Lack of association of the KIR and HLA class I ligands with ZIKV infection in south and southeast of Brazil

BACKGROUND Zika virus (ZIKV) is an emerging arbovirus associated with foetal malformations and neurological complications. The infection is usually associated with mild symptoms. The comparison between the allelic frequency of polymorphic genes in symptomatic infected individuals in the population can clarify the pathogenic mechanisms of ZIKV. During ZIKV infection, cytokines are produced and natural killer (NK) cells are recruited, whose activation depends on signaling pathways activated by specific receptors, such as killer cell immunoglobulin-like receptors (KIR). These molecules interact with human leukocyte antigen (HLA) class I ligands and are encoded by polymorphic genes. OBJECTIVES This study aimed to evaluate the frequency of allelic variants of the genes encoding the KIR receptors and their HLA class I ligands in 139 symptomatic ZIKV-patients and 170 controls negative for the virus, and to evaluate the role of these variants for ZIKV susceptibility. METHODS KIR and HLA class I genes were genotyped using the polymerase chain reaction-sequence specific oligonucleotide (PCR-SSO) technique. FINDINGS No significant differences in the frequency distribution of KIRs and KIR-HLA in patients compared to controls were observed. MAIN CONCLUSIONS KIR and its HLA ligands might play a minor role in ZIKV infection in the south and southeast Brazilian individuals.

The influence of HLA/HIV genetics on the occurrence of elite controllers and a need for therapeutics geotargeting view

The interaction of HIV-1, human leukocyte antigen (HLA), and elite controllers (EC) compose a still intricate triad. Elite controllers maintain a very low viral load and a normal CD4 count, even without antiretrovirals. There is a lot of diversity in HIV subtypes and HLA alleles. The most common subtype in each country varies depending on its localization and epidemiological history. As we know EC appears to maintain an effective CD8 response against HIV. In this phenomenon, some alleles of HLAs are associated with a slow progression of HIV infection, others with a rapid progression. This relationship also depends on the virus subtype. Epitopes of Gag protein-restricted by HLA-B*57 generated a considerable immune response in EC. However, some mutations allow HIV to escape the CD8 response, while others do not. HLA protective alleles, like HLA-B*27, HLA-B*57 and HLA-B*58:01, that are common in Caucasians infected with HIV-1 Clade B, do not show the same protection in sub-Saharan Africans infected by HIV-1 Clade C. Endogenous pathway of antigen processing and presentation is used to present intracellular synthesized cellular peptides as well as viral protein fragments via the MHC class I molecule to the cytotoxic T-lymphocytes (CTLs). Some epitopes are immunodominant, which means that they drive the immune reaction to some virus. Mutation on an anchor residue of epitope necessary for binding on MHC class I is used by HIV to escape the immune system. Mutations inside or flanking an epitope may lead to T cell lack of recognition and CTL escape. Studying how immunodominance at epitopes drives the EC in a geographically dependent way with genetics and immunological elements orchestrating it may help future research on vaccines or immunotherapy for HIV. 2021 Sociedade Brasileira de Infectologia. Published by Elsevier España, S.L.U. This is an open access article under the CC BY-NC-ND license

Antiepileptic drug-induced severe cutaneous adverse reactions and HLA alleles: A report of five cases with lymphocyte activation test

Antiepileptic drugs (AEDs) can induce severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. We performed HLA genotyping and lymphocyte activation tests (LATs) for five AED-induced SCAR patients (three males and two females; aged 40–66 years old). Three patients were treated with carbamazepine (CBZ) for pain control, one was treated with phenytoin (PHT) for seizure prevention, and one was treated with valproic acid (VPA) for seizure prevention. One patient was diagnosed with CBZ-induced DRESS syndrome and the remaining patients were diagnosed with SJS. All patients recovered from SCARs after stopping suspicious drugs and supportive care. LATs were conducted to confirm the culprit drug responsible for inducing SCARs; and LAT results were positive for the suspected culprit drugs, in all except in one case. HLA-A,

HLA-A*24:02/B*51:01 haplotype and lamotrigine-induced cutaneous adverse drug reactions in Koreans

