Review Ageing and ocular surface immunity Alireza Mashaghi, Jiaxu Hong, Sunil K Chauhan, Reza Dana Schepens Eye Research ABSTRACT infection and autoimmunity as well as to increased Institute, Massachusetts Eye The prevalence of ocular surface immunopathologies is severity of autoimmunity.10 Age-related immune and Ear Infirmary, Harvard enhanced in the elderly. This increased prevalence has been system changes affect both the innate11 and the Medical School, Boston, 12 Massachusetts, USA attributed to age-related dysregulation of innate and adaptive arms of immunity. A decrease in nearly adaptive immune system responses. Age-related changes in all innate Toll-like receptor (TLR)-induced Correspondence to ocular surface immunity have similar and distinct responses and higher levels of many proinflamma- Dr Reza Dana, Schepens Eye characteristics to those changes seen in other mucosal tory cytokines are observed in the elderly.10 The Research Institute, fi Massachusetts Eye and Ear tissues. This mini review provides a brief outline of key bene ts of vaccination to prevent infectious disease Infirmary, Harvard Medical findings in the field of ocular ageing, draws comparisons are also limited in the elderly, predominantly due School, 20 Staniford Street, with other mucosal tissues and, finally, discusses age-related to the inability to maintain long-term adaptive Boston, MA 02114, USA; changes in the context of immunopathogenesis of infectious immune responses.13 Age-related deficiencies in [email protected] keratitis and dry eye disease, two of the most common maintaining telomeres and DNA stability cause Received 14 September 2015 inflammatory disorders of the ocular surface. excessive apoptosis of lymphocytes. This process Revised 26 April 2016 can add to the severity of certain diseases. For Accepted 19 June 2016 example, in rheumatoid arthritis, increased apop- Published Online First tosis of naive T cells leads to impairment of T cell 4 July 2016 INTRODUCTION With time, the human body loses many homeostatic regeneration and a dramatic change in the T cell mechanisms, leading to increased vulnerability to repertoire; suppressing this phenomenon by reju- organ dysfunction and ultimately death. Ageing not venating the immune system reduces the severity of only leads to body dysfunction per se, but also the disease.9 Table 1 summarises age-related enhances the susceptibility to foreign invaders such changes in the frequencies and functions of as viruses and bacteria due to dysfunction or dysre- immune cells. gulation of the immune system.1 What molecular Alterations of mucosal immunity by age have and cellular mechanisms underlie ageing? been documented both in human and animal Hallmarks of ageing include genomic instability, models. A reduction in lymphoreticular tissues, telomere attrition, epigenetic alterations, loss of pro- antigen-specific IgA antibody responses and lack of teostasis, dysregulated nutrient sensing, mitochon- oral tolerance induction are three hallmarks of drial dysfunction, cellular senescence, stem cell mucosal ageing in the gastrointestinal track.14 15 exhaustion and altered intercellular communica- Peyer’s patches in the gastrointestinal mucosa tion.2 For postmitotic cells, such as neurons and shrink with age and have reduced frequencies muscle cells, these processes lead to a gradual loss of of naive CD4+ T cells and dendritic cells (DCs).16 normal structure and function, the so-called In the respiratory system, though ‘chronological ageing’.3 For continuously dividing nasopharyngeal-associated lymphoreticular tissue cells, like those of the epithelia of the skin or gut, remains intact during ageing,14 age-related immune ‘replicative ageing’ further challenges the function deficits, known as immunosenescence, have been of tissues in which these cells reside. Replicative shown to increase respiratory infections.17 A diffe- ageing refers to the accumulation of cellular rent onset of immunosenescence in gastrointestinal, damage, such as telomere shortening and nasopharyngeal and ocular mucosa has been replication-associated DNA mutations, that occurs reported, but the general immune response is during the process of cell division.34Despite similar similar in young and old.14 trends,5 interindividual variations in ageing are sig- For the ocular mucosa, a plausible theory based nificant.67Precisely what causes the heterogeneity on the above observation in other tissues is that the in the rate of progression and the onset of rapidity and specificity of the immune response in age-related dysfunctions remains largely unknown. both the inflammatory and regulatory arms of the Understanding the ageing process, though limited, immune system are reduced with ageing. As we allows for novel diagnostic and