The importance of class I and class II HLA in cadaveric renal transplantation

The importance of avoiding mismatches (MM) at Class I and Class II HLA antigens in cyclosporine-treated renal allograft patients is controversial. In order to assess the role of HLA, 200 consecutive cadaveric renal allografts over a 4-year period were analysed. All patients received cyclosporine/predinisone immunosuppression and 75% were induced with ALG. Minimum follow-up period was one year. HLA A, B, DR, DQ, and DRw52/53 typing were available on 77-100% of allografts. A beneficial effect was noted at the HLA A locus. One-year survival was 87.2% in the 0 and 1 HLA A MM group combined vs 73.8% in the 2 HLA A MM group (p less than 0.05). The mean creatinine level at one year was also lower in the 0 plus 1 MM vs 2 MM group: 152.8 mumol/L vs 184.8 mumol/L, respectively (p less than 0.05). Significantly fewer rejection episodes occurred in the 0 and 1 HLA DQ MM group combined vs the 2 MM group. Steroid-resistant rejection episodes (SRRE) were not associated with the number of HLA MM. Patients who had an SRRE had significantly higher mean current and historical peak panel reactive antibodies (PRA) than patients who did not have SRRE. These results indicate that avoiding mismatches at the HLA A locus may improve renal allograft survival, and matching at HLA DQ may predispose patients to a more quiescent post-transplant course. The degree of preoperative sensitization may be an important etiologic factor in SRRE.     

HLA class II antibodies in transfusion-related acute lung injury

BACKGROUND: Transfusion-related acute lung injury (TRALI) is a serious, sometimes fatal, complication of transfusion. Granulocyte and HLA class I antibodies present in blood donors have been associated with TRALI. HLA class II antibodies have recently been described in a few cases of TRALI. STUDY DESIGN AND METHODS: Donors involved in TRALI reactions reported to a blood center over an 18-month period were tested for HLA class I and II antibodies as well as granulocyte antibodies, if HLA antibodies were not identified. RESULTS: HLA class II antibodies were identified, in at least one donor, in 7 (64%) of 11 cases of TRALI. HLA class I antibodies were identified in combination with HLA class II antibodies in 5 of these 7 cases. HLA class I antibodies were exclusively identified in 2 cases. Granulocyte antibodies were identified in 1 case, and no antibodies were identified in another. CONCLUSION: In addition to HLA class I antibodies, HLA class II antibodies are associated with TRALI. Testing of donors for HLA class II antibodies as well as HLA class I and granulocyte antibodies is recommended as part of the investigation of suspected cases of TRALI.     

Cytotoxic T cell recognition of an endogenous class I HLA peptide presented by a class II HLA molecule

Human leukocytes were stimulated in vitro with peptides corresponding in sequence to the highly variable helix of the alpha 1 domain of various HLA-B and -C molecules. A CD4+ CD8- cytotoxic T cell line, CTL-AV, that is specific for the HLA-B7 peptide presented by HLA-DR11.1 was obtained. The HLA-DR11.2 molecule, which only differs at three residues from HLA-DR11.1, did not present the HLA-B7 peptide to CTL-AV. Peptides from the alpha 1 domain helix of other HLA-A and HLA-B molecules, but not HLA-C molecules, competed with the HLA-B7 peptide for binding to HLA-DR11.1. A cell line (WT50) that coexpresses HLA-B7 and HLA-DR11.1 was killed by CTL-AV in the absence of any added HLA-B7 peptide. The processing and presentation of HLA-B7 in these cells appears to be through the endogenous, and not the exogenous, pathway of antigen presentation. Thus, Brefeldin A inhibits presentation and chloroquine does not. Furthermore, introduction of purified HLA-B7 molecules into HLA-DR11.1+, HLA-B7- cells by cytoplasmic loading via osmotic lysis of pinosomes, but not by simple incubation, rendered them susceptible to CTL-AV killing. These results provide an example of class II major histocompatibility complex (MHC) presentation of a constitutively synthesized self protein that uses the endogenous pathway of antigen presentation. They also emphasize the capacity for presentation of MHC peptides by MHC molecules.     

