Phase 2 - Immunology Flashcards
What is the purpose of the immune system
To distinguish between self and non-self and protect self from non-self
What is the immune system made up of
Cells and soluble factors
Characteristics of the innate system
First line of defence
Barrier to antigen
Instinctive
Present from birth
Non-specific
Slow response
No memory
Independent of lymphocytes (but does include phagocytes and monocytes/macrophages)
Characteristics of adaptive system
SpecificAquired/learned (from initial exposure to specific non-self)Has memory to specific antigensQuicker response second time onwardsDependant on lymphocytesAntibodies
Which cells are involved in the innate immune system
NeutrophilsEosinophils (mainly functions in parasitic reactions)Basophils (mainly functions in allergic infections)Monocytes (kidney shaped nucleus - only found in blood) - release cytokines and produce complement components- become macrophages when they leave blood and enter tissuesMast cells - involved in allergic reactions, lots of histamine involved (from blood but reside in tissue)Dendritic cell - major antigen presenting cells (present to macrophages and t cells) - found in epithelium(Things like skin, tears, mucocilliary escalator are all part of innate response)
Which cells are involved in the adaptive system
Lymphocytes* T cells- T regulatory cells- T helper cells (CD4)- Cytotoxic T cells (CD8)- Cytokine production* B cells- Plasma cells (antibody production)Monocytes (only found in blood) - release cytokines and produce complement components
Cell components of the immune system
Lymphocytes- T cells* T regulatory cells* T helper cells (CD4)* Cytotoxic T cells (CD8)* Cytokine production- B cells* Plasma cells** Antibody productionPhagocytes- Mononuclear cells* Monocytes/ Macrophages** Cytokine production** Complement production- Polymorphonuclear cells* Neutrophils* Eosinophils* BasophilsOther cells- Mast cells- Natural killer cells- Dendritic cells
What do soluble factors (humoral componant) of the blood consist of
ComplementAntibodies (aka immunoglobulins)CytokinesChemokines
What is complement and what does it do
- 20 proteins produced by the liver- mostly exist in an inactive state- activated via cascades * there are 3 activation pathways- only activated for the immune response- They have 3 modes of action:* Direct lysis* Attracting leukocytes to site of infection - chemotaxis (works by releasing chemotaxes - C3a, C5a)* Opsonisation (coating invading organism to increase the chance of them being phagocytosed)
Makeup of antibodies
Consists of 2 heavy chains and 2 light polypeptide chains- Has a Fc region which is the same on all antibodies- Has a Fab region (variable region) which is specific to the target and is where the binding site is located- Can exist as free in solution or membrane bound to B cells
Functions of antibodies
- bind to specific antigens- acts as adapter to link microbe to phagocyte- Neutralise toxins by binding to them- Activate complement (classical pathway) - Increase opsonisation and stimulate phagocytosis - agglutination, precipitation(-> cell lysis + chemoattraction)
Type of antibodies in blood
IgG - most abundant - 75% of antibodies found in serum (small, can get almost anywhere - can CROSS PLACENTA)- HIGHLY SPECIFICIgM - large molecule (PENTAMERIC) - only found within blood - HIGHEST CAPACITY to ACTIVATE COMPLEMENT- not super specificIgA - two versions: normal or DIMER - dimer is in secreted substances e.g. saliva - MUCOSAL - MAIN Ab in COLOSTRUM and neonate gutIgE - BOUND to MAST cells and BASOPHILS- involved in ALLERGIC reaction and HELMINTH infection - production can be driven by eosinophils- LEAST ABUNDANT in bloodIgD
What are cytokines and name the four main ones
Proteins secreted by immune and non-immune cells- Interferon- Interleukin- Colony stimulating factor- Tumour necrosis factor
What are interferons, where are they released from and what do they do?
- type of cytokine- IFN alpha and beta produced by infected cells- IFN gamma produced by activated T cells- induces antiviral resistance in uninfected cells
What are interleukins, where produced and function
type of cytokineProduct of many cellsaround 35 diff typesPro (IL1) or Anti inflammatory (IL10)Can cause:- Cell division- Cell differentiation- Cell secretions
What are colony stimulating factors and what do they do
type of cytokineDirects division and differentiation of bone marrow stem cells- can have specific interleukins for specific leukocytes
What is tumour necrosis factor, where is it released and what does it do?
