Abstract
Background: When aiming to restore myelin tolerance using antigen-specific treatment approaches in MS, the wide variety of myelin-derived antigens towards which immune responses are targeted in multiple sclerosis (MS) patients needs to be taken into account. Uncertainty remains as to whether the myelin reactivity pattern of a specific MS patient can be predicted based upon the human leukocyte antigen (HLA) class II haplotype of the patient. Methods: In this study, we analyzed the reactivity towards myelin oligodendrocyte glycoprotein (MOG), myelin basic protein (MBP) and proteolipid protein (PLP) peptides using direct interferon (IFN)-γ enzyme-linked immune absorbent spot (ELISPOT). Next, the HLA class II haplotype profile was determined by next-generation sequencing. In doing so, we aimed to evaluate the possible association between the precursor frequency of myelin-reactive T cells and the HLA haplotype. Results: Reactivity towards any of the analyzed peptides could be demonstrated in 65.0% (13/20) of MS patients and in 60.0% (6/10) of healthy controls. At least one of the MS risk alleles HLA-DRB1*15:01, HLA-DQA1*01:02 and HLA-DQB1*06:02 was found in 70.0% (14/20) of patients and in 20.0% (2/10) of healthy controls. No difference in the presence of a myelin-specific response, nor in the frequency of myelin peptide-reactive precursor cells could be detected among carriers and non-carriers of these risk alleles. Conclusion: No association between HLA haplotype and myelin reactivity profile was present in our study population. This complicates the development of antigen-specific treatment approaches and implies the need for multi-epitope targeting in an HLA-unrestricted manner to fully address the wide variation in myelin responses and HLA profiles in a heterogeneous group of MS patients.
Highlights
In autoimmune diseases, immune responses are derailed causing immunity towards self-proteins.In the particular case of multiple sclerosis (MS), loss-of-tolerance towards myelin proteins is presumed to underlie the immunopathogenesis of the disease
100 mL of blood was collected by venous puncture and was further processed for myelin reactivity screening or human leukocyte antigen (HLA) class II haplotyping
Identifying patients that would benefit from treatment with a particular therapy may aid in future patient-tailored therapeutic management of the disease
Summary
Immune responses are derailed causing immunity towards self-proteins.In the particular case of multiple sclerosis (MS), loss-of-tolerance towards myelin proteins is presumed to underlie the immunopathogenesis of the disease. Myelin reactivity has been demonstrated to be patient-dependent [2,3] as well as time-dependent, as indicated by fluctuations in the myelin reactivity profile occurring over the course of the disease Both disappearance and re-emergence of reactivity towards specific peptides [2], as well as expansion of the reactivity profile to additional myelin-derived peptides [4,5,6,7] have been described. The latter is known as epitope spreading and is believed to play an important role in the progression of the disease, as observed both in MS and in its animal model, experimental autoimmune encephalomyelitis (EAE) [5,6,8]. Results: Reactivity towards any of the analyzed peptides could be demonstrated in 65.0% (13/20) of MS patients and in 60.0% (6/10) of healthy controls
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