HLA Allele Frequencies in Pediatric and Adolescent Multiple Sclerosis Patients HLA Allele Frequencies in Pediatric and Adolescent Multiple Sclerosis Patients

Early-onset (pediatric and adolescent) multiple sclerosis (MS) is a chronic autoimmune and neurodegenerative disorder of the central nervous system, which accounts for 3–5% of all MS cases. The major histocompatibility complex (MHC) with its polymorphisms has been the genetic locus with the most robust association with adult MS, since its first discovery in the 1970s. Nowadays, human leukocyte antigen (HLA) typing studies and genome-wide association studies (GWAS) have tried to provide insight into the genetics of early-onset MS and their role in disease diagnosis, prognosis, and therapeutic decision- making. Fundamental genetic similarities have emerged, supporting the assumption that MS shares similar genetic variants and biological processes in all age groups. In this chap- ter, we considered it useful to collect all the available data concerning the HLA distribution in early-onset MS, given the absence of a review paper with such an approach. We additionally aimed toward the summarization of the association of the HLA frequencies in early-onset MS and the main acquired demyelinating disorders that are considered in dif- ferential diagnosis of early-onset MS, like ADEM, NMO/NMOSD, and anti-MOG encepha-lopathy, for further understanding and current or future research in this promising field.


Introduction
Early-onset (pediatric and adolescent) multiple sclerosis (MS), which accounts approximately for 3-5% of all MS cases worldwide, has recently aroused the interest of the scientific community regarding its underlying pathogenetic mechanisms, both autoimmune demyelination and neurodegeneration of the central nervous system (CNS) [1][2][3]. Additionally, in this specific age, other acquired demyelinating diseases are in the MS differential diagnosis of everyday practice, like ADEM, anti-MOG encephalopathy, and optic neuritis [4]. Recently, anti-NMO, anti-MOG, and other autoantibodies have been established as strong biomarkers of the previously referred newly emerged clinical entities or a key element of classical demyelinating diseases, like MS, especially of early onset [5,6].
Nevertheless, for four decades now, the HLA alleles have been globally recognized as the core genetic (risk or protective) component in adult MS. Since the early 1970s, the major histocompatibility complex (MHC) with its polymorphisms on chromosome 6p21.3 [7,8] has been the genetic locus with the most robust association with MS. In specific, DRB1*1501 (split of DR2), along with DRB1*0301 and DRB1*1301, has been found to confer risk for MS, while HLA-A*0201 protection against MS [9]. Genome-wide association studies (GWAS) regarding earlyonset MS are still ongoing, in contrast with large-scale cohorts of adult-onset MS patients. However, single nucleotide polymorphisms (SNPs) of more modest effect have been detected that influence the risk of both adult-and early-onset MS, equalizing the genetic burden of these age groups [10][11][12]. The HLA alleles that have been studied in early-onset MS concern mainly the class II DRB1* and DQB1* loci, although DPB1* alleles confer susceptibility in adult-onset MS as well [13]. Thus, HLA immunogenetics in early-onset MS apart from the lower number of worldwide studies needs an extension to the whole HLA class I and class II systems, given the increased role that was in MS risk and MS association with vitamin D, body mass index (BMI), hormones, estrogen receptor, gender, EDSS score, disease course, MRI findings, cognitive status, and most importantly neutralizing antibody formation and response to treatment [8,[14][15][16][17][18].
In this chapter, we present the available data concerning the HLA distribution in early-onset MS, in parallel with the other acquired demyelinating diseases, given the increased knowledge that has recently emerged in this promising field. We also aimed to include all this useful data in a workable table.
On the other hand, a series of studies pleads against these remarks and claims no correlation of DRB1*15 status and age of disease onset [33][34][35][36][37][38][39]. In a Korean population, close linkage of DRB3*02, DRB1*13, and DQB1*03 was also associated with the risk of childhood MS, while DRB1*1501 was not as high as in Western children [40].
A remarkable DRB1-genotyping study in Australia in 2010 declared the first results indicative of the significance of the epistatic interactions at the HLA-DRB1 locus. Carriage of the DRB1*1501 risk allele alone was not significantly associated with age at disease onset, while the DRB1*0401 allele was associated with a reduced age at onset when combined with DRB1*1501 [41].
Regarding Greece, Anagnostouli et al. in 2003 noticed for the first time the higher frequency of DRB1*1501 in MS patients [42]. In 2011, Kouri et al. [43] observed no significant correlations among DRB1*1501, DQB1*0602, and DQA1*0102 alleles with age at onset, an observation repeated by Anagnostouli et al. in 2014 [20]. Anagnostouli et al. attributed this discrepancy either to a possible parent of origin effect, relying on Ramagopalan et al.' observation that only maternally transmitted DRB1*15 promotes a lower age of MS [44], or to fluctuations of vitamin D levels among different populations [45]. New findings in this former are the putative predisposing role of DRB1*03 allele and the protective role of the DRB1*16 allele for early-onset MS [20].
While the role of HLA alleles in early-onset MS has been well studied, this is not the case in other young-onset acquired demyelinating diseases, especially acute disseminated encephalomyelitis (ADEM) and neuromyelitis optica (NMO), its main differential diagnoses. In Table 1, we summarize the available data regarding the HLA allele distribution in early-onset MS, ADEM, and NMO, and despite the obvious lack of information, the primary results demonstrate clear genetic diversity [12,[46][47][48][49].

