EYE IMMUNOLOGY

Ophthalmic immunology

Protective mechanisms

Question.1

Diversity Vs Tolerance

Question.2

Tolerance

Clonal DeletionReceptor editingAnergyIgnoranceDownregulation by: Treg

Diversity Vs Tolerance

Mechanisms of immune privilege in the eye

First, the eye is filled with immunosuppressive factors including:

• neuropeptides• melanocyte stimulating hormone• somatostatin • vasoactive intestinal peptide • calcitonin gene related peptide • cytokines (e.g. TGFβ-2)• complement inhibitors • inhibitor of NK cell activity (macrophage inhibitory factor) .

Mechanisms of immune privilege in the eye

• Second, the low expression of MHC class II in the eye limits antigen presentation.

Mechanisms of immune privilege in the eye

• Third, stromal cells from the iris, ciliary body and retina of the eye are able to convert immune T cells to regulatory (Treg) cells .

Furthermore retinal pigment epithelial (RPE) cells that line the borders of the eye are able to directly inhibit primed T cells.

Mechanisms of immune privilege in the eye

• Fourth, death inducing molecules like PDL-1 and FasL are expressed by stromal cells in the eye and induce apoptosis of immune cells that transgress ocular boundaries

Mechanisms of immune privilege in the eye

• Fifth, Immobility of Dendritic Cells Within the Anterior Chamber and Anterior Chamber Associated Immune Deviation

failure of these antigen-bearing cells to migrate to the local lymph nodes . The inability to migrate is consistent with the known lack of lymphatics within the eye

Immune response without inflammationImmune response without inflammation

Anterior chamber associated immune deviation

In this model, the placement of antigen into the anterior chamber of the eye induces a characteristic immune response that includes the absence of complement fixing antibodies and Th1 and Th2 immune responses specifically to that antigen. However, the animal remains perfectly capable of responding to the antigen.

Generation of Foxp3+ CD8+ Treg cells :T-cell receptor α-chain fragments from apoptotic cells arepresented in the class I pathway. This event generates CD8 killer cells,which are capable of deleting the CD4 T cells

a. Cross-Immunization

b. Co-Stimulation of anergic clones

by superantigen

Termination of Tolerance

Immunological Pathomechanisms

HLA-B27 ≈ arrestinHLA-B27 ≈ arrestin

Conjunctivitis

Keratitis

Scleritits and Uveitis

Termination of Tolerance

Scleritits

Uveitis

Uveitis

Uveitis

Uveitis

Panuveitis

Presentation of auto antigen because of MHC II expression on melanocyte perhaps to viral infection

Uveitic condition in sympathic ophthalmia

Inflammation of the pars plana, a part of the ciliary body.

Therapeutic implicationsTherapeutic implications• T cell–targeting therapies such as: cyclosporine, FK-506, and rapamycin, which are already FDA

approved and in clinical use and Humanized CD25-specific antibody (daclizumab)

• Anti-TNF therapy

• IFN-α is being used with considerable success to treat uveitis in patients with Behçet disease and has been approved in Europe

• Oral tolerance to arrestin

• IL-17 neutralization therapy

• Blockade of the chemokine receptors CXCR3 and CXCR5

• VLA4-specific monoclonal antibody is an FDA approved treatment for multiple sclerosis and Crohn disease

• Why are mismatched cadaver cornea grafts accepted 60–70% of the time in humans?

Post-transplant event: These events are local episodes of alloantigen independent inflammation, such as a loosened transplant suture, bacterial suture-associated infection, or herpetic infection recurrence. These lead to recruitment of alloreactive cells, angiogenesis, lymphangiogenesis, and upregulation of MHC molecules on the graft cells, and sequelae, which in combination lead to an acute onset rejection response.

When antigen injected into the anterior chamber , vitreous or sub-retinal space induces peripheral tolerance to that antigen.

Phcogenic Uveitis

AIDS

• Because cotton-wool spots are an early sign of AIDS, the ophthalmologist may be the first physician to alert the patient to the existence of this serious disorder.