Genetic Influence on Treatment Response in Psoriasis: New Insights into Personalized Medicine.

Psoriasis is a chronic inflammatory disease with an established genetic background. The HLA-Cw*06 allele and different polymorphisms in genes involved in inflammatory responses and keratinocyte proliferation have been associated with the development of the disease. Despite the effectiveness and safety of psoriasis treatment, a significant percentage of patients still do not achieve adequate disease control. Pharmacogenetic and pharmacogenomic studies on how genetic variations affect drug efficacy and toxicity could provide important clues in this respect. This comprehensive review assessed the available evidence for the role that those different genetic variations may play in the response to psoriasis treatment. One hundred fourteen articles were included in this qualitative synthesis. VDR gene polymorphisms may influence the response to topical vitamin D analogs and phototherapy. Variations affecting the ABC transporter seem to play a role in methotrexate and cyclosporine outcomes. Several single-nucleotide polymorphisms affecting different genes are involved with anti-TNF-α response modulation (TNF-α, TNFRSF1A, TNFRSF1B, TNFAIP3, FCGR2A, FCGR3A, IL-17F, IL-17R, and IL-23R, among others) with conflicting results. HLA-Cw*06 has been the most extensively studied allele, although it has only been robustly related to the response to ustekinumab. However, further research is needed to firmly establish the usefulness of these genetic biomarkers in clinical practice.

Impact of Functional Polymorphisms on Drug Survival of Biological Therapies in Patients with Moderate-to-Severe Psoriasis.

Biological therapies (BTs) indicated for psoriasis are highly effective; however, not all patients obtain good results, and loss of effectiveness is the main reason for switching. Genetic factors may be involved. The objective of this study was to evaluate the influence of single-nucleotide polymorphisms (SNPs) on the drug survival of tumor necrosis factor inhibitors (anti-TNF) medications and ustekinumab (UTK) in patients diagnosed with moderate-to-severe psoriasis. We conducted an ambispective observational cohort study that included 379 lines of treatment with anti-TNF (n = 247) and UTK (132) in 206 white patients from southern Spain and Italy. The genotyping of the 29 functional SNPs was carried out using real-time polymerase chain reaction (PCR) with TaqMan probes. Drug survival was evaluated with Cox regression and Kaplan-Meier curves. The multivariate analysis showed that the HLA-C rs12191877-T (hazard ratio [HR] = 0.560; 95% CI = 0.40-0.78; p = 0.0006) and TNF-1031 (rs1799964-C) (HR = 0.707; 95% CI = 0.50-0.99; p = 0.048) polymorphisms are associated with anti-TNF drug survival, while TLR5 rs5744174-G (HR = 0.589; 95% CI = 0.37-0.92; p = 0.02), CD84 rs6427528-GG (HR = 0.557; 95% CI = 0.35-0.88; p = 0.013) and PDE3A rs11045392-T together with SLCO1C1 rs3794271-T (HR = 0.508; 95% CI = 0.32-0.79; p = 0.002) are related to UTK survival. The limitations are the sample size and the clustering of anti-TNF drugs; we used a homogeneous cohort of patients from 2 hospitals only. In conclusion, SNPs in the HLA-C, TNF, TLR5, CD84, PDE3A, and SLCO1C1 genes may be useful as biomarkers of drug survival of BTs indicated for psoriasis, making it possible to implement personalized medicine that will reduce financial healthcare costs, facilitate medical decision-making and improve patient quality of life. However, further pharmacogenetic studies need to be conducted to confirm these associations.

HLA-Cw6 allele and biologic therapy are protective factors against liver fibrosis in psoriatic arthritis patients.