Type of cytokine- TNF alpha and beta - released by macrophages- proinflammatory (especially TNF alpha)- mediate cytotoxicity
What are chemokines
Leukocyte cheoattractants
What is the innate system composed of
Physical and chemical barriersPhagocytic cellsBlood proteins- Complement
What happens during an inflammatory response to physical trauma
CoagulationLeukocyte recruitment - acute inflammationKill pathogensClear dead cellProlifereation of cells to repairRemodel extracellular matrix - remove clot
What is inflammation, what does it result from
- series of reactions that brings cells and molecules of immune system to sites of infection and damage- can result from tissue damage and/or infection
What are the 3 key processes of inflammation and subsequent hallmarks of inflammation?
Increased blood supplyIncreased vascular permeabilityIncreased leukocyte transendothelial migration (Extravasation)Hallmarks of inflammation:- red- swelling- heat
Which cells are associated with recognising non-self?
In blood:- Monocytes- NeutrophilsIn tissues- Macrophages- Dendritic cells
What happens at sites of inflammation which results in extravasation occuring
Macrophage releases TNF when it needs help - coats endothelial cells, makes them stickyneutrophils roll on these sticky endothlelial cells - when neutrophil hits chemokines present on endothelial surface it becomes activated - firm attachment bonds form due to intergin - chemokine gradient causes extravasation - helps macrophage
What occurs when sensing non-self
Pattern recognition receptors (PRRs) recognise Pathogen associated molecular patterns (PAMPs) on bacteria- Lectin to recognise sugars, scavenger receptors for identifying lipids on bacteriaMultiple ways for leukocytes to bind to bacteria Phagocytes engulf - Proteolytic degradation - forms a phagolysosomeSome fragments of bacterial peptide gets combined with MHC to present the antigen on the phagocyte surfaceMacrophages can take in around 50 microbes at a time
Why is adaptive immunity necessary?
Microbes can evade innate immunity- Decoy proteins- some bacteria can live within macrophages* Intracellular viruses and bacteria can hide from innate immunity
What occurs in cell mediated immunity
- Cells connect with each other to activate each other- Requires intimate cell contact* antigen presenting cells connect to T cells* T cells connect to B cells
What substance does cell-mediated immunity require
Major histocompatibilty complex (MHC)- is the thing that allows cells to present antigens
Characteristics of MHC
Class I- Intracellular antigen presentation (EG with viruses)- Present in all cells- Leads to activation of Cytotoxic T cells* Kill infected cellClass II- Extracellular antigens- Result from phagocytosis- Only found on antigen presenting cells- Leads to T helper cells* Help B cells make antibodies to an extracellular pathogen(class II are the ones you think of with typical antigen presentation after phagocytosis, class I is intracellular and helps activate cytotoxic t cells)
Process of cell mediated immunity
Phagocytic cells present antigens via the Major Histocompatibility complex (class II)T cell receptors recognise and bind to the Major Histocompatibility complex, and the antigen it is associated withLeads to:- Division- Differentiation- Effector Functions- Memory
Stages of T cell activation
Starts with naive t helper cells- becomes activated- CD8 cells (when combined with MHCI/peptide) become Cytotoxic T cells (Tc)* these release perforins and granulysin and directly kill cells- CD4 cells:* in the presence of high levels of IL-12 - becomes Th1 helper cells ** makes macrophages more active and helps kill intracellular pathogens* at a modereate level of stimulation (by IL-12?) - becomes Th2 helper cells** activates B cells** Helps antibody production in humoral response
What is humoral immunity. Explain the process which occurs.
The immune response that occurs from the activation of B cellsProcess of activation:- B cells identify antigens via binding to their membrane-bound antibodies- B cells present this antigen on MHC II - Th2 cells (primed by binding to antigen-presenting cells) bind to B cells presenting the specific antigen- Th2 secrete cytokines- Triggers B cells to clonally expand and differentiate- Differentiate into:* Plasma cells* B memory cells
What are characteristics of B cells
B cells express membrane-bound Immunoglobulin (IgM or IgD)Each B cell can make 1 antibody type – specific to one epitope of an antigen (epitope is the specific site where the antibody can bind)Born with all possible antibodies complementary to every possible epitopeAnti-self antibodies (antibodies that react to anything that is self) are killed during development
What is an epitope
The specific site on an antigen where an antibody can bind
What type of PRRs are there
Secreted and circulating PRRsCell associated PRRs (more traditional receptors)
What do PRRs (pattern recognition receptors) do
They recognise patterns that are typically associated with non-selfExamples:- LPS (lipopolysaccharides)- gram-positive/gram-negative bacteria- dsRNA- CpG motifs
Types of secreted and circulating PRRs
- Antimicrobial peptides secreted in lining fluids, fromepithelia, and phagocytes.* Defensins, cathelicidin* Lectins and collectins: carbohydrate-containingproteins that bind carbohydrates or lipids in microbewalls. Activate complement, improve phagocytosis.Surfactant is also involved * Mannose binding lectin (deficiency syndromes),surfactant proteins A and DE.g. Pentraxins. Proteins like CRP (non-specifc marker of infection - used to recognise clinically - has some antimicrobial action) can react with the C proteinof pneumococci, activate complement, andpromote phagocytosis.
