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Pathophys > Ocular Immunopathology > Flashcards

Ocular Immunopathology Flashcards

1
Q

Name the 4 types of Hypersensitivity Responses

A
  • Exaggerated or inappropriate variants of patterns of protective mechanisms
  • Type I - Immediate Hypersensitivity (anaphylactic reactions)
  • Type II - Cytotoxic reactions
  • Type III - Immune complex reactions
  • Type IV - cell mediated or “delayed” hypersensitivity
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2
Q

Describe Type I Hypersensitivity

A
  • Immediate hypersensitivity - Th2 cell mediated
  • Mast cell with IgE on surface encounters antigen
  • Degranulation produces wheal (increased permeability) & flare (vasodilation)
  • If local, the result is chemosis, itching, redness
  • If systemic, can produce asphyxiation from laryngeal edema, suffocation from bronchial smooth muscle constriction, or shock (rapid drop in BP shunting fluid to peripheral edema)
  • Late phase reaction (4 hrs to a few days) mediated by leukotrienes (formerly known as SRS-A)
  • Tx by desensitization, mast cell stabilizers, anti-histaminics
  • Granules must fuse w/ cell membrane for release. If mast cell membrane “stabilized” granules cannot fuse. If no release = no activity
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3
Q

Describe type II hypersensitivity

A
  • Cytotoxic Reactions
  • Binding of specific antibody to an antigen on a cell leads to cell damage and/or lysis
  • Three variants
    • Complement mediated: IgG or IgM binds, activating complement to C9 fraction-mediated lysis
    • Antibody binding leads to opsonization
    • ADCC - antibody binds and exposed Fc fragment causes cell lysis through NK and monocyte activation
  • Systemic disease ex. include
    • Myasthenia Gravis - target antigen is ach receptor
    • Graves Disease - target antigen is TSH receptor
    • Insulin-resistant diabetes - target is insulin receptor
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4
Q

Describe type III hypersensitivity response

A
  • Soluble antigen + soluble antibody = forms an immune complex.
  • Circulating immune complex can deposit in vessel walls, activating complement resulting in chemotaxis
    • Antibody excess = leads to rapid complex deposition and local arthus reaction (e.g. khoadadust line)
    • RA = rheumatoid factor is produced - an IgM autoantibody to IgG leading to immune-complex deposition in joints, etc
    • These conditions worsen with each subsequent exposure & include occupational allergies
    • Antigen + Antibody form an immune complex. These immune complex can deposit in vessels walls, activating complement leading to chemotaxis & tissue destruction
    • Ex. of systemic immune complex - mediated disease
      • SLE
      • Polyarteritis nodosa (PAN)
      • Reactive arthritis (Reiter’s Syndrome)
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5
Q

Describe type IV cell - Mediated or “Delayed” Hypersensitivity

A
  • Primarily TH-1 mediated, occur 18-24 hours after exposure, leading to lymphokine release & monocyte/macrophage activation
  • Variants include:
    • Contact hypersensitivity: Langerhans cells (e.g. poison ivy, medicamentosa)
    • Granulomatous hypersensitivity - persistent antigenic presence in macrophages that cannot be destroyed or by persistent immune complexes (Chalazia)
      • In UK, this class V
    • Cutaneous basophil hypersensitivity - reaction consists of erythema, without the induration typical of classical delayed hypersensitivity reactions. The erythema is accompanied by an infiltration of primarily basophils. The response is T-cell directed & MHC restricted ​
      • ​This interesting variant is likely a component of CL-related giant papillary conjunctivitis & mechanical irritation
  • Diseases
    • ​RA - citrullunated proteins
    • MS - anti-myelin basic proteins
    • Type I DM - pancreatic beta cell antigens
    • Inflammatory Bowel disease - cross reactivity of bacterial & self antigens
    • Psoriasis
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6
Q

What are the differences between Th-1 & Th-2 cells?

A
  • TH-1 & TH-2 cells are sub-classes of T helper cells. Cytokines of each group tend to inhibit the cells of the other group.
  • Th-1 ​​
    • Prodce IFN-y & IL-2
    • Th-1 cells usually dominate responses against intracellular pathogens such as viruses & bacteria
    • Granulomas produced in TB are therefore TH-1 dominated
  • Th-2
    • ​produce IL-4, IL-5, IL-6, IL-10, & IL-13
    • dominate against extracellular pathogens
    • Granulomas produced in response to foreign materials therefore TH-2 dominated
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7
Q

What is regional immunity?