OBJECTIVES: To evaluate the association between liver fibrosis and the HLACw6 allele in psoriatic arthritis (PsA) patients. METHODS: A retrospective longitudinal study involving PsA patients with determination of the HLA-Cw6 allele was performed. Liver fibrosis was estimated by using the FIB-4 (fibrosis-4) score. A multivariate logistic model was undertaken to assess the odds ratio (OR), with its 95% confidence interval, of liver fibrosis after adjustment for potential confounding factors. RESULTS: A total of 209 PsA patients were included: 25.3% HLA-Cw6 were positive, 59.8% were receiving biological disease-modifying anti-rheumatic drugs (bDMARDs), 29.6% had arterial hypertension (AHT), 24% dyslipidaemia, and 4.2% acute myocardial infarction (AMI). The HLA-Cw6 allele was more frequent in PsA patients with normal FIB-4 values (p=0.024), as opposed to AHT (p=0.002), AMI (p=0.023) and dyslipidaemia (p=0.030), which were found more frequently in subjects with altered FIB-4 values. The presence HLA-Cw6 and the use of bDMARDs were confirmed as protective factors against liver fibrosis (OR 0.210, 0.062-0.707, p=0.012 and OR 0.397, 0.166-0.949, p=0.038, respectively). Conversely, AHT emerged as a risk factor (OR 2.973, 1.125-7.858, p=0.028). CONCLUSIONS: In PsA, the HLA-Cw6 allele and bDMARDs behave as protective factors for liver fibrosis, while AHT is an independent risk factor.

Associations between HLA-Cw1 and Systemic Treatment Response of Asian Psoriasis Patients.

INTRODUCTION: Psoriasis is a chronic inflammatory disease with a strong genetic background, particularly the human leukocyte antigen (HLA). HLA-Cw6 has been shown to be the major disease susceptibility locus and affects the phenotypes and treatment response in psoriasis; however, the prevalence of HLA-Cw6 is far lower than HLA-Cw1 in some Asian countries. OBJECTIVES: The aim of this study was to determine whether HLA-Cw1 predisposes psoriasis patients to different treatment responses of biologics and other systemic therapy. METHODS: This retrospective case-control study included 126 patients with moderate to severe plaque-type psoriasis who had been genotyped and treated in a special psoriasis clinic. HLA-Cw1-positive and -negative patients were compared. RESULTS: Our results showed that HLA-Cw1-negative patients were significantly more likely to respond (achieve Psoriasis Area and Severity Index [PASI] 75 after a 12- to 16-week treatment course) to biologics (including etanercept, adalimumab, ustekinumab, secukinumab, ixekizumab, and guselkumab; odds ratio [OR] 1.99, 95% confidence interval [CI] 1.17-3.44, p = 0.0122) and especially to ustekinumab (OR 3.27, 95% CI 1.03-11.30; p = 0.0496). An HLA-Cw1 allele dose effect was also found. The results remained after multivariate logistic regression analysis. HLA-Cw1-negative patients also showed significantly greater improvement of PASI in ustekinumab and biologics (p = 0.0044 and p = 0.0064, respectively), with other biologics showing non-significant trends. HLA-Cw1 status did not affect the treatment responses of non-biologic systemic treatment, including phototherapy. CONCLUSION: There is an association between HLA-Cw1 and treatment response to biologics, but not to non-biologics, in our Asian population of patients with moderate to severe psoriasis; however, the exact mechanism and role of HLA-Cw1 remain to be investigated.

KIR2DS1-HLA-C status as a predictive marker for benefit from rituximab: a post-hoc analysis of the RICOVER-60 and CLL8 trials.