therapeutic interven- discuss in the subsequent sections, this reduction tions. In a number of model organisms, the ageing may lead to autoimmune disease and increased process was observed to slow down or even arrest tissue damage as a result of infection. We also temporarily. A number of genes as well as environ- discuss how age-related changes in the frequencies mental factors (eg, dietary restriction) appear to of ocular immune cells and their expression of extend not only the life span, but also maintain various cytokines and chemokines18 are associated health.8 Rejuvenating the immune system has turned with increased autoimmunity. out to be a real possibility, with beneficial impact on 189 the progression and severity of diseases. AGEING AND OCULAR SURFACE IMMUNITY fi To cite: Mashaghi A, The tear lm, lacrimal glands, corneal and conjunc- Hong J, Chauhan SK, et al. AGEING AND THE IMMUNE SYSTEM tival epithelia, and meibomian glands ensure the Br J Ophthalmol The immune system undergoes profound changes integrity and function of the ocular surface.19 Studies – 2017;101:1 5. with age, which leads to higher susceptibility to using human subjects as well as animal models Mashaghi A, et al. Br J Ophthalmol 2017;101:1–5. doi:10.1136/bjophthalmol-2015-307848 1 Review response that involves T cells. The destructive nature of HSV Table 1 Age-associated changes in the immune system infection has been attributed primarily to the CD4+ Th1-type Innate inflammatory immune response within the cornea rather than a Neutrophils Reduced function including chemotaxis, microbial killing cytopathic response elicited by the virus itself.43 For a given and phagocytosis. load of virus at the eye or trigeminal ganglion, old mice show a Macrophages Defective chemotaxis, cytokine production and more severe keratitis.43 phagocytosis HIV infection is another viral infection that affects the ocular DCs Change in the balance of plasmacytoid DCs and myeloid surface. HIV-infected individuals undergo accelerated biological DCs 45 Natural killer cells Decreased proliferationReduced production of TNF-α, ageing mediated by increased cellular senescence. For IL-2, IL-12 and IL-2R example, corneal endothelial cells in patients with HIV show Adaptive increased variation in cell size and lower cell density, consistent B cells Reduced B cell lymphopoiesis; reduced CD4+ T cell help; with HIV-related accelerated senescence, especially among those reduced quantity and quality of antibodies with poor immune recovery.46 The effect of HIV on other cell CD4+ T cells Reduced IL-2 production; dampened co-stimulation types and resident immune cells is poorly understood and CD8+ T cells Reduced repertoire; increased frequencies of memory remains to be investigated; however, it is known that both HIV cells infection and ageing are characterised by a deficiency in the Tregs Increased frequencies number of competent T cells. Recent studies show that antiretro- For more information, please see McKay et al89 and references therein. viral therapy, despite the adequate recovery of CD4+ T cell DCs, dendritic cells; IL, interleukin; TNF, tumour necrosis factor. counts and suppression of viremia, is less efficient in restoring the immune system in older patients.47 HIV-infected children exhibit premature biological ageing with accelerated immune suggest that these guardians of the ocular surface integrity senescence, which particularly affects the CD8+ cell subset. are affected in the course of ageing; for example, the lacrimal HIV infection itself also seems to influence the ageing process – gland is affected due to exposure to oxidative stress.20 27 rather than exposure to antiretroviral therapy for prophylaxis or Age-related physiological changes of the ocular surface have been treatment.48 The influence of HIV on accelerated senescence of – reported;25 28 however, the effect of ageing on ocular surface ocular cells can be complicated by a number of associated path- immunity remains poorly understood. Immunological mechanisms ologies, such as Kaposi sarcoma, a highly vascularised tumour, play a pivotal role in regulating the ocular surface environment as as well as with HSV keratitis, fungal keratitis (eg, Candida para- well. Immune cells directly or via secretion of immunomodulatory psilosis and Candida albicans) and uveitis, which are more factors actively protect the ocular surface.19 Resident corneal severe in elderly HIV-infected patients.49 50 antigen-presenting cells,29 30 regulatory T cells31 32 and T helper 1 Bacterial keratitis is a serious corneal infectious disease that can (Th1) cells33 are among key cellular players in immune homeosta- result in severe visual disability. Pseudomonas aeruginosa infection sis. Regulatory T cells, for example, suppress autoreactive