Increased frequency of HLA-DR2 in patients with paroxysmal nocturnal hemoglobinuria and the PNH/aplastic anemia syndrome

Abstract

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...

Prevalence and clinical association of clonal T-cell expansions in Myelodysplastic Syndrome

“…Variables previously linked to clinical response to immune suppression include bone marrow hypocellularity, presence of HLA-DR15 expression, younger age, lower platelet count, blast percentage and shorter duration of transfusion requirement, which are primarily features associated with favorable prognosis. 5,13,14,18,19,55,56 The presence of clonal T cells was not significantly associated with any of the clinical factors examined, although there was a slight positive trend with increasing IPSS risk category. Multivariable analyses were limited by small sample size, thus, our data do not preclude the possibility that multiple clinical factors combined may be more strongly associated with immunologic activation than any single factor.…”

“…[4][5][6][7][8][9][10][11][12] Univariant and multivariant statistical analyses have identified clinical and biological features associated with clinical response to immunosuppressive therapy, which served as the basis for the generation of response predictive models. [4][5][6][13][14][15][16][17][18] In these analyses, bone marrow hypocellularity, HLA-DR15 phenotype, younger age, lower platelet count and shorter duration of transfusion requirement were associated with response to immunosuppressive therapy. 5,14,19 Analogous to aplastic anemia, elimination of a hematopoietic suppressor T-cell population is hypothesized to underlie treatment response to immunosuppression in this subset of MDS patients.…”

Large granular lymphocyte (LGL)-like clonal expansions in paroxysmal nocturnal hemoglobinuria (PNH) patients

“…Clinical overlap with immunemediated aplastic anemia (AA) has suggested the hypothesis of an autoimmune pathophysiology of PNH. In support, association with particular HLA-antigens (HLA-DR1501) 5 and abnormalities of the immune system such as oligoclonality of the TCR repertoire have been described in PNH. 6,7 The TCR repertoire is physiologically extremely diverse, as a result of somatic V-(D)-J rearrangement and the contribution of nongermline N nucleotides; 8 dominance of a few TCRs over the heterogeneous repertoire is typical of oligoclonal T-cell immune response.…”

Roles of DRB1∗1501 and DRB1∗1502 in the pathogenesis of aplastic anemia

“…Several studies have revealed the frequency of HLA-DR15 to be significantly higher in patients with AA and MDS possessing PNH-type blood cells and in florid PNH than in normal controls [10,12], however, the relationship between DRB1 alleles corresponding to DR15 and increased PNH-type cells in AA has not yet been studied in detail. The close relationship between HLA-DR15 and the expansion of PNH clones suggests that the T-cell responses against certain antigen presented by HLA-DR15 or other HLA-class II alleles in linkage disequilibrium with DR15 in hematopoietic stem cells may cause bone marrow failure, thus allowing PNH-type stem cells to survive.…”