Day 13 (1): Ocular Immunology and Inflammation Flashcards
What is uveitis?
- intraocular inflammation involving the uveal tract (iris, ciliary body, choroid)
- 10 - 15% of blindness
- young and middle-aged population
- irreversible blindness due to the permanent damage on the intraocular structures brought about by the inflammatory response
- the DEGREE of inflammatory response dictates whether visual function will be affected
- precise etiology and pathogenesis unknown
- involves BOTH innate and adaptive response
Elements:
1. Genetic susceptibility
2. Triggers (infection, autoimmunity, trauma, neoplasm)
What are the cells involved in the immune response?
INNATE RESPONSE
A. Granulocytes/PMN WBCs
- Neutrophils
- Basophils (blood), Mast cells (tissues)
- Eosinophils
B. Agranulocytes
- Monocytes (blood), Macrophages (tissues)
- Epithelioid cells: specialized macrophages which form Giant Cells
C. Natural Killer Cells: granular non-antigen-specific lymphocytes
D. Dendritic cells: antigen-presenting cells
- Langerhans cells: specialized dendritic cell in the conjunctiva
ADAPTIVE RESPONSE
A. B-Lymphocytes
- Plasma cells: produce antibodies
- Memory B-cells: subsequent infections
- T-independent B-cells
B. T-Lymphocytes
- (CD8) Cytotoxic/Killer T-cells: directly kills cells
- (CD4) Helper T-cells: activates B-cells
- Memory T-cells: either cytotoxic or helper
Discuss the components and the characteristics of the INNATE and ADAPTIVE immune response.
INNATE RESPONSE
- first line of defense against all pathogens
- activated immediately and functions primarily within the first 12 hours of infection
- pre-programmed and non-antigen-specific
- important in uveitic entities induced by INFECTION
1st line defense: Epithelial barrier
2nd line defense:
- Effector cells: Neutrophils, Monocytes, Macrophages, Dendritic cells, NK cells
- Pattern recognition receptors: Toll-like receptors, NOD proteins)
- Acute phase proteins: Cytokines, CRP, Complement, Antimicrobial peptides
ADAPTIVE RESPONSE
- second line of defense activated hours to days after the infection
- customized and antigen-specific
- activated lymphocytes depend on the type of antigen presented by the APCs
- important in uveitic entities induced by AUTOIMMUNE RESPONSES
Lymphoid organs:
1. Primary: Bone Marrow
2. Secondary: Lymph nodes, Spleen, MALT, CALT
Effector Cells:
1. T-lymphocytes: cell-mediated immunity
2. B-lymphocytes: antibody-mediated immunity
Distinct from innate response for 2 reasons:
1. Priming: requires initial contact with an antigen through an APC for activation
2. Memory: subsequent antigen exposure produces a more rapid and robust response through memory lymphocytes
What are the functions of the different lymphocytes in adaptive immunity?
A. B-lymphocytes
- Humoral (antibody-mediated) immunity
- activated to Plasma cells which exit to tissues
- responsible for the memory response in subsequent infections
- produce antibodies which:
- Neutralize microbes
- Enhance phagocytosis by opsonization
- Activate the complement system
B. T-lymphocytes
- Cell-Mediated Immunity
- Cytotoxic T-lymphocytes (CD8)
- direct killing of infected cells - Helper T-lymphocytes (CD4)
- calls for reinforcements by induction of inflammation, recruitment of macrophages, activation of more lymphocytes
What are the immune cells found in the eye?
Ocular Surface
- Dendritic cells (APC)
- Helper (CD4) T-cells
- T-suppressor cells
Cornea
- Langerhans cells (APC)
- Lymphocytes: only in the peripheral epithelium
Conjunctiva
1. Epithelium
- Langerhans cells (APC)
- Cytotoxic (CD8) T-cells
- Goblet cells
- Substantia propria
- Innate: Polymorphonuclear WBCs, Mast cells, Macrophages, NK cells
- Adaptive: Plasma cells (with Ig), Lymphocytes
What are Antigen-Presenting Cells?
Cells that bind, take up and degrade microbial agents and products and present them to other cells (especially effector cells of the Adaptive Immune System) for a more robust immune response
What are Toll-like Receptors?
- Transmembrane receptors located in APCs that identify and process pathogen-associated molecular patterns with antigen binding
- Successful binding induces the expression of proinflammatory cytokines, chemokines and MHC molecules
- locations in the uveal tract:
- Perivascular
- Sub-epithelial
What is the Complement system?
