Georgopoulos AP, James LM. Persistent Hypothesis: The Human Leukocyte Neuromedicine (HLA) Connection. J Neurol Neuromed (2018) 3(6): 27-31 www.jneurology.com www.jneurology.com Journal of Neurology && NeuromedicineNeuromedicine

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Persistent Antigens Hypothesis: The Human Leukocyte Antigen (HLA) Connection Lisa M. James1,2,3, Apostolos P. Georgopoulos1,2,3,4* 1Brain Sciences Center, Department of Veterans Affairs Health Care System, Minneapolis, MN, 55417, USA 2Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN 55455, USA 3Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN 55455, USA 4Department of Neurology, University of Minnesota Medical School, Minneapolis, MN 55455, USA

Article Info Human Leukocyte Antigen (HLA) Overview

Article Notes HLA play a critical role in immune protection from foreign Received: December 1, 2018 antigens including viruses, bacteria, and parasites1. Located in the Accepted: December 24, 2018 Major Complex (MHC) of , HLA genes *Correspondence: code for glycoproteins that exist on the surface of most cells in order Dr. Georgopoulos AP, Brain Sciences Center (11B), Minneapolis to facilitate immune surveillance and initiate an immune response to VAHCS, One Veterans Drive, Minneapolis, MN 55417, USA; eliminate foreign antigens. There are two main classes of HLA (Class I E-mail: [email protected]. and Class II) that support the elimination of cytosolic or extracellular © 2018 Georgopoulos AP. This article is distributed under the foreign antigens through destruction and production, terms of the Creative Commons Attribution 4.0 International respectively. HLA genes have evolved to be the most highly polymorphic License in the human genome, thereby maximizing species resistance to foreign antigens and promoting survival. Nonetheless, successful elimination of foreign antigens is predicated on a match between one’s HLA and derived from foreign antigen . Each person has a limited repertoire of HLA proteins inherited in a Mendelian fashion for each class. Fortunately, each HLA can match with various epitopes and, since everyone has one or two at each of the classical loci (Class I HLA-A, B, and C and Class II HLA-DP, DQ, and DR), a large number of antigens can be effectively eliminated. The Match

that can bind and, therefore, be eliminated. Although the overall structure of ClassThe structure I and Class of IIthe HLA HLA molecules molecule differ, determines they are the similar specific in epitopes that for both classes polypeptide chains form a binding groove. It is variation within the binding groove that contributes to high polymorphism. For instance, within the Class II HLA DRB1*13 family alone there are 330 known variants2, although some alleles such as DRB1*13:01 and DRB1*13:02 are much more common than others forms of the allele. DRB1*13:01 and DRB1*13:02 differ by a single in

the electrostatic properties of the binding groove3. Indeed, seemingly thesmall β-chain; differences yet that conferred difference by singlehas been amino shown acid tosubstitutions significantly result alter 4 that translate into the differential ability to effectively eliminate foreign antigens. in variations in charge, stability, and binding affinity so across HLA classes. Class I HLA molecules, which are expressed on nucleatedThose differences cells, present are amplified small across (8-10 different amino genes acid andresidues) even more from proteolytically degraded intracellular viruses, bacteria, and tumors to cytotoxic T cells for degradation. The process is facilitated by transport of the cytosolic peptides to the endoplasmic reticulum where they

