PATHOGENIC MECHANISMS OF UVEITIS - cvm.ncsu.edu · PATHOGENIC MECHANISMS OF UVEITIS. Brian C....

PATHOGENIC MECHANISMS OF UVEITIS

Brian C. Gilger, DVM, MS, Dipl. ACVO, Dipl. ABT

Professor of Ophthalmology

North Carolina State University

College of Veterinary Medicine

Raleigh, North Carolina, USAbgilger@ncsu.edu

PATHOGENTIC MECHANISMS OF UVEITIS - OVERVIEW

• Anatomy• Physiology• Immunology / uveitis• Pathogenic

Mechanisms

Anatomy• Iris• Ciliary body• Choroid

UVEITIS - UVEAL TRACT

UVEITIS - UVEAL TRACT

Anatomy• Iris• Ciliary body• Choroid

Function• Vascular • Light control• Accommodation• Aqueous production

Blood-ocularBarrier

Blood-aqueous barrier

Blood-retinal barrier

IMMUNOLOGY / UVEITISImmune “privileged” Site

Develops through the presence of:

• Immune ignorance

• Immune tolerance

• Development of an immunosuppressive microenvironment

IMMUNE IGNORANCE

•“There is no one there”

•When presentation of an antigen to the immune system is impeded

•Due to ocular tissue lack of:• Activated leukocytes

• low #s of APCs

IMMUNE TOLERANCE• I know you are there, but I don’t

care:

• Active induction of immune non-responsiveness of the systemic immunity to antigens in the aqueous humor

• Anterior chamber immune deviation (ACAID)

• Anergy of CD4+ T helper cells when stimulated by non-professional APCs

IMMUNOSUPPRESSIVE MICROENVIRONMENT

• Aqueous humor• Immunosuppressive

substances, such as TGFb

• If tolerance or ignorance is impaired then uncontrolled access to antigens occurs with severe inflammation +/-development of autoimmune disease

OCULAR IMMUNOLOGY

www.streilein-foundation.org

Review:

• The eye has evolved a complex network of mechanisms to maintain immunological homeostasis

• Designed to respond rapidly to environmental and microbial insults, whereas maintaining tolerance to self-antigens and commensal microbes

• Activation of the innate and adaptiveimmune response is tightly regulated to limit bystander tissue damage.

• Aberrant activation of the immune system can result in autoimmunity to self-antigens

PATHOPHYSIOLOGY - UVEITIS

Breakdown of the Blood -Aqueous Barrier

• Influx of inflammatory cells

• Plasma and blood products

ACUTE UVEITIS

UVEITISAfferent (induction) Stage Efferent (expression) Stage

Naïve CD4+ T cell

APC+Ag(Periphery)

ActivationClonal expansion

Migration &Penetration into eye

In situ antigen recognition andlocal production of cytokinesand chemokines

Induction of adhesion moleculeson retinal blood vessels

Breakdown of blood retinal barrier

Photoreceptor damageand retinal scarring

TGF-β

IL-6

TH17

TH2

Naıve CD4 + T cells differentiate into effector subsets depending on the nature of the environment in which exposure to the antigen occurs

Merida, 2015

Naıve CD4 + T cells differentiate into effector subsets depending on the nature of the environment in which exposure to the antigen occurs

Caspi, 2011 IOVS

PATHOGENIC MECHANISMS

Specific and the nonspecific activated Tcells penetrate the eye at random in small numbers; however, only antigen specific cells (or auto-antigen) recruit cells and cause uveitis

Caspi, 2011 IOVS

TH17 EFFECTOR T CELL• TH17 cells are a subset of CD4+ T-helper cells that produce IL-17.

• IL-17 is involved in inducing and mediating proinflammatory responses

• The increased expression of chemokines attracts other cells, including neutrophils but not eosinophils.

• Data from experimental uveitis models in rodents also point to a significant role of IL-17 in uveitis.

• In ERU, strong immunoreactivity for IL-17 in the non-pigmented ciliary epithelium and in mononuclear cells infiltrating the iris and ciliary body suggested that IL-17-secreting TH17 cells play a role in the pathogenesis of ERU.

