Although there is increasing evidence that virus-specific cytotoxic-T-lymphocyte (CTL) responses play an important role in the control of human immunodeficiency virus (HIV) replication in vivo, only scarce CTL data are available for the ethnic populations currently most affected by the epidemic. In this study, we examined the CD8؉ -T-cell responses in African-American, Caucasian, Hispanic, and Caribbean populations in which clade B virus dominates and analyzed the potential factors influencing immune recognition. Total HIV-specific CD8؉ -T-cell responses were determined by enzyme-linked immunospot assays in 150 HIV-infected individuals by using a clade B consensus sequence peptide set spanning all HIV proteins. A total of 88% of the 410 tested peptides were recognized, and Nef-and Gag-specific responses dominated the total response for each ethnicity in terms of both breadth and magnitude. Three dominantly targeted regions within these proteins that were recognized by >90% of individuals in each ethnicity were identified. Overall, the total breadth and magnitude of CD8؉ -T-cell responses correlated with individuals' CD4 counts but not with viral loads. The frequency of recognition for each peptide was highly correlated with the relative conservation of the peptide sequence, the presence of predicted immunoproteasomal cleavage sites within the C-terminal half of the peptide, and a reduced frequency of amino acids that impair binding of optimal epitopes to the restricting class I molecules. The present study thus identifies factors that contribute to the immunogenicity of these highly targeted and relatively conserved sequences in HIV that may represent promising vaccine candidates for ethnically heterogeneous populations.
Many autoimmune diseases are associated with HLA alleles, and such a relationship also has been reported for aplastic anemia (AA). AA and paroxysmal nocturnal hemoglobinuria (PNH) are related clinically, and glycophosphoinositol (GPI)-anchored protein (AP)-deficient cells can be found in many patients with AA. The hypothesis was considered that expansion of a PNH clone may be a marker of immune-mediated disease and its association with HLA alleles was examined. The study involved patients with a primary diagnosis of AA, patients with myelodysplastic syndrome (MDS), and patients with primary PNH. Tests of proportions were used to compare allelic frequencies. For patients with a PNH clone (defined by the presence of GPI-APdeficient granulocytes), regardless of clinical manifestations, there was a higher than normal incidence of HLA-DR2 (58% versus 28%; z ؍ 4.05). The increased presence of HLA-DR2 was found in all frankly hemolytic PNH and in PNH associated with bone marrow failure (AA/PNH and MDS/PNH). HLA-DR2 was more frequent in AA/PNH (56%) than in AA without a PNH clone (37%; z ؍ 3.36). Analysis of a second cohort of patients with bone marrow failure treated with immunosuppression showed that HLA-DR2 was associated with a hematologic response (50% of responders versus 34% of nonresponders; z ؍ 2.69). IntroductionIdiopathic aplastic anemia (AA) shows striking similarities to diseases of other organ systems with classically established autoimmune pathophysiology: AA frequently affects younger individuals, there is laboratory evidence for immune activation and destruction of the target organ by autoreactive T cells, 1 and patients often respond to immunosuppressive therapies. 2 Many autoimmune diseases have clear associations with particular HLA alleles: ankylosing spondylitis with HLA-B27 is the classical example, but similar relationships have been found in psoriasis (HLA-B13, HLA-B17-Cw6), rheumatoid arthritis (HLA-DR1 and HLA-DR4), juvenile diabetes mellitus (HLA-B8, HLA-B15, and HLA-B54), and multiple sclerosis (HLA-B7 and HLA-DR2). In hematology, agranulocytosis secondary to clozapine (HLA-B38, HLA-DR4, and DQw3) or methimazole (HLA-DR8) and mixed cryoglobulinemia in hepatitis C virus-infected patients (HLA-B8 and HLA-DR3) exemplify links between immunogenetics and pathophysiology. [3][4][5][6] Fundamentally, the presence of particular HLA alleles likely allows for preferential presentation of particular peptides, perhaps derived from autoantigens, to specific T cells, driving the autoimmune process.In AA, HLA associations have also been examined. [7][8][9][10][11][12][13][14][15][16][17][18][19] An increased frequency of HLA-DR2 has been reported in some but not all studies. [9][10][11][12][13]16 An association with class I alleles (especially HLA-A2) has been inconsistently identified. 7,10,[13][14][15] The presence of HLA-DR15 (split of DR2) was associated with good response to cyclosporine therapy, suggesting that this allele may be a specific predisposing factor for the development of immune-med...
The extent and importance of autoimmune mechanisms in myelodysplastic syndrome (MDS) and the role of immunosuppression in the treatment of this disease are not well defined. We report overrepresentation of HLA-DR2 and its serologic split HLA-DR15 in both MDS and aplastic anemia (AA). Four clinically and ethnically defined patient groups were analyzed. The HLA-DR15 antigen frequencies among North American white MDS patients (n = 72) and AA patients (n = 59), who received immunosuppressive treatment at the National Institutes of Health (NIH), were 36% and 42%, respectively. These antigen frequencies were significantly higher than that of the control population of 240 North American white NIH blood donors typed for HLA antigens by the same molecular technique (HLA-DR15, 21.3%,P = .01 for MDS, P < .001 for AA). Among North American white patients reported in the International Bone Marrow Transplant Registry (IBMTR), 30% of 341 MDS patients and 33% of 364 AA patients were positive for HLA-DR2. These antigen frequencies were higher than those reported for the general North American white population (HLA-DR2, 25.3%, P = .089 for MDS,P = .01 for AA). The DR15 and DR2 frequencies were significantly increased in MDS refractory anemia (RA) (P = .036 and P = .01, respectively) but not MDS refractory anemia with excess blasts. In the NIH MDS patients, HLA-DR15 was significantly associated with a clinically relevant response to antithymocyte globulin (ATG) or cyclosporine immunosuppression (multivariate analysis, P = .008). In MDS with RA, DR15 may be useful as a guide to pathophysiology, prognosis, and treatment.
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