Association of I and II class HLA antigens with Cushing's syndrome]

Incidence of class I and II HLA antigens was studied in 69 patients suffering from Icenko--Cushing syndrome. Positive association was reported for antigens DRw53, DQw3, DR4, DR5, negative for antigen DR2. Antigen combinations DR5, DR7 and DR4, DR5 proved more prevalent. The risk to develop the disease rose 2-3-fold in case of HLA-DR5 phenotype occurrence with antigen DR4 or DR7. Association with DRw53 and DQw3 antigens showing wide specificity seemed most significant.     

中国北方汉族人HLA-Ⅰ、Ⅱ类基因与HBV水平感染及预后相关性研究

目的探讨人类白细胞抗原Ⅰ、Ⅱ类基因与乙型肝炎病毒(HBV)感染及其预后的相关性。方法采用PCR-SSP方法分别对102名慢性持续性HBV感染者(实验1组)、76名急性HBV感染者(实验2组)及1383名中华骨髓库山东分库无血缘关系自愿骨髓捐献者(对照组)作HLA-Ⅰ、Ⅱ类基因分型检测,将结果作统计学处理。结果HLA-DR9、DR12在实验组(实验1组+2组)中的分布频率较对照组明显增高(P<0.01);HLA-DR8在实验1组的分布频率明显高于实验2组(P<0.01);HLA-DR13,DR15在实验1组中的频率明显低于实验2组(P<0.01,P<0.05)。结论HLA-DR9可能有助于HBV对宿主的感染;HLA-DR8,DR12可能有助于HBV对宿主的持续感染,对HBV感染的慢性化有促进作用;HLA-DR13,DR15可能有助于宿主对HBV的清除,对HBV感染的慢性化有抑制作用。     

Subsets of childhood acute lymphoblastic leukaemia in Croatia

As a contribution to epidemiological studies on distribution of acute lymphoblastic leukaemia (ALL) subsets in different countries, we investigated blast cell immunophenotype in 54 children with ALL from the western part of Yugoslavia. The subtype incidences were: common, 75.9%; null, 7.4%; T, 11.1%; B, 1.9%; and unclassifiable, 3.7%. This resembles the ALL pattern registered in developed countries. Hence, differences in socioeconomic status between our population and developed European countries do not result in an appreciably altered incidence of childhood leukaemia subtypes.     

HLA class II Ab in TRALI donors

FcγRIIIb 'null' individuals do not express the HNA-1a, -1b & -1c alloantigens and the reported incidence of this condition in the Caucasian population is between 1 in 1000 and 2000. The majority of FcγRIIIb 'null' individuals have been identified following the investigation of neonatal alloimmune neutropenia due to maternally transferred anti-FcγRIIIb antibodies.
This report describes a healthy, male blood donor who was screened for the presence of granulocyte-specific antibodies as part of a foetal concentration donor accreditation programme. The donor's serum was found to contain anti-HNA-1a IgM (and weak IgG) antibodies using an immunofluorescence test. Anti-lymphocyte antibodies were not detected. Further investigation was undertaken to determine whether the antibodies were alloimmune or autoimmune in origin. Granulocyte membrane bound IgG and IgM was within the normal range and the granulocytes were unreactive both with monoclonal FcRIIIb and HNA-1a antibodies in immunofluorescence tests. HNA-1a and HNA-1b PCR products could not be amplified from the donor's genomic DNA using an SSP technique. It was concluded that the donor was FcγRIIIb 'null'. The donor denied any history of blood transfusion or surgical procedures; nor was there any evidence of such procedures in early life. This suggests either that HNA-1a antibodies may, in some circumstances, be 'naturally occurring' or that the antibodies detected may be part of an autoimmune response to 'HNA-1a like' structures on other tissues. This is the first time that anti-HNA-1a antibodies have been reported in an FcγRIIIb 'null' individual.
There was no history of transfusion reactions associated with the use of the donor's blood products. However, the donor was withdrawn from the donor panel because HNA-1a IgM antibodies have been implicated in Transfusion Related Acute Lung Injury.     

