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The Official Scientific Journal of Delhi Ophthalmological Society
Immunological Basis of Symptomatology in Ocular Diseases
Upma Awasthi, Shalini Mohan
Ganesh Shankar Vidyarthi Memorial Medical College, Kanpur, India
Corresponding Author:
Upma Awasthi MBBS, MS
Consultant Ophthalmologist
Phaco and Vitreo-Retina Surgeon
New Delhi 
Email Id: upma.awasthi2@gmail.com
Received: 16-SEP-2017 Accepted: 17-OCT-2017 Published Online: 27-FEB-2018
DOI: http://dx.doi.org/10.7869/djo.325
Abstract
Hypersensitivity reactions are our own immune responses to various triggering factors. These immune responses result in different clinical presentations of various ocular diseases. Various cytokines, interleukins are responsible for a myriad of symptoms and thus our therapy should be targeted on specific immunological pathways. In this article we have summarized various ocular diseases with the causative immune pathways thus simplifying the underlying cause. This article will help in understanding why similar looking diseases may have requirement for different modalities of treatment or why similar medications may work in different ocular diseases.
Keywords : ocular immunology, hypersensitivity reactions, ocular mast cells, immune reactions

Introduction
Human beings live in an environment with substances capable of producing immunologic responses. These responses are protective many times but can also be damaging to tissues. Various reactions produced from the exposure to exogenous or endogenous antigens are termed as Hypersensitivity Reactions. The mast cells play a major role as these cells are the source of various mediators of immune reactions. Therefore, ocular diseases can be classified accordingly and their presentations can be different because of the underlying immunologic reactions1-15 (Table 1).


Ocular Mast Cells
The mast cells play a major role in pathogenesis of immune reactions. The ocular mast cells are present mainly in substantia propria of the conjunctiva, although they are also found in in lesser numbers in the choroid stroma and meninges of the optic nerve (perivascular location).16
Mediators released by mast cells can be classified into two groups:17,18

1. Preformed / Primary mediators: these are 
  • Histamine, 
  • Proteoglycans, 
  • Neutral Proteases (tryptase, chymase, cathepsin G, human mast cell carboxypeptidase) and 
  • basic Fibroblast Growth Factor (bFGF).

2. Newly generated / Secondary mediators: these are 
  • Prostaglandins (PG)D2
  • Leucotrienes (LT)C4
  • Interleukins(IL) 4,5,6 &13 and 
  • Tumour Necrosis Factor-a (TNF-a).

Mast cells are of two types16:
  • MCT cells
  • MCTC cells

MCT cells: These cells contain only tryptase which has no action on glandular cells. Therefore, whenever these types of cells predominate, the discharge is watery in nature.

MCTC cells: These cells contain both tryptase and chymase18. The chymase increases mucous production and therefore, when these type of cells are released predominantly, the discharge is mucoid.

Immune Reactions
A. Type I Reactions:
These are mediated mainly by Histamine secreted by mast cells. When the ocular surface is exposed to environmental exogenous allergen, the resident TH2 cells activate naïve B cells. This results in increased production of IgE B cells which secrete IgE. These in turn get cross-linked to the IgE receptors present on mast cell surface. It causes degranulation of mast cells.1,3 Histamine released acts via three receptors19-22 (Figure 1). Among other primary mediators, Neutral Proteases acts by cleaving the peptide bond and symptoms depend on the types.16 (Figure 2). Cytokines (LT-C4, IL-4,5 6,13) have their main role in VKC and AKC23-28 (Figure 3). These ongoing immunological reactions in conjunction also bring some other characteristic features in the clinical scenario e.g. papilla, Tranta’s spots29 (Figure 4).









Giant Papillary Conjunctivitis (GPC)
It’s a classical example of type 1 reaction. It is also termed as Contact lens associated papillary conjunctivitis because of its high incidence in contact lens wearers. These patients are predisposed to develop GPC and usually have a history of other atopic conditions.30 Contact lenses develop rapidly a complex coating of various substances e.g cellular debris, lipids etc after insertion onto the eye.31 Even with the best of cleaning regimens, coating cannot be removed completely.32 This coating acts as an antigenic stimulus in GPC patients (Figure 5).