A
  • Pathogens have specific strategies for gaining access to different tissues
  • Each of these tissues has specialized responses that are variants on the general pattern in order to optimize protection while prioritizing critical functions of that tissue or organ
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8
Q

What is GALT/MALT?

A
  • Gut/Mucosa Associated Lymphoid Tissue
  • Antigen placed on a mucosal surface ilicits a large IgA response
  • Exposure to one mucosa confers immunity on all mucosa but not skin. Indeed skin responses improperly expressed in mucosa are damaging (ex. cicatricial pemphigoid)
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9
Q

What is unique about the eyes immune system?

A
  • No intraocular lymphatic supply - nodes are not the primary reactive immune organ
  • Avascular tissues - HIV in corneal transplants does not transmit disease
  • No langerhans cells in central cornea
  • Ocular immune privileges
  • ACAID (Anterior Chamber Associated Immune Deviation) - tolerance to antigens
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10
Q

The only tissue with a lymphatic supply is the _____.

A

Conjunctiva

In some conditions these vessels dilate and can be seen directly

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11
Q

Epibulbar tumors and Intraocular tumors require what types of work up?

A

Epibulbar = lymphatic & vascular work up for METS

Intraocular = only vascular work ups

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12
Q

Inside the eye, the kinds of standard inflammatory responses that work well in the skin and other tissues can be worse than the diseases itself in terms of reducing vision. What are some examples?

A

Corneal ulcer w/ secondary uveitis

Endophthalmitis

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13
Q

How does the eye react to antigens?

A
  • Minimize cell-mediated inflammation
  • Minimize antibody-dependent reactions that involve significant complement activation
  • Allow antibody-dependent reactions that activate complement minimally if at all
  • Systemically suppress a potential delayed type hypersensitivity response to antigen presented inside the eye
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14
Q

How does type I hypersensitivity work and what are some examples?

A
  • Mast cells bind IgE via their Fc receptor. If subsequently an allergen, by binding to 2 IgE molecules cross-links the Fc receptors, the mast cell degranulates & releases mediators that produce allergic reactions. Hypersensitivity usually appears on repeated contact with the allergen
  • Examples of type I allergic reactions
    • Anaphylaxis
    • Atopic asthma
    • Atopic eczema
    • Acute drug allergy
    • Hay fever
  • Usually blood-borne for systemic response or a response at a surface such as cornea and conjunctiva rather than intraocular
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15
Q

How does type II hypersensitivity work and what is an example?

A
  • Cytotoxic hypersensitivity
  • rare reactions that are typically caused by IgG and IgM antibodies.
  • This response may occur when target antigen is part of the surface of specific host cell or tissue
  • associated with autoimmune disease, drug reactions, and transplantations
  • Occur when IgG and IgM antibodies bind to host cells and tissues to form complexes that activate complement pathway which eliminated host cells
  • These are the responses that reject tumor cells and reject grafts leading to cell death by C9 or NK cells deployment
  • Ex. Corneal Graft Rejection, KPS Descemets folds, stromal haze = acute rejection,
  • Soluble immune complexes (antigen & IgG or IgM) are deposited in the tissue. complement is activated and PMN cells (to lesser extent monocytes) are attracted, causing local tissue damage & inflammation
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16
Q

How does type IV hypersensitivity work?

A
  • T cells sensitized to antigen and release lymphokines during second contact w/ antigen
  • Cytokines induce an inflammatory response, they also activate and attract macrophages, which release inflammatory mediators.
  • Antibodies produced against fixed cellular or tissue antigens are usually the autoantibodies; less frequently they are produced against extrinsic antigens. This is the delayed type hypersensitivity.
  • A variant of this is response seen in granulomatous disease
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17
Q

What are the 3 main manifestation of ocular immune privilege?

A
  • selectively anti-inflammatory and immunosuppressive intraocular microenvironment
  • a prolonged acceptance of solid tissue and tumor allografts in the anterior chamber
  • an induction of systemic tolerance to eye-derived antigens
18
Q

What are the ocular immune privileges 5 primary features?