DEVELOPMENT OF INFLAMMATIONCytokine function leading to inflammation:

1. Induce endothelial cells, RPE, CE to produce prostaglandins and NO

2. Endothelial cells become adhesive• Induction of adhesion molecules

3. Induce chemokine production (IL-8, MCP-1, lymphotactin, RANTES)• Attract monocytes and leukocytes

4. Induce endothelial changes• Increased extravasation of cells

Aqueous flare and cellswith acute inflammation

TOLL-LIKE RECEPTORS AND THE EYE• Part of innate immune system

• First line defense against pathogens

• Type I transmembrane proteins• Extracellular (exodomain) -

recognition• Intracellular (ectodomain) -

signaling

• Each TLR recognizes a pathogen-associated molecular pattern (PAMP)

• Different PAMPs stimulate different TLRs and induce distinct patterns of cellular response.

Toll receptor (TLR)

Exodomain

Extracellular

Intracellular

Ectodomain

N terminus

C terminus

Juxtamembrane region

Transmembrane region

BB loopTIRDomain

Allows eye to avoid ACAID in infections?

TOLL-LIKE RECEPTORSPathogen-associated molecular patterns (PAMPs) Infections

Damage associated molecular patterns (DAMPs). Tissue damage

PATHOGENIC MECHANISMS

Specific and the nonspecific activated Tcells penetrate the eye at random in small numbers; however, only antigen specific cells (or auto-antigen) recruit cells and cause uveitis

Caspi, 2011 IOVS

Intraocular TLR – Link between innate and adaptive immune system?Toll-like receptors (TLRs) are integral to the initial recognition of organisms or antigens

•TLR2 is an important component of the initial ocular response to B. cereus endophthalmitis

Novosad BD, et al. PLoS ONE 2011; 6(12)

•Up-regulation of TLR-2 and -9 in the ciliary body and TLR-2 in the iris in eyes with immune-mediated uveitis

Yi, Gilger. J Vet Clin 2009; 26 6 520-523

CHRONIC AND RECURRENT UVEITIS

1. In inflammation - general loss of tolerance “OK, now I care that you are there!”

2. Adaptive immune system is up-regulated “Call to arms – armies mobilized”

3. Cross reaction between infectious agents and self-antigens “Innocent bystander injury” / Autoimmunity

4. Epitope is recognized.

5. Neoepitopes are formed, recognized- New inflammatory process

develops

Chronic ocular disease and autoimmunity

Random ocular penetration of peripherally activated CD4+ Tcells

Deeg CA, et al. Inter- and Intramolecular Epitope Spreading in Equine Recurrent Uveitis. IOVS 2006:47:652-656.)

A B A B AA B

T T

TT

T

Ocular tissueantigens

Inflammation results in the influx of inflammatory cells

A B A B A BA B

T T

TT

T

Deeg CA, et al. Inter- and Intramolecular Epitope Spreading in Equine Recurrent Uveitis. IOVS 2006:47:652-656.)

Inflammation results in the influx of inflammatory cells and reaction to self-antigen

A B A B A BA B

T T

TT

T

Deeg CA, et al. Inter- and Intramolecular Epitope Spreading in Equine Recurrent Uveitis. IOVS 2006:47:652-656.)

Inflammation results in the influx of inflammatory cells

A B A B A BA B

TT

T

TT T

Autoimmunity

Deeg CA, et al. Inter- and Intramolecular Epitope Spreading in Equine Recurrent Uveitis. IOVS 2006:47:652-656.)

Inflammatory episode ceases when regulatory cells get the upper hand in inflammation.

A B A B A BA B

TT

R R R R

Deeg CA, et al. Inter- and Intramolecular Epitope Spreading in Equine Recurrent Uveitis. IOVS 2006:47:652-656.)

The next Inflammatory episode generated by a shift of response to another epitope of the same autoantigen

A A B A BA B

TT

B2

Deeg CA, et al. Inter- and Intramolecular Epitope Spreading in Equine Recurrent Uveitis. IOVS 2006:47:652-656.)

Neoepitope

The next inflammatory episode generated by a shift of response to another epitope of the same autoantigen

A A B A BA B

T

B2

Intramolecular spreading

Deeg CA, et al. Inter- and Intramolecular Epitope Spreading in Equine Recurrent Uveitis. IOVS 2006:47:652-656.)

