Day 9 (2): Pathophysiology of Ocular Inflammation Flashcards
(39 cards)
What is the immune system?
- complex network of interacting cells, cell products and processes that work to defend the body against pathogens
Components:
1. Cellular components
- WBC: neutrophils, eosinophils, basophils, monocytes, lymphocytes
- Dendritic cells
- Natural Killer cells
- Tissue components
- Primary lymphoid tissue: bone marrow, thymus
- Secondary lymphoid tissue: lymph nodes, spleen
How are immune cells classified according to progenitor cells?
Hematopoeitic Stem Cells
- differentiate into:
- Myeloid Progenitor Cells
- RBCs
- Platelets
- MYELOcytes: mostly INNATE response
+ Neutrophils
+ Basophils
+ Mast cells
+ Eosinophils
+ Monocytes (Macrophages, Langerhans cells): BOTH
+ Dendritic cells: ADAPTIVE - Lymphoid Progenitor Cells
- LYMPHOcytes:
+ Natural Killer cells: INNATE
+ T-lymphocytes: CELL-mediated ADAPTIVE response
+ B-lymphocytes: ANTIBODY-mediated ADAPTIVE response
What are the cells involved in the INNATE immune response?
A. Granulocytes/Polymorphonuclear Leukocytes
- presence of granules in the cytoplasm
- multilobulated nucleus
- Neutrophil
- most abundant granulocyte
- phagocytic: bacteria, viruses
- releases granule products and cytokines - Basophils/Mast cells
- possess high-affinity receptors for IgE
- effector cells in IMMEDIATE hypersensitivity
- basophils: in the blood
- mast cells: in connective tissues - Eosinophils
- receptors for IL-5: responsible for it’s development
- effector cells in DELAYED hypersensitivity (atopy, asthma) and parasitic infections
- NOT a major effector cell in the eye except in helminthic infection
B. Agranulocytes
- no granules in the cytoplasm
- unilobulated nucleus
Monocytes/Macrophages: BOTH innate and adaptive
- can be activated into effector cells after exposure or phagocytosis of complement-coated pathogens or mediators
- innate: phagocytic cells that clear debris and pathogens
- adaptive: antigen-presenting cells to T-lymphocytes
- monocytes: in the blood
- macrophages: activated monocytes found in tissues
- Langerhans cells: special type in conjunctiva
C. Natural Killer cells (Non-T, Non-B cells)
- large, granular LYMPHOcytes
- cytotoxic lymphocytes involved in the INNATE response
- analogous to cytotoxic T cells of adaptive response
- provide rapid responses to viral infections, intracellular pathogens and tumor formation
- unique ability to recognize and kill stressed cells in the absence of antibodies and MHC, allowing for a much faster response
- named “natural killers” because they do not require activation to kill cells that are missing “self” markers of MHC class I.
- important because harmful cells that are missing MHC I markers cannot be detected and destroyed by other immune cells
What are the cells involved in ADAPTIVE immune response?
A. Dendritic cells
- antigen-presenting or accessory cells of myeloid OR lymphoid descent
- process and present antigens to T-lymphocytes
- initiates the process of quiescence in lymphocytes
B. Lymphocytes
- requires subsequent maturation in peripheral or secondary lymphoid tissues
- classified into 3 types based on surface markers
- B-cells
- develop in the BONE MARROW
- MOST require T-cells to be present for activation
- differentiates into:
+ Plasma cells: produce antibodies
+ Memory B-cells: for faster response in subsequent infections
+ T-independent B-cells: response to encapsulated bacteria with OPS layer enabling them to evade T-cells - T-cells
- develop in the THYMUS
- differentiates into:
+ Cytotoxic/Killer (CD8) T-cells: directly kill virus-infected cells
+ Helper (CD4) T-cells: indirect destruction by cytokine signaling to activate B-cells
+ Memory T-cells: may either have cytotoxic or helper functions
What are the two basic classifications of immune responses?
Immune Response
- sequence of molecular and cellular events which rid the host of an offending stimulus
Innate Immune Response/Natural Immunity
- genetically PRE-PROGRAMMED NON-SPECIFIC response determined by PRE-EXISTING receptors for a WIDE range of stimuli
- produce GENERIC mediators that recruit NON-SPECIFIC effector cells
- different stimuli –> generalized response
Adaptive Immune Response
- TAILORED response elicited by NEWLY-CREATED receptors in reaction to a UNIQUE antigen
- generate antigen-SPECIFIC mediators and effector cells which only act upon the particular antigen
- specific antigen –> unique response
- lengthy process because of the antigen processing and generation of unique mediators and effectors by specialized tissues of the immune system
What happens when an antigen is encountered by the body?
- Recognition
- foreign antigen is detected by receptors of the INNATE system - Activation
- activated receptors recruit pre-formed mediators and effector cells - Response
- pattern recognition and phagocytosis by macrophages
- inflammation by recruitment of other cells of the innate response
- maturation of macrophages and dendritic cells into antigen-presenting cells to activate the ADAPTIVE immune response
Compare the innate and adaptive immune response.
