Search

Background: De novo donor-specific antibody (dnDSA) generation and acute rejection (AR) are the main factors affecting long-term graft survival. This study aims to investigate human leukocyte antigen (HLA) eplet mismatching (MM), delayed graft function (DGF), and tacrolimus (TAC) trough levels on the occurrence of dnDSA and AR in the early stages after kidney transplantation (KT)., Methods: This retrospective study included 526 cases of deceased donation KT. The effects of DGF, HLA eplet MM, and TAC trough levels on dnDSA and AR occurrence were analyzed with logistic regression analysis., Results: Multivariate logistic regression analysis showed the independent risk factor of dnDSA generation was HLA B eplet MM (OR: 1.201, 95% CI: 1.007-1.431, P = 0.041). The independent risk factors of AR occurrence include DGF (OR: 4.045, 95% CI: 1.047-15.626, P = 0.043), HLA B eplet MM (OR: 1.090, 95% CI: 1.000-1.187, P = 0.050), and TAC trough levels at 12 months (OR: 0.750, 95% CI: 565-0.997, P = 0.048). HLA B eplet MM combined with DGF and TAC trough levels at 12 months increased the predictive value of dnDSA (AUC 0.735) and AR (AUC 0.730) occurrence. HLA B eplet MM > 9 and TAC trough levels below 5.95 ng/mL at 12 months could increase the risk of early AR occurrence., Conclusions: HLA B eplet MM, DGF, and TAC trough levels at 12 months after KT could affect the occurrence of dnDSA and AR in the early stage of KT., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

Natural killer (NK) cell development largely depends on killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) class I ligands. In the current study, we investigated the role of KIR genes, HLA ligands, and KIR-HLA combinations in vulnerability or protection against prostate cancer (PC). To analyze the frequency of 16 KIR genes and 5 HLA ligands, polymerase chain reaction with sequence-specific primers (PCR-SSP) was conducted in 150 PC patients and 200 healthy controls (CNs). KIR2DL5 (p = 0.0346, OR = 0.606, CI = 0.3916-0.9336), KIR2DS5 (p = 0.0227, OR = 0.587, CI = 0.3793-0.9139), HLA-B Bw4 Thr80 (p = 0.0401, OR = 0.3552, CI = 0.1466-0.9059), HLA Bw4 (p = 0.0190, OR = 0.4744, CI = 0.2656-0.8521), and T4 gene cluster (including KIR2DS5-2DL5-3DS1-2DS1 genes) (p = 0.0194, OR = 0.5575, CI = 0.3449-0.8938) had a lower frequency in the PC patients compared to the control group. Moreover, a lower frequency of the genotypes contacting activating KIR (aKIR) > inhibitory KIR (iKIR) (p = 0.0298, OR = 0.5291, CI = 0.3056-0.9174) and iKIR + HLA < aKIR + HLA (p = 0.0183, OR = 0.2197, CI = 0.0672-0.7001) in PC patients compared to the CNs implies a protective role for aKIR genes. In the case of KIR-HLA interactions, we detected a significant association between KIR3DS1 + + HLA-A Bw4 + (p = 0.0113, OR = 0.5093, CI = 0.3124-0.8416) and KIR3DL1 - + HLA-A Bw4 + (p = 0.0306, OR = 0.1153, CI = 0.0106-0.6537) combinations and resistance to prostate cancer. In contrast, the presence of KIR3DL1 in the absence of HLA-A Bw4 (p = 0.0040, OR = 2.00, CI = 1.264-3.111), HLA Bw4 (p = 0.0296, OR = 2.066, CI = 1.094-3.906), and HLA-Bw4 Thr80 (p = 0.0071, OR = 2.505, CI = 1.319-4.703) genes probably predisposes to prostate cancer. Carrying the CxT4 genotype in PC patients was positively associated with lower tumor grades (Gleason score ≤ 6) (p = 0.0331, OR = 3.290, and CI = 1.181-8.395). Altogether, our data suggest a protective role for aKIRs, HLA-B Bw4 Thr80 , and HLA Bw4 ligands as well as a predisposing role for certain KIR-HLA combinations in prostate cancer. The findings of this study offer new insight into the population's risk assessment for prostate cancer in men. Additionally, predicting immunotherapy response based on KIR-HLA combinations aids in implementing the most effective therapeutic approach in the early stages of the disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Trichloroethanol (TCOH), as a metabolite of trichloroethylene, has sensitization in the pathogenesis of trichloroethylene-induced hypersensitivity dermatitis (TIHD) which the human leukocyte antigen (HLA)-B∗13:01 gene is strongly associated with it. However, it is still obscure how TCOH participates in the pathogenesis of TIHD. Here, we demonstrate that TLR2 and TLR4 signaling through MyD88 and TRAF6-dependent pathway could activate NF-κB by promoting degradation of the inhibitor IκB-α to stimulate the process of NF-κB nuclear translocation. Besides, the crucial molecules of antigen processing and presentation, including TAP1, LMP2, LMP7, and HLA-B* 13:01, were all enhanced and the abundance of HLA-B* 13:01 on the surface of CIR-B* 13:01 cells was also up-regulated with the TCOH concentration increasing. Notably, we used 50 μM pyrrolidinedithiocarbamate (ammonium) to effectively inhibit the activation of NF-κB, which could effectively reverse the stimulation of antigen processing and presentation in TCOH-treated CIR-B* 13:01 cells. Taken together, we speculated that TCOH could promote the abundance of HLA complex on the antigen-presenting cells via TLR2 and TLR4/NF-κB to induce the severe reactivation of T lymphocytes, leading to the extreme immune response., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Hematopoietic cell transplantation from HLA-haploidentical related donors is increasingly used to treat hematologic cancers; however, characteristics of the optimal haploidentical donor have not been established. We studied the role of donor HLA mismatching in graft-versus-host disease (GVHD), disease recurrence, and survival after haploidentical donor transplantation with posttransplantation cyclophosphamide (PTCy) for 1434 acute leukemia or myelodysplastic syndrome patients reported to the Center for International Blood and Marrow Transplant Research. The impact of mismatching in the graft-versus-host vector for HLA-A, -B, -C, -DRB1, and -DQB1 alleles, the HLA-B leader, and HLA-DPB1 T-cell epitope (TCE) were studied using multivariable regression methods. Outcome was associated with HLA (mis)matches at individual loci rather than the total number of HLA mismatches. HLA-DRB1 mismatches were associated with lower risk of disease recurrence. HLA-DRB1 mismatching with HLA-DQB1 matching correlated with improved disease-free survival. HLA-B leader matching and HLA-DPB1 TCE-nonpermissive mismatching were each associated with improved overall survival. HLA-C matching lowered chronic GVHD risk, and the level of HLA-C expression correlated with transplant-related mortality. Matching status at the HLA-B leader and HLA-DRB1, -DQB1, and -DPB1 predicted disease-free survival, as did patient and donor cytomegalovirus serostatus, patient age, and comorbidity index. A web-based tool was developed to facilitate selection of the best haploidentical-related donor by calculating disease-free survival based on these characteristics. In conclusion, HLA factors influence the success of haploidentical transplantation with PTCy. HLA-DRB1 and -DPB1 mismatching and HLA-C, -B leader, and -DQB1 matching are favorable. Consideration of HLA factors may help to optimize the selection of haploidentical related donors.