Page 27 of 31 Georgopoulos AP, James LM. Persistent Antigens Hypothesis: The Human Leukocyte Antigen (HLA) Connection. J Neurol Neuromed (2018) 3(6): 27-31 Journal of Neurology & Neuromedicine are loaded onto Class I molecules and exported to the of functioning, the concept of HLA-disease cell surface for presentation to CD8+ cytotoxic T cells associations is counterintuitive. That is, HLA’s primary for cell destruction. Class II HLA, which are expressed function is host protection. Accordingly, there also exists on and antigen presenting cells including robust evidence of HLA protective effects. To that end, macrophages, dendritic cells, and , present protective HLA alleles have been observed in conditions larger peptides (12-20 amino acid residues) derived from including autoimmune disorders6,16, HIV17,18, B endocytosed exogenous antigens including viruses and and C19, malaria20, and Gulf War Illness15,21, among others. bacteria to CD4+ T cells which stimulate the production Furthermore, certain HLA alleles have been shown to of . For Class II molecules, antigen binding is exert protective effects in healthy individuals, minimizing facilitated by Cathepsin S which removes an invariant age-related brain changes typically attributed to “normal” chain that blocks binding. Despite all of these differences, aging22,23(see below). Class I and Class II HLA share the same overarching goal In many cases, protective effects have been shown to and work in concert to maximize elimination of foreign vary by population19. HLA is known to vary by ethnicity antigens. HLA-Disease Associations adaptations related to population differences in pathogen exposure.and/or locale,Nonetheless, presumably some alleles reflecting appear evolutionary to more The HLA region of the genome is associated with broadly promote protection across a wide variety of the greatest number of human diseases5. Given its role diseases and populations. For example, HLA-DRB1*13 in immune system functioning it is not surprising that has been shown to be protective against Hepatitis B and HLA has been implicated in a host of autoimmune and C19 and various autoimmune conditions16,24 across several infectious diseases6 populations. Similarly, variants of the DRB1*13 allele have also implicated HLA in diseases ranging from group have been shown to protect against the development schizophrenia7 and autism; however,8 to neurodegenerative more recent diseases studies of Gulf War Illness15, and protect against brain atrophy in such as Alzheimer’s disease9,10 and Parkinson’s disease11. Gulf War veterans20. Furthermore, the protective effects Reports of HLA-disease associations have typically been of DRB1*13 have been observed in cognitively healthy derived from population studies in which certain genes women with carriers evidencing minimal age-related brain atrophy and functional brain changes relative to This particular approach of identifying risk-related genes non-carriers22,23. Of note, within the DRB1*13 allele family, isare complicated found to be moreby high prevalent linkage in disequilibrium.specific disease groups.Due to variations at the protein level confer differential protection. high within the HLA region, some For example, while DRB1*13:02 has been associated with combinations of genes, referred to as haplotypes, are broad protective effects, DRB1*13:01, which differs by only inherited together thereby leading to potential “mistaken a single amino acid residue, has shown both protective23,25 identity” in terms of disease risk12. and risk effects3,26. The differential effects are presumably Etiopathological models underlying HLA-disease associated with changes in the binding groove that affect associations have been summarized elsewhere5,6 antigen binding and subsequent elimination. prevailing models implicate non-mutually exclusive processes including alterations in repertoire,. Briefly, An alternative: Persistent Antigen Hypothesis molecular mimicry, aberrant antigen recognition, and In light of the biological role of HLA in immune system ineffective interactions of the antigen-HLA complex with surveillance and regulation coupled with observed T cells as promoting disease susceptibility. A multitude HLA-associated disease protection, we have proposed of viral escape mechanisms may also contribute to an alternative model of disease susceptibility referred diseases via disruption of immune system functioning13,14. to as the Persistent Antigen hypothesis. Essentially, Despite extensive study of mechanisms underlying HLA- maintenance of immune system functioning rests on disease associations, the fact remains that in most cases successful elimination of foreign antigens, a process that the mechanisms remain poorly understood and likely partially depends on a match between the antigen and represent genetic vulnerability coupled with environmental an individual’s HLA composition. In contrast, the absence insults6,15. Further, as compellingly discussed elsewhere12, of an antigen-HLA match prevents the elimination of the most prevailing theories of HLA-disease association are antigen. Consequently, a persistent antigen may lead to inconsistent with the biology, epidemiology, and evolution 27, and atrophy21,22. of HLA molecules. The Persistent Antigen hypothesis contends that the HLA- antigeninflammation, match cell is damage,a critical step for the elimination of HLA Protective Effects Given the biological and evolutionarily adaptive role of of an HLA-antigen match, any number of downstream HLA in the clearance of foreign antigens and maintenance processesforeign antigens involved and in health foreign maintenance; antigen recognition, in the absence cell