Complement
- plasma proteins that augment the opsonization of pathogens by antibodies and induction of inflammation
- “compliments” the antipathogenic activity of Ab
- secreted by hepatocytes and monocytes
A. Pathways for C3 Convertase Production:
- Classical Pathway
- activated by the ADAPTIVE immune system or by a SPECIFIC antigen - Alternative Pathway
- activated by the INNATE immune system secondary to any antigen (NON-SPECIFIC) - Lectin Pathway
B. COMMON Pathway
1. C3 convertase (C4BC2A) cleaves C3 into:
- C3: most important protein in the system
- C3A: anaphylatoxin (for inflammation)
- C3B: opsonin for opsonization
- Another C3B binds to C3 convertase to form C5 convertase (C4BC2AC3B) w/c cleaves C5:
- C5A: anaphylatoxin (for inflammation)
- C5B: initiates formation of MAC - C5B binds to complements C6-C9 to form the Membrane Attack Complex (C5BC6C7C8C9)
What is the Membrane Attack Complex?
- pore-like structure composed of complements C5B, C6, C7, C8 and multiple copies of C9
- binds to the outer surface of the plasma membranes of pathogens to form transmembrane channels which disrupt the membrane and cause cell lysis
What are the three main functions of the complement system?
- Opsonization (C3B)
- complement coats pathogens and enhances the phagocytic capabilities of the macrophages
- similar to how antibodies work - Inflammation and chemotaxis (C3A, C5A)
- complement fragments that act as chemoattractants to recruit more phagocytes and inflammatory cells to the inflammation site
- activates mast cells which release histamine and other vasoactive products which induce vasodilation - Cell lysis (MAC: C5BC6C7C8C9)
- pore-forming structure that causes cell lysis and death
What are immunoglobulins?
- glycoprotein molecules produced by plasma cells (activated B-lymphocytes)
Types:
1. IgM: largest, first to appear and to be lost; cannot cross placenta due to size
- IgG: 2nd to appear but lasts for a long time; able to cross the placenta; most abundant
- IgA: found in tears and mucosa
- IgE: produced only in response to allergy and parasitic infections; induces basophil and mast cell degranulation to release histamine and vasoactive products
- IgD: antigen receptor on B-lymphocytes
Note: B-lymphocytes
- surface contains IgM and IgD
What are cytokines?
- peptides important in cell signalling
- Interleukins (1, 2, 4, 6, 10, 12)
- regulates the activity of immune effector cells, fibroblasts and IFN-Y production - Interferon-Gamma (IFN-Y)
- tumor cell destruction
- inhibition of T-lymphocyte proliferation - Tumor Necrosis Factor (TNF)
- Chemokines
- Transforming Growth Factors (TGF) and Platelet-Derived Growth Factors (PDGF)
- Vasoactive Intestinal Peptides
What is the Human Leukocyte Antigen (HLA) complex or the Major Histocompatibility Complex (MHC)
- 4-megabase region on Chromosome 6 that codes for cell surface proteins essential for the immunologic specificity, transplant rejection and autoimmunity
- found on all antigen-presenting cells
Functions:
1. Tissue-antigen that allows the immune system to bind to, recognize, and tolerate itself (autorecognition)
2. Chaperone for intracellular peptides that are presented to T cell receptors (TCRs) as potential foreign antigens
Types:
1. MHC Class I: HLA-A, -B, -C
- CD8/Cytotoxic T-lymphocytes
- T-regulatory cells
- T-suppressor cells
- NK cells
- MHC Class II: HLA-D
- CD4/Helper T-lymphocytes
- B-lymphocytes
- APC: Monocytes, Macrophages, Dendritic cell
What are Helper T-lymphocytes?
- responds to MHC Class II receptors in APCs
- activates naive CD8 T-cells and B-cells
- prototype: delayed hypersensitivity reactions
A. Th1-Mediated
- produce IL2, IL12, IFN-Y, TNF-B
- helps IgG secretion
- examples:
1. Type IV (Delayed) Hypersensitivity
2. PPD reaction
3. Intracellular and fungal infections
4. T-cell mediated autoimmune diseases
5. Transplant rejection
B. Th2-Mediated
- produce IL4, IL5, IL10
- helps IgE and IgA secretion
- examples:
1. Parasitic infections
2. Allergic reactions
3. Asthma
4. Atopy
What are Cytotoxic T-lymphocytes?
- respond to MHC Class I receptors in APCs
- interacts w/ IL2 & IL12 made by T-helper cells
- kills infected cells by:
- Perforins: glycoproteins responsible for pore formation in cell membranes causing cell lysis
- Fas ligand: member of the TNF family that induces apoptosis
