In Alzheimer's disease (AD), the elevated expression of MHC class I molecules calls for further investigation to understand how these immune responses influence neurodegeneration. AD is the most prevalent form of dementia, primarily defined by the pathological accumulation of two aberrant proteins: amyloid-beta (Aβ) and hyperphosphorylated tau, together with neuroinflammation (O'Brien and Wong, 2011). Multiple lines of evidence suggest that increased levels of microglial MHC I molecules in AD may play a critical role in disease progression (Kellogg et al., 2023; Kim et al., 2023; Tooyama et al., 1990). Indeed, in the brains of AD patients, MHC I expression has been detected in microglia, albeit at a relatively low level (Tooyama et al., 1990). More recently, it has been demonstrated that microglial MHC I is expressed at significantly higher levels compared to other CNS cell types and that this expression increases with aging in both human and mouse models (Kellogg et al., 2023). Moreover, in the 5XFAD mouse model of AD, Zhou et al. (2020) found a significant upregulation of MHC I genes compared to wild-type (WT) mice, emphasizing their relevance in AD pathology. Furthermore, Goddery et al. (2021) determined that MHC I-expressing microglia are primary drivers of CD8⁺ immune cell infiltration and responses within the brain. Consistent with this, several studies have reported increased numbers of parenchymal and peripheral CD8⁺ T cells in AD patients, shedding light on a potential role for MHC class I molecules in AD (Larbi et al., 2009; Lueg et al., 2015; Unger et al., 2020). Additionally, there is evidence that neurons express MHC class I molecules under certain pathological conditions, including AD, and that amyloid beta plays a role in regulating the expression of MHC-I molecules (Kim et al., 2023). Although less is known about tau protein as an antigen in the context of CD8⁺ T cell recognition, it might also undergo processing and presentation in a similar manner, especially in stressed neurons. Evidence from one study indicates that reducing MHC-I expressions alleviates tau pathology in primary neurons expressing ApoE4 and in the hippocampi of mice with tau pathology (Zalocusky et al., 2021). Another study found that activated microglia in tauopathy show a notable increase in MHC-I expression (Chen et al., 2023). Together, these findings suggest that investigating MHC I-mediated immune responses in microglia and neurons could provide valuable insights into AD progression and potential therapeutic targets.

The expression of MHC class I molecules in ALS suggests a multifaceted role that calls for additional investigation to untangle its diverse effects on disease pathology. Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurological disorder that targets both upper and lower motor neurons. Microglia have been found to have a pivotal role in modulating the neuroinflammatory process in ALS (Vahsen et al., 2023; Barreto-Núñez et al., 2024). Notably, work by Nardo et al. (2018), using β2-microglobulin-deficient SOD1G^93A mutant mice—obtained by crossing female C57BL6.129P2-B2mtm1Unc/J (B2M KO) mice with C57BL/6JSOD1^G93Amale mice— demonstrated that the lack of both spinal microglial MHC I and CD8⁺ T cell infiltration led to enhanced survival, delayed disease progression, and a significant reduction in the proinflammatory response. In contrast, in the sciatic nerves of these mice, the outcomes were the opposite, suggesting a complex role for these immune components in ALS pathology (Nardo et al., 2018). Consistent with this, microglia near motor neurons showed an increased expression level of MHC I in C57SOD1G^93A mice during disease progression (Nardo et al., 2013; Chiarotto et al., 2017). On the other hand, it has also been reported that neuronal MHC I expression has a beneficial effect on axonal regeneration and neuron survival overall (Oliveira et al., 2004; Tomiyama et al., 2023) and can protect against astrocyte-mediated neurotoxicity (Song et al., 2016). Overall, these findings suggest a dual role for MHC I in ALS, which may vary depending upon its site-specific expression and stage of disease.