Page 28 of 31 Georgopoulos AP, James LM. Persistent Antigens Hypothesis: The Human Leukocyte Antigen (HLA) Connection. J Neurol Neuromed (2018) 3(6): 27-31 Journal of Neurology & Neuromedicine destruction, and antibody production would be disrupted Age-related changes in brain structure and function have been widely investigated and reviewed elsewhere37. For associations5,6. Thus, the Persistent Antigen hypothesis, example, age-related brain atrophy at the rate of 2-5% includingwhich highlights those the specifically fundamental implicated role of the in HLA-antigen HLA-disease volume loss per decade beginning around age 40 has been match, is complementary to other etiopathological models 38. However, we recently showed HLA of HLA-disease associations. protection against age-related brain atrophy in cognitively healthyfirmly established women22. Remarkably, we also demonstrated Our research on Gulf War Illness (GWI) provides an HLA protection against changes in brain functioning illustrative example. GWI is a neuroimmune condition28 of in cognitively healthy women, even in the presence of uncertain etiology that has affected one-third of US veterans apolipoprotein E4, a well-known Alzheimer’s disease deployed to the 1990-1991 Gulf War29. GWI is characterized risk gene23 by diffuse, chronic symptoms including fatigue, joint and antigen matching protects the brain (and other organs) muscle pain, and neurocognitive and mood disruptions, as . Thus, we hypothesize that efficient HLA- well as gastrointestinal, respiratory, and skin problems30,31. from what has typically been referred to as “normal” age- Given the overlap of GWI symptoms with known autoimmune related deterioration. In contrast, the absence of an HLA- conditions and evidence of abnormal immune responses in antigen match may hinder elimination of foreign antigens veterans with GWI32-34, we investigated HLA involvement that might otherwise result in subtle, accumulative damage such as that ascribed to cellular senescence39,40 and ultimately neurodegenerative diseases including frequentwith GWI. in We those identified with GWI 6 HLA - that alleles is, thatGWI werewas associatedpresent in Alzheimer’s disease. withhealthy genetic GW veteranslack of HLA but protection were absent15. We or hypothesized significantly that less Conclusion this genetic vulnerability coupled with environmental hits including multiple, often concurrent vaccinations and/or The Persistent Antigen hypothesis provides a novel chemical or other toxic exposures that have been implicated in GWI27 underlie the development of GWI and explain why rooted in the biological role of HLA in eliminating foreign perspective on HLA-disease associations that is firmly one-third of veterans were affected whereas the remainder antigens via HLA-antigen matching. Thus, the Persistent were not. That is, the former may not have been able to Antigen hypothesis suggests a plausible mechanism underlying a multitude of diseases in which immune and between the pathogenic epitopes and HLA proteins whereas theeffectively latter was eliminate afforded pathogens genetic dueprotection to an insufficient that presumably match HLA-antigen matching contributes to antigen persistence inflammatory processes are implicated – that is, lack of facilitated effective elimination of pathogens derived from which ultimately leads to disease. This, of course, suggests the various environmental exposures that were associated that both exposures to foreign antigens and genetic with service during the Gulf War27. vulnerability that precludes their elimination are integral in disease development. On the other hand, limited exposure Notably, HLA proteins are expressed on most cells (Class to foreign antigens and/or genetic protection may limit I on nucleated cells and Class II on professional antigen disease and enhance longevity. Indeed, we suspect that presenting cells), providing widespread protection in these very factors contribute to the enhanced longevity observed in several isolated communities referred to as the “blue zones”41. Finally, the Persistent Antigen damage.the case Indeed, of HLA-antigen multiple matching;systems and however, organs are the involved absence hypothesis also implies potential treatment avenues along inof HLA-antigenGWI including matching the brain, in GWIlungs, may gastrointestinal inflict widespread tract, the lines of personalized precision immunotherapy aimed and musculoskeletal systems. Regarding GWI effects on the at facilitating the elimination of circulating persistent brain, infection, autoimmunity, and stress have been shown antigens which we are currently pursuing42,43. to result in loss of the blood-brain barrier integrity35, which may permit entry of circulating pathogens into the brain, Acknowledgments ultimately leading to several GWI brain-related symptoms The contents do not represent the views of the U.S. including fatigue, pain, and neurocognitive mood symptoms. Department of Veterans Affairs or the United States Government. This work was supported by a grant from brain atrophy, particularly involving subcortical structures36. the United States Department of Defense (award number WeRemarkably, have also the shown presence that GWIof protective is associated HLA haswith been significant shown W81XWH-15-1-0520). to protect against brain atrophy in Gulf War veterans21. References The implications of the Persistent Antigen hypothesis 1. Meuer SC, Hussey RE, Hodgdon JC, et al. Surface structures involved in extend well beyond Gulf War Illness. In fact, we have recently demonstrated HLA protective effects on 218: 471-473. target recognition by human cytotoxic T lymphocytes. Science. 1982; maintaining healthy cognitive function across the lifespan. 2. Robinson J, Halliwell JA, Hayhurst JH, et al. The IPD and IPD-IMGT/

Page 29 of 31 Georgopoulos AP, James LM. Persistent Antigens Hypothesis: The Human Leukocyte Antigen (HLA) Connection. J Neurol Neuromed (2018) 3(6): 27-31 Journal of Neurology & Neuromedicine