A
  • blood ocular barrier
  • absent lymphatic drainage pathways
  • soluble immunomodulatory factors in aqueous humor
  • immunomodulatory ligands on the surface of ocular parenchymal cells
  • indigenous, tolerance-promoting antigen-presenting cells (APCs)
19
Q

What is the purpose of ocular immune privilege

A
  • The eye is one of only 3 immunologically privileged sites. The other 2 are brain & testes
  • In or on the eye, it can be the case that the havoc created by the non-specific entrance of white cells is greater threat to vision than the disease itself. If your skin develops a scar in such a battle it does not compromise continued function. Not so in the eye.
  • The purpose of immune privilege is produce limited local immunosuppression to reduce damage done by infiltrating leukocytes, other inflammatory cells and complement-dependent responses
20
Q

Describe MHC class I & II

A
  • MHC I
    • ​Class I molecules are found on all nucleated cell and on platelets (ex HLA- A, B, and C)
    • Their function is to display fragments of proteins from WITHIN the cell to T cells. healthy cells will be ignored, while cells containing foreign proteins will be attacked by the immune system
  • MHC II
    • ​Class II molecules are found only on a few specialized cell types, including macrophages, dendritic cells & B cells all of which are professional APC (ex. HLA - D)
    • The peptides presented by class II molecules are derived from extracellular proteins
21
Q

What are the three different strategies of ocular immune privilege?

A
  • Immunologic ignorance
    • ​corneal cells have reduced expression of MHC class I molecules & do not express MHC class II molecules
    • The normal cornea lacks blood & lymphatic vessels
  • Peripheral tolerance to ocular derived antigens
    • ​The immunologic hallmarks of ACAID include the generation of primed cytotoxic (CD8) T cells & B cells that produce non-complement-fixing antibodies, as well as the inhibition of delayed type hypersensitivity (CD4 Th1) and B cells that secrete complement fixing antibodies
    • Central & peripheral tolerance to self antigens
      • ​Central tolerance - Immature lymphocytes specific for self antigens may encounter these antigens in the generative lymphoid organs and are deleted.
      • Peripheral tolerance - Mature self-reactive lymphocytes may be inactivated or deleted by encounter with self antigens in peripheral tissues.
  • Development of intraocular immunosuppressive microenvironment
    • ​There are also local factors within the eye that inhibit the components of the immune response to reinforce the protection provided by immune privilege
    • Immunosuppressive and anti-inflammatory factors in AH
22
Q

What are the effects of innate ocular immunomodulation?

A
  • Decrease severity of inflammation
  • Create permissive environment for foreign tissue such as allgorafts (corneal transplant)
    • This is true even though the supplemental immunosuppresion used to control rejection is applied topically rather than symmetrically
  • Create permissive environment for tumor allografts
    • tumors would be rapidly destroyed if placed under skin of animal but are tolerated in eye
  • There are several immunomodulatory factors that are both cell-fixed and soluble (ex. Fas is cell-fixed and TGF-B is soluble)
23
Q

Describe cell fixed immunomodulators FAS (aka CD95)

A
  • many immune cells, including neutrophils, monocytes, macrophage and lymphocytes express Fas
  • If cells bearing Fas encounter the ligand for this receptor, a cascade of events leads to apoptosis of these cells, taking them out of the inflammatory loop
24
Q

What is the FAS ligand?

A
  • constitutively expressed on cells of normal cornea, anterior uvea & retina
  • When inflammatory cells arrive in these locations, many of them encounter and bind this ligand, causing them to die before playing a role in the inflammatory event
  • If you inject herpes virus into the eye of a Fas-ligand deficient animal, the ensuing aggressive inflammatory response almost invariable destroys the eye
  • If you inject herpes virus into the eye of a normal animal whose cornea, and uvea and retina express Fas-ligand, a relatively minor inflammatory response ensues
  • If you take a graft from a normal mouse and transplant it into another normal mouse, that graft will be rejected only about half of the time even when no tissue matching is done in advanced
  • If you take a corneal graft from a mouse that genetically does not express Fas-ligand and tranplant its cornea into the eye of a normal mouse, it will be rejected every time
25
Q

Explain the inhibition of alternate pathway for complement activation

A
  • complement is active at low levels in the healthy eye
  • Soluble factors in AqH also inhibit activation of complement via alternative pathway. This pathway, among other fxns, commonly leads to chemotactic attraction of white cells.
  • This prevents formation of C3a and C5a, both chemotactic to white cells, and leading to formation of C9 induced cell lysis
  • iC3b, when it is produced, also inhibits antigen-specified delayed type hypersensitivity
26
Q

Describe soluble immunomodulators TGF-B in inflammation?