Background: The role of low levels of circulating donor specific antibodies (DSA) producing negative flow cytometry cross match is not completely defined. The purpose of this study was to examine the clinical significance of preexisting low levels of class I DSAs in flow cytometry cross match (FC CM) negative first kidney transplant recipients (KTRs)., Methods: All of the KTRs (n=41) had low levels of anti-class I antibodies only. The kidney transplant outcome was evaluated by the development of a deleterious effect (DE) in recipients in the study cohort (Group 1: DE+, Group 2: DE-). Positivity for DE was determined based on the following criteria: biopsy proven transplant glomerulopathy (TG), de novo development of DSAs, increasing MFI values for preexisting DSAs, and the development of biopsy proven AMR. Anti-HLA antibodies were tested using single antigen Luminex technology. The HLAMatchmaker computer algorithm was used for the immunogenicity analysis of antibody verified (AbVer) mismatched eplets (MME) at the HLA-A and B loci., Results: The results of this study showed that the number of AbVer MME is larger (P=0.03) in the group of KTR who developed DE. We also demonstrated that the number of AbVer MME is a strong predictor of post-transplant DE. These results indicate that persistent weakly reactive DSA is not a significant risk factor for the development of post-transplant DE and that recipients with such antibodies can be successfully transplanted., Conclusions: Immunogenicity of AbVer MME at HLA-A and B loci is strong predictor of post-transplant increases of the MFI values of preexisting or de novo developed DSA in the FC CM negative first KTR. Avoiding of transplants with more than eleven Class I AbVer MMEs may be the optimal approach to reduce the risk of kidney graft failure., (Copyright © 2017. Published by Elsevier B.V.)