Antiepileptic drugs (AEDs) have been known to induce cutaneous adverse drug reaction (cADR), ranging from a mild maculopapular eruption (MPE) to potentially life-threatening cADRs such as Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Despite studies examining mechanisms associated with human leukocyte antigen (HLA), the association between lamotrigine (LTG)-induced cADR and HLA alleles still has room to investigate. We investigated HLA-A,-B, and -C alleles in LTG-induced cADR. The medical records of four patients with LTG-induced cADR were retrospectively reviewed. All patients were treated with LTG for epilepsy. All recovered from cADR after stopping LTG treatment and receiving intensive care. HLA-A, -B, and -C genotyping was performed in all four patients using a PCR-sequence-based typing (SBT) method. Two patients had SJS, and the other two had MPE due to LTG. The range of latency to cADR after the initial LTG dose was 19–42 days. Two patients experienced cross-reactivity with other aromatic or new AEDs. Expression of the HLA-A*24:02/B*51:01 haplotype was detected in three (75%) patients with LTG-induced cADR. The other patient carried homozygous HLA-B*58:01 alleles. The results suggest that Korean individuals with the HLA-A*24:02/B*51:01 haplotype may be susceptible to LTG-induced cADR. Further investigations are necessary to confirm these findings.

Relationship between survivin/HLA classI molecules expression and survival of patients withc lear cell er nal cell carcinoma / 中华泌尿外科杂志

Objective To investigate the expression of survivin/Human leukocyte antigen class I ( HLA-Ⅰ) proteins and its physiological significance in clear cell renal cell carcinoma ( CCRCC ) . Methods Immunohistochemistry was used to analyze survivin/HLA-Ⅰ protein expression in 90 cases of CCRCC and 10 normal tissues to study relationships with clinical symptoms and disease prognosis . Resutl s The level of survivin protein expression was found to be significantly higher in CCRCC tissues 82.2%( 74/90) than in normal tissues( 0/10).However, the relative amount of HLA-Ⅰprotein in colorectal cancer tis-sue was also found to be significantly lower 67.8%(61/90) than in normal tissues 90%(9/10).Survivin expression was associated with tumor grade , stage,and lymph node metastasis ( P=0.000, P=0.016, and P=0.001, respectively ) .Conversely , lost HLA-Ⅰexpression did not have any associations with clinicopath-ological data (P>0.05).Survivin negative patients (25.0%, 4/16) had a higher tumor-free survival rate than patients (52.7%, 39/74)with survivin expression (P=0.037).Patients (27.6%, 8/29) with normal HLA-Ⅰlevels had a higher tumor-free survival rate than those ( 60.7%, 37/61) with reduced HLA-Ⅰlev-els (P=0.020).The univariate and multivariate analyses indicated that expression of survivin and HLA indi -vidually and in combination were independent predictors for CCRCC patient survival . Conclusions Over-expression of survivin but reduced HLA-Ⅰ expression is associated with CCRCC development and progres-sion.

Clinical Significance of Antibodies Against Platelet HLA Class I in Children with Idiopathic Thrombocytopenic Purpura / 대한수혈학회지

BACKGROUND: A previous history of transfusion has been known to be associated with production of anti-HLA class I antibodies. However, platelet glycoproteins are the main target of idiopathic thrombocytopenic purpura (ITP). The mechanism of antibody production is known to differ significantly between glycoproteins and anti-HLA class I. The aim of this study was to evaluate the clinical significance of anti-HLA class I antibodies in childhood ITP. METHODS: Enrollment for the normal control group targeted 48 people who visited Gyeongsang National University Hospital from 1990 to 2010, and 48 young children with ITP. Anti-glycoproteins and anti-HLA class I antibodies were tested using the Modified Antigen Capture Enzyme-linked immunosorbent assay (MACE) kit. RESULTS: The positive rate of anti-HLA antibodies was significantly different [36/39 (92.3%) vs 29/46 (63%)] [ITP group vs normal control group] (P=0.002). The mean positive S/C ratio of anti-HLA antibodies was also significantly different (3.55 vs 1.51) [ITP group vs normal control group] (P=0.0000). The positive rate of anti-HLA did not differ significantly between the transfused group and the non-transfused group [12/12 (100%) vs 24/27 (88%)] [transfused ITP vs non-transfused ITP]. The mean positive S/C ratio of anti-HLA antibodies did not differ significantly between the transfused ITP group and the non-transfused ITP group (4.30 vs 3.25) [transfused ITP vs non-transfused ITP]. Consecutive testing showed that positive rate and positive S/C ratio of anti-HLA antibodies did not change significantly between sampling times in both groups [transfused ITP vs non-transfused ITP] (P=1.00 and P=0.15). CONCLUSION: Anti-HLA class I antibodies may be involved in childhood ITP. Transfusion did not affect the course of childhood ITP.