The next inflammatory episode generated by a shift of response to another epitope of the same autoantigen

A A B A BA B

T

B2

Intramolecular spreadingT T

T T

T

Deeg CA, et al. Inter- and Intramolecular Epitope Spreading in Equine Recurrent Uveitis. IOVS 2006:47:652-656.)

The next inflammatory episode generated by a shift of response to another autoantigen.

A A B A BA B

TT

B2

Deeg CA, et al. Inter- and Intramolecular Epitope Spreading in Equine Recurrent Uveitis. IOVS 2006:47:652-656.)

The next inflammatory episode generated by a shift of response to another autoantigen.

A A B A BA B

T

T

B2

Intermolecular spreading

Deeg CA, et al. Inter- and Intramolecular Epitope Spreading in Equine Recurrent Uveitis. IOVS 2006:47:652-656.)

The next inflammatory episode generated by a shift of response to another autoantigen.

A A B A BA B

T

B2

Intermolecular spreading

Deeg CA, et al. Inter- and Intramolecular Epitope Spreading in Equine Recurrent Uveitis. IOVS 2006:47:652-656.)

The next inflammatory episode generated by a shift of response to another autoantigen.

A A B A BA B

T

B2

Intermolecular spreading

TTT

TT

TT

Deeg CA, et al. Inter- and Intramolecular Epitope Spreading in Equine Recurrent Uveitis. IOVS 2006:47:652-656.)

RESOLUTION OF UVEITIS

RESOLUTION OF UVEITISResolution of uveitis:• Dependent on the presence of T regulatory cells (Tregs)

(CD4+Foxp3+ cells).

• In disease process, when % of Foxp3+ T cells increases to10% of the total CD4+ cells; acute inflammation rapidly resolves.

• Foxp3+ Tregs are instrumental in bringing about spontaneous resolution and in maintaining remission (Silver, et al 2015).

• Foxp3+ Tregs maintains a state of remission by acting locally within the eye to dampen acute inflammation and prevent its recurrence (Silver, et al 2015).

• Human leukocyte antigen (HLA)-G may induce expression of CD4+Foxp3+ Tregs

TO EFFECTIVELY TREAT UVEITIS:Decrease activation:

• Prevent systemic inflammation / activated T-cells• Induce tolerance to antigens by APC /dendritic• Minimize exposure of ocular antigens to Th17 cells• Inhibit T-cell function and cytokine release

Decrease inflammation• Limit production of PG and NO• Decrease adhesion molecule function• Decrease or inhibit chemokines• Enhance expression of CD4+Foxp3+ Treg cells

REFERENCESDeeg CA, et al. Inter- and Intramolecular Epitope Spreading in Equine Recurrent Uveitis. Invest Ophthalmol Vis Sci 2006:47:652-656

Gilger BC. Immunology of the ocular surface. In, Williams DA Ed, Veterinary Clinics of North America Small Animal. Elsevier, Philadelphia, 2008;38:223-231.

Novosad BD, et al. Role of Toll-Like Receptor (TLR) 2 in Experimental Bacillus cereusEndophthalmitis. PLoS ONE 2011; DOI: 10.1371/journal.pone.0028619

Pflugfelder, S. C. and M. E. Stern. Immunoregulation on the ocular surface: 2nd Cullen Symposium. Ocul Surf 2009; 7(2): 67-77.

Redfern et al. Experimental Eye Research, 2010; 90; 6: 679 - 687

Stern, M. E., C. S. Schaumburg, et al. Autoimmunity at the ocular surface: pathogenesis and regulation. Mucosal Immunol 2010: 3(5):425-442.

Stern ME, et al. Dry Eye as a Mucosal Autoimmune Disease. International Reviews of Immunology 2013 32:1,19-41

Yi NY, Gilger BC. Quantitative Differences in mRNA Expression of Toll-like Receptor (TLR)-2, -4, and -9 in Normal Equine Eyes and Eyes with Equine Recurrent Uveitis. J Vet Clin 2009; 26 6 520-523.

QUESTIONS / COMMENTS?

South Kaibob TrailGrand Canyon National Park

April 2008