INNATE: non-specific stimuli producing a generalized response
Trigger: non-specific stimuli
Receptor-specificity: non-specific and pre-made
Speed: fast/hours (pre-programmed)
Effector cells: non-specific and pre-made (WBCs)
Memory: none; similar responses regardless of antigen or previous exposure
ADAPTIVE: specific stimuli producing a tailored response
Trigger: specific immunity acquired after a previous exposure
Receptor-specificity: antigen-specific
Speed: slow/days (still need processing and generation)
Effector cells: pre-made (WBCs) + antigen-specific (T and B cells)
Memory: enhanced specific response with succeeding exposures
What are the 3 phases of the Immune Response Arc of adaptive immunity?
Phase 1: Afferent Phase
- antigen stimulation, recognition and presentation
Phase 2: Processing Phase
- antigen processing in secondary lymphoid tissue (lymph nodes)
Phase 3: Efferent Phase
- production of antigen-specific mediators and effector cells to mount a tailored response directed only towards the specific antigen
Discuss the 1st Phase or the Afferent Phase of the Immune Response Arc.
Steps:
1. Recognition
- antigen stimulates and is recognized by pre-made receptors
- Transport
- antigen is transported by APCs via lymphatic channels to the lymph node - Presentation
- antigen is presented by APCs to T-cell receptors
Discuss the 2nd Phase or the Processing Phase of the Immune Response Arc.
Processing Phase
- conversion of antigenic stimulus into an immunologic response
- APCs present antigenic fragments to the naive lymphocytes in the lymph nodes causing their differentiation and activation
Steps:
1. Helper T-cell detection
- requires trimolecular complex: APC HLA molecule + antigen fragment + T cell antigen receptor
- Helper T-cell activation and differentiation
- undergo cell division, mediator synthesis and receptor expression
- release cytokines (especially IL2) for B cell and cytotoxic T-cell activation - B-cell and cytotoxic T-cell differentiation
- begin as naive lymphocytes
- activated by cytokine signaling from helper T-cells
Discuss the 3rd Phase or the Effector Phase of the Immune Response Arc.
- activated lymphocytes further secrete mediators and effectors which rid the body of the offending antigen
- 3 possible effector responses:
+ predominantly ANTIBODY-mediated
+ predominantly CELL-mediated
+ combined mechanism
Components:
1. Naive CD8 cells –> Cytotoxic T-cells
- express CD8 surface markers
- respond to MHC Class I receptors in APCs
- destroys tumor cells and virus-infected cells
- produce cytotoxic cytokines (TGF-B) and pore-forming molecules
- Naive CD4 cells –> Helper T-cells
- express CD4 surface markers
- responds to MHC Class II receptors in APCs
- activates naive CD8 T-cells and B-cells
- involved in delayed hypersensitivity reactions
- Th1 cells: produce IL2, IL12, IFN-Y, TNF-B; helps IgG secretion
- Th2 cells: produce IL4, IL5, IL10; helps IgE and IgA secretion
- Th17 cells: autoimmunity
- Regulatory T-cells: suppressive immunity - Naive B-cells –> Activated B-cells
- responds to MHC Class II receptors in APCs
- produce antibodies
+ IgA: secretory
+ IgE: allergens
+ IgG1 or 3: antibody-dependent cell-mediated cytotoxicity
+ IgG4: agglutination; delayed but long-lasting response
+ IgM: complement formation; immediate but short-lived response
What are Major Histocompatibility Complex molecules?
- 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
Discuss the ANTIBODY-mediated effector response.
- antibodies produce an immune response by attaching to antigens and forming immune complexes via 3 steps:
1. Neutralization - blocks ability of pathogen to attach to host cell
2. Opsonization - coating of pathogen with complement to enhance phagocytosis
3. Agglutination - multiple Ab bind on the Ag causing the complex to precipitate or deposit
Scenarios:
1. intravascular Ab attach to circulating Ag and form circulating immune complexes
2. in conditions with altered vascular permeability: passive leakage of Ab (especially IgG) can bind to tissue-bound Ag and form complexes that deposit in the tissues
3. B cells can actively infiltrate into tissues becoming PLASMA cells and produce Ab locally
- complex deposition in the tissues activate the complement cascade and trigger a local inflammatory response
End-point: Membrane-Attack Complex formation
- pore-like structures composed of activated complement
- attach to pathogens, forming an opening in the cell and causing cell lysis
What is the Goldman-Whitmer coefficient?
- compares the ratio of a SPECIFIC Ab in the intraocular fluid and serum to the ratio of TOTAL Ab in the two compartments
- differentiates between local Ab production and passive leakage from the blood
- GWC > 4: indicates local production within eye
Formula:
Specific Ab (ocular fluid)/Specific Ab (serum) ---------------------------------------------------------------- Total Ab in intraocular fluid/Total Ab in serum
What is the complement cascade?