Conclusions
The well-established HLA-DRB1*15:01 allele associated with adult-onset MS appears to confer increased susceptibility to early-onset MS too, supporting a fundamental similarity in genetic contribution to MS risk, regardless of age at onset. Regarding whether HLA-DRB1*1501 by itself lowers the age at onset of MS, the results are conflicting and possibly related to both genetic and environmental epistatic mechanisms and in particular those through HLA-DRB1*04. Moreover,  HLA-DRB1*04 also appears to bind with high affinity to myelin oligodendrocyte glycoprotein (MOG) epitopes, whose role in early-onset demyelinating disorders has been widely studied, in both familial MS patients and asymptomatic relatives, indicating that the humoral immune reactivity against MOG is partially under control of certain HLA class II alleles [50][51][52][53][54]. This observation could guide therapy, as HLA-DRB1 * 0401 allele is associated with greater risk of developing neutralizing antibodies against interferon beta (IFN-) in adult studies, resulting in poorer therapeutic outcome [55]. Finally, the putative relation of DRB1*03 allele with earlyonset MS is also interesting, as this allele has been associated not only with a presumed better MS prognosis but also with NMO [46], a mainly humoral immunological entity.
Accumulating data highlights the role of HLA-genotype and especially HLA-DRB1*1501 in regulating the immune response to a range of environmental factors, modulating the risk of MS appearance. Research has mainly focused on viral infections, especially EBV [56][57][58], CMV, and HSV-1 [58]. In specific, Epstein-Barr nuclear antigen-1 seropositivity has been associated with an increased risk of MS, while a remote infection with CMV with a lower risk. A strong interaction has been found between HSV-1 status and HLA-DRB1 in predicting MS, as HSV-1 has been associated with an increased risk of MS only in DRB1*15 carriers. Moreover, obesity and higher body mass index (BMI) during adolescence, rather than childhood, seem to be critical in determining MS risk [59], while tobacco smoke exposure and HLA-DRB1*15 interact to increase risk for MS in children diagnosed with monophasic acquired demyelinating syndromes [60]. Finally, as research regarding the role of gut bacteria in the development of central nervous demyelinating disorders robustly expands, possible protective correlations of specific bacteria through interplay with specific HLA alleles emerge in animal models of MS, expanding our knowledge regarding disease pathogenesis [61,62]. Larger studies in early-onset MS populations are required in order to clarify these possible correlations which may also expand to other HLA alleles, proving the interplay among cellular activity, humoral activity, and environment in MS and their possible impact in therapeutics.
In conclusion, HLA alleles emerge as a primary biomarker in both early-and adult-onset MS, regarding genetic risk, outcome, and differential diagnosis. We strongly believe that larger HLA-genotyping studies regarding early-onset demyelinating disorders are needed, in different ethnic groups, in order to clarify, replicate, and expand the already limited existing results. We also believe that these future studies will aim toward personalized therapeutics and generally precision medicine in early-onset MS patients.