It is hypothesised that associations between adverse drug reactions and specific alleles of the human leukocyte antigens arise due to specific interactions between the human leukocyte antigen molecules and the causative drug that stimulate immune responses targeting drug exposed tissues. To date this has only been definitively demonstrated for abacavir, an antiretroviral that causes a systemic adverse drug reaction, abacavir hypersensitivity syndrome, solely in HLA-B*57:01 + individuals. Whilst this has informed the modification of abacavir to remove immunogenicity, there remains an imperative to define other interactions between drugs and specific HLA in order to understand the scope of interactions that can drive T cell mediated drug hypersensitivity. Here we review the current state of understanding of these interactions., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Chronic thromboembolic pulmonary hypertension (CTEPH) is a form of pulmonary hypertension caused by non-resolving thromboembolisms of the pulmonary arteries. In Japan, in contrast to Western countries, CTEPH is more prevalent in women. A Japanese multicenter study reported that a form of CTEPH unrelated to deep vein thrombosis is associated with HLA-B⁎5201, suggesting that this form of CTEPH may be associated with vasculopathy. CTEPH can be cured by pulmonary endarterectomy, provided that the thrombi are surgically accessible; thus, early diagnosis is important, and all patients with exertional dyspnea should be evaluated for pulmonary hypertension. Ventilation/perfusion scans provide an excellent non-invasive means to distinguish CTEPH from pulmonary arterial hypertension. Similarly, computed tomographic pulmonary angiograms allow for the detection of thrombi and evaluation of pulmonary hemodynamics in a minimally invasive manner. Importantly, the absence of subpleural perfusion on pulmonary angiograms can suggest the presence of small vessel disease. Small vessel disease might be involved in the pathogenesis of CTEPH, and its detection is essential in preventing operative death. Although no modern therapies for pulmonary arterial hypertension have been approved for treatment of CTEPH, a recent randomized control trial of riociguat in patients with CTEPH demonstrated that riociguat significantly improved 6-min walking distance. Further investigations into treatments that target endothelial dysfunction and hyperproliferative CTEPH cells are needed. Recently, balloon pulmonary angioplasty has emerged as a promising treatment modality in Japan. A specialized medical team, including at least one expert surgeon, should make decisions regarding patients' candidacy for pulmonary endarterectomy and/or balloon pulmonary angioplasty., (© 2013 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

The National Marrow Donor Program maintains a registry of volunteer donors for patients in need of a hematopoietic stem cell transplantation. Strategies for selecting a partially HLA-mismatched donor vary when a full match cannot be identified. Some transplantation centers limit the selection of mismatched donors to those sharing mismatched antigens within HLA-A and HLA-B cross-reactive groups (CREGs). To assess whether an HLA mismatch within a CREG group ("minor") may result in better outcome than a mismatch outside CREG groups ("major"), we analyzed validated outcomes data from 2709 bone marrow and peripheral blood stem cell transplantations. Three-hundred and ninety-six pairs (15%) were HLA-DRB1 allele matched but had an antigen-level mismatch at HLA-A or HLA-B. Univariate and multivariate analyses of engraftment, graft-versus-host disease, and survival showed that outcome is not significantly different between minor and major mismatches (P = .47, from the log-rank test for Kaplan-Meier survival). However, HLA-A, HLA-B, and HLA-DRB1 allele-matched cases had significantly better outcome than mismatched cases (P < .001). For patients without an HLA match, the selection of a CREG-compatible donor as tested does not improve outcome.

Takayasu arteritis (TA) is characterized by a 'pulseless' condition and occurs frequently in young females from Asian and South American countries. It has been associated with Mayor Histocompatibility Complex (MHC) genes in different populations. Recent data indicate direct participation of HLA-B alleles in the susceptibility to the disease. This fact was explored in an associative study with TA to establish if some region in the exon 2, intron 2 or in the exon 3 of HLA-B alleles is common in the alleles associated with TA and at the same time to know if a specific sequence or an epitope, more than an allele, would be responsible for the susceptibility to this vasculitis. We studied HLA-B alleles of 12 Mexican patients with TA using PCR-SSP and sequencing. The analysis by PCR-SSP in 12 patients showed that five of them showed the B*15 allele, three the B*40 allele and two the B*39 allele, the remaining two presented the B*44 allele. Sequence analysis enabled us to define that the B*39 subtypes are B*3908; B*15 subtypes are B*1510, B*1515, B*1522 and B*1531; and the B*40 subtypes are B*4005 and B*4008. An individual with B*51 (B*5107) and another with B*52 (B*5201) alleles were also identified. The sequences of the intron 2 seem be heterogeneous. Analysis at the 63 and 67 positions of HLA-B alleles showed that 9 of them have similarity in some of these positions with the residues detected in the B*5201 and B*3902 alleles associated with TA in Asian populations. The results indicate that there is heterogeneity in the alleles associated with TA in Mexicans but, in spite of that heterogeneity, the alleles associates can be separated into three groups: B*39, B*15 and B*40, whose subtypes are rare and apparently of recent generation in Mexico, probably by recombination events at intron 2 level. The sequences analysis also shows that most of the alleles detected in the Mexican patients share two epitopes described in the susceptibility alleles in Asian populations, suggesting that these epitopes could be responsible for the susceptibility to develop the disease in spite of the allele in which are found.

The characteristics of nine monoclonal antibodies (MoAbs) produced using the uninduced cells of a human erythroleukemia line (HEL) as immunogen are described. These antibodies were grouped into four categories by their differences in recognition of normal cells and cells of hemopoietic cell lines. The four MoAbs of group A recognize determinants that are expressed in a large proportion of normal bone marrow cells and other mature cells. The two MoAbs of group B (53/5, 53/6) and the two MoAbs of group C (54/23, 54/39) recognize small proportions of bone marrow cells, whereas the single MoAb of group D (53/10) essentially recognizes only HEL cells. Competition experiments revealed two pairs of competing Abs (53/5 and 53/6; 54/23 and 54/39). In complement-dependent cytotoxicity of progenitors, 53/6 produced 90%-100% inhibition of CFU-E, BFU-E, and CFU-C growth; 54/39 30%-60% inhibition of BFU-E and CFU-C growth; 53/10 produced a variable degree of inhibition of CFU-E and BFU-E. Cell sorting using 53/6 resulted in approximately a 10-12-fold enrichment of CFU-E, BFU-E, and CFU-C among the positive cells. Cell sorting with 54/23 resulted in recovery of over 90% of BFU-E and 100% of CFU-C among the 23.5% of sorted cells showing strong or intermediate positivity. These findings suggest that HEL cells possess surface characteristics that are expressed in several classes of hemopoietic progenitors.

