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to a lesser extent in other ependymal cells (not in the MG; [31,32] IL-23R, associated with SLE, Crohn’s disease
choroid plexus), in situ in lipopolysaccharide-activated and psoriasis; and finally, TNFAIP3, involved in control
microglia and on retinal astrocytes (Müller cells). [26] of unbiquitination, associated with RA, SLE, Crohn’s
It is abundant in the grey matter of the spinal cord, disease and psoriasis. [31] As far as MG is concerned,
the periventricular and periaqueductal area. Outside despite of the well-established link between the thymus
the CNS, it is found on epithelial cells of the kidney gland and MG (human thymus tissue has been shown
collecting ducts, airways, parietal cells of the stomach, to express AChR, which is widely thought to be a
skeletal muscle sarcolemma and colon. [27] AQP4-IgG triggering mechanism in early-onset AChR-MG), recent
serum levels are found to correlate with NMO disease evidence suggests that AQP4 is also expressed in human
activity, distinct phenotypic features (gender, course thymus suggesting a similar and early involvement of
and co-existing autoimmunity), severity and response the thymus in NMO-spectrum diseases (NMOSD). [33-36]
to treatment. [25] In patients with isolated ON or isolated HLA-DRB1*03 and especially the whole haplotype,
longitudinally extensive TM, AQP4-antibodies have HLA A1-B8-DR3-DQ2, is the most commonly attributed
been shown to predict conversion to NMO. [25] Recent to MG in the Caucasians, an haplotype common and in
researches have shown that patients’ sera with MS, other autoimmune diseases. [32] HLA-DRB1*03 allele is
acute disseminated encephalomyelitis, systemic lupus highly frequent in the NMO-IgG positive patients, as
erythematosus (SLE) and Sjögren syndrome (SS) we explain in detail below and it could be one of the
were negative for AQP4-antibodies. [28,29] However, links between MG and NMO. [37]
Alexopoulos et al. [28] managed to demonstrate that,
despite the negativity of the serum in antibodies, NEUROMYELITIS OPTICA AND HUMAN
13% of the sera with relapsing-remitting MS reacted LEYKOCYTE ANTIGEN
with the epitope AQPaa252-275 (NMO-positive sera
exhibited reactivity against the intracellular epitope According to the results of the researches that have been
AQPaa252-275 in this study, confirming previous conducted in Japanese, conventional MS is associated
observations). with the HLA-DRB1*15:01 allele, [12,38,39] while OSMS,
which is now accepted as a component of the NMO
Additional immunological components participate. [25] spectrum, is associated with the HLA-DPB1*05:01. [40-45]
NMO lesions contain large numbers of macrophages, HLA-DPB1*05:01 is the most common DPB1 allele
eosinophils and neutrophils, on which AQP4-IgG in Japanese, [46] which may explain the frequent
acts by binding to Fc receptors, as well as on B-cells, occurrence of anti-AQP4 antibody in Japanese OSMS.
[42]
which produce interleukin (IL)-6. IL-17 and IL-6 are Nevertheless, Fukazawa et al. [44] in 2006 came to the
the main pro-inflammatory cytokines which are found conclusion that HLA-DPB1*05:01 plays an important
to be elevated in the serum and cerebro-spinal fluid role in the development of MS in general, but not in
of patients with NMO. [25] T-cells, though fewer, are OSMS. The strong association of HLA-DPB1*05:01
also certainly relevant, as T-helper cells are involved with OSMS may be due to the over-representation
in B-cell isotype switching and affinity maturation. of the HLA-DPB1*03:01 allele among individuals in
The possible role of natural killer cells and glutamate- the non-OSMS group, a question that needs further
mediated excitotoxicity has also been discussed. [25] Of investigation. The observed protective effect of HLA-
course, it has become clear that NMO is associated with DRB1*01 in anti-AQP4-negative MS patients is in
certain HLA alleles, which are extensively described accordance with findings in Caucasians. [47,48]
below.
It is also estimated that there is a protective effect of
NEUROMYELITIS OPTICA AND OTHER HLA-DRB1*09 in anti-AQP4-negative MS patients,
AUTOIMMUNE DISEASES probably by reducing the susceptibility attributed
to HLA-DRB1*15, as individuals with a HLA-
There is a strong association between NMO and DRB1*09/HLA-DRB1*15 genotype have a decreased
other autoimmune diseases, especially in NMO-IgG risk of anti-AQP4-negative MS. [39] Recently, HLA-
positive patients: co-existence with autoimmune DRB1*09 was also shown to be negatively associated
thyroid disease, SLE, SS, celiac disease, sarcoidosis, with ulcerative colitis. [49] Thus, it is assumed that HLA-
or myasthenia gravis (MG) has been described in a DRB1*09, or some genes in linkage disequilibrium
higher frequency than it could be by chance. [30] This with it, protect against certain autoimmune diseases,
co-association could be due to common genetic factors, at least in Japanese, as it is quite rare in Caucasians.
such as HLA and non-HLA genes, including PTPN22, a Moreover, a predisposing effect of HLA-DRB1*12 in
[39]
tyrosine phosphatase associated with type-1 diabetes, anti-AQP4-positive MS has been found. Interestingly,
rheumatoid arthritis (RA), SLE, Crohn’s disease and HLA-DRB1*12 has been reported to increase the risk of

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