BACKGROUND: The addition of rituximab to chemotherapy has substantially improved outcomes for patients with B-cell malignancies. The mechanisms of action of rituximab include activation of natural killer cells. Killer-cell immunoglobulin-like receptors (KIRs) mediate natural killer cell function through interaction with HLA. We evaluated the clinical impact of KIR-HLA genotypes on rituximab-containing therapy. METHODS: For this post-hoc analysis, we used data from the RICOVER-60 trial (NCT00052936) as the discovery cohort and the CLL8 trial (NCT00281918) as the validation cohort. RICOVER-60 included patients aged 61-80 years with aggressive B-cell lymphoma treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) with or without rituximab. CLL8 included patients aged 30-81 years with chronic lymphocytic leukaemia treated with chemotherapy (fludarabine and cyclophosphamide; FC) with or without rituximab. We evaluated the KIR and HLA-C status of 519 patients with available blood samples in the RICOVER-60 trial and the KIR2DS1 and HLA-C status of 549 patients with available blood samples in the CLL8 trial, and evaluated their associations with event-free survival (RICOVER-60), progression-free survival, and overall survival (RICOVER-60 and CLL8). FINDINGS: In the RICOVER-60 trial, 201 (39%) patients were positive for KIR2DS1, 79 (15%) were homozygous for HLA-C2, and 36 (7%) were positive for KIR2DS1 and homozygous for HLA-C2. In the CLL8 trial, 206 (38%) patients were positive for KIR2DS1, 75 (14%) were homozygous for HLA-C2, and 26 (5%) were positive for KIR2DS1 and homozygous for HLA-C2. In the RICOVER-60 trial, both KIR2DS1 and HLA-C status were identified as independent risk factors for survival. KIR2DS1 positivity, homozygosity for HLA-C2, and subsequent KIR2DS1-HLA-C status were associated with adverse clinical outcome in patients receiving rituximab-containing therapy (event-free survival for patients with KIR2DS1-HLA-C2/C2 vs all other patients, HR 2·6 [95% CI 1·4-4·7], p=0·0015; progression-free survival, 2·7 [1·5-5·1], p=0·0013; overall survival, 2·8 [1·5-5·4], p=0·0016) but not in patients receiving CHOP chemotherapy only (event-free survival, 0·9 [0·5-1·7], p=0·85; progression-free survival, 1·1 [0·6-2·0], p=0·81; overall survival, 1·2 [0·6-2·4], p=0·53). A significant interaction between KIR2DS1-HLA-C status and rituximab was observed (p=0·018 for event-free survival and p=0·034 for progression-free survival). In contrast to all other patients, those positive for KIR2DS1 and homozygous for HLA-C2 did not benefit from adding rituximab to CHOP chemotherapy (event-free survival, 1·9 [0·8-4·6], p=0·16; progression-free survival, 1·4 [0·6-3·4], p=0·48; overall survival, 1·6 [0·6-4·3], p=0·33). In the CLL8 trial, KIR2DS1-HLA-C status was confirmed as a predictive marker for benefit from rituximab therapy (p=0·024 for the interaction of KIR2DS1-HLA-C status and rituximab regarding progression-free survival). In contrast to all other patients, those positive for KIR2DS1 and homozygous for HLA-C2 did not benefit from adding rituximab to FC chemotherapy (progression-free survival, 2·1 [0·9-4·9], p=0·094; overall survival, 2·6 [0·5-12·7], p=0·21). INTERPRETATION: Assessment of KIR2DS1 and HLA-C genotype might identify patients who would not benefit from rituximab, thereby allowing alternative therapies to be given. Further validation of these findings in prospective clinical trials is needed. FUNDING: F Hoffman La Roche.

Soluble Human Leukocyte Antigen Molecules Detected in Orofacial Cleft Patients: A Case-Control Study

Abstract Objective: To compare soluble HLA-C and HLA-DR molecules present in the plasma of orofacial cleft and non-orofacial cleft populations. Material and Methods: Orofacial cleft patients were recruited using an accidental sampling approach (n=15). Peripheral blood was collected from the participants and processed for Enzyme Linked Immunosorbent Assay (ELISA) against HLA-C and HLA-DR with specific antibodies. The absorbance was calculated utilizing ELISA reader. Data were statistically analyzed using an independent t-test to compare the disease and control groups. Results: The levels of soluble HLA-C and HLA-DR were significantly higher in the diseased group compared to the control group (p<0.05). Conclusion: The role of HLA molecules in non-communicable disease and congenital anomalies, particularly orofacial cleft, remains speculative despite the positive results of this study and those of previous investigations. It suggests that the variables examined may affect specific pathways involved in the pathogenesis of orofacial cleft, and predispose the individuals concerned to the oral cleft.

HLA-C*12:02 is strongly associated with Xuesaitong-induced cutaneous adverse drug reactions.