RPRL 15I4 inbred chickens are nearly histocompatible except for the B5 and B15 haplotypes that determine the major transplantation antigens. B5B5 and B15B15 15I4 chickens were equally and highly susceptible to tumors induced by Marek's disease, Rous sarcoma, or avian leukosis viruses (ALV), suggesting both of these haplotypes may determine a general influence leading to tumor development. The 15I4 birds were highly susceptible to erythroblastosis, and most developed immunological tolerance to the virus after ALV infection.

Fifty adult Japanese patients with biopsy-proven idiopathic membranous nephropathy (IMN) were typed for HLA-A, B, and DR antigens, and additional B cell alloantigens designated the MT system. The phenotype frequencies of HLA-DR2 (80.0 vs. 36.0%) and MT1 (96.0 vs. 49.5%) appeared to be significantly increased in the patient group when compared to those of a control. There were lower frequencies of DR4, DRw9, MT3, and MT4 in these particular patients. The decreases of MT3 and MT4 were statistically significant but those of DR4 and DRw9 were not. These results suggest that HLA-DR2 and MT1 antigens are related to the occurrence of IMN in the Japanese population.

The distribution of the major histocompatibility antigens HLA-A,B,C, (HLA) on dendritic cells of normal human skin was studied by immunoelectron microscopy and a 4-step immunoperoxidase technique utilizing monoclonal antibodies. Light microscopy revealed peripheral staining for HLA of epidermal and pilar infundibular keratinocytes. In the epidermis, the staining was present from the basal layer to the upper stratum spinosum. In the follicles below the level of the infundibulum, HLA was detected only on rare intraepithelial dendritic cells. These dendritic cells could not be identified in the epidermis due to the HLA staining of the surrounding keratinocytes. Similar cells stained diffusely with anti-T6 antibody; the keratinocytes did not. Immunoelectron microscopy demonstrated: (1) the presence of HLA staining of keratinocyte membranes from the stratum basalis to the level of the upper stratum spinosum and in the pilar infundibulum, (2) the possible absence of HLA on melanocytes, (3) the presence of focal HLA staining of the membranes of epidermal and follicular dendritic cells that contained Birbeck granules and were, therefore, Langerhans cells, (4) dendritic mononuclear cells within the follicular epithelium, which although devoid of Birbeck granules, exhibited similar reactivity with anti-HLA antibody. These findings suggest that HLA antigens are present on the membranes of Langerhans cells, but are not demonstrable on melanocytes in normal human skin.

Narcolepsy has long been known to have a hereditary familial basis. All of 37 patients with narcolepsy expressed the major histocompatibility complex antigen HLA DR2 compared with 21.5% of 200 normal controls. This finding confirms the genetic basis for the disease, and furthermore links it with the short arm of chromosome 6. If the sleep disturbance in narcolepsy is due to a gene-determined defect in a neurotransmitter or receptor factor, the responsible agent may be DR2 itself or an enzyme determinant linked to DR2. This is the strongest HLA-disease association so far discovered.

HLA-A, B, and C antigens were determined in 52 patients with idiopathic Parkinson's disease and HLA-D antigens in 29 patients. In comparison with a representative sample of the Finnish general population, no significant deviations in HLA types of patients with Parkinson's disease were found. The patients with a slowly progressing disease had Cw3 antigen more often than the patients with a rapid progression.

HLA-A, B, C typing were performed in 72 caucasians with rheumatoid arthritis. HLA-DR typing were accomplished in 40 patients among these 72 subjects. DR4 was clearly increased with a frequency of 55 p. 100 versus 18 p. 100 in controls. We did not find an association between DR4 and the presence of rheumatoid factor. Clinical and biological signs are similar in rheumatoid arthritis with and without DR4. Two other HLA antigens, B40 and Cw3, were increased and their frequency was twice as high in patients as compared with controls. A synthesis of six studies published in the world confirms the elevation of B40 in this disease and later on suggests the elevation of Cw3 which is often linked with B40. The association of rheumatoid arthritis with B40 and Cw3 can be explained by a linkage disequilibrium between DR4 and B40 on the one hand, between DR4 and Cw3 on the other hand.

