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Immunological Aspects of Inhibitor Development in Haemophilia
patients with mild/moderate haemophilia A, researchers found that
Table 1: Examples of Antibody Formation Against Commonly
mutations at residues Arg593, Arg2150, Arg2159 or Ala2201
Used Protein Therapeutics
eliminated FVIII epitopes and recognition by monoclonal antibodies.
23–26
Interestingly, there are reports of inhibitory antibodies in patients with
Recombinant Drug Proteins Disease/Treatment
Insulin Diabetes
mild haemophilia that recognise exogenous but not endogenous FVIII,
Human growth hormone Pituitary dwarfism
supposedly because of highly immunogenic mutations.
23,27
Human granulocyte-macrophage Patients with chemotherapy-resistant
colony-stimulating factor solid tumours
A patient with mild haemophilia carrying an Arg2150His substitution in Interferon alpha Chronic viral hepatitis
the C1 domain presented with a high-titre inhibitor towards allogeneic
Hairy cell leukaemia
FVIII demonstrated only that the immune system could distinguish
Basal cell carcinoma
between the two types of FVIII at the B-cell level as well as the T-cell
Chronic myeloid leukaemia
Cutaneous T-cell lymphoma
level; FVIII-specific T cells could recognise peptides containing Arg2150,
Erythropoietin Chronic renal failure
but not recombinant FVIII carrying the Arg2150His substitution,
Patients receiving chemotherapy
suggesting that wild-type FVIII contains T-cell epitopes in the C1
Coagulation factors Haemophilia
domain that are absent in the mutant FVIII.
28
Furthermore, peptides
Source: Schellekens and Casadevall, 2004.
2
encompassing Arg2150 were able to interact with multiple human
leukocyte antigen (HLA) class II molecules, suggesting that a restricted [OR] 4.0, 95% confidence interval [CI] 1.4–11.5; p=0.008).
38,39
A
number of T-cell epitopes that promiscuously interact with multiple microsatellite polymorphism in the promoter region of the interleukin-10
HLA class II molecules are involved in initiating immune responses in (IL-10) gene (allele 134) has been highly correlated with inhibitor
patients with an Arg2150His substitution.
28
This may explain why some information; inhibitors were present in 72.7% of patients with this
patients with mild/moderate haemophilia A carrying this and other specific allele compared with 37.5% of patients lacking the allele (OR 4.4,
mutations have an increased propensity to develop FVIII inhibitors, as 95% CI 21–9.5; p<0.001).
33
Allele 134 is associated with increased
well as the observed lack of association between HLA class II alleles and secretion of IL-10, which promotes the differentiation, proliferation and
inhibitor formation.
29
antibody production of B-lymphocytes. This has been proposed to confer
patients with a phenotype that upregulates B-cell activity in response to
An Immunogenetic Predisposition to antigenic stimuli with FVIII infusion, and ultimately inhibitor development.
Inhibitor Development This increase in B-cell clones is considered to be the pathophysiological
Studies from patients with autoimmune diseases show that several mechanism of the polymorphism in patients with systemic lupus
co-stimulatory and regulatory molecules involved in eliciting an erythymatosus and myasthenia gravis.
40,41
A significant association has
immune response have significant potential in pathophysiology, and also been found between the -318 SNP C/T SNP in the promoter region
may confer susceptibility to antibody-mediated diseases. Indeed, of the cytotoxic T-lymphocyte-associated protein-4 (CTL4) gene and the
European studies have suggested that certain HLA haplotypes may development of inhibitors; the presence of the T allele is proposed to
affect the risk of developing inhibitors.
30–32
Weak correlations were confer a protective effect by enhancing production of the protein and
drawn between inhibitor development and HLA class I/II genotypes, upregulated CTLA-4 activity on activated T-cells to counteract any signals
where A3, B7, C7, DQA1*0102, DR15 and DRB1*1501 can be that induce an immune response to infused FVIII. In this regard, patients
designated as risk alleles (relative risk [RR] 1.9–4.0). Conversely, the lacking the T allele were much more likely to develop inhibitors compared
C2, DQA0103, DQB0602 and DR13 alleles have been associated with with those carrying the allele (57.6 versus 31.2%).
42
a decreased risk (RR 0.1–0.2), occurring less frequently in inhibitor
patients than in non-inhibitor patients. However, the Malmö Inhibitor Development in Haemophilia B
International Brother Study failed to confirm these associations.
33
More The data on inhibitor development in haemophilia B are extremely
recent findings support the initial idea that HLA haplotypes are limited due to the relatively lower incidence of this form of the disease.
involved in the development of inhibitors.
34
The study associated The development of inhibitors against FIX is not commonly observed in
HLA-A 34, DRB1*0405 and DRB 1301 with inhibitor development, and clinical practice, but often presents concomitantly with or is heralded
HLA-A30, B13, B15, B57, Cw12, DQB1 0303 and DPB1 0201 with by an allergic and anaphylactic reaction, the aetiology of which
some degree of protection against inhibitor development. remains unclear.
43
Studies analysing the composition of antibodies in
plasma samples of haemophilia B inhibitor patients presenting with an
Polymorphisms in immunomodulatory genes have also been implicated allergic phenotype have suggested that the allergic response may be
in influencing the risk of inhibitor development. The tumour necrosis associated with transient IgG1-subclass antibody production, as these
factor alpha (TNF-α) locus and the HLA class I/II alleles are closely antibodies, though present in plasma procured at the time of allergic
associated in the MHC complex. The TNF-α cytokine possesses episode, were absent when plasma samples were obtained at a later
potent pro-inflammatory and immunomodulatory properties, and time (four days to over four weeks later).
44
polymorphisms in this gene have been linked to autoimmune antibody-
mediated diseases such as systemic lupus erythymatosus, inflammatory Few of the risk factors implicated in the development of FVIII
bowel disease and myasthenia gravis.
35–37
The -308 G/A single nucleotide inhibitors, such as positive family history of inhibitors,
45,46
African or
polymorphism (SNP) in the promoter region of the TNF-α gene is Latino ethnicity,
47
haemophilia genotype,
48
type of FVIII product
associated with increased production and secretion of TNF-α, and used,
49
age at first exposure to FVIII and frequency and intensity of FVIII
inhibitors have been reported in 72.7, 39.7 and 46.9% of patients administration,
50–52
have been as thoroughly explored in the domain of
possessing the -308 A/A, G/G and G/A genotypes, respectively (odds ratio haemophilia B due to the infrequency of FIX inhibitor development.
EUROPEAN HAEMATOLOGY 29
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