.High probability values were related to an early transplantation with a good HL-A match. Low probability figures were related to a high percentage of non-transplanted patients and a long waiting time before transplantation. Blood group A patients were transplanted twice as frequently as group O patients. We recommend that consideration be given to the calculated histocompatibility probability at each cadaver kidney transplantation.

THE blood vessels of allografted organs are important sites for immunological injury1–3. In vivo, this is thought to be the result of interactions between antigenic determinants on donor vessel endothelium and recipient immunocompetent cells and antibodies. In vitro, damage to cultured pig endothelium by cytotoxic xeno- and alloantisera in the presence of rabbit complement has previously been described4. In addition, both canine5and human6endothelial cells are capable of stimulating allogeneic lymphocytes to blastogenesis and DNA synthesis, thus demonstrating the ability of endothelium to initiate directly an immunoproliferative response in vitro.

IT has been shown that papain-solubilised HL-A antigens consist of two polypeptide chains, which may be separated under dissociating conditions1,2. Peterson et al.3have shown that β-2-microglobulin (β-2-m) constitutes one of the two polypeptide chains in papain-solubilised HL-A antigens. In these antigens, β-2-m represents a constant small subunit (molecular weight 11,800), whereas a larger subunit (30,000–31,000) carries the allo-antigenic specificity. The studies by Peterson et al. do not exclude the possibility that the two subunit structure of HL-A antigens might be a product of the solubilisation process. It has previously been reported4that β-2-m, which also occurs in biological fluids5, is present in high concentrations on the surface of lymphocytes. The present study was designed to establish whether β-2-m is part of the intact HL-A molecule in the cell membrane. Experiments were performed in which the blocking of HL-A antigens6,7, β-2-m and other lymphocyte membrane components were induced by selected ahtisera. Furthermore, to study the relationship between these cell membrane components and the antigen receptors on lymphocytes, the different antisera were also tested for their ability to induce or inhibit lymphocyte activation in vitro. Methodological details are published elsewhere8.

INVESTIGATIONS using highly selected lymphocytotoxic and complement-fixing platelet antibodies have made it possible to define a considerable number of antigens belonging to the HL-A system. These antisera are determined by genetic information belonging to a still unknown number of closely linked loci, subloci or mutational sites. Most of the known HL-A antigens seem to belong to two series, ‘LA’ and ‘4’, each of which contains a number of mutually exclusive genes and corresponding antigens. An ever increasing number of antigens are being identified1–5. The various genes and corresponding antigens, which can be determined, are given in Table 1.