An association between HLA-DR7 and the steroid sensitive idiopathic nephrotic syndrome in the children has already been reported. Immunogenetic data in the less frequent steroid resistant form of this disease have never been published. In this study, we analyse HLA-A, B and DR typing in 99 cases of nephrotic children divided in 72 with the steroid sensitive (SS) form and 27 with the steroid resistant (SR) syndrome, in comparison with those of 207 healthy controls; Bf allotypes were determined in 53 of the patients. The results show the increased frequency of DR7 in the SS syndrome (75% vs 30%, RR = 6.9, pc less than 10(-6), while the SR one is more associated to DR3 (52% vs 27%, RR = 3, p less than 0.004). In the SS patients, atopy is associated to DR7 (p less than 0.001), which is not the case in the SR group. Furthermore, a high relative risk is associated to the phenotype DR3/DR7 (30% vs 4%; RR = 9.3; pc less than 0.0004), for the SR disease; besides, this phenotype is associated to an early onset of the disease and to lesions of focal sclerosis. Thus a heterozygous effect in the SR form of idiopathic nephrotic syndrome of children has been demonstrated; the steroid sensitive and the steroid resistant forms of the disease seem to have different immunogenetic components.

An up-dated survey of the information pertaining to the role of genetic factors in susceptibility to multiple myeloma is attempted. Our own results include the HLA-A, B, and C types in 68 patients, the G1m and Km allotypes in 86 patients, and the frequencies of ABO blood groups in 126 patients with multiple myeloma. The allotype G1m(x) was significantly (p less than 0.05) more frequent in the patient group. Since the results in the literature on a possible HLA association have been inconsistent, all relevant available data were combined for an assessment of 379 patients versus 5041 controls. In this comparatively large patient group, the previously reported increase of HLA-4c (HLA-B5 + B18 + Bw35) complex could be confirmed and identified as a weak (RR = 1.7) but significant (p less than 0.05) association of susceptibility to multiple myeloma with HLA-B5. Evaluation of G1m allotypes in the combined sample of 258 patients and 4550 controls and Km in 179 and 2457, respectively yielded no significant differences.

The association of human and bovine beta 2-microglobulins with detergent solubilized HLA-A,B antigens was analyzed by a direct binding assay using radiolabeled beta 2-microglobulin and an immunoadsorbent containing a monoclonal antibody to the HLA-A,B heavy chains. Binding of beta 2-microglobulin to HLA-A,B heavy chains could be saturated with respect to the amount of membrane glucoprotein in the system and reached steady state after 6 h at 37 degrees C. Inhibition of [125I]beta 2-microglobulin binding to HLA-A,B heavy chains by beta 2-microglobulin purified from human urine or bovine colostrum resulted in identical inhibition curves and apparent dissociation constants of 1 X 10(-8) M. This evidence suggests that beta 2-microglobulins from different species have similar binding sites for HLA-A,B heavy chains.

Seventy-seven chronic alcoholics with liver disease were studied to evaluate the HLA antigen association. There were no significant differences of HLA antigen phenotype frequencies (PF) between the patients and controls regarding A and C loci, (62 healthy Japanese). Prevalences of HLA-B40 complex (B40 . 48 . 13) and DRW9 tended to increase among chronic alcoholics. When chronic alcoholics were divided according to whether they had liver cirrhosis or not, the cirrhosis group (42 cases) revealed a significantly higher frequency of HLA-DRW9 (chi 2 = 10.88, p less than 0.001, corrected p less than 0.05, relative risk (R.R.) = 4.17) as compared to controls. There was also a tendency of B40 complex to increase in frequency (chi 2 = 5.51, p less than 0.05, R.R. = 2.65) in the cirrhosis group. Haplotype frequency and linkage disequilibrium parameters of HLA-B40 . 48-DRW9 were significantly higher than those of controls. Moreover, the increased frequency of DRW9 in the cirrhosis group was similar to that in autoimmune disease like ulcerative colitis or SLE. These data suggest that HLA-DRW9 and/or HLA-B40-DRW9 might be closely associated with susceptibility to developing alcoholic cirrhosis and that autoimmune mechanisms might be involved partly in its etiology.

261 multiple sclerosis (MS) patients were HLA-A and -B typed and 94 were HLA-D typed. The results were compared to those of controls typed for HLA-A; HLA-B (356) and HLA-D (113). We confirm and extend earlier findings (Oger et al. 1980b) that some phenotypes could modulate the expression of the MS susceptibility gene linked to B7-DR2: DR3 was found together with DR2 in 12/94 MS and only 3/113 controls and could be marker for an "augmentor" gene. In contrast, B35 and DR1 as well as B12 and DR7 could be markers of protector genes. We compared typing results of patients subgrouped on clinical features. 61 patients with progressive evolution showed increased A1, A1-B8, B8-DR3 and A1-B8-DR3 when compared to 200 patients with remitting evolution. When compared to controls both groups showed increased B7 but only the remitting group showed increased DR2. 71 patients with "benign MS" showed increased B7-DR2 and A3-B7-DR2. 54 patients with "severe disease" showed increased DR3 and A1-B8-DR3 when compared to controls. Both groups showed increased B7 (49.2% and 44.4% versus 25.5% for controls). 120 patients treated greater than 5 years with azathioprine were divided into "no progression" and "progression" while treated. Both groups showed increased B7 when compared to controls. DR2 was increased only in the "no progression" group. B8-DR3 and A1-B8-DR3 were found increased in the "progression" group only. We conclude that two forms of MS exist with different HLA profiles.