Studies on multiple sclerosis (MS) underscore the influence of MHC molecules, with emerging evidence suggesting a protective role for certain MHC class I alleles, though the mechanisms remain unclear. MS is a progressive autoimmune neurodegenerative disease that is typically associated with demyelination and the infiltration of immune cells into the CNS. Given the inflammatory profile of MS, numerous studies have highlighted the importance of MHC molecules in MS pathology (Ramagopalan and Ebers, 2009; Maghbooli et al., 2020). However, the precise mechanism(s) by which different classes of MHC molecules can significantly alter MS pathology require further attention. Whereas more attention has been focused on the role of MHC II molecules in MS, which will be discussed in detail later in this review, a few studies have highlighted the role of MHC I in MS disease pathology. Indeed, work by Bergamaschi et al., found that, in an Italian cohort of MS patients and controls, a specific (and common) HLA-class I allele (HLA-A^*02) mediated a protective effect, thus reducing MS risk in this population (Bergamaschi et al., 2010). Similarly, another study also demonstrated a similar protective potential for the same HLA class I allele in regulating the risk of MS in a humanized mouse model of MS (Friese et al., 2008). Given the current knowledge of the impact of HLA class I alleles on MS susceptibility and pathology, further research is still needed to examine how MHC I molecules on cells like microglia may alter MS pathology. This will help us better understand the genetic basis of MS susceptibility and identify potential avenues for future studies and clinical applications.

The involvement of MHC class I molecules in Parkinson's disease (PD) has gained attention, with increased expression seen in neurons, but more research is needed to explore their impact on microglial-mediated inflammation. PD is another prevalent progressive neurodegenerative disease that predominantly targets the dopaminergic neurons, thus impairing motor functions. Although neuroinflammation is known to significantly contribute to PD pathology, the underlying mechanisms regulating these inflammatory responses are not yet fully understood. Interestingly, it was previously described that the expression levels of neuronal MHC class I were increased in PD (Wang et al., 2021). However, research into the role of MHC class I molecules on microglia in PD is particularly limited. Thus, addressing this knowledge gap will be critical for a more comprehensive understanding of the disease.

In AD, the genes encoding the HLA-DRB1 and HLA-DRB5 MHC II molecules are considered to be AD risk genes (Patel et al., 2021; Mathys et al., 2019) and overall MHC II expression is found to be elevated in ADRD pathology. In histological analyses of AD patient vs. non-AD brains, MHC II molecule protein expression is elevated on microglia that positively stain with the lectin Ricinus communis agglutinin—particularly microglia clustered around senile plaques and neurofibrillary tangles (Perlmutter et al., 1992). Similarly, in another cohort of post-mortem AD brain tissue, there was an increase in HLA-DR staining around dense-core plaques, but this did not co-localize with IBA1 or CD68 reactive (Hendrickx et al., 2017), however, this could be due to the expression pattern of these molecules and the difficulty of staining human tissue. Using RNA sequencing analyses, “disease-associated microglia” (DAMs) have been found in AD and shown to have increased expression of MHC II (Keren-Shaul et al., 2017; Mathys et al., 2019). Interestingly, in CK-p25 mice which have many hallmark features of AD, there are two types of DAMs which are defined by increased expression of MHC II molecules and Type 1 IFNs, which can be produced by macrophages (Mathys et al., 2019). In the 5XFAD mouse model of AD, the injection of cultured Aβ-specific CD4⁺ T helper type 1 cells directly into the brain, resulted in an increase in the colocalization of IBA1⁺MHC II⁺ cells with Aβ (Mittal et al., 2019). These cells also had a much more amoeboid morphology rather than ramified and the MHC II⁺ cells had a higher co-localization to Aβ compared to MHC II- cells (Mittal et al., 2019). Interestingly, 5XFAD mice crossed with MHC II-deficient mice had an increase in the IL-6 and IFN-γ proinflammatory cytokines at 6 months of age, along with an increased plaque load (Mittal et al., 2019). These data indicate that the antigen-presenting molecules are crucial in AD pathology by potentially triggering the clearance of Aβ. Moreover, 5XFAD mice treated with a flavonoid from Hibiscus sabdariffa, Gossypetin, had a reduction in both Aβ and IBA1⁺MHC II⁺ cells (Jo et al., 2022). In the tauopathy mouse model TE4, treatment with PLX3397 reduced IBA1⁺ cells and MHC II⁺ cells and reduced CD3⁺ T cells. Treatment with anti-CD4 and anti-CD8 antibodies in TE4 mice also reduced MHC II⁺ cells in the dentate gyrus (Chen et al., 2023). In two transgenic rat lines expressing human truncated tau protein, the spontaneously hypertensive rat only had a small percentage of microglia expressing MHC II (1.6%), while the Wistar-Kyoto background has almost a fourth of microglia expressing MHC II (23.2%) (Stozicka et al., 2010). Interestingly, the spontaneously hypertensive rat had more overall neurofibrillary load (Stozicka et al., 2010). More recently, in APOE3 and APOE4 mouse models transfected with humanized tau, only the APOE4 mice showed an increased surface level of MHC II on CD11b⁺ CD45⁻ microglia (Lu et al., 2024). Furthermore, in these mice, there was a connection between APOE4 enhancing cholesterol accumulation in microglia that have elevated levels of MHC II, and in microglia where capsaicin was used to increase calcium levels in the endoplasmic reticulum, they had reduced MHC II expression (Lu et al., 2024). Overall, these studies suggest that MHC II molecules may play a role in altering the Aβ plaque load and tau in ADRD.