 

B. Type II Reactions:
These reactions are mediated by antibodies directed towards antigens present on the cell surface and extracellular matrix.1,9

a) Complement and Fc- receptor mediated inflammation
In these reactions, antibodies get deposited in extracellular matrix such as basement membranes(BM) and matrix thereby causing inflammation induced tissue injury.1 A prototype of this reaction in ocular diseases is Pemphigoid. In Bullous pemphigoid, antibodies are against ß-4 integrin and laminin of extracellular matrix(ECM) or basement membrane zone (BMZ) of conjunctival cell surface.33 In Cicatricial pemphigoid, antibodies are against Type VII Collagen of BM.34 This creates a difference in symptomatology of the two diseases.35,36 (Figure 6). 



b) Antibody mediated cellular dysfunction
In these types of reactions, antibodies are directed against cell surface receptors. This causes impairment or dysregulation of cellular function.1 A prototype of this type is Ocular pemphigus vulgaris in which there is formation of flaccid bullae1,37,38 (Figure 7).

c) Mooren’s ulcer
The pathogenesis of Mooren’s ulcer is not very clear.9,39 These patients have circulating antibodies which are thought to be directed against an unknown molecule in the stroma of the cornea.39 The peripheral cornea is a prone area because the limbal capillary arcade serves as a source of cells40 (Figure 8).

C. Type III Reactions (Arthus Reactions):
Arthus reaction is a localized area of tissue necrosis resulting from acute immune-complex vasculitis.41 As the antigen diffuses into the vascular wall, it binds with the preformed circulating antibody. Large immune-complexes are formed locally which precipitate in the vessel walls and trigger an inflammatory reaction.

Scleritis
In this disease, immune-complexes get deposited in the episcleral and scleral peforating capillaries and postcapillary venules.11 It leads to complement activation and platelet aggregation.41 In some cases, Type IV reaction subsequently ensues11 (Figure 9). 



Phacoanaphylactic endophthalmitis
Phacoanaphylactic endophthalmitis is a non-granulomatous type of uveitis but along with type III reactions, type II and IV reactions also play a role in its pathogenesis.10,42 Other non-granulomatous uveitis e.g. atopic uveitis, seasonal uveitis come under type I reaction.1,6 These different types of uveitis have a final common pathway19-21,25,43 (Figure 10).
Despite having same immunological reactions, the symptoms and signs are more marked in uveitis. This is because of high vascularity and loose architecture of uveal tissue.43

D. Type IV Reactions:
They are initiated by antigen activated (sensitized) T lymphocytes (TH1 cells). On subsequent exposure, antigen presenting cells (APCs) take the antigen to previously sensitized TH1 cells. This leads to activation of TH1 cells44 (Figure 11).



Phlyctenular Keratoconjunctivitis
It is usually due to delayed hypersensitivity to tubercli, exotoxins of Staphylococcus. In some cases Chlamydia, Candida, Cryptococcus may be the underlying cause. Clinical presentation depends on the involved location12-14 (Figure 12). 

Sympathetic Ophthalmia
It is a rare granulomatous uveitis of insidious or acute onset. It affects the fellow eye usually within 3 months of severe trauma to the other eye involving the uveal tissue. The characteristic features are mutton fat keratic precipitates (KPs), moderate to severe vitritis and multiple yellowish-white choroidal lesions. It represents an autoimmune inflammatory response against choroidal melanocytes mediated by T cells43,45 (Figure 13).



Summary
This article summarizes various immunologic reactions by simplified flowcharts. These flowcharts illustrate the underlying cause of clinical spectrums of various ocular diseases. Different ocular diseases have a different underlying immune reaction and thus need a different treatment strategy. We can plan our treatment strategy with knowledge of causative mediators and can also plan research for targeting different immune pathways and mediators.