Platelet transfusions from donors matched for cross-reactive antigens have been shown to be effective in providing hemostasis in alloimmunized thrombocytopenic patients. A significant number of these transfusions, however, fail to provide posttransfusion platelet recoveries. We investigated incompatibility in the Bw4/bw6 system as a possible explanation for these failures. The Bw4/Bw6 system is a biallelic antigen system closely associated with HLA-B. HLA-B locus antigens that are cross-reactive frequently differ in their Bw4/Bw6 specificity. Posttransfusion platelet recoveries from 21 alloimmunized thrombocytopenic patients homozygous for Bw4 or Bw6 and transfused with both Bw4/Bw6 compatible and incompatible platelets were analyzed. The mean 1-hr posttransfusion recovery was 84% following Bw4/Bw6-compatible platelets versus 52% with Bw4/Bw6-incompatible platelets (p less than 0.02). Twenty-four hours following transfusion, mean recoveries were 44% and 24%, respectively, (p less than 0.01). A subgroup of 8 patients (38%) was identified who had markedly lower responses following Bw4/Bw6-incompatible transfusions as compared to Bw4/Bw6-compatible transfusions (mean recoveries: 1 hr--compatible 100%, incompatible 27%, p less than 0.001; 24 hr--compatible 45%, incompatible 7%, p less than 0.01). These data suggest that the Bw4/Bw6 antigen system has clinical significance for some patients requiring platelet transfusion therapy and, when appropriate, should be considered in the selection of donors.

Refractoriness occurs in many patients receiving multiple platelet transfusions. We used a sensitive ELISA assay to assess the utility of crossmatching HLA-A,B matched single donor platelets in 51 consecutive, typical refractory patients. Of the 222 transfusions evaluated at 1 to 4 hours posttransfusion, only 17 of 54 (31%) with positive crossmatches had corrected platelet count increments of greater than or equal to 7,500/microL. In contrast, 95 of 168 (57%) of those with negative crossmatches had such increments (P less than .001). Regardless of the results of the crossmatch, HLA-A,B, and ABO matching had independent influences on transfusion outcome. The median corrected 1- to 4-hour increment for crossmatch negative transfusions was 13,300/microL for A/BU grade matches, 9,700 for BX, and 7,800 for C. Increments were 10,000/microL for ABO-identical transfusions and 5,900 for transfusions of platelets ABO incompatible with the recipient's plasma antibodies. When the donor platelets were ABO compatible, but the donor plasma contained ABO antibodies to the recipient's platelets, the increment was intermediate (8,200/microL). The most important factor in predicting platelet survival was the crossmatch, followed by HLA-A,B and ABO, each having independent predictive value. These data demonstrate that the predictive value of a negative crossmatch may be considerably less than that reported in previous studies with stable, less ill patients. In typical refractory patients, there appear to be mechanisms of platelet destruction that are related to HLA-A,B and ABO but are not detected with current crossmatch methods. We hypothesize that soluble plasma HLA-A,B and ABO antigens contribute to the destruction of donor and sometimes recipient platelets by an immune complex or other "innocent bystander" mechanism. With our crossmatching technique, HLA-A,B and ABO match grades remain relevant to platelet transfusion therapy in some refractory patients.

An immunoelectron microscopic technique was used to analyse the distribution in term human placentae at the ultrastructural level of three antigens recognized by recently developed monoclonal antibodies. Two of the antigens (recognized by NDOG-1 and NDOG-2) were present only on the outer villous membrane of the syncytiotrophoblast. The other (HLA-A, B, C) was absent from syncytiotrophoblast and present on some capillary endothelial cells and on Hofbauer cells in the villous stroma.

Recent evidence suggests that HLA-A,B antigens present on human platelets, are acquired from plasma. Using hypertonic acid chloroquine (200 mg/ml, pH 5.0, 1 hr, 4 degrees C), we demonstrate elution of most or all HLA-A2 and HLA-B7,40 immunoreactive material from platelets. Corresponding antigens on human lymphocytes were not affected by this treatment. These findings are consistent with the hypothesis that HLA-A,B antigens are adsorbed onto platelet surfaces.

Six cases of immature teratoma of the ovary were karyotyped and analyzed for chromosomal heteromorphisms, enzyme polymorphisms, and HLA specificities to determine their mechanism of origin. Three cases were chromosomally abnormal, with karyotypes of 48,XX, +14, +21; 47,XX, +20; and 47,XXX, respectively. The tumors with 48,XX, +14, +21 and 47,XX, +20 karyotypes were heterozygous for chromosomal heteromorphisms which were identical to those of their host and therefore originated from a premeiotic cell or failure of meiosis I. Both had a poor prognosis. The 47,XXX tumor and the three cases with normal karyotypes were homozygous for chromosome heteromorphisms and either homozygous or heterozygous for enzyme and HLA markers and therefore originated from a failure of meiosis II or duplication of a mature haploid ovum. All four had an uneventful postoperative course. These observations show that immature teratomas are like cystic teratomas in having at least three separate mechanisms of origin. However, they are unlike cystic teratomas in having a high proportion with chromosome abnormalities and a high rate of malignant transformation.