In ALS gene expression changes for MHC II have shown to be increased in certain types of ALS. ALS is associated with the RNA/DNA-binding proteins, FUS, EWSR1, TAF15, and MATR3. These were found to influence MHC II-mediated antigen presentation via regulation of the MHC class II transactivator (CIITA) (Chi et al., 2023). In a subtype of ALS called Glia, there is a significant increase in HLA-DOA gene expression in comparison to controls, frontotemporal dementia, and the two other subtypes of ALS OX (oxidative stress dysregulation) and TD (dysregulation of transcription) (Eshima et al., 2023). This is particularly important as HLA-DOA forms a heterodimer with HLA-DOB in lysosomes which helps mediate peptide loading onto MHC II molecules. Moreover, in ALS-Glia, there is a high contribution of glial cells, where the “DAM” microglia found in AD are also observed here (Eshima et al., 2023). Although there has been little work on the role of MHC II molecules in ALS, existing data suggest a role for MHC class II molecules in disease progression and as a potential therapeutic target.

Huntington's disease (HD) is an inherited disorder that causes the progressive loss of neurons with very little analysis of MHC II, only showing histological increases of MHC II. Few studies have analyzed MHC II-encoding or related genes in HD. In higher grade HD patient post-mortem brain sections, who were not diagnosed with any other neurological disease, activated microglia are MHC II⁺ (Sapp et al., 2001). This is in contrast to the number of peripheral MHC II⁺ macrophages which remained unchanged in HD patients (Pido-Lopez et al., 2018; Trager et al., 2014). These studies therefore indicate possible functional effects of MHC II molecule expression in microglia in HD.

In MS the MHC II HLA genes were overall found to be increased. MS has some alleles in the HLA-DQB1, HLA-DQA1, and HLA-DRB1 loci are associated with an increased risk of developing MS. Interestingly, the HLA-DRB1 haplotype in MS patients is different, depending upon the geographical region in which they reside (Ramagopalan and Ebers, 2009). Additionally, the HLA-DR15 allele has one of the strongest risk associations for MS (Martin et al., 2021). Commonly, in post-mortem MS tissue, HLA expression is used as a diagnostic for inflammatory activation in lesion areas (Luchetti et al., 2018). In post-mortem MS brain sections, HLA-DR-DQ-DP was found most predominately in white matter areas, although it was still present in the gray matter (Hendrickx et al., 2017). Of note, HLA-DR-DQ-DP staining was found particularly more in active MS lesions compared to inactive MS lesions across different cohorts (Luchetti et al., 2018; Hendrickx et al., 2017; Bo et al., 1994). This HLA-DR-DQ-DP staining was co-localized frequently with CD68, a lysosomal marker used to help measure activation, but less with IBA1⁺ cells, which were amoeboid in shape, but did co-localize with IBA1⁺ foamy macrophages (Hendrickx et al., 2017; Bo et al., 1994). Although this staining did not co-localize frequently with IBA1⁺ microglia/macrophages, it did not co-localize at all with astrocytic or endothelial markers (Bo et al., 1994). Interestingly, the microglia clusters (or nodules) in MS express more HLA-DR-DP-DQ than in post-mortem human stroke microglia clusters (van den Bosch et al., 2024). These clusters in MS are also shown to contain partially demyelinated axons (van den Bosch et al., 2024). These studies demonstrate the importance of understanding microglia/macrophages near lesion areas, as well as the importance of which markers are used to assess the lesion areas. Overall, various MHC II alleles are associated with a higher incidence of MS, the microglia/macrophages with the highest expression of these alleles are located near lesion areas. Understanding microglia/macrophages in lesion areas and their expression of MHC II could potentially lead to better therapeutic targets, more work and advancement of technology is needed to understand how these cells may initiate or contribute to MS lesions.

