The quantitative and qualitative pentapeptide overlap between the four human TF DLX proteins and NREP vs. the set of 25 virus proteomes is shown in Table 1.

At a first glance, the following points become apparent when considering Table 1:

The pentapeptide matching between viral and neural proteins illustrated in Table 1 has an experimentally documented immunologic potential. As a matter of fact, exploration of the Immune Epitope DataBase (IEDB; www.immuneepitope.org; Vita et al., 2015) shows that almost all shared pentapeptides are also part of hundreds of epitopes that have been experimentally validated as immunopositive in humans. Using the epitope aa length as a filter, Table 2 is restricted to n-mer sequences with n < 12.

A comparative analysis of DLX expression in fetal and adult neurogenic areas of the human brain was conducted using the online database and resources of the Allen Institute for Brain Science (Lein et al., 2007; Miller et al., 2014). Figure 1 reports laser microdissection microarray analyses showing that the transcript expression of the four TFs ranges from medium to high in the fetal transient structures of forebrain (ventricular zone and ganglionic eminence) (Figure 1A), and reaches the lowest but still detectable value in the adult neurogenic dentate gyrus (Figure 1B, subareas CA1, CA2, CA3, and CA4). Notably, only DLX5 and DLX6 appear to be expressed in basal ganglia of adult brain, that is, substantia innominata, caudate nucleus, nucleus accumbens, and putamen (Figure 1B). The control neuronal regeneration-related protein NREP is widely expressed through almost all fetal and adult brain areas, except the fetal ventricular zone and ganglionic eminence (Figure 1A) as well as the dentate gyrus area in the adult brain (Figure 1B).

On the whole, Figure 1 theoretically supports the possibility that the cross-reactivity scenario outlined in Tables 1, 2 may occur in neurogenic areas in the fetal life of an individual and then possibly recur in adulthood. However, from an immunological point of view, a condition that is necessary for the cross-reactivity hypothesis to be biologically plausible depends on sufficient DLX antigen expression in the brain. In other words, data of Figure 1 need to be substantiated in a protein context.

Actually, few data are available on DLX protein expression in humans. Rakic and Zecevic (2003) studied DLX expression in the late human embryonic period (Carnegie stages 19–20) and showed that DLX2 protein was widely distributed through the ganglionic eminence and dorsal telencephalon. Moreover, immunocytochemistry based on a pan-DLX antibody that recognizes DLX 1, 2, 5, and 6 revealed that, in the developing brain, 11 gestational week, DLX protein expression is present in all cortical layers, including layer I and the subpial granular layer (SGL). Almost all small GABAergic cells of the SGL were labeled with the pan-DLX antibody. Successively, using the same pan-DLX antibody, Jakovcevski et al. (2011) showed labeling of the neocortical VZ/SVZ and of the cortical plate in human fetal forebrains during the first half of gestation.

Such experimental results obtained in human fetal developing brain are flanked by data collected from the Human Protein Atlas (https://www.proteinatlas.org/on DLX1 and DLX5 protein expression in the adult human brain. The data are shown in Figure 2. It can be seen that human DLX1 and DLX5 have a protein expression from low to medium level, that is, sufficient to sustain immune cross-reactions. No protein expression data were available for DLX2 and DLX6 proteins. The control NREP had the highest levels of protein expression (from medium to high in the cerebral cortex and the cerebellum).

In essence, we found a vast and unexpected peptide sharing between DLX proteins and numerous infectious agents that constellate human life, from prenatal time to adulthood. The peptide platform defined in Table 1 has also a high immunologic potential, as documented in Table 2, so that, on the whole, data from Tables 1, 2 show the existence of a wide immunologic peptide platform common to viral and human DLX proteins. Moreover, data on protein expression from literature (Rakic and Zecevic, 2003; Jakovcevski et al., 2011) and Figure 2 (www.proteinatlas.org; Uhlén et al., 2015; Thul et al., 2017), although few in numbers and fragmentary, support the possibility that mild, subclinical anti-DLX autoimmune damage in the fetal brain structures evoked by maternal viral infections (and consequent maternal immune activation) may be followed in the adult brain by additional damage after a second encounter with the same pathogen or novel infection with a different agent sharing the same epitopic sequences.