A solid-phase radioimmunoanalysis of plasma membrane molecules solubilized in the presence of detergent was developed. From a crude cell lysate, membrane molecules were specifically immobilized by solid-phase adsorbed monoclonal antibodies. Analysis of these molecules was easily performed with radiolabeled monoclonal antibodies of different specificities. This technique was used to analyze the HLA-DR and HLA-A,B,C molecules expressed by RAJI cells. It was possible (a) to determine which epitopes are expressed on the same molecules; (b) to define subsets of HLA molecules according to the epitopes which they express, and (c) to perform quantitative analysis of HLA molecules on a crude cell lysate.

Fifty-eight scalp biopsies were immunohistologically investigated with monoclonal antibodies against HLA-ABC, HLA-DR, and T6 antigens. The following 3 groups were compared: control biopsies obtained from healthy volunteers (n = 5) or patients with unrelated scalp diseases (n = 6); biopsies from untreated alopecia areata (AA), obtained either from untreated patients (n = 19) or from the untreated side in patients receiving unilateral treatment with the contact allergen diphencyprone (DCP) (n = 13); biopsies obtained from the treated side in patients receiving unilateral treatment with DCP (n = 13). While HLA-ABC antigens were strongly expressed by epidermal keratinocytes and the infundibular epithelium of hair follicles in all biopsies, these antigens were either not detectable or only faintly expressed on the subinfundibular epithelium and the hair matrix in the control series. By contrast, 30 out of 32 biopsies from untreated AA showed expression of HLA-ABC antigens on hair matrix epithelium, and the subinfundibular epithelium was HLA-ABC-positive in 15 out of 32 cases. In the biopsies from treated AA, HLA-ABC antigens were expressed on hair matrix epithelium in 9 out of 13 cases, and on the subinfundibular epithelium in 1 case. In the controls and untreated AA, HLA-DR expression was confined to dendritic cells in the epidermis and the follicular infundibulum. Its expression on hair matrix epithelium was found in 15 out of 32 biopsies from untreated AA and in 4 out of 13 biopsies from treated AA. In the control series, intrabulbar T6+ dendritic cells were either absent or present in low numbers. High numbers of intrabulbar T6+ cells were present in 7 out of 32 biopsies from untreated AA and in 0 out of 13 biopsies from treated AA. The data show that abnormal expression of class I major histocompatibility (MHC) antigens on hair matrix epithelium is a constant feature in AA, whereas class II MHC antigens are less frequently expressed. Topical immunotherapy with DCP, which induced expression of HLA-DR in epidermal keratinocytes in 6 out of 13 cases, reduced the abnormal expression of both HLA-ABC and -DR antigens in the epithelium of lower hair follicles in AA.

Two methods for the detection of murine monoclonal antibodies against determinants of the human major histocompatibility complex (MHC) were evaluated. These methods are based upon the function of Fc receptors; the erythrocyte antibody rosette inhibition test (EAI test) using B-lymphocytes and the immune phagocytosis inhibition test (IPI test) using monocytes. Compared to the EAI test the IPI test was technically easier and gave better discrimination between positive and negative results. The inhibition by antibodies of monomorphic class II MHC or polymorphic HLA-DR antigens was stronger in the IPI than in the EAI test. Antibodies against HLA-DQ and DP antigens evoked inhibition only using the EAI test. Using IgG derived from placenta in different dilutions the detection of its anti-HLA antibodies was more readily achieved in the IPI test than in the EAI test.

One hundred eighty-five consecutive corneal transplants were performed in recipients selected on the basis of the best available HLA-A,B and DR match. Endothelial rejection-free transplant survival in this group was compared to a retrospective historical control group of 199 consecutive transplants performed in recipients selected on the basis of age and longest wait criteria. The two groups were comparable with regards to primary diagnosis, preoperative corneal vascularization, donor and recipient age, and operative techniques. Thirty-eight transplants in the study group and 28 transplants in the control group were at high risk for endothelial transplant rejection. At 12 months, the estimated rejection-free survival (Kaplan-Meier method) of the high-risk study group transplants was 87% compared to 74% for the high-risk historical control group and transplants. This difference did not reach the significant level of 0.05 with the log-rank test. The 12-month estimated rejection-free survival of low-risk study group and historical control group transplants were similar. In the study group, the 12-month estimated rejection-free survival of well-matched transplants was 95% compared to 83% for poorly matched transplants (log rank, P less than 0.02). These findings suggest that a relationship exists between HLA-A,B and DR compatibility of donor and recipient and the corneal rejection-free transplant survival.

Twenty-one Caucasian couples with two or more idiopathic fetal losses and with either no live-born children or with only one live-born child were typed for HLA-A, B, and DR antigens, and mixed lymphocyte responses of the maternal lymphocytes to stimulation by paternal lymphocytes were studied. The mixed lymphocyte response results showed that women who experienced habitual fetal loss had normal immune responses, thereby lending less credence to the idea that a defective immunologic response is involved in problem pregnancies. The data were pooled and analyzed with those of similar reports, and there was a strong indication that aborting couples shared a greater portion of the chromosome that contains the major histocompatibility complex (MHC) than would be expected in random matings.