Quantification of soluble serum HLA class I antigens in healthy volunteers and AIDS patients

A solid-phase enzyme immunoassay (ELISA) has been used to quantify human soluble Class I histocompatibility antigens in serum samples from voluntary blood donors and AIDS patients. Statistical analysis of the results showed significantly raised levels (p less than 0.01) of free HLA Class I in sera from AIDS patients (2.95 +/- 1.80 micrograms/ml) when compared with the blood donors (1.06 +/- 0.6 micrograms/ml). The assay is specific, reproducible and easy to perform. Potential uses of this determination are discussed.     

Autoreactive T cell clones specific for class I and class II HLA antigens isolated from a human chimera

T cell clones of donor origin that specifically react with recipient cells were obtained from a SCID patient successfully reconstituted by allogeneic fetal liver and thymus transplantation performed 10 yr ago. The majority of these clones displayed both cytotoxic and proliferative responses towards PBL and an EBV-transformed B cell line derived from the patient. In addition, these T cell clones had proliferative and cytotoxic responses towards the parental PBL, EBV cell lines, and PHA blasts. Blocking studies with anti-class I and anti-class II HLA mAbs indicated that the activity of the CD4+ T cell clones was specifically directed against class II HLA antigens of the recipient. On the other hand, the cytotoxic and proliferative responses of the CD8+ T cell clones were specific for class I HLA antigens which are ubiquitously expressed on the recipient cells. Thus, the establishment of transplantation tolerance observed in this stable human chimera is not due to the elimination of host-reactive T cells from the repertoire and suggests the presence of a peripheral autoregulatory suppressor mechanism.     

Clinical and immunological aspects of HLA class I deficiency

Human leukocyte antigen (HLA) class I deficiency is a rare disease with remarkable clinical and biological heterogeneity. The spectrum of possible manifestations extends from the complete absence of symptoms to life-threatening disease conditions. It is usually diagnosed when HLA class I serological typing is unsuccessful; flow cytometric studies then reveal a severe reduction in the cell surface expression of HLA class I molecules (90-99% reduction compared to normal cells). In most cases to date, this low expression is due to a homozygous inactivating mutation in one of the two subunits of the transporter associated with antigen processing (TAP), critically involved in the peptide loading of HLA class I molecules. Although asymptomatic cases have been described, TAP deficiencies are usually characterized by chronic bacterial infections of the upper and lower airways, evolving to bronchiectasis, and in half of the cases, also skin ulcers with features of a chronic granulomatous inflammation. Despite the defect in HLA class-I-mediated presentation of viral antigens to cytotoxic T cells, the patients do not suffer from severe viral infections, presumably because of other efficient antiviral defence mechanisms such as antibodies, non-HLA-class-I-restricted cytotoxic effector cells and CD8+ T-cell responses to TAP-independent antigens. Treatment is at present exclusively symptomatic, and should particularly focus on the prevention of bronchiectasis, which requires early detection.     