Cell associated PRRs
- Receptors that are present on the cell membraneor in the cytosol of the cells.* Recognise a broad range of molecular patternsTLRs are main familyActivate proinflammatory pathwayInterferon for dealing with viruses
Membrane bound PPRs
- Family of receptors that may participate inpathogen recognition and particularly in pathogenphagocytosis, the C-type Lectin receptors* Mannose receptor on macrophages (fungi).* Dectin-1, Dectin-2. Widespread on phagocytes,helps recognise beta glucans in fungal walls.Scavenger receptors on macrophages (non-specific)
Examples of intracellular pathogens
- Viruses multiply in the cytoplasm of cells* Bacteria such as Salmonella burst out from thephagolysosome and multiply in the cytoplasm ofmacrophages
What are giant cells
Large multinucleated cells formed by fusion of various cells like macrophages, epithelioid cells, monocytes etc.Found at site of chronic inflammation/oother granulomatous conditions
Primary Lymphoid organs
Bone marrow - origin siteThymus - T cell maturation site
Secondary lymphoid organs
Lymph nodes - site of dendritic cell, B and T-cell interactionsSpleen - removes RBCs and Ab-coated bacteriaMuscosal associated lymphoid tissues e.g. GUT ASSOCIATED LYMPHOD TISSUE (GALT) - has most plasma cells in body* includes PAYER’S PATCHES
Tertiary lymphoid organs (TLOs)
Transient germinal centresUsually ectopic lymph node-like structures formed during chronic infection, GvHD, autoimmunity.- e.g. in MS, TLOs form in brain - produce anti-myelin antibody -> demyelination
What occurs at lymph nodes
Dendritic cells enter via afferent lymphatics- present Ag to naive CD4 cells in PARACORTEX.-> become effector cells or memory cells- cells exit via efferentSite of interaction between innate and adaptive cells
What do lymphoid follicles (like Peyer’s patches) mainly consist of
B cells
Diff parts of the spleen and their function
Red pulp - mechanical filtration of RBCsWhite pulp - active immune responses through humoral/cell-mediated. * Primary follicle - rich in B cells* Marginal zone* Periateriolar lymphoid sheath (PALS) - rich in T cellsAlso stores RBCs, lymphocytes etc - can be released in hypovolaemia/-oxia - and clear old plts from circulation
Types of PRRs
Membrane bound- Toll-like Receptors (TLRs)- C-type Lectin Receptors (CLRs)Cytoplasmic- NOD-like receptors- RIG-I-like receptors
What are PRRs and what do they do
Germline encoded Pattern Recognition Receptors (evolutionary conservation)Detects Pathogen-Associated Molecular Patterns (PAMPS) and Damage Associate Molecular Patterns (DAMPS)
Types of TLRs
Typically:- TLRs detecting genetic material are located on ENDOSOME WITHIN CELLS- TLRs detecting other bacterial material - CELL SURFACETLR 5 - Five for Flagellin (flagellated bacteria)** TLR 2 - detectes LIPOTEICHOIC ACID (peptidoglycan wall of gram +ve)- Two for TB - DETECTS MYCOBACTERIA** TLR 4 - LPS on G-veTLR 9 - Nine for Non-methylated CpG (cytosine-guanine) - found in bacterial/viral DNATLR 3/7/8 - viral RNA
NOD 1/2 function
activate NF-kB pathway -> APOPTOSISactivated via CARD domains on NODs
Function of dendritic cell
PhagocyticPROFESSIONAL ANTIGEN PRESENTING CELL (MHC II)- can even CROSS-PRESENT
Which chemokine receptor guides DCs to secondary lymph organs
CCR7
Differences in function of Dendritic cells once mature
Increased Co-stimulatory moleculesINCREASED MHC II expressionINCREASED secretion of PRO-INFLAM CYTOKINESINCREASED CCR7 expressionIncreased GlycolysisDECREASED PHAGOCYTIC capacity
How do plasmacytoid dendritic cells repond to viral infection
Release IFN alpha and beta
Which interleukin is particularly associated with acute inflammation
IL-8 - attracts Neutrophils!!