Xuesaitong (XST) is mainly used to treat cardiovascular and cerebrovascular diseases, sometimes causing cutaneous adverse drug reactions (cADRs) with unknown mechanisms of pathogenicity or risk factors. We aimed to verify whether human leukocyte antigen (HLA) alleles are associated with XST-related cADRs in Han Chinese population. We carried out an association study including 12 subjects with XST-induced cADRs, 283 controls, and 28 XST-tolerant subjects. Five out of 12 patients with XST-induced cADRs carried HLA-C*12:02, and all of them received XST via intravenous drip. The carrier frequency of HLA-C*12:02 was significantly high compare to that of the control population (Pc = 4.4 × 10-4, odds ratio (OR) = 21.75, 95% CI = 5.78-81.88). Compared with that of the XST-tolerant group, the patients who received XST through intravenous drip presented a higher OR of cADRs (Pc = 0.011, OR = 27.00, 95% CI = 2.58-282.98). The results suggest that HLA-C*12:02 is a potentially predictive marker of XST-induced cADRs in Han Chinese, especially when XST is administered via intravenous drip.

HLA-C*06:02 genotype is a predictive biomarker of biologic treatment response in psoriasis.

BACKGROUND: Biologic therapies can be highly effective for the treatment of severe psoriasis, but response for individual patients can vary according to drug. Predictive biomarkers to guide treatment selection could improve patient outcomes and treatment cost-effectiveness. OBJECTIVE: We sought to test whether HLA-C*06:02, the primary genetic susceptibility allele for psoriasis, predisposes patients to respond differently to the 2 most commonly prescribed biologics for psoriasis: adalimumab (anti-TNF-α) and ustekinumab (anti-IL-12/23). METHODS: This study uses a national psoriasis registry that includes longitudinal treatment and response observations and detailed clinical data. HLA alleles were imputed from genome-wide genotype data for 1326 patients for whom 90% reduction in Psoriasis Area and Severity Index score (PASI90) response status was observed after 3, 6, or 12 months of treatment. We developed regression models of PASI90 response, examining the interaction between HLA-C*06:02 and drug type (adalimumab or ustekinumab) while accounting for potentially confounding clinical variables. RESULTS: HLA-C*06:02-negative patients were significantly more likely to respond to adalimumab than ustekinumab at all time points (most strongly at 6 months: odds ratio [OR], 2.95; P = 5.85 × 10-7), and the difference was greater in HLA-C*06:02-negative patients with psoriatic arthritis (OR, 5.98; P = 6.89 × 10-5). Biologic-naive patients who were HLA-C*06:02 positive and psoriatic arthritis negative demonstrated significantly poorer response to adalimumab at 12 months (OR, 0.31; P = 3.42 × 10-4). Results from HLA-wide analyses were consistent with HLA-C*06:02 itself being the primary effect allele. We found no evidence for genetic interaction between HLA-C*06:02 and ERAP1. CONCLUSION: This large observational study suggests that reference to HLA-C*06:02 status could offer substantial clinical benefit when selecting treatments for severe psoriasis.

Pharmacogenomics and the resulting impact on psoriasis therapies.

Psoriasis is a model disease for the development of pharmacogenomic markers of treatment response, with ready access to diseased tissue and objective validated outcome measures. With the application of state-of-the-art technologies and investment in careful experimental design, the goal of stratified medicine in psoriasis may be possible. Current pharmacogenomic studies in psoriasis show excellence in many areas, including the investigation of a broad range of psoriasis therapies. To facilitate the advent of stratified medicine in psoriasis, uniformity of study design is required, with high quality, consistent phenotyping strategies for participants; definitions of outcome; and the publication of reproducible methodologies.

Characterization of 236 novel alleles at the HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1 loci from China Marrow Donor Program.

Two hundred and thirty-six novel human leukocyte antigen (HLA) alleles are described from volunteer donors of the China Marrow Donor Program: 71 HLA-A alleles, 79 HLA-B alleles, 43 HLA-C, 16 HLA-DRB1 alleles, 26 HLA-DQB1 and 1 HLA-DPB1. Two hundred and thirteen (90.3%) of the 236 novel alleles are single nucleotide substitution variants when compared with their most homologous allele. Seventy-eight of these single nucleotide variants are silent substitutions. The remaining novel alleles differ from their most similar allele by two to four nucleotide substitutions. Some of the novel alleles encode amino acid changes at positions not previously reported to be polymorphic, such as codons 57, 62, 67, 41 and 52 in HLA-A alleles; codons 133, 156, 201 and 215 in HLA-B alleles; codons 74, 208 and 225 in HLA-C; codons 25, 32 and 72 in HLA-DRB1; codons 20, 39 and 77 in HLA-DQB1.