HLA-A and B phenotypes were determined in 38 patients with Cushing's syndrome (29 Cushing's diseases, 9 others etiologies) and compared with those of 591 normal subjects. No significant differences was found in the HLA antigens distribution in the two groups. However the series is too small to definitely support the hypothesis of a lack of correlation with HLA. Indeed, the increased prevalence of B8 antigen in Cushing's disease (28%) as compared to that in the control group (17%), although not statistically significant, emphasizes the need for further typing of HLA-DR, particularly RDw3 which is known to be linked to D8 through desequilibrium and associated with several autoimmune diseases.

The mechanism of action responsible for the beneficial effect of alpha-interferon (alpha-IFN) in patients with hairy cell leukemia (HCL) is still unknown. Direct antineoplastic and immunomodulating effects on both the host immune system and the hairy cells themselves have been implicated. To evaluate whether lymphokines have any regulatory effect on antigens of the major histocompatibility complex (MHC) on hairy cells and whether this corresponds to prognostic clinical parameters, we studied splenic hairy cells from ten previously untreated patients. The samples were incubated with recombinant human alpha-IFN, gamma-IFN (gamma-IFN), and interleukin-2 (IL-2). In an indirect staining procedure, cells were labeled with monoclonal antibodies (MoAb) to HLA ABC and HLA DR surface structures and subjected to cytofluorimetric analysis. Results concerning the expression of MHC class I and HLA DR antigens were mixed for incubation of hairy cells with gamma-IFN and IL-2, whereas alpha-IFN had a distinct effect on HLA DR antigen expression. alpha-IFN strongly enhanced the intensity of staining with HLA DR MoAb in six patients, and it increased the percentage of MoAb-positive cells in five of these samples. In contrast, the staining intensity in samples from four patients was reduced considerably on alpha-IFN treatment. In this group, two samples showed a sharp alpha-IFN-induced decrease in the number of HLA DR MoAb-positive cells from originally high values, and in one sample the very low percentage of positive cells was unaffected by alpha-IFN exposure. These two groups of patients whose hairy cells displayed contrasting HLA DR expression on incubation with alpha-IFN in vitro, were found to differ in their subsequent clinical course.

130 patients with severe aplastic anaemia, conditioned with high-dose cyclophosphamide, showed sustained engraftment of marrow from HLA-identical siblings. Most patients (55%) had no acute graft-versus-host disease (GVHD), 11% had transient grade I, and 34% had moderate to severe (grades II-IV) acute GVHD. The relation between the donors' (and the patients') HLA antigens and the incidence of grades I-IV acute GVHD was explored. There was no association with HLA-A antigens, but a significant correlation with HLA-B antigens. Patients with HLA-B18 had an estimated acute GVHD incidence nearly three times that of other patients, whereas the incidence in the presence of HLA-B8 or HLA-Bw35 was estimated to be about half that in the absence of these alleles.

Branhamella catarrhalis initiated DNA synthesis in human blood or spleen cells enriched for B lymphocytes but did not activate T-lymphocyte-enriched fractions. Monoclonal antibodies were used to determine which B-cell surface molecules were of importance for the activation signal. The addition of monoclonal antibodies reactive with IgD, HLA class I antigens, and B2-microglobulin to B lymphocyte cultures selectively inhibited the B-lymphocyte response to B. catarrhalis. Antibody binding to IgD and class I antigens did not inhibit B-cell proliferation following stimulation with anti-IgM beads, Staphylococcus aureus, or Epstein-Barr virus. This suggests that surface IgD is of major importance for B-lymphocyte stimulation by B. catarrhalis. Since B. catarrhalis binds HLA-ABC containing liposomes it is suggested that a similar binding of B. catarrhalis to HLA-ABC on the surface of B lymphocytes serves as an accessory factor that stabilizes the binding of B. catarrhalis to surface IgD. Activation of human B lymphocytes by B. catarrhalis resulted in changes of cell surface molecules that were quantitatively and qualitatively similar to those that resulted from the activation by S. aureus. Therefore although these two bacteria appear to activate B cells in a similar manner, they induce B-cell proliferation through interactions with different cell surface structures.

Fifty-five adult biopsy-proven patients with idiopathic membranous nephropathy were examined for HLA-A, B and DR antigens, and for the Bf allotypes. The phenotype frequencies of HLA-DR3 (52 vs. 23%) and HLA-B8 (46 vs. 24%) showed a significant increase in the IMN patient group compared to those of controls from the same region. The supraphenotype in which the combination of DR3-B8 alleles in Bf SS homozygotes occurred was significantly more common in the patient group than in the controls. A subset of six individuals carrying antigens DR3, B8, and common Bf*S alleles was identified, and the clinical course of those patients was found to be significantly worse compared to the rest of the patients. The present results do not support the existing suggestion that the clinical course of these diseases in Caucasians is determined by antigens B18 and the rare Bf allele (Bf*F1). It seems likely that IMN is not a single disease but a renal lesion that can result from several combinations of genetic predisposition and environmental stimuli.