HLA Database: allele variant databases. Nucleic Acids Research. 22. James LM, Christova P, Lewis SM, et al. Protective Effect of Human Leukocyte Antigen (HLA) Allele DRB1* 13: 02 on Age-Related Brain November 15, 2018. Gray Matter Volume Reduction in Healthy Women. EBioMedicine. 2015; 43: D423-431, version 3.34.0, release date 10-18-18. Retrieved 3. of the HLA-DR P9 -binding pocket and susceptibility to 23. 2018;James 29:LM, 31-7. Dolan S, Leuthold AC, et al. The effects of human leukocyte Hov JR, Kosmoliaptsis V, Traherne JA, et al. Electrostatic modifications antigen DRB1* 13 and apolipoprotein E on age-related variability of synchronous neural interactions in healthy women. EBioMedicine. 4. primaryStern LJ, sclerosingBrown JH, Jardetzkycholangitis. TS, Hepatology. et al., Crystal 2011; structure 53: 1967-1976. of the human

24. 2018;Furukawa 35: 288-94.H, Oka S, Tsuchiya N, et al. The role of common protective class II MHC protein HLA-DR1 complexed with an influenza virus alleles HLA-DRB1*13 among systemic autoimmune diseases. Genes 5. peptide.Trowsdale Nature. J, Knight 1994; JC. 368: Major 215–221. histocompatibility complex genomics

25. Immun.van der 2017;Woude 18: D, 1–7. Lie BA, Lundström E, et al. Protection against 6. andGough human SC, Simmonds disease. Ann MJ. Rev The Genom HLA region Hum Genet. and autoimmune 2013; 14: 301–323. disease: anti-citrullinated protein antibody-positive is predominantly associated with HLA-DRB1*1301: a meta-analysis 453-65. of HLA-DRB1 associations with anti-citrullinated protein antibody- Associations and mechanisms of action. Curr Genomics. 2007; 8(7): 7. Brucato N, Guadalupe T, Franke B, et al. A schizophrenia-associated positive and anti-citrullinated protein antibody-negative rheumatoid HLA locus affects thalamus volume and asymmetry. Brain Behav 1236-1245. arthritis in four European populations. Arthritis Rheum. 2010; 62: 26. Fainboim L, Canero VMC, Marcos CY, et al. Protracted, but not acute, 8. Immun.Torres AR, 2015; Maciulis 46: 311-8. A, Stubbs EG, et al. The transmission disequilibrium test suggests that HLA-DR4 and DR13 are linked to autism spectrum hepatitis a virus infection is strongly associated with HLA-DRB*1301,

33: 1512-1517. 9. Lambert JC, Ibrahim-Verbaas CA, Harold D, et al. Meta-analysis of a marker for pediatric . Hepatology. 2001; disorder. Hum Immunol. 2002; 63(4): 311-6. 27. Institute of Medicine National Research Council. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s Vaccines. Washington, DC: National Academies Press, 2000. 10. Steele NZ, Carr JS, Bonham LW, et al. Fine-mapping of the human disease. Nat Genet. 2013; 45: 1452-1458. 28. Georgopoulos AP, James LM, Carpenter AF, et al. Gulf War illness (GWI) control study. PLOS 2017, 10.1371/journal.pmed.1002272. leukocyte antigen locus as a risk factor for Alzheimer disease: a case– 11. Nalls MA, Plagnol V, Hernandez DG, et al. International Parkinson 29. asWhite a neuroimmune RF, Steele L, disease. O’Callaghan Exp Brain JP, Res.et al. 2017; Recent 235(10): research 3217-3225. on Gulf War illness and other health problems in veterans of the 1991 Gulf Disease Genomics Consortium Imputation of sequence variants for 74: 449-475. War: effects of toxicant exposures during deployment. Cortex. 2016; identification of genetic risks for Parkinson’s disease: a meta-analysis 30. Fukuda K, Nisenbaum R, Stewart G, et al. Chronic multisymptom 12. ofHoloshitz genome-wide J. The association quest for studies.better Lancet.understanding 2011; 377: of 641–649.HLA-disease 280: 981-988. 16(87): 93-101. illness affecting Air Force veterans of the Gulf War. JAMA. 1998; association: scenes from a road less travelled by. Discov Med. 2013; 31. Steele L. Prevalence and patterns of Gulf War illness in Kansas 13. Lucas M, Karrer U, Lucas A, et al. Viral escape mechanisms--escapology veterans: association of symptoms with characteristics of person,