Soluble HLA-G and HLA-A,-B,-C serum levels in patients with allergic rhinitis.

BACKGROUND: Allergic rhinitis (AR) is characterized by Th2-polarized immune response. Soluble HLA (sHLA) molecules play an immunomodulatory activity. So far, however, no study investigated them in AR. OBJECTIVE: The aim of this study was to evaluate sHLA-G and sHLA-A,-B,-C serum levels in AR patients with pollen allergy and in a group of healthy controls. METHODS: Forty-nine AR patients were enrolled. A group of healthy nonallergic subjects was considered as control. sHLA-G and sHLA-A,-B,-C serum levels were determined by immunoenzymatic method. The study was conducted during the winter, such as outside the pollen season. RESULTS: Allergic patients had significantly higher levels of both sHLA-G (P < 0.0001) and sHLA-A,-B,-C (P = 0.011) molecules than normal controls. Moreover, there was a significant relationship between these two soluble molecules (r = 0.69) in allergic patients. CONCLUSION: The present study provides the first evidence that both sHLA-G and sHLA-A,-B,-C serum levels are significantly increased in AR patients with pollen allergy.

New insights and therapies for teenage psoriasis.

PURPOSE OF REVIEW: Psoriasis is an important disorder in the adolescent population and has a tremendous physical and psychological impact on patients. It is important to understand the genetics, various clinical presentations, comorbidities, and treatment options associated with psoriasis. RECENT FINDINGS: The human leukocyte antigen-C gene likely contains a susceptibility locus for psoriasis. Cytokines interleukin-12 and interleukin-23 have been implicated in the pathogenesis of psoriasis as well. Psoriasis is likely associated with an increased risk of myocardial infarction, metabolic syndrome, Crohn's disease, and depression; it is difficult to assess the implications in the adolescent population. SUMMARY: Psoriasis is not rare in the adolescent population. It is important for physicians to be aware of the different clinical presentations as well as the spectrum of treatment options that are available.

Relationship between soluble HLA-G and HLA-A,-B,-C serum levels, and interferon-gamma production after sublingual immunotherapy in patients with allergic rhinitis.

Allergic rhinitis (AR) is characterized by a T-helper (Th)-2 (Th2) polarized immune response. Soluble human leukocyte antigen (sHLA) molecules play an immunomodulatory role. Specific immunotherapy is the only causal treatment for AR and is able to shift the immune response to Th1 polarization. The aim of this study was to evaluate the relationship between sHLA-G and sHLA-A,-B,-C serum levels and interferon-gamma (IFN-gamma) production in AR patients with pollen allergy before and after a preseasonal course of sublingual immunotherapy (SLIT). A total of 40 AR patients with pollen allergy were enrolled and given a course of preseasonal SLIT for 3 months. Serum sHLA-G and sHLA-A,-B,-C levels were determined by enzyme-linked immunoabsorbent assay, and cell production of IFN-gamma was evaluated by enzyme-linked immunoabsorbent spot assay at baseline and 3 months after the end of the SLIT course. There was a significant relationship between sHLA-G serum level change and IFN-gamma increase as well as between sHLA-A,-B,-C level change and IFN-gamma increase after SLIT. The present study provides the first published evidence that the reduction of sHLA molecules serum levels and the increased IFN-gamma production after SLIT in AR patients with pollen allergy are significantly related phenomena.

Identification of HLA-CW3, GNAS and IMPA as cytotoxic T-lymphocyte (CTL) target antigens using an allogeneic mixed lymphocyte tumor cell culture (MLTC) system and subsequent cDNA library screening.