A
  • Cells in both anterior & posterior segments constitutively secrete TFG-B
  • The concentration of TGF-B in aqueous humor is enough to inhibit T-cell activation and clonal proliferation
  • Significantly lower concentrations are found in pt with various uveitis syndromes
  • Higher levels are found in pt with POAG
27
Q

Describe soluble immunomodulators TGF-B & MIF in allograft and tumor tolerance

A
  • AqH from normal eyes can prevent lysis of susceptible target cells by NK cells in vitro
  • At least 2 factors in normal aqueous stop NK cell killing: TGF-B and Macrophage migration inhibitory factor (MIF)
  • TGF-B inhibitory activity on NK cells is delayed in time, whereas MIF acts quickly to disarm NK cells
  • NK cells, left alive, would attack and destroy foreign tissue via cell lysis
28
Q

What is the role of IL-1 and what targets IL-1?

A
  • proinflammatory cytokine driving joint inflammation, as well as systemic signs of inflammation, such as fever and acute phase protein production (e.g. c-reactive protein)
  • Current therapy targeting IL-1 in JIA is based on recombinant form of the IL-1 receptor antagonist
    • Anakinra binds to IL-1 receptor without eliciting a signal, thus competing with the binding of the 2 natural ligands, IL-1a and IL-1B
    • Cornea and RPE both express Il-1 receptor antagonist (IL-1Ra), providing a presumptive control mechanism for IL-1 mediated events
    • Topical applications of IL-1RA has significant positive effect on corneal allograft survival
29
Q

What is ACAID (Anterior Chamber Acquired Immune Deviation)?

A
  • A systemic immune response in which antigens placed in the AC of the eye elicit supression of the delayed hypersensitivity response
  • The induction of ACAID is dependent on infiltration of circulating monocytes in response to antigen that eventually emigrate to the thymus and spleen where they induce regulatory T cells that inhibit the inductive or effector phase of a cell-mediated DTH response
  • ACAID therefore protects the eye from collateral damage of an immune response to an antigen by suppressing a future potentially damaging response to that antigen
  • In essence it erases memory of an event that would otherwise be initiating event in spleen-mediated Type IV hypersensitivity response that would produce progressively worse inflammatory responses on subsequent encounters of the same antigen.
  • Induction of ACAID to autoantigens is reportedly induced by inoculating the AC with retinal autoantigens followed by a demonstration that such mice are subsequently resistant to the induction of experimental autoimmune uveitis by immunization with the same autoantigen
  • Ex. CMV retinitis
30
Q

Describe what occurs when failure of ACAID (stromal HSK) happens

A
  • An immune response to viral antigen rather than replicating virus ( so steroids are ok)
  • Spread of virus from face to eye induce virus-specific ACAID and the delayed hypersensitivity response is suppressed. Virus is cleared by other immune effectors and the cornea is left cleared & unscarred
  • If langerhans cells have aberrantly migrated into the central cornea, these APCs elicit delayed hypersensitivity, not ACAID, and scarring results
31
Q

Describe the different between skin and mucosa

A
  • Skin has thick protective barrier that provides a dry surface and does not have to interact with the environment to allow nutrients, or oxygen to be exchanged, or to extract sensory information from the environment such as taste & smell
  • Internal tissue are maintained sterile. If anything gets in, a significant response is mounted (except those tissues that maintain immune privilege (eyes, brain, gonads)
  • Mucosae, however, are stuck in the middle
  • They have to leave themselves vulnerable in order to achieve their various purposes of air exchange, smell and taste, absorption and secretion of food and water. These usually require a moist surface which is more supportive of microbial growth than a dry one
32
Q

Antigens & Pathogens on foods

A
  • We cook them to reduce pathogenic bacteria then subject them to stomach acid to kill still more pathogens and denature potentially antigenic proteins - but some still get through intestines
33
Q

How many bacteria are in the intestines?