In this context, different immunological pathogenic mechanisms might be theoretically account for the neuronal damage according to the type of immune response, i.e., humoral vs. cell-mediated, and the timing of infection-induce maternal immune activation in relationship to the expression patterns of DLX proteins in the fetus (see Figure 1). The main hypothesis that we considered here relates to maternal infection and consequent immune activation that may also be antecedent to pregnancy and are followed by antibody–mediated neuronal damage in the fetus due to cross-reactions with DLX proteins. In such a scenario, the passage in the fetus of maternal memory B cells (Vernochet et al., 2005, 2007) against epitopes shared between the pathogen(s) and DLX proteins might induce an immune response targeting the developing nervous systems, where DLX proteins are expressed early (see Figure 1). Cellular damage from (auto)antibodies targeting intracellular antigens, like the DLX family of TFs may be, not only plays a pathogenic role in a variety of autoimmune diseases (Racanelli et al., 2011) but even represents a promising therapeutic strategy for cancer treatment (Weisbart et al., 2012; Wang et al., 2015; Chan et al., 2016). The notion that autoantibodies can penetrate living cells is not new. Alarcon-Segovia et al. (1978) showed that antibodies can penetrate living cells. In more recent years, more evidence has accumulated showing autoantibody penetration into different types cell, including neurons, and proposing mechanisms that may explain a pathogenic role of internalized immunoglobulins in autoimmune diseases (Koren et al., 1995; Koscec et al., 1997; Portales-Pérez et al., 1998; Ruíz-Argüelles et al., 1998, 2003, 2007; Ronda et al., 2002; Proulx et al., 2009). Moreover, a nuclear-penetrating lupus anti-DNA autoantibody, 3E10, has been found to inhibit DNA repair and selectively kill certain cancer cells that are highly vulnerable to DNA damage (Weisbart et al., 2012), and, of special importance, nuclear-penetrating anti-dsDNA autoantibodies could possibly function as a pathogenic autoimmune factor for lupus nephritis (Im et al., 2015). Bearing even more relevance to the present discussion, antibodies targeting intracellular antigens, like for instance the glutamic acid decarboxylase, appear to be also involved specifically in neuropsychiatric disorders, like CNS lupus (Karimifar et al., 2013), limbic encephalitis (Matà et al., 2008), schizophrenia (Najjar et al., 2012), and autism (Rout et al., 2012). Indeed, the glutamic acid decarboxylase isoforms (Gad1 and Gad2), which regulate GABA synthesis from the excitatory neurotransmitter glutamate and whose expression is activated by DLX1 and/or DLX2 (Stühmer et al., 2002a,b; Le et al., 2017), share numerous pentapeptides with the 25 viral proteomes (see Supplementary Table 1). Hence, a scenario emerges where immune responses following infections might cause a cascade of multiple crossreactions at multiple levels (i.e., DLX, GAD) of the intracellular mechanisms regulating the function of GABAergic neurons and altering the excitation and inhibition ratio, which is necessary for normal neural circuit function and whose imbalance contributes to neurodevelopmental diseases (Kang, 2017; Maffei et al., 2017; Ye and Kaszuba, 2017; Catavero et al., 2018; Garret et al., 2018).

On the other hand, a cell-mediated mechanism could also theoretically be implied in the cross-reactive immune-mediated subclinical damage of the fetal nervous systems, since memory T-cell trafficking between mother and fetus is also a well-known phenomenon (Jeanty et al., 2014). Nevertheless, the hypothesis of a cell-mediated response would need to take into account the late MHC expression in the fetal CNS (Elmer and McAllister, 2012; Zhang et al., 2013, 2015; McAllister, 2014) that might not sit well with the very early pattern of expression of the DLX-proteins in the fetus seen in Figure 1. However a later cell-mediated damage, and even the possible occurrence of both humoral and cell-mediated responses at different stages of the fetal neural development, can still be hypothesized.

Based on data from Figure 2 and, consequently, confining our discussion to DLX1 and DLX5 proteins, we observe that infection-induced immune cross-reactions might have functional, spatial, and temporal implications:

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.