Allogeneic mixed lymphocyte tumor cell cultures (MLTCs) were established using lymphocytes from non-small-cell lung cancer (NSCLC) patient UKY-53 and HLA-A2+ NSCLC tumor cells (UKY-29). The tumor cells expressed the lymphocyte costimulatory molecule CD80 (UKY29.7). Cytolytic activity showed the cytotoxic T-lymphocytes (CTL) lysed UKY-29, but not K562 or Daudi. The CTL also lysed: HLA-A2+ and -A24+ tumor cell lines from a number of tumor histologies. The CTL also lysed Epstein Barr virus transformed (EBV) B-cells, UKY-29EBV, autologous to the stimulating cell line, UKY29TC. These data suggested the presence of both tumor-specific and allogeneic reactivities in the bulk CTL population. Subsequent cDNA cloning analysis and sequencing demonstrated that the bulk CTL population was recognizing: (i) allogeneic target HLA-CW3, and two minor histocompatibility antigens; (ii) guanine nucleotide-binding protein, G(S) (GNAS), and (iii) inositol myophosphatase (IMPA). All three antigens, we believe, were restricted by HLA-A2. Whereas the system described was initially intended to identify tumor-associated antigens recognized by CTL, the nature of the allogeneic system provides a unique opportunity for the identification of epitopes that confer both allo and minor antigen recognition.

Comprehensive screening for human immunodeficiency virus type 1 subtype-specific CD8 cytotoxic T lymphocytes and definition of degenerate epitopes restricted by HLA-A0207 and -C(W)0304 alleles.

For this report, the rapid identification and characterization of human immunodeficiency virus type 1 (HIV-1)-derived broadly cross-subtype-reactive CD8 cytotoxic T lymphocyte (CTL) epitopes were performed. Using a gamma interferon (IFN-gamma) Elispot assay-based approach and a panel of recombinant vaccinia viruses expressing gag, env, pol, and nef genes representing the seven most predominant subtypes and one circulating recombinant form of HIV-1, the subtype specificity and cross-subtype reactivity of a CD8 response were directly measured from circulating peripheral blood mononuclear cells (PBMC). Enhanced sensitivity of detection of CD8 responses from cryopreserved PBMC was achieved using autologous vaccinia virus-infected B-lymphoblastoid cell lines as supplemental antigen-presenting cells. Of eleven subjects studied, six exhibited broadly cross-subtype-reactive CD8-mediated IFN-gamma production (at least seven of eight subtypes recognized) to at least one major gene product from HIV-1. Screening of subjects showing broadly cross-subtype-specific responses in the vaccinia virus-based enzyme-linked immunospot (Elispot) assay using a panel of overlapping peptides resulted in the identification of cross-subtype responses down to the 20-mer peptide level in less than 3 days. Three subjects showed broad cross-subtype reactivity in both the IFN-gamma Elispot assay and the standard chromium release cytotoxicity assay. Fine mapping and HLA restriction analysis of the response from three subjects demonstrated that this technique can be used to define epitopes restricted by HLA-A, -B, and -C alleles. In addition, the ability of all three epitopes to be processed from multiple subtypes of their parent proteins and presented in the context of HLA class I molecules following de novo synthesis is shown. While all three minimal epitopes mapped here had previously been defined as HIV-1 epitopes, two are shown to have novel HLA restriction alleles and therefore exhibit degenerate HLA binding capacity. These findings provide biological validation of HLA supertypes in HIV-1 CTL recognition and support earlier studies of cross-subtype CTL responses during HIV-1 infection.

Efficient delivery of Antennapedia homeodomain fused to CTL epitope with liposomes into dendritic cells results in the activation of CD8+ T cells.

