Maci Winn

BIOL 4500

The Major Histocompatibility Complex and Disease

The major histocompatibility complex (MHC) is a group of closely related genes that function in immune response. These genes encode for cell surface glycoproteins that bind foreign antigens and present them to T-cells. MHC class I genes monitor the intracellular environment by binding peptides derived from viral proteins and cancer cells, and by presenting the foreign antigens to cytotoxic T-cells. MHC class II genes monitor the extracellular environment by presenting peptides derived from parasites to the helper T-cells (Sommer, 2005). MHC class III genes are not structurally related to classes I and II, but they encode genes functioning in the complement system. This includes the genes encoding for inflammatory cytokines and molecular chaperones that are important in the immune response.

MHC variation can play a role in many inflammatory and autoimmune diseases. One example is celiac disease. Celiac disease (CD) is an immune-mediated disease triggered by the consumption of gluten proteins and has a strong genetic component. CD causes damage to the intestinal walls, and causes a disruption of nutrient absorption. There are numerous known genetic MHC variants that play a role in CD and these variants have shown to contribute to about one fourth of the genetic inheritability. However their role in the progression of the disease is largely unknown. The human leukocyte antigen (HLA) system is a gene complex responsible for encoding the MHC proteins in humans. Around 90% people with CD carry the MHC alleles that encode HLA-DQ2, the gene mainly responsible for the genetic risk of the disease (Sollid et al., 1989). HLA-DQ complexes are composed of two different subunits: alpha and beta, which are encoded by two different genes of the class II MHC region: HLA- DQA1 and HLA-DQB1 (Dieli-Crimi et al., 2015).

Another example is inflammatory bowel disease (IBD). Foreign antigen presentation by intestinal epithelial cells (IEC) is crucial for intestinal homeostasis (Bar et al., 2013).  The IECs are continuously exposed to a high concentration of luminal non-pathogenic antigens, and the immunological tolerance against them is necessary for homeostasis. Loss of this tolerance has shown to assist in the development of multiple intestinal pathologies. Problems in the MHC I and II pathways alter the activations of the CD8 and CD4 T-cells secreted by IECs. Other studies showed that IECs are capable of secreting CD8 and CD4 cells under inflammatory conditions. This pro-inflammatory antigen presentation may also play a role in the mucosal inflammation found in Crohn’s disease and ulcerative colitis.

MHC pathways can also play a role in autoimmune diseases by enriching (over-representing) specific pathways in the body. In type-1 diabetes and rheumatoid arthritis, the MHC gene set showed to be more enriched than any other type of pathway by several orders of magnitude. The MHC has also shown to be responsible for over half of the component for type-1 diabetes, and at least one third of the genetic component for rheumatoid arthritis (Carbonetto et al., 2013).

The MHC can also be a key factor in the progression of many brain diseases by playing a neuro-inflammatory role. Parkinson’s disease (PD) is a motor disorder characterized by a lack of dopamine resulting in resting tremors, Bradykinesia, and rigidity of the body. These symptoms can be accompanied with mood and sleep disorders as well. Neuronal MHC class I expression regulates synaptic plasticity during brain development, and regulate axonal regeneration after injury. Neuronal MHC class I expression also functions in infections that cause an overexpression and may initiate T-cell mediated responses that may lead to neuronal death. Human domapinergic neurons have showed to be more susceptible to MHC class I induction, which could result in abnormally high oxidative stress in these neurons. This result of oxidative stress could result an immune mechanism that activates microglia, leading to neurotoxicity and the advancement of PD pathogenesis (Cebrián et al., 2014).

Schizophrenia (SCZ) is a psychiatric disorder characterized by abnormal social behavior including hallucinations, delusions, negative symptoms, and overall cognitive issues. This disorder has a substantial impact on the quality of life for patients and affects one percent of the population worldwide. There are multiple subtypes of SCZ including catatonic, disorganized, paranoid, residual, and undifferentiated. Although there is abundant evidence that SCZ is a neurological disease, the exact cause is unknown. Factors including genetics, environmental pressures, hormone imbalances, and drug abuse have all been studied in correlation with SCZ. SCZ is known to have a high genetic heritability (between 65 and 81%) and evidence suggests a polygenic inheritance (Moons et al., 2016).