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
Complement Cascade
- series of steps that result in the formation of different complement by enzyme activation
- part of the INNATE immune system: not adaptable and doesn’t change
- recruited and brought into action by Ab of the adaptive immune system
- activation of a small number of complement in the beginning is amplified with each successive reaction forming a RAPID and EXTENSIVE immune response
Pathways:
1. Classical Pathway: Ag-Ab complexes bind C1 and cleave C4 and C2 to form C3 convertase (C4BC2A)
- Lectin Pathway: serum lectin binds mannose in the pathogen and interacts with mannose-associate serine proteases to cleave C4 and C2 and form C3 convertase
- Alternative Pathway: continuously activated at low levels as a result of spontaneous C3 hydrolysis
- doesn’t rely on pathogen-binding Ab like 1 & 2 - Common Pathway:
- C3 convertase (C4BC2A) cleaves C3 into:
+ C3A: anaphylatoxin (for inflammation)
+ C3B: for opsonization
- another C3B binds to C3 convertase to form C5 convertase (C4BC2AC3B) which cleaves C5 into:
+ C5A: anaphylatoxin (for inflammation)
+ C5B: initiates formation of MAC - Terminal Pathway
- initiated by C5B
- formation of 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 ways in which complement activation can protect the body from pathogens?
- Anaphylatoxins: C3A, C5A
- small fragments of complement that act as chemoattractants to recruit more phagocytes and inflammatory cells to the site of complement activation - Opsonization
- large numbers of activated complement generated by the cascade bind covalently to pathogens, enhancing the phagocytic capabilities of macrophages - Membrane-Attack-Complex: C5B, C6, C7, C8, C9
- final product of the terminal pathway
- pore-forming structure that causes cell lysis and death
Discuss the LYMPHOCYTE-mediated effector response.
A. CD4/Helper T-cells
- responds to MHC Class II receptors in APCs
- activates naive CD8 T-cells and B-cells
- prototype: delayed hypersensitivity reactions
- Th1-Mediated
- responsible for Delayed (IV) Hypersensitivity
- produce IL2, IL12, IFN-Y, TNF-B
- helps IgG secretion
- examples:
+ intracellular and fungal infections
+ T-cell mediated autoimmune diseases
+ transplant rejection
+ PPD reaction - Th2-Mediated
- produce IL4, IL5, IL10
- helps IgE and IgA secretion
- examples:
+ parasitic infections
+ allergic reactions
+ asthma
+ atopy
B. CD8/Cytotoxic T-cells
- respond to MHC Class I receptors in APCs
- interacts with IL2 and IL12 produced by helper T-cells
- kills infected cells by:
1. Perforins: glycoproteins responsible for pore formation in cell membranes causing cell lysis
2. Fas ligand: member of the TNF family that induces apoptosis
What is Immune Tolerance?
- state of immune UNRESPONSIVENESS to self antigens
- in effect, the immune system should NOT attack the body’s own cells
- loss leads to Autoimmune Diseases
- CENTRAL Immune Tolerance
- occurs during lymphocyte development in the thymus (T-cells) and bone marrow (B-cells)
- T-cells and B-cells that can bind to self-antigens are eliminated or differentiated into regulatory T cells
- prevents the maturation of autoreactive lymphocytes - PERIPHERAL Immune Tolerance
- occurs after release of mature lymphocytes into the lymph nodes or peripheral tissues
- regulatory T cells induce suppression of autoreactive cells that have escaped the mechanisms of central tolerance
What are immunologic microenvironments and regional immunity?
- each organ and tissue has it’s own immunologic microenvironment and particular immune response arc
- regional immunity exists because of the different immunologic microenvironments in the different organ systems of the body
What comprise the anatomic immunologic ocular barriers?
- Blood-Retina Barrier: tight junctions
- OUTER: between RPE cells
- INNER: between retinal vessel endothelium - Blood-Aqueous Barrier: tight junctions between inner NON-pigmented epithelium of the ciliary body and posterior pigmented epithelium of the iris
- Limited afferent delivery of local antigens to lymph nodes
- Immunosuppressive ocular microenvironment
Where are the different ocular immune microenvironments?
- even within the eye, there exists regional differences in ocular immunity
- Conjunctiva
- Cornea and sclera
- Anterior chamber, iris, ciliary body and vitreous
- Retina, RPE and choroid
Describe the immunologic microenvironment of the conjunctiva.
+ (+) lymphatics
+ resident APCs: dendritic cells, Langerhans cells and macrophages
+ specialized immune compartment: follicles
+ resident effector cells: mast cells, T-cells, B-cells, RARE PMNs
+ resident effector molecules: ALL (mostly IgE, IgG, IgA and complement)
+ immunoregulation: Mucosa-Associated Lymphoid Tissue (MALT)
Describe the immunologic microenvironment of the cornea and sclera.
+ lymphatics and Langerhans cells ONLY at limbus
+ NO APCs in the central cornea and sclera
+ NO specialized immune compartments and resident effector cells