The in vivo induction of a CTL response using Antennapedia homeodomain (AntpHD) fused to a poorly immunogenic CTL epitope requires that the Ag is given in presence of SDS, an unacceptable adjuvant for human use. In the present report, we developed a hybrid CTL epitope delivery system consisting of AntpHD peptide vector formulated in liposomes as an alternative approach to bypass the need for SDS. It is proposed that liposomes will prevent degradation of the Ag in vivo and will deliver AntpHD recombinant peptide to the cytosol of APCs. We show in this work that dendritic cells incubated with AntpHD-fused peptide in liposomes can present MHC class I-restricted peptide and induce CTL response with a minimal amount of Ag. Intracellular processing studies have shown that encapsulated AntpHD recombinant peptide is endocytized before entering the cytosol, where it is processed by the proteasome complex. The processed liposomal peptides are then transported to the endoplasmic reticulum. The increase of the CTL response induced by AntpHD-fused peptide in liposomes correlates with this active transport to the class I-processing pathway. In vivo studies demonstrated that positively charged liposomes increase the immunogenicity of AntpHD-Cw3 when injected s.c. in mice in comparison to SDS. Moreover, addition of CpG oligodeoxynucleotide immunostimulatory sequences further increase the CD8+ T cell response. This strategy combining lipid-based carriers with AntpHD peptide to target poorly immunogenic Ags into the MHC class I processing pathway represents a novel approach for CTL vaccines that may have important applications for development of cancer vaccines.

HLA and HPA typing in idiopathic thrombocytopenic purpura patients treated with Kami-kihi-to.

We performed human leukocyte antigen (HLA) and human platelet antigen (HPA) in patients with Kami-kihi-to-responsive idiopathic thrombocytopenic purpura. The HLA-A2, A61 and Cw1 were significantly increased in responders compared with nonresponders, as were HLA DRB1 *0901, DRB1 *1502, and DPB1 *0501. In contrast, HLA DPB1 *0201 and DPB1 *0901 were significantly decreased in responders. The a/b genotype of HPA-2 and a/a genotype of HPA-3 were markedly increased in nonresponders, and anti-GPIb antibody was also increased. These results suggest that HLA, HPA, and anti-GP antibody studies may predict the response of idiopathic thrombocytopenic purpura to Kami-kihi-to.

A simian immunodeficiency virus envelope V3 cytotoxic T-lymphocyte epitope in rhesus monkeys and its restricting major histocompatibility complex class I molecule Mamu-A*02.

The use of the simian immunodeficiency virus (SIV) macaque model for assessing human immunodeficiency virus vaccine strategies will be facilitated by the characterization of predominant SIV cytotoxic T-lymphocyte (CTL) epitopes and their restricting major histocompatibility complex (MHC) class I molecules in macaque species. We now define a rhesus monkey SIVmac CTL epitope in the third hypervariable region of the envelope glycoprotein of the virus. This epitope, YNLTMKCR, contains the first two amino acids of a cysteine-cysteine loop which is the SIVmac analog of the human immunodeficiency virus type 1 V3 loop. We also employed one-dimensional isoelectric focusing to characterize the MHC class I molecule of the rhesus monkey that binds this SIVmac envelope peptide fragment. Cloning and sequencing the cDNA encoding this rhesus monkey MHC class I molecule demonstrates that it is a newly described HLA-A homolog, Mamu-A*02. This viral CTL epitope and its restricting MHC class I molecule will facilitate the use of the SIVmac rhesus monkey model for studies of envelope-based vaccine strategies and for exploring AIDS immunopathogenesis.

HLA-antigens in oral submucous fibrosis.

HLA-typing was carried out on 122 areca nut chewers who attended hospitals for complaints unrelated to the habit. The subjects were South Africans of Indian extraction. The study did not include haplotypes. Palpable fibrous bands in the mouth indicated oral submucous fibrosis. The subjects were divided into 4 groups based on specific oral symptoms and signs. Groups A and B were without fibrous bands. Group A (47 subjects) included those with one or no symptoms while group B (28 subjects) suffered from 2 to 7 oral symptoms. Group C (17 subjects) had oral symptoms and represented early or mild oral submucous fibrosis and exhibited at least one discrete palpable fibrous band. Group D (30 subjects) were classic oral submucous fibrosis cases with multiple bands. The high occurrence of oral submucous fibrosis in this study group (39%) is similar to the occurrence in comparable age groups reported earlier in South Africa and is conceivably due to the higher age range of the subjects and their relatively long exposure to the areca nut. We were unable to demonstrate a specific pattern of HLA-antigen frequencies in chewers with or without the disease. Furthermore, there were no differences between the study population and the controls. It is concluded that there is not necessarily a HLA-associated susceptibility in oral submucous fibrosis.