High frequency of melanoma-associated antigen or HLA class I loss does not correlate with survival in primary melanoma

Melanoma-associated antigens are at the center of many immunotherapeutic trials in melanoma. Little is known about the impact of antigen expression on the natural course of disease. We stained 110 cases of primary melanoma with a median follow-up of 13 years (range 10-18 years) for melanoma-associated antigens gp100, MelanA/MART-1, MAGE-3, tyrosinase, and for HLA class I molecules. Of 91 cases evaluated, we found immunoreactivity for gp100, MelanA/MART-1, and tyrosinase in 88%, 80%, and 87% of primary tumors, respectively, for MAGE-3 in 37% and for HLA class I in 86% of primary tumors. Loss, that is, heterogeneous expression within primary tumors, was most pronounced for gp100 (73% of primary tumors) and least for MAGE-3 (27% of primary tumors). MelanA/MART-1 and tyrosinase expression loss was 58% and 59% of primary tumors, respectively. There was a high rate of expression loss for HLA class I (74%). Univariate and multivariate statistical analysis of expression in primary tumors and loss of melanoma antigens as well as HLA class I in individual primary tumors showed no significant correlation to overall survival. Loss of gp100 and loss of tyrosinase expression showed a negative survival trend over homogeneous expression of these antigens, although not reaching statistical significance (P = 0.08 and P = 0.09, respectively). We conclude that loss of melanoma antigen expression as well as HLA class I expression is a frequent observation in primary melanoma. However, no statistically significant correlation between loss of these antigens in individual primary tumors and negative impact on overall survival was found in our cohort.     

Gorilla class I major histocompatibility complex alleles: comparison to human and chimpanzee class I.

14 gorilla class I major histocompatibility complex (MHC) alleles have been isolated, sequenced, and compared to their counterparts in humans and chimpanzees. Gorilla homologues of HLA-A, -B, and -C were readily identified, and four Gogo-A, four Gogo-B, and five Gogo-C alleles were defined. In addition, an unusual Gogo class I gene with features in common with HLA-A and its related pseudogene, HLA-H, is described. None of the gorilla alleles is identical or even closely related to known class I alleles and each encodes a unique antigen recognition site. However, the majority of polymorphic substitutions and sequence motifs of gorilla class I alleles are shared with the human or chimpanzee systems. In particular, elements shared with HLA-A2 and HLA-B27 are found in Gogo-A and -B alleles. Diversity at the Gogo-B locus is less than at the Gogo-A locus, a trend the opposite of that seen for HLA-A and -B. The Gogo-C locus also appears to have limited polymorphism compared to Gogo-A. Two basic Gogo-C motifs were found and they segregate with distinctive sets of HLA-C alleles. HLA-A allels are divided into five families derived from two ancient lineages. All chimpanzee A alleles derived from one of these lineages and all gorilla alleles derive from the other. Unlike chimpanzee Patr-A alleles, the Gogo-A alleles do not clearly partition with one of the HLA-A families but have similarities with two. Overall, gorilla class I diversity appears from this sampling to show more distinctions from class I HLA than found for chimpanzee class I.     

HLA class II antibodies in transfusion-related acute lung injury (TRALI). A case report.

TRALI, a serious complication of blood transfusion, is underdiagnosed. Anti-granulocyte and anti-HLA class I molecules in donors or recipients and very recently, lipids in stored blood as well as anti-HLA class II have been associated with the syndrome. We present a TRALI case which occurred in a 56 year old woman after plasma transfusion. HLA class II antibodies were identified in the donor and were correlated with the recipients' HLA antigens. The presence of HLA class II antibodies without anti-HLA class I has been reported in very few cases and may facilitate the understanding of the pathogenesis of the syndrome.     

Murine cytotoxic T lymphocyte recognition of individual influenza virus proteins. High frequency of nonresponder MHC class I alleles

We determined the MHC restriction of CTL responses to five individual influenza virus proteins. Four viral proteins failed to be recognized in conjunction with three of the five class I alleles of the H-2k and H-2d haplotypes, while the fifth was recognized only in conjunction with a single allele. This indicates that there is a significant chance that a given class I allele will be associated with low responsiveness or nonresponsiveness for a given foreign protein. This explains, at least in part, why MHC-linked nonresponsiveness is frequently detected in polyclonal antiviral CTL responses. Most importantly, these findings support the idea that responsiveness to foreign antigens is a critical factor in maintaining the high degree of MHC class I polymorphism in outbred populations.