A
  • human body consist of about 100 trillion cells, carries about 10x as many microorganisms in the intestines
  • Bacteria represents approx 60% of dry mass of feces
34
Q

Describe Commensal bacteria

A
  • useful for host such as fermenting unused energy substrates, training immune system, competing with and therefore controlling growth of harmful, pathogenic bacteria, regulating the development of the gut, producing vitamins for the host (such as biotin and vit K), and producing hormones to direct the host to store fats
35
Q

When can antigens and pathogens be a major issue?

A
  • What lands on skin is not a problem if you do not use your fingers and hands to transfer thismaterial to your mucosal surfaces. What you inhale and what gets into your eyes can be an issue.
36
Q

The basic conundrum of mucosa in the gut & how do we address the issue?

A
  • Your mucosae, especially the gut, have to deal w/ huge load of antigen and pathogens continuously
  • They cannot mount a response to everything that comes by so there must be a mechanism for carefully distinguishing what can be tolerated and what cannot
  • But the system also has to ensure that once something is identified that cannot be tolerated the response must be swift and effective
  • and it makes sense that the experience learned about an antigen or pathogen (either good or bad) . that is encountered by one mucosal surface should be shared with the other mucosae that may later encounter it
  • To address this issue, we have the MALT SYSTEM
    • ​surface tolerance
    • Memory & communication
    • exposure of one mucosa will initiate memory of that event to provide an acquired immune response at next encounter or reinforce tolerance at the next encounter
    • But in this system, that acquired response (either tolerance or decisive action) is conferred not just on the surface that encountered the antigen/pathogen but on virtually all other mucosal surfaces simultaneously
37
Q

What are the roles of M cells?

A
  • Special epithelial cells associated with peyer’s patches and lymphoid follicles that actively take up particulate matter from the intestinal contents
  • M cells have basal processes that extend into the local organized mucosal associated lymphoid tissue (O-MALT)
  • M cells can be exploited to serve as a transepithelial conduit for macromolecules & microorganisms
  • Microorganisms such as salmonella, yersinia, shigella and campylorbacter have learned to exploit the M cell transport system, using them as a means to rapidly infect the mucosa and to promote systemic infection
38
Q

Describe the ocular surface of cornea & conjunctiva

A
  • cornea
    • ​Immune-privilege & angiogenic privilege both are present
    • No lymphoid cells under physiological conditions
    • MHC class II presenting langerhans cells only in peripheral cornea
    • Few bone-marrow derived macrophage-like cells in anterior and posterior stroma
  • conjunctiva
    • ​lamina-propria rich in CALT
    • presence of specialized endothelial venules for regulated migration of lymphoid cells
    • Diffuse lymphoid populations in all conjunctival zones (lymphocytes CD4 & CD8 cells & plasma cells IgA secretions)
    • Lymphoid follicles with B cells & parafollicular T cells normally present
    • Macrophages, dendritic langerhans cells, mast cells, frequent in lamina propria. Existence of M cells known in rat conjunctiva but only suspected, not proven in humans.
    • Granulocytes emigrate only if recruited during immune response
39
Q

Antigens contacting the ocular surface - CALT

A
  • APCs w/ MHC II bind to antigen on surface of eye
  • Conjunctival associated lymphoid tissue (CALT) - macrophages & langerhans from limbal region act as APC’s
  • Epithelium that lies on CALT have microvillae which aids in capturing antigen on ocular surface. (Similar to M cells in gut)
  • Langerhan cells exhibiting MHC II cross epithelium & present to T lymphocytes & lymphatic channels drain to regional lymph nodes
  • Antigen-sensitized CD4 & CD8 T cells migrate into thoracic duct or lymphatic duct to reach the blood stream.
  • These migrating cell enter effector sites (all mucosal surface) where terminal differentiation, synthesis, and transportation of IgA occur.
    • Sensitizing & tolerance of one mucosal surface sensitizes/tolerance all.
40
Q

Intranasal immunization against HSV

A

infection by using a recombination glycoprotein D fused with immunomodulating proteins, the B subunit of E.coli heat-labile enterotoxin and IL-2

Pathophys (9 decks)

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