14. taughtAlcami byA, viruses.Koszinowski Int J Exp UH. Pathol. Viral 2001;mechanisms 82(5): 269-86.of immune evasion. 1002. place, and time of military service Am J Epidemiol. 2000; 152: 992- 32. Broderick G, Ben-Hamo R, Vashishtha S, et al. Altered immune 15. TrendsGeorgopoulos Microbiol. AP, 2000; James 8(9): LM, 410-8. Mahan MY, et al. Reduced Human pathway activity under exercise challenge in Gulf War Illness: an Leukocyte Antigen (HLA) protection in Gulf War Illness (GWI).

33. exploratoryHotopf M, David analysis. A, Hull Brain L, et Behav al. Role Immun. of vaccinations 2013; 28: as 159–169. risk factors for 16. EBioMedicine.Bettencourt A, 2016;Carvalho 3: 79-85. C, Leal B, et al. The protective role of HLA-

http://dx.doi.org/10.1155/2015/948723. ill health in veterans of the Gulf war: cross-sectional study. BMJ. 2000; DRB1*13 in autoimmune dis eases. J Immunol Res. 2015; 948723. 34. 320:Johnson 1363–1367. GJ, Slater BC, Leis LA, et al. Blood biomarkers of chronic 17. Pereyra F, Jia X, et al. International HIV Controllers Study, The major genetic determinants of HIV-1 control affect HLA class I peptide 35. inflammationEsposito P, Gheorghe in Gulf War D, Illness.Kandere PLoS K, One.et al. 2016; Acute 11(6): stress e0157855 increases

18. presentation.Goulder PJ, Walker Science. BD. 2010; HIV and 330: HLA 1551-7. class I: an evolving relationship. permeability of the blood–brain-barrier through activation of brain 36. mastChristova cells. P, Brain James Res. LM, 2001; Engdahl 888: BE, 117–127. et al. Subcortical brain atrophy in 19. .Singh R, Kaul 2012; R, Kaul 37: A,426-40. et al. A comparative review of HLA associations with hepatitis B and C viral infections across global populations. World 37. GulfRaz N, War Rodrigue Illness. KM. Exp Differential Brain Res. 2017; aging 235:of the 2777-2786. brain: patterns, cognitive

20. Hill AV, Allsopp CE, Kwiatkowski D, et al. Common West African HLA J Gastroenterol. 2007; 13(12): 1770-87. 38. Enzinger C, Fazekas F, Matthews PM, et al. Risk factors for progression antigens are associated with protection from severe malaria. Nature. correlates and modifiers Neurosci Biobehav Rev. 2006; 30: 730-748. of brain atrophy in aging: six-year follow-up of normal subjects.

21. James LM, Christova P, Engdahl BE, et al. Human leukocyte antigen 1991; 352: 595-600. 39. Baker DJ, Petersen RC. Cellular senescence in brain aging and (HLA) and Gulf War Illness (GWI): HLA-DRB1*13:02 spares Neurology. 2005; 64(10): 1704-11. neurodegenerative diseases: evidence and perspectives. J Clin Invest. 126-131. subcortical atrophy in Gulf War veterans. EBioMedicine. 2017; 26: 2018; 128(4): 1208-1216.

Page 30 of 31 Georgopoulos AP, James LM. Persistent Antigens Hypothesis: The Human Leukocyte Antigen (HLA) Connection. J Neurol Neuromed (2018) 3(6): 27-31 Journal of Neurology & Neuromedicine

40. Kirkland JL, Tchkonia T. Cellular senescence: a translational 42. Georgopoulos AP, Tsilibary EP, Souto EP, et al. Adverse effects of Gulf War Illness (GWI) serum on neural cultures and their prevention by

41. perspective.Poulain M, HermEBioMedicine. A, Pes G. 2017; The 21:Blue 21-8. Zones: areas of exceptional longevity around the world. Vienna Yearbook of Population Research. 43. healthyTsilibary serum. CEP, Souto J Neurol EP, Neuromed. James LM, 2018;et al. 3(2):Human 19-27. (IgG) neutralizes adverse effects of Gulf War Illness (GWI) serum in Neural cultures: Paving the way to immunotherapy for GWI. J Neurol 2013 Jan 1; 87-108.

Neuromed. 2018; 3(5): 23-28.

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