References

  1. Robbins & Cotran. Pathologic basis of disease. Philadelphia: Elsevier; 2004. Diseases of Immunity; pp. 205-10.
  2. Friedlander MH. Current concepts in ocular allergy. Ann Allergy 1991; 67:5-10, 13.
  3. Anand MK. Hypersensitivity reactions, Immediate: emedicine Allergy and Immunology. Apr 21, 2010.
  4. Buckley RJ. Vernal keratoconjuctivitis. Int Ophthalmol Clin 1988; 28:303-8.
  5. Bielory L. Differential diagnoses of conjunctivitis for clinical allergist- immunologists. Ann Allergy Asthma Immunol 2007; 98:105-14.
  6. Khurana AK. Comprehensive Ophthalmology. New age international; 2005. Ocular Injuries; pp. 158.
  7. Bielory L. Immunology and allergy clinics of North America-Ocular allergy. Immunol Allergy Clin N Am 2008; 28:35.
  8. Foster CS, Rola H, Erik L. Cicatricial pemphigoid: emedicine Ophthalmology. Dec 12,2008.
  9. Gottsch J, Liu S, Stark W. Mooren’s Ulcer and evidence of stromal graft rejection after penetrating keratoplasty. Am J Ophthalmol 1992; 113:412-17.
  10. Robert H. Phacoanaphylaxis. emedicine Ophthalmology. July 8, 2009.
  11. Fong LP, Sainz de la Maza M, Rice BA, Kupferman AE, Foster CS. Immunopathology of scleritis. Ophthalmology 1991; 98:472–79.
  12. Khurana AK. Comprehensive Ophthalmology. New age international; 2005. Ocular Injuries; pp. 102-3.
  13. Allansmith MR, Ross RN. Phlyctenular keratoconjunctivitis. Duane’s Clinical Ophthalmology, revised edition. Harper amp; Row, Philadelphia 1991; Vol. 1: 1–5
  14. Srivastava D, Misra RN, Chaturvedi RP, Ahmad J. Immunological study in cases of phlyctenular Kerato-conjunctivitis at `T’ cell level. Indian J Ophthalmol 1983; 31:627-8.
  15. Khurana AK. Comprehensive Ophthalmology. New age international; 2005. Ocular Injuries; pp. 160.
  16. Irani AM, Butrus SI, Tabbara KF, Schwartz LB. Human Conjunctival mast cells: distribution of MCT and MCTC in vernal conjunctivitis and giant papillary conjunctivitis. J Allergy Clin Immunol 1990; 86:34–40.
  17. Bielory L. Immunology and allergy clinics of North America-Ocular allergy. Immunol Allergy Clin N Am 2008; 28:25-42.
  18. Sommerhoff CP, Caughey GH, Finkbeiner WE, Lazarus SC, Basbaum CB, Nadel JA. Mast cell chymase, a potent secretagogue for airway gland serous cells. J Immunol 1989; 142:2450–56.
  19. Polk RE, Healy DP, Schwartz LB, Rock DT, Garson ML, Roller K. Vancomycin and the red-man syndrome: pharmacodynamics of histamine release. J Inject Dis 1988; 157:502–7.
  20. Black JW, Duncan WA, Durant CJ, Ganellin CR, Parsons EM. Definition and antagonism of histamine H2 receptors. Nature 1972; 236:385-90.
  21. Arrang JM, Garbarg M, Lanelot JC, Lecomte JM, Pollard H, Robba M et al. Highly potent and selective ligands for histamine H3 receptors. Nature 1987; 327:117-23.
  22. Abelson MB, Leonardi A, Smith L, Fregona IA, George MA, Secchi AG. Histaminase activity in patients with vernal keratoconjunctivitis. Ophthalmology 1995; 102:1958–63.
  23. Leonardi A. Vernal Keratoconjunctivitis: pathogenesis and treatment. Prog Retin Eyes Res 2002; 21:319–39.
  24. Leonardi A, Radice M, Fregona IA, Plebani M, Abatangelo G, Secchi AG. Histamine effects on conjunctival fibroblasts from patients with vernal conjunctivitis. Exp. Eye Res 1999; 68:739–46.
  25. Solomon A, Zamir E, Levartovsky S, Frucht-Pery J. Surgical management of clinical plaques in vernal keratoconjunctivitis: a clinic-pathologic study. Cornea 2004; 23:608–12.