One hypothesis of SCZ pathogenesis is the involvement of the immune system implicating infections and cytokine abnormalities. Evidence has also shown a strong association with MHC markers and specific HLA alleles.  However, immune dysfunction is only present in some subsets of patients with SCZ (Miller, 2016). Multiple sclerosis (MS) is a disease of the central nervous system that is characterized by demyelination of nerve fibers and scar tissue formation that disrupts the transport of nerve impulses. Myelin dysfunction is also evident in SCZ and could suggest shared risk factors of MS and SCZ. One study found significant genetic correlation between MS and SCZ, and found involvement of the same HLA alleles in the risk for each disease (Andreassen et al., 2015). These results show that there are possibly shared molecular pathways of MS and SCZ. Many of the signals shared between these two diseases are located on chromosome 6, which is where the genes encoding the MHC are located. The DRB1*03:01 and DQB1*02:01 MHC alleles that showed to increase risk of MS were found to decrease the risk for SCZ, showing opposite directionality in the association of MS and SCZ (Andreassen et al., 2015). However, the exact loci and MHC variants involved in the pathogenesis of the diseases are unknown.

MHC variants influence numerous biological traits in vertebrates, and increased diversity has shown to increase the effectiveness of the immune system by making it defensive to a larger variety of pathogens. However, many studies show that MHC variation can also result in an increased risk of multiple diseases because of strong genetic components and in some cases, overexpression. Future MHC studies could provide insight into possible gene therapy applications for many physiological and psychological diseases.  

References

Andreassen, O., BA, L., Bettella, F., Dale, A., Desikan, R., Djurovic, S., & ... Zuber, V. (2015). Genetic pleiotropy between multiple sclerosis and schizophrenia but not bipolar disorder: differential involvement of immune-related gene loci. Molecular Psychiatry, 20(2), 207-214. doi:10.1038/mp.2013.195;

Bär, F., Sina, C., Hundorfean, G., Pagel, R., Lehnert, H., Fellermann, K., & Büning, J. (2013). Inflammatory bowel diseases influence major histocompatibility complex class I ( MHC I) and II compartments in intestinal epithelial cells. Clinical & Experimental Immunology, 172(2), 280-289.

Carbonetto, P., & Stephens, M. (2013). Integrated Enrichment Analysis of Variants and Pathways in Genome-Wide Association Studies Indicates Central Role for IL-2 Signaling Genes in Type 1 Diabetes, and Cytokine Signaling Genes in Crohn's Disease. Plos Genetics, 9(10), 1-19.

Cebrián, C., Loike, J. D., & Sulzer, D. (2014). Neuronal MHC-I expression and its implications in synaptic function, axonal regeneration and Parkinson's and other brain diseases. Frontiers In Neuroanatomy, 81-9.

Dieli-Crimi, R., Cénit, M. C., & Núñez, C. (2015). The genetics of celiac disease: A comprehensive review of clinical implications. Journal Of Autoimmunity, 6426-41.

Gutierrez-Achury, J., Zhernakova, A., Romanos, J., Wijmenga, C., Pulit, S. L., Trynka, G., & ... de Bakker, P. W. (2015). Fine mapping in the MHC region accounts for 18% additional genetic risk for celiac disease. Nature Genetics, 47(6), 577-578.

Moons, T., De Hert, M., Gellens, E., Gielen, L., Sweers, K., Jacqmaert, S., & ... Claes, S. (2016). Genetic Evaluation of SCZ Using the Illumina HumanExome Chip. Plos ONE, 11(3), 1-12. doi:10.1371/journal.pone.0150464

Sollid, L. M., Markussen, G., Ek, J., Gjerde, H., Vartdal, F., Thorsby, E. (1989). Evidence for a primary association of celiac disease to a particular HLA-DQ alpha/beta heterodimer, J. Exp. Med. 169 345e350.

Sommer, S. (2005). The importance of immune gene variability (MHC) in evolutionary ecology and conservation. Frontiers in Zoology, 2, 16.