In PD, MHC II levels are increased in animal models. These increased levels of MHC II molecules have been observed in mouse models of PD using unilateral injections of full length human α-synuclein into the substantia nigra pars compacta (Harms et al., 2013). Injection of human α-synuclein into MHC II-deficient mice prevented this increase as well as the activation of CD11b⁺ microglia; dopaminergic neuron loss was also reduced (Harms et al., 2013). In Dark agouti (DA) and DA.VRA4-congenic rats, the latter of which display lower levels of the MHC II regulatory gene Mhc2ta (the rat equivalent of CTIIA), were similarly injected with human α-synuclein. As expected, compared to DA rats, there was reduced expression of MHC II molecules in the DA.VRA4 rats. Interestingly, unlike the MHC II-deficient mice described above, there was more propagation of α-synuclein in the brains of DA.VRA4 rats (Jimenez-Ferrer et al., 2021). Notably, in the areas of α-synuclein propagation, there were more IBA1⁺MHC II⁺ vs. IBA1⁺MHC II- cells. Additionally, the IBA1⁺MHC II⁺ cells had a more amoeboid morphology (Jimenez-Ferrer et al., 2021). DA.VRA4 rats also showed the greatest cell loss in the nigra and developed a progressive forelimb akinesia (Jimenez-Ferrer et al., 2021). Regardless of rat type, MHC II⁺ cells colocalized with α-synuclein (Jimenez-Ferrer et al., 2021). When nude rats, which lack T cells, were injected with human α-synuclein, there was no increase in MHCII (Subbarayan et al., 2020). Of note, the lower levels of Mhc2ta (i.e., CIITA) expression in DA.VRA4 rats are correlated with higher levels of TNF (Fredlund et al., 2024). This is a bit counter-intuitive, as one would expect CIITA (and thereby, MHC II) and TNF to be regulated in parallel during an inflammatory response. Overall, observations demonstrating that α-synuclein propagation and its impact on glial activation, as well as neuronal loss, may be influenced by MHC class II molecules.

