HI23/24 - Immunology of the Eye and Autoimmune Diseases

Biomedical Sciences IV

What structures protect the eye at the ocular surface?

Eyelids, conjunctiva, corneal and conjunctival epithelium, and tear film.

What are the components of the tear film that contribute to immunity?

Secretory IgA, antimicrobial proteins (lactoferrin, lysozyme, defensins), mucins (MUC1, MUC4, MUC16), and blinking-induced clearance.

What is the role of secretory IgA in the tear film?

Neutralizes pathogens, prevents adherence, facilitates immune exclusion.

What is the function of lactoferrin?

Binds iron required for bacterial growth.

What is the function of lysozyme?

Breaks down peptidoglycan in bacterial cell walls.

What is the function of defensins?

Create pores in microbial membranes.

What is the role of mucins?

Trap microbes, stabilize tear film, provide lubrication.

What immune cells are present in the conjunctiva?

Dendritic cells and other antigen-presenting cells.

What immune cells reside in the ocular epithelium?

CD8+ T cells, innate lymphoid cells, NK cells, γδ T cells.

Why is the eye associated with a dampened immune response?

To prevent inflammation that could impair vision.

What is ocular immune privilege?

The eye's ability to limit immune and inflammatory responses to preserve vision.

Why is immune privilege necessary in the eye?

The eye has limited regenerative capacity, and inflammation can cause vision loss.

What classical experiment demonstrated ocular immune privilege?

Medawar’s 1940s experiment showing that foreign grafts in the anterior chamber were tolerated, unlike grafts placed elsewhere.

What physical barriers contribute to ocular immune privilege?

• Blood-retinal barrier (tight junctions)

• Retinal pigment epithelium

• Bruch’s membrane

• Lack of efferent lymphatics

• Aqueous humor drainage via trabecular meshwork instead of lymphatics

What immunosuppressive molecules exist in the ocular microenvironment?

TGF-β, IL-10, macrophage inhibitors, NK cell inhibitors, complement regulators.

What does TGF-β do in the eye?

Suppresses NK cells, macrophages, T cells, promotes regulatory T cell development.

What mechanisms suppress T cell activation in the eye?

• Downregulation of CD4 and CD8

• Low CD86 in uveal tissues

• IDO enzyme in APCs (depletes tryptophan)

• Fas/FasL-induced apoptosis of activated T cells

• Complement regulators

What is ACAID?

A systemic immune tolerance induced when antigens enter the anterior chamber.

What cells mediate ACAID?

F4/80+ macrophages, regulatory T cells, and TGF-β signaling.

Does ACAID activate Tregs or effector T cells?

Primarily Tregs.

How does release of previously “hidden” ocular antigens cause disease?

Leakage into bloodstream or presentation by APCs activates autoreactive T/B cells → immune attack on the eye.

What is immune tolerance?

The immune system's ability to avoid attacking self-antigens.

What is autoimmunity?

A harmful immune response against self-antigens.

What is autoimmune disease?

Tissue damage caused directly by autoimmune activity.

What is a rheumatic disease?

Autoimmune inflammation of connective tissues.

How does autoimmunity differ from autoinflammation?

• Autoimmunity = adaptive immunity (T/B cells) reacting to self

• Autoinflammation = innate immune activation without antibodies or autoreactive T cells

• Diseases often exist on a continuum

What are the main strategies the body uses to maintain tolerance?

• Evasion: Immune privilege

• Elimination: Central and peripheral tolerance

• Engagement: Regulatory T cell suppression

Where does central tolerance occur for B and T cells?

• B cells: bone marrow

• T cells: thymus

What is negative selection?

Elimination of self-reactive lymphocytes before they enter circulation.

What gene allows thymic cells to express peripheral self-antigens?

AIRE (Autoimmune Regulator).

What causes anergy in lymphocytes?

Lack of required co-stimulation.

What do B cells require for activation?

T-helper cell signals (CD40/CD40L and cytokines).

What do T cells require for activation?

Antigen presentation + co-stimulation from activated dendritic cells.

What do Tregs secrete?

TGF-β and IL-10.

How do Tregs suppress immune responses?

• Induce apoptosis in effector T cells

• Suppress APC co-stimulatory molecules

• Cytokine suppression

What Treg defects lead to autoimmunity?

Low numbers, poor function, or effector T cell resistance.

What six major triggers contribute to autoimmune disease?

1. Genetics (especially HLA)

2. Diet

3. Infections

4. Environmental exposures (smoking, UV)

5. Hormonal changes

6. Loss of immune privilege

Which sex develops more autoimmune diseases?

Women (78% of cases).

Why are women more prone to autoimmunity?

Stronger antibody and TH2 responses.

Why are men more prone to worse acute disease outcomes?

Stronger TH1 inflammatory responses.

What characterizes acute autoimmune diseases?

• Occur before age 50

• TH1/IFN-γ mediated

• Cell-mediated destruction

What characterizes chronic autoimmune diseases?

• Occur after age 50

• TH2/IL-4 mediated

• Autoantibody-driven

• Fibrosis common

What autoantibodies are associated with autoimmune disease?

ANA, anti-DNA, RF, anti-Sm, anti-Ro, anti-La.

What defines a Type II autoimmune reaction?

IgG/IgM antibodies target cell-surface or matrix antigens.

What are the 4 possible consequences of Type II antibody binding?

• Opsonization/phagocytosis

• Complement activation

• ADCC by NK cells

• Altered cellular signaling

What is the target antigen in pemphigus vulgaris?

Desmosomal proteins in epithelial junctions.