Class-I human leukocyte alleles in leprosy patients from Southern Brazil / Alelos leucocitários humanos em pacientes com hanseníase do sul do Brasil

INTRODUCTION: The present study was designed to investigate a possible role of HLA (histocompatibility leucocyte antigen) class-I alleles (HLA-A, -B, and -C) in leprosy patients from Southern Brazil. METHODS: Two hundred and twenty-five patients with leprosy and 450 individuals for the control group were involved in this research. HLA genotyping was performed through PCR-SSO protocols (One Lambda, USA); the frequency of these alleles was calculated in each group by direct counting, and the frequencies were then compared. RESULTS: There was an association between HLA-A*11 (6.9 percent vs 4.1 percent, p=0.0345, OR=1.72, 95 percent CI=1.05-2.81), HLA-B*38 (2.7 percent vs. 1.1 percent, p=0.0402, OR=2.44, 95 percent CI=1.05-5.69), HLA-C*12 (9.4 percent vs. 5.4 percent, p=0.01, OR=1.82, 95 percent CI=1.17-2.82), and HLA-C*16 (3.1 percent vs. 6.5 percent, p=0.0124, OR=0.47, 95 percent CI=0.26-0.85) and leprosy per se. In addition, HLA-B*35, HLA-C*04, and HLA-C*07 frequencies were different between lepromatous (LL) and tuberculoid (TT) patients. However, after adjusting for the number of alleles compared, Pc values became nonsignificant. CONCLUSIONS: Although our results do not support the previous findings that HLA class-I alleles play a role in leprosy pathogenesis, we suggest new studies because of the importance of the association between the HLA and KIR in the innate immune response to leprosy.

INTRODUÇÃO: O presente estudo foi desenhado para investigar um possível papel para os alelos HLA (histocompatibility leucocyte antigen) de classe I (HLA-A, -B, and -C) em pacientes com hanseníase do sul do Brasil. MÉTODOS: Duzentos e vinte e cinco pacientes com hanseníase e 450 indivíduos para o grupo-controle foram envolvidos nesse estudo. O genótipo HLA foi determinado por protocolos PCR-SSO (One Lambda, USA) e, a frequência desses alelos foi calculada em cada grupo por contagem direta e, após, comparadas. RESULTADOS: Houve associação entre HLA-A*11 (6,9 por cento vs 4,1 por cento; p = 0,0345; OR = 1,72; CI = 1,05 - 2,81), HLA-B*38 (2,7 por cento vs 1,1; p = 0,0402; OR = 2,44; CI 95 por cento = 1,05-5,69), HLA-C*12 (9,4 por cento vs 5,4 por cento; p = 0,01; OR = 1,82; CI 95 por cento = 1,17-2,82) e HLA-C*16 (3,1 vs 6,5 por cento; p = 0,0124; OR = 0,47; CI 95 por cento = 0,26-0,85) e hanseníase per se. Além disso, as frequências de HLA-B*35, HLA-C*04 e HLA-C*07 foram diferentes entre os pacientes com as formas lepromatosa (LL) e tuberculoide (TT). Contudo, após o ajuste para o número de alelos comparados, os valores de p se tornaram não significativos. CONCLUSÕES: Embora nossos resultados não sustentem as conclusões anteriores de que os alelos HLA de classe I desempenham um papel na associação com a patogênese da hanseníase, sugerimos novos estudos devido à importância da associação entre HLA e KIR na resposta imune inata à hanseníase.

