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allergic disorders, such as asthma, [50] urticaria, [51] and As a conclusion, it is clear that quite different HLA-
food allergy. [52] Finally, HLA-DRB1*04/HLA-DRB1*04, alleles are correlated to NMO/NMOSD compared
HLA-DRB1*04/HLA-DRB1*14, and HLA-DRB1*04/ to MS patients, reflecting different underlying
HLA-DRB1*15 genotypes increase the risk of non-NMO immunopathogenic mechanisms. Particularly, the well-
MS, probably by interaction with DRB1*15 allele. [39] established and most frequent HLA-DRB1*15:01 allele,
associated with MS, plays rather a protective role for
In contrast, researches in Caucasian populations have NMO. In addition, rare alleles, HLA-DRB1*12, like
come to the conclusion that the HLA-DRB1*03 allele HLA-DRB1*01 and especially HLA-DRB1*09, play a
is highly frequent in the NMO-IgG positive patients, core role in NMO risk or protection respectively and
while DPB1*05:01 is quite rare both in patients obviously in immonopathogenesis, in some ethnic
and healthy controls. [37] We should also highlight groups. On the other hand, it is clear that different HLA
the negative association between HLA-DRB1*15:01 alleles are associated with different ethnic groups, like
and NMO, which indicates a possible protective Eastern NMO (association with the HLA-DPB1*05:01),
role. [53,54] In this point, the observation that NMO-IgG- which in turn are specifically associated with certain
positive and negative patients differ mostly in terms clinical/paraclinical features.
of gender and the association of other autoimmune
diseases, could imply that HLA-DRB1*03 is associated Moreover, the comorbidity of NMO with other
with the NMO-IgG presence, but not with NMO autoimmune diseases is still under further investigation,
per se and raise the question of whether NMO-IgG although it seems that so far this comorbidity is highly
is epiphenomenon or pathogenic. [37] In reply to this, reflected in HLA profile and anti-AQP4 antibody
Arellano et al. [55] found that hAQP4281-330 is the presence, suggesting common pathways in their
dominant linear immunogenic determinant of hAQP4 immunopathogenesis.
in the context of HLADRB1*03:01. Within hAQP4281-
330 are two dominant immunogenic determinants that In MS there is also comorbidity with other autoimmune
induce differential Th phenotypes. In recent times, diseases, like SLE, Hashimoto’s thyroiditis, etc.,
Asgari et al. [27,53] reported a high frequency of HLA- However, this co-existence presumes rarer than in NMO,
DQB1*04:02 in NMO patients, an allele described although more investigation studies are warranted to
to be associated with autoimmune diseases such as prove this notion.
primary biliary cirrhosis, type-1 diabetes and juvenile
idiopathic arthritis, but he didn’t show any correlation In this paper, we tried to focus only on the HLA-
with HLA-DRB1*03. immunogenetics of NMO, since the HLA molecule is
a core component of the trimolecular complex, which
In Brazilian cohorts, NMO patients present a is involved in antigen-presentation, as the first step of
high frequency of the HLA-DRB1*03 allele and the immune response. However, as in MS, similarly
extremely low frequency of the HLA-DRB1*15. In in NMO, many non-MHC genes are candidates for
addition to this, the same study showed that HLA- the overall genetic burden. First, genes correlated to
DRB1*01 allele is associated with NMO and benign immune system and immunogenetics, namely IL-7
MS, a correlation that indicates that this allele receptor polymorphisms, [59] IL-2 receptor a chain gene
[60]
may influence the outcome of these demyelinating polymorphisms and CD6, interferon regulatory factor
disorders. [56] We would like to emphasize once 8 and tumor necrosis factor receptor superfamily [61]
more that HLA-DRB1*01 has a protective effect in polymorphisms and secondly, the polymorphisms of
anti-AQP4-negative MS patients in Japanese and the promoter region of cytochrome-P450-7A1 gene [62,63]
Caucasians. [47,48] In African-Americans, none OSMS and AQP4 genetic variations [64] are involved.
patient carries the HLA-DRB1*1501 allele, [57] while
in Afro-Carribeans, NMO has been associated with Regarding MS, it has been shown that specific alleles,
the HLA-DRB1*03 allele [Table 2]. [58] in particular HLA-DRB1*04:01, HLA-DRB1*04:08 and
HLA-DRB1*16:01, are associated with an increased
DISCUSSION risk of antiinterferon beta antibody development. [65] As
a result, the poorer therapeutical outcome highligths
To the best of our knowledge, this is the first review the importance of the stratification of patients to
aiming at summarizing all the results concerning HLA responders and nonresponders, according to HLA-
allelic frequencies in NMO and NMOSD, worldwide. genotyping. Similarly, Warabi et al. [66] concluded
[1]
Apart from a detailed description of HLA allelic that patients carrying the NMO-specific HLA allele
frequencies in all genotyped NMO ethnic groups, we DPB1*05:01 showed a poor prognosis following
created a workable table including all this information, interferon beta-1b treatment. The crucial role of the
for an easier reader’s approach. AQP4-antibodies in the pathogenesis of NMO has been

Neuroimmunol Neuroinflammation | Volume 1 | Issue 2 | September 2014 47