Risky business of inhibitors: HLA haplotypes, gene polymorphisms, and immune responses

Abstract

The development of neutralizing antibodies against factor VIII (FVIII inhibitors) and factor IX (FIX inhibitors) is the major complication in hemophilia care today. The antibodies neutralize the biological activity of FVIII and FIX and render replacement therapies ineffective. Antibodies are generated as a result of a cascade of tightly regulated interactions between different cells of the innate and the adaptive immune system located in distinct compartments. Any event that modulates the repertoire of specific B or T cells, the activation state of the innate and adaptive immune system, or the migration pattern of immune cells will therefore potentially influence the risk for patients to develop inhibitors. This chapter reviews our current understanding of different pathways of antibody development that result in different qualities of antibodies. Potential differences in differentiation pathways leading to high-affinity neutralizing or low-affinity non-neutralizing antibodies and the potential influence of gene polymorphisms such as HLA haplotype, FVIII haplotype, and polymorphisms of immunoregulatory genes are discussed. Learning Objectives• To understand that FVIII and FIX inhibitors are only the tip of the iceberg: antibodies are generated as a result of a cascade of tightly regulated interactions between different cells of the innate and the adaptive immune system located in distinct compartments • To understand that any event that affects the activation state of the innate or the adaptive immune system, the repertoire of specific B or T cells, or the migration pattern of immune cells potentially influences the risk for patients to develop FVIII or FIX inhibitors Neutralizing antibodies against FVIII and FIX are the major challenge in replacement therapies for patients with hemophiliaThe development of neutralizing antibodies against factor VIII (FVIII inhibitors) and factor IX (FIX inhibitors) is the major complication in hemophilia care today. The antibodies neutralize the biological activity of FVIII and FIX and render replacement therapies ineffective. FVIII inhibitors develop in ϳ20%-32% of patients with severe hemophilia A (plasma FVIII activities Ͻ1%) and in ϳ3%-13% of patients with moderate (plasma FVIII activity 1%-5%) and mild (plasma FVIII activity 5%-25%) hemophilia A. 1,2 Recently, Eckardt et al 3 reported that the risk for patients with mild and moderate hemophilia A to form inhibitors increases with an increasing number of days of exposure to FVIII products and might be higher than anticipated.Most FVIII inhibitors bind to functionally important domains of FVIII and prevent its interaction with other coagulation factors such as factors IIa, IXa, and X and VWF or with phospholipids. 4 Other FVIII inhibitors have catalytic activities and hydrolyze the protein. 4 FIX inhibitors are seen less frequently than FVIII inhibitors. Their overall incidence is 1%-3% for all patients with hemophilia B treated with FIX products and 9%-23% for patients with severe hemophilia B who express plasma FIX activit...

Comparative profiling of HLA-DR and HLA-DQ associated factor VIII peptides presented by monocyte-derived dendritic cells

“… 9 Several genetic and non-genetic risk factors have been associated with the incidence of inhibitor development. 10 – 17 Among them, the HLA haplotype of patients has been linked to the presence of FVIII inhibitors. 13 – 16 Located on the short arm of chromosome 6, the class II HLA gene complex contains three loci, DP, DQ and DR. Each of these loci encodes at least one alpha chain (DPA, DQA and DRA, respectively) and a variable number of beta chain polypeptides (DPB, DRB and DQB, respectively).…”

Predicting the Development of Anti-Drug Antibodies against Recombinant alpha-Galactosidase A in Male Patients with Classical Fabry Disease

“…To further optimize predictive accuracy in future models other variables could be included, that were not present in our current dataset. Studies in Pompe disease and hemophilia describe a potential influence of certain gene polymorphisms, such as the HLA haplotype [35][36][37]. In hemophilia, the presence of so-called danger signals before or during the first infusions (e.g., recent surgery, bleeds, vaccinations and active infections) were associated with an increased risk for iADA development [38].…”

Quantitative HLA‐class‐II/factor VIII (FVIII) peptidomic variation in dendritic cells correlates with the immunogenic potential of therapeutic FVIII proteins in hemophilia A

“…Under our Gate-Keeper hypothesis, a requirement for the-development-of-inhibitors in a PWHA is the ability of his HLAcII-molecules to tightly bind FVIII-derived-peptides generated by his: 1) DCs to present to naïve-FVIII-specific CD4-T-cells, which-via immune-synapse-formation with these APCs-receive critical signals to become T H -cells; and 2) FVIII-specific-B-cells to-present to the FVIII-specific-T H -cells, which-via immune-synapse-formation-provide the signals these B-cells need to become plasma-cells that secrete neutralizing-anti-FVIII-antibodies. For this reason, a straightforward candidate for genetic-association-analysis of inhibitor-pathogenesis (and arguably the earliest investigated candidate) has been the highly-polymorphic genes encoding HLAcII-molecules [9]. The haplotype DQB1*06:02/DRB1*15:01 was associated with inhibitors in three studies [7,9,10].…”

“…The etiology of inhibitors is complex as it involves the multifaceted-immune-system and the immunologically-relevant characteristics of different FVIIIs and treatment strategies [2]. Moreover, in addition to these environmental-variables, inhibitor-risk is influenced by genetic-variables [3] including the: highly-heterogeneous set of F8-mutations [4]; functionallydistinct single-nucleotide-variations (SNVs) in immune-response-genes [5]; and haplotypes of nonsynonymous (ns)-SNVs in genes that encode the (i) class-II-(cII)-human-leukocyte-antigen-(HLA)-system, i.e.-DPA1/DPB1,-DQA1/DQB1-&-DRA/DRB1/DRB3/DRB4/DRB5- [6][7][8][9],-and (ii) all or part of FVIII (i.e., F8,-F8 I22I -&-F8 B ) [10][11][12]. The immunogenicity risk of pdFVIIIs versus rFVIIIs has been studied/debated for years [13].…”