Major components of neutrophil phagolysosme
ALPHA-DEFENSINSLACTOFERRIN
What is resp burst? What happens in resp burst
Killing mechanism of neutrophils (oxygen dependant)- Electrons pumped into phagolysosome by NADPH OXIDASE- Combine with O2 to make SUPRAOXIDE IONS- ions combine with PROTONS to make PEROXIDE (bacteriacidal)- peroxide can also be CHLORINATED by MYELOPEROXIDASE to make HYPOHALOUS ACID (bactericidal)
Process of neutrophil extravasation
- E-selectin (an adhesion molecule on the capillary endothelium), is activated by IL-1 and TNF-α from damaged cells and binds to the glycoprotein CD15 on neutrophils in blood. 2. This causes neutrophils in the blood to slow down and roll along the endothelium lining. 3. ICAM-1 on endothelium (induced by LPS, IL-1, TNF-α) binds to integrin on neutrophil; the neutrophil stops. 4. Diapedesis: neutrophil squeezes through endothelium (holes caused by C3a, C5a, chemokines, histamines, prostaglandins, leukotrienes (causing smooth muscle contractions in the bronchioles))
How do eosinophils deal with parasitic infections
Release CATIONIC GRANULES (e.g. MAJOR BASIC PROTEIN)Release ROS(eicosanoids, leukotrienes, elastase among other molecules)
Function of mast cells. Site. And relation to Ig?
Plays important role in ALLERGIC reactions + PARASITIC infections- MAIN source of HISTAMINEFound in MUCOSAL SURFACESIgE binds to antigens and presents Fc region to activate mast cells
What do activated mast cells release and what do those substances do
HISTAMINE- increase VASC PERMIABILITY- SMOOTH muscle CONTRACTIONCytkines:- !L4, IL13 - promotes Th2 DIFF and IgE PRODUCtion- TNFa - TISSUE INFLAMMATIONLipid MediatorsLeukotrinesPROSTAGLANDINS- collectively -> vasc perm, SM contract, MUCUS secretion, are CHEMOATTRACTANTS
What is required for cells to develop in into mast cells
Stem cell factor (a cyotkine + growth factor)
What is Antibody-dependant Cellular Cytotoxicity. What occurs in ADCC?
Independant mechanism that does not require complement and uses only 1 CELL TYPE (typically NAT KILLER CELLS)(Typically) IgG binds to SURFACE ANTIGENS on infected/cancerous cells (or VIRAL PROTEINS during VIRAL REPLICATION). NK have CD16 Fc receptors and CROSS-LINK with antibody Fc region.- triggers DEGRANULATION of LYTIC agents -> CELL APOPTOSIS
What do NK cell lytic granules contain
PERFORIN and granzymes- induce apoptosis + cell lysis
How do NK cells differentiate between self and non-self
By PRESENCE of MHC 1- CANCER cells typically DOWNREGULATE MHC 1NK has INHIBITORY RECEPTORS activated by MHC I. If not enough MHC present - NK activate + try to kill cell
What stimulates cytotoxic T cells to attack tumour cells
The cytokines produced by NK cells(also specifically they kill cells with endogenous antigens)
Which cells are professional antigen presenting cells
MacrophagesB-cellsDendritic cells (most potent - go to 2ndry organs - aid adaptive response)
What do professional APCs do
Present EXOGENOUS Ag in context of MHC-II- processed in ER
How are endogenous proteins presented? By which cells?
Present in CYTOSOL (e.g. viral/cancer-related)- processed in ENDOSOMESPresented in context of MHC I- found in ALL CELLS (EXCEPT RBCs)
How do dendritic cells activate Tc cells
CROSS-PRESENTATION- present EXOGENOUS antigens on MHC 1
What is an immune synapse
When immune cells bind together
What 3 things are essential for a response to occur at an immune synapse
- Binding of PRIMARY RECEPTORS (e.g. MHC II to TCR on