Clinical features of pemphigus vulgaris?

• Painful oral lesions first

• Skin blistering

• Burning vesiculobullous lesions

• Nikolsky’s sign positive

Possible triggers of pemphigus vulgaris?

Medications, dietary components, idiopathic.

Treatment of pemphigus vulgaris

Systemic steroids and immunosuppressants.

What other diseases are associated with pemphigus vulgaris?

RA, Sjögren’s, SLE.

What is the target antigen in mucous membrane pemphigoid?

Hemidesmosomes in basement membrane.

Symptoms of mucous membrane pemphigoid?

• Oral and conjunctival blistering

• Desquamative gingivitis

Treatment for mucous membrane pemphigoid?

Steroid gels; systemic therapy for advanced disease.

Describe the staging of Ocular Cicatricial Pemphigoid (OCP).

• Stage I: Chronic conjunctivitis, fibrosis

• Stage II: Fornix shortening (<11 mm)

• Stage III: Symblepharon formation

• Stage IV: Ankyloblepharon, keratinization, severe adhesions

What is the autoantibody in Graves disease?

IgG autoantibody that stimulates the TSH receptor, resulting in hyperthyroidism.

What are the symptoms of Grave’s disease?

Heat intolerance, irritability, weight loss, tachycardia, exophthalmos.

How does thyroid eye disease develop?

Autoantibodies stimulate orbital fibroblasts → produce GAGs → inflammation → muscle enlargement and fat expansion.

What are the key symptoms of thyroid eye disease?

• Lid retraction

• Proptosis

• Diplopia

• Optic neuropathy

What is the autoantibody in Myasthenia Gravis?

IgG against acetylcholine receptors.

What is the pathophysiology of MG?

Receptor blockade + internalization → weak neuromuscular transmission.

What are the symptoms of MG?

Ptosis, diplopia, fatigue, trouble swallowing, dyspnea.

What defines a Type III autoimmune reaction?

Immune complex deposition (IgG + soluble antigen) causing inflammation and complement activation.

What immune complexes are typical in Systemic Lupus Erythematosus (SLE)?

IgG binding to DNA, histones, and nucleoproteins.

Who is most affected by SLE?

Women (90%).

Clinical features of SLE?

• Butterfly rash

• Photosensitivity

• Arthritis

• Renal disease

• CNS involvement

• Hematologic abnormalities

What is epitope spreading in SLE?

Damage releases new antigens → more autoantibodies → broadened immune attack.

Common autoantibodies in SLE?

ANA, anti-dsDNA, anti-Sm.

What defines Type IV hypersensitivity?

T-cell mediated immune response.

What cells are involved in Type IV hypersensitivity?

CD4+ TH1 cells (macrophage activation) and CD8+ cytotoxic T cells (direct killing).

Why are Type IV responses delayed?

Time is needed for antigen processing and T-cell recruitment.

What is the mechanism of Hashimoto’s Thyroiditis?

TH1-mediated inflammation destroys thyroid tissue.

What is the resulting condition of Hashimoto’s Thyroiditis?

Hypothyroidism.

Symptoms of Hashimoto’s Thyroiditis?

Fatigue, weight gain, depression, gingival edema, enlarged tongue.

What forms in the thyroid in HT?

Ectopic lymphoid tissue (“germinal center–like structures”).

What mediates Type 1 diabetes?

CD8+ T cells destroy pancreatic beta cells.

Physiologic result of Type I diabetes?

No insulin production. Can lead to diabetic retinopathy long term.

Symptoms of Type I diabetes?

Polyuria, polydipsia, polyphagia, weight loss.

What cells are attacked in Multiple Sclerosis?

Oligodendrocytes and myelin.

What environmental factor increases MS risk?

Higher latitude and EBV infection.

What is the mechanism for MS?

TH1 cells + macrophages + autoantibodies cause demyelination.

What are the ocular manifestations of MS?

Optic neuritis, ocular motor dysfunction.

What glands are targeted in Sjogren’s syndrome?

Lacrimal and salivary glands.

Major symptoms of Sjögren’s Syndrome?

Keratitis sicca, xerostomia (dry mouth, dry eyes)

What are the associated antibodies of sjogren’s syndrome?

Anti-Ro (SSA) and anti-La (SSB).

Who is most affected in Sjogren’s?

Women (9:1).

What diseases often coexist with Sjogren's?

RA and SLE.

What is the mechanism for Juvenile Idiopathic Arthritis?

T cells attack synovium in children <16 years.

What is the major ocular complication for Juvenile Idiopathic Arthritis?

Chronic uveitis. (Cataracts in kids)

Mechanisms of joint damage in Rheumatoid Arthritis?

• Immune complexes (ACPAs)

• T-cell–mediated inflammation

• Release of MMPs

• TNF-α, IL-6, RANK-L activation

• Bone erosion

RA ocular complications?

Dry eye (secondary Sjogren's), episcleritis, scleritis, corneal melt, uveitis, retinal vasculitis.

Characteristics of Behcet’s disease?

• Multisystem inflammatory vasculitis

• Oral and genital ulcers

• Ocular inflammation in 70%

Ocular features of Behcet’s Disease?

• Recurrent anterior/posterior uveitis

• Necrotizing vasculitis

• Retinal damage

Mechanism of psoriasis vulgaris?

TH1/TH17/TH22 activation + autoinflammatory pathways.

What triggers keratinocyte activation in psoriasis vulgaris?

DAMPs and MAMPs released from injured cells, resulting in hyperproliferation and scaling plaques.