Determining the role of MR1, if any, in homeostatic or neuroinflammatory processes is ongoing. The low permeability of the blood-brain barrier (BBB) is essential for maintaining brain homeostasis (Huang et al., 2020). The breakdown of the BBB into a “leakier” state is an early-stage event of the disease process in Alzheimer's disease (Wyatt-Johnson and Brutkiewicz, 2020). Otherwise, toxins, cytokines and immune cells could infiltrate into the brain and possibly trigger excessive microglial activation, resulting in neuroinflammation (Zhang et al., 2022). It has been shown that MR1 has a role in the stability of the BBB of C57BL/6 mice as they age. For example, one study demonstrated that MR1-deficient mice (lacking both MR1 and MAIT cells) have an increase in ROS accumulation and exhibit meningeal barrier leakage compared to WT mice. These results imply that MR1 is a protective factor for maintaining the meningeal barrier structure in WT mice (Zhang et al., 2022). Further experiments showed that IBA⁺ cells were increased in the hippocampus and cortex of mice lacking MR1 (Zhang et al., 2022). Excessive microglial activation may contribute to neuroinflammation through the release of an array of proinflammatory cytokines like IL-6, IL-1β, IL-18, TNF-α, and IFN-γ, all capable of causing injury to neurons (Landry and Embers, 2022). In fact, reduced cognitive function was observed in MR1 KO mice in both Y-Maze and Morris Water Maze assessments. This reduction was ameliorated after the transfer of MAIT cells to MR1 KO mice (Zhang et al., 2022); thus, these data suggest that MR1-independent, MAIT cell-dependent responses can have an impact in the CNS. In the 5XFAD mouse model of AD, MR1-deficient 5XFAD mice showed a significantly delayed accumulation of Aβ in the hippocampus until 8 months of age, when compared to 5XFAD mice that are MR1⁺. In the cortex, this significant difference in the Aβ burden between 5XFAD and MR1-deficient 5XFAD mice was still present at 8 months (Wyatt-Johnson et al., 2023). Moreover, higher levels of MR1 were found in IBA1⁺ microglia/macrophages that were closer to amyloid plaques than those at greater distances or as compared to WT mouse IBA1⁺ cells. Notably, this result was also demonstrated in the brain tissue of AD patients as compared to non-AD controls (Wyatt-Johnson et al., 2023). Considering that the gut microbiome is altered in AD patients (Bello-Corral et al., 2023) and the importance of MAIT cells in maintaining gut immune homeostasis (Jabeen and Hinks, 2023), examined together, these data suggest that MR1 has a possible role in AD pathology.

Expression of MR1 is increased in the brain lesions of Multiple Sclerosis patients. Like most of the neurodegenerative diseases discussed so far, there is a limited amount of data discussing any correlation between MR1 expression and the progression or overall pathology of MS. Much of what has been published is in relation to MAIT cell activation or the overall MAIT cell population, with little analysis on MR1 itself (Lv et al., 2023). There is an increased expression of MR1 localized in MS-associated brain lesions regardless of the form of MS (i.e., Primary Progressive, Progressive Relapsing, Relapsing-Remitting, and Secondary Progressive) in which the patient presents. Enhanced MR1 expression was detected in patient tissue associated with the three states of MS white matter lesions: (1) active, (2) chronic active, and (3) normal but notable for inflammatory mediators (Salou et al., 2016). It was found that with the increase in MR1 expression, the number of MAIT cells in the CSF increased in those with MS. It is understandable, considering the proinflammatory nature of the MR1/MAIT cell axis, that the increased expression of MR1 has often been correlated with a worsening prognosis (Salou et al., 2016). Thus, overall, MR1 levels are positively correlated with lesion areas in the brains of human MS patients, suggesting possible contributions of this MHC class I-like molecule in MS pathology development and disease progression.

The response to antibody-mediated blocking of CD1d varies between different dementia mouse model systems. In Alzheimer's disease, there have been no studies focused on changes in CD1d expression in the brains of patients or how their levels may compare to healthy controls (Sieberts et al., 2020). There has been at least one study utilizing the 3xTg-AD mouse model that indicated CD1d-neutralizing antibodies did not significantly affect the cognitive function of mice (Iba et al., 2024). These studies therefore imply that CD1d does not contribute to AD, although a simple explanation could be that the anti-CD1d antibodies used do not block NKT cell/CD1d interactions. In contrast, an interesting study of another form of dementia, Lewy Body Disease (LBD) in α-synuclein transgenic mice (a model for LBD), showed that treatment with anti-CD1d antibodies decreased the numbers of NKT cells and reduced neuroinflammation (Iba et al., 2024). Thus, the disparate responses to CD1d blocking in AD vs. LBD model systems emphasize the need for further research into the effects of targeting CD1d in multiple forms of dementia.

The role of CD1d in MS is not well understood. In a study of MS patient tissue, immunoreactive CD1d was largely found in areas of active CNS demyelination compared to controls (Muir et al., 2020). Moreover, the percentage of CD1d-positive cells was higher in active lesions. It was also noted that CD1d-positive cell density was greatest at the edges of lesions as compared to the center (Muir et al., 2020). Overall, in MS CD1d appears to be associated with lesions but the how it may impact these areas remains unknown.