  26. Trochme SD, Kephart GM, Allansmith MR, Bourne WM, Gleich GJ. Conjunctival deposition of eosinophil granule major basic protein in vernal keratocojunctivitis and contact lens-associated giant papillary conjunctivitis. Am J Ophthalmol 1989; 108:57-63.
  27. Zoster CS. The pathophysiology of ocular allergy: current thinking. Allergy 1995;50(21 suppl):6-9. [Discussion 34-8].
  28. Leonardi A, Borghesan F, Faggian D, Secchi A, Plebani M. Eosinophil cationic protein in tears of normal subjects and patients affected by vernal keratoconjunctivitis. Allergy 1995; 50:610–3.
  29. Bielory L. Immunology and allergy clinics of North America-Ocular allergy. Immunol Allergy Clin N Am 2008; 28:62.
  30. Donshik PC. Giant papillary conjunctivitis. Trans Am Ophthalmol Soc 1994; 92:687-744.
  31. Bielory L. Immunology and allergy clinics of North America-Ocular allergy. Immunol Allergy Clin N Am 2008; 28:95-6.
  32. Fowler SA, Allansmith MR. The effect of cleaning soft contact lenses: a scanning electron microscopic study. Arch Ophthalmol 1981; 99:1382-6.
  33. Chan RY, Bhol K, Tesavibul N, Letko E, Simmons RK, Foster CS et al. The role of antibody to human ß-4 integrin in conjunctival basement membrane separation: possible in vitro model for ocular cicatricial pemphigoid. Invest Ophthalmol Vis Sci 1999; 70:2283–90.
  34. Sitaru C. Experimental models of epidermolysis bullosa acquisita. Exp. Dermatol 2007; 16:520–31.
  35. Nguyen QD, Foster CS. Cicatricial pemphigoid diagnosis and treatment. Int Ophthalmol Clin 1990; 36:41–60.
  36. Bernauer W, Wright P, Dart JK, Leonard JN, Lightman S. The conjunctiva in acute and chronic mucous membrane pemphigoid: an immunohistochemical analysis. Ophthalmology 1993; 100:339–46.
  37. Bianciotto C, Herreras Cantalapiedra JM, Alvarez MA, Mendez Diaz MC. Conjunctival blistering associated with pemphigus vulgaris: report of a case. Arch Soc Esp. Ophthalmol 2005; 80:365–8.
  38. Valliant L. Bullous autoimmune disease of the oral mucosa. Rev. Stomatol Chir Maxillofac 1999; 100:230–9.
  39. Sangwan VS, Zafirakis P, Foster CS. Mooren’s Ulcer: Current concepts in management. Indian J Ophthalmol 1997; 45:7-17.
  40. Khurana AK. Comprehensive Ophthalmology. New age international; 2005. Ocular Injuries; pp. 130-31.
  41. Robbins & Cotran. Pathologic basis of disease. Philadelphia: Elsevier; 2004. Diseases of Immunity; pp. 213-15.
  42. Little J, Langman J. Lens antigens in intraocular tissues of the human eye. Arch Ophthal 1064; 72:820–5.
  43. Khurana AK. Comprehensive Ophthalmology. New age international; 2005. Ocular Injuries; pp. 159-61.
  44. Robbins and Cotran. Pathologic basis of disease. Philadelphia: Elsevier; 2004. Diseases of Immunity; pp.215–18.
  45. Khurana AK. Comprehensive Ophthalmology. New age international; 2005. Ocular Injuries; pp. 380-81.


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Upma Awasthi, Shalini MohanImmunological Basis of Symptomatology in Ocular Diseases.DJO 2018;28:9-13
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Upma Awasthi, Shalini MohanImmunological Basis of Symptomatology in Ocular Diseases.DJO [serial online] 2018[cited 2018 Oct 24];28:9-13. Available from: http://www.djo.org.in/articles/28/3/ImmunologicalBasisofSymptomatologyinOcularDiseases.html
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