Alterations of HLA class I and II antigen expression in preinvasive, invasive and metastatic cervical cancers

HLA expression is altered in a large variety of human cancers. We performed immunohistochemical staining on tissues from normal, preinvasive, invasive and metastatic cervical cancer tissues using anti-HLA class I or class II antibody. In tissues from normal squamous epithelium, carcinoma in situ (CIS) and microinvasive carcinoma (MIC), the expressions of HLA-B, C heavy chains and class II heavy chain were significantly decreased as disease progressed. When the expression patterns were compared between primary and metastatic squamous cell carcinoma (SCC) lesions, statistically significant down-regulation of HLA class I and class II antigen in metastatic lesions was observed. The rates of HLA-B, C heavy chains and class II heavy chain expressions were all significantly down-regulated compared to the down-regulation rate of class I beta2-microglobulin (beta2m) in invasive squamous lesions, and the expressions of class II heavy chain in metastatic lesions was decreased further than that in primary lesions. Unlike SCC, the degree of HLA class I and class II loss was not evident as disease progressed in early stage of adenocarcinoma. In invasive adenocarcinoma lesions, only the expression of HLA-B, C heavy chains was decreased and no differences were seen in HLA-B, C heavy chain expression patterns between primary and metastatic lesions. These results suggest that alterations of HLA class I and II expressions seem to occur at a particular step in cervical cancer development and depend on tissue types: when the tumor becomes invasive and starts to metastasize.

Alterations of HLA Class I and II Antigen Expressions in Borderline, Invasive and Metastatic Ovarian Cancers / 대한암학회지

PURPOSE: The relationship between altered HLA expressions and ovarian carcinogenesis is not fully elucidated. MATERIALS AND METHODS: Histological evaluation comprised 20 serous adenocarcinoma, 5 borderline serous malignancy, 10 mucinous adenocarcinoma, 15 borderline mucinous malignancy. We used monoclonal antibodys to HLA class I beta2-microglobulin, class I B/C and class II heavy chain. RESULTS: There was no statistical difference in HLA expressions between borderline serous malignancy and normal ovarian tissue. In serous adenocarcinoma, beta2-microglobulin, B/C and class II heavy chain expressions were down-regulated. In metastatic cancer, B/C and class II ex pressions were also down-regulated. But the HLA expression of tumor or normal stromal tissue in primary tumor, were not down-regulated compared with the tissues in metastasis. In borderline mucinous malignancy, class II expressions were down-regulated. In mucinous adenocarcinoma, beta2-microglobulin, B/C and class II expressions were down-regulated. In metastatic ovarian cancer, B/C and class II expressions were down-regulated. But, in borderline malignancy, the result failed to reach statistical significance except class II of borderline mucinous malignancy. CONCLUSION: Loss of HLA class I and II molecules in invasive ovarian cancers raises the possibility that this could be a mechanism for tumor cells to have invasiveness.

Alterations of HLA Class I and II Antigen Expressions in Preinvasive, Invasive and Metastatic Cervical Cancers / 대한암학회지

PURPOSE: The relationship between altered HLA expressions and cervical carcinogenesis is not fully elucidated. MATERIALS AND METHODS: The histological evaluation comprised of 21 microinvasive squamous cell carcinoma (SCC), 26 invasive SCC, 3 microinvasive adenocarcinoma and 9 invasive adeno carcinoma of cervix. We used monoclonal antibodys (mAbs) to HLA class I beta2-microglobulin (L368), HLA class I B/C heavy chains (HC-10) and HLA class II heavy chain (LG II-612.14). RESULTS: In tissues from microinvasive SCC, the expressions of B/C heavy chains and class II heavy chain were significantly decreased. The expressions of beta2-microglobulin, B/C chains, and class II heavy chain in SCC were all significantly decreased. Especially, in the metastatic tissue from the same patient, the expressions of beta2-microglobulin and B/C chains showed to be somewhat decreased compared to those in primary tumor tissues, and the expression of class II heavy chain was decreased further than that in primary lesion. In primary invasive adenocarcinoma, the expression of B/C chains was significantly decreased. CONCLUSION: These results suggest that alterations of HLA class I and II expressions seem to occur at a particular step in tumor development and depend on tissue types: when the tumor becomes invasive and starts to metastasize.

HLA Class I Typing for Umbilical Cord Blood / 대한임상병리학회지

BACKGROUND: Accurate HLA typing is important for umbilical cord blood (UCB) transplantation as well as bone marrow transplantation. However, HLA class I typing by standard microcytotoxicity method has been often unsatisfactory for UCB samples. This study was conducted to investigate the characteristics of cytotoxic reaction in HLA class I microlymphocytotoxicity testing for UCB. METHODS: We compared the strength index (SI) and the frequencies of HLA antigens with weak reaction between 87 UCB and 103 adult peripheral blood samples by analysis of reaction score in microlymphocytotoxicity typing using Terasaki Oriental HLA-ABC (72) Well Tray (One Lambda, USA). RESULTS: The mean SI of UCB samples in HLA class I typing was significantly lower than that of adult blood (78.5% vs. 96.8%). The SI of 100% among UCB and adult blood samples were 24.1% and 71.8%, respectively. Among HLA-A, B, C antigens, those showing significantly high frequencies of weak reaction in UCB were HLA-A31, B48, B51, B59, B61, Cw3 and Cw7. Cytotoxic reactions of Bw4 and Bw6 in UCB were significantly weaker than those in adult blood. CONCLUSIONS: The strategy of using a supplementary DNA typing method in selected cases with doubtful or unreliable results in serological typing would be effective for an accurate HLA class I typing of UCB samples.

A Study on the Procurement of HLA Class I Typing Trays Using Gushed Out Blood During Placental Delivery / 대한수혈학회지

BACKGROUND: Microlymphocytotoxicity test is most widely used for HLA Class I typing but almost all laboratories depend on imported HLA Class I typing trays. Matching criteria for the selection of HLA-matched platelets to treat platelet refractoriness is not as strict as for bone marrow transplantation. Therefore, with the acquisition of various antisera against high frequency HLA antigens, self-made HLA typing trays can be used for HLA typing of HLA-matched platelet donors. METHODS: 140 samples obtained during placental delivery were tested for the presence of HLA antibodies against a well-characterized panel of 90 cells. Specificity of HLA antisera were determined by evaluating the correlation coefficient r of the 2x2 table, kappa2 test. Antisera strength was evaluated by the strength index. RESULTS: HLA antibodies were detected in 25 samples by primary screening and 23 samples also showed a positive reaction in secondary screening (16%). Among 23 samples, 11 antisera were of reagent grade quality and 7 were monospecific antisera. DISCUSSION: Imported HLA typing trays can be replaced by harvesting HLA antisera against HLA antigens which are relatively common in Koreans through continuous HLA antibody screening using gushed out blood during placental delivery.

A Study the Procurement of HLA Class I Typing Trays Using Gushed Out Blood During Placental Delivery

BACKGROUND: Microlymphocytotoxicity test is most widely used for HLA Class l typing but almost all laboratories depend on imported HLA Class 1 typing trays. Matching criteria for the selection of HLA- matched platelets to treat platelet refractoriness is not as strict as for bone marrow transplantation. Therefore, with the acquisition of various antisera against high frequency HLA antigens, self-made HLA typing trays can be used for HLA typing of HLA-matched platelet donors. METHODS: 140 samples obtained during placental delivery were tested for the presence of HLA antibodies against a well-characterized panel of 90 cells. Specificity of HLA antisera were determined by evaluating the correlation coefficient r of the 2 x 2 table, x2 test. Antisera strength was evaluated by the strength index. RESULTS: HLA antibodies were detected in 25 samples by primary screening and 23 samples also showed a positive reaction in secondary screening(16%). Among 23 samples, 1 1 antisera were of reagent grade quality and 7 were monospecific antisera. DISCUSSION: Imported HLA typing trays can be replaced by harvesting HLA antisera against HLA antigens which are relatively common in Koreans through continuous HLA antibody screening using gushed out blood during placental delivery. (Korean J Blood Transfusion 10(1): 53-60, 1999)

Surface Markers Expression in Pre-and Post-CD80(B7-l) Gene Transfected Human Tumor Cell Lines / 中国肿瘤生物治疗杂志

A crucial role in eliciting anti-tumor immunity of costimulatory molecule CD80(B7-1) has been demonstrated by animal experimental studies.In this paper, CD80 expression in human tumor cell lines and EBV-transformed B cell was detected using RT-PCR and FACS methods. The results showed that CD80 expression of Raji and EBV-transformed B cell was positive but that of 3AO,MCF-7,MDA-453,MKN-45, Hela was negative. We have constructed retroviral vector CD80-pLN,transfected package cell PA317, screened high titer rctrovirus supernatant then infected human tumor cell lines and gained CD80 positive tumor cell clones. With pre-and post-CD80-transfected human breast carcinoma cell line MDA-453,the upregulated expression of ICAM-I, HLA class I molecule was observed, but the expression of HLA class II molecule wasn't changed.

Nuclear protein binding patterns in the 5'-upstream regulatory elements of HLA class I genes

The expression of MHC class I genes has been thought to be regulated by two major cis-acting regulatory elements. The first region, enhancer A (Enh A) spanning from positions -210 to -165 contains perfect palindrome (PP), TGGGGATTCCCCA. The PP is well-conserved both in mouse and human MHC class I genes, even though the PP is disrupted by 2 bp substitutions (TGAGGATTCTCCA) in HLA-C genes. Three proteins binding to the Enh A of HLA-A and -B locus genes, but very weakly or nearly not to the Enh A of HLA-C locus gene have been identified. To determine functional importance of the PP for binding of trans-acting protein, mutant DNA probes were made by site-directed in vitro mutagenesis and then electrophoretic mobility shift assay was performed. HLA-A mutant DNA probe, in which the PP is disrupted, shows the same nuclear protein binding pattern as that of the HLA-C gene, and HLA-C mutant DNA probe, in which the PP is introduced, shows the same nuclear protein binding pattern as that of the wild type HLA-A gene. These data suggest that the perfect palindrome and its cognate DNA binding nuclear protein play an important role in the HLA class I gene regulation, and thus the lower expression of HLA-C antigen may be ascribed to no or very weak factor binding to the nonpalindromic sequences of HLA-C upstream DNA.

Distribution of HLA class I alleles and haplotypes in Korean

The antigen (phenotype), gene (allele) and haplotype frequencies of HLA class I were analysed in 4,622 Koreans. With allele frequencies of over 0.05, the most frequent HLA-A,-B and -C antigens were A2, A24, A33, A11, A26, A31; B62, B51, B44, B54, B61, B35, B58, B60; Cw3, Cw1, Cw4, Cw7. Of these A2, A24, Cw1 and Cw3 were present in very high frequencies, respectively (0.3211, 0.2200, 0.2204, and 0.3737). The most common haplotypes with frequencies larger than 0.02 were A2-Blank, A33-B44, A33-B58, A11-B62, A24-B51, A24-B54, A2-B27, B54-Cw1, B58-Cw3, B51-Blank, B61-Cw3, B62-Cw4, B35-Cw3, B44-Blank, B60-Cw3, B27-Cw1, A2-Cw3, A2-Cw1, A24-Cw1, A33-Cw3, A26-Cw3, and A11-Cw4. A significant negative linkage disequilibrium was found for the haplotypes of A2-B7, A2-B44, A2-B58, A24-B13, A24-B27, A33-B54 and A33-B62, of which frequencies were larger than 0.003. The B-C and A-C haplotypes which showed the significant negative linkage disequilibrium were B44-Cw1, B51-Cw1, B44-Cw3,B62-Blank, A2-Cw4, A2-Blank, A11-Cw3, A11-Blank and A33-Cw1 and had frequencies higher than 0.01. The findings presented here could be used per se to estimate the populational relationships or as the control data for HLA-disease investigation. Furthermore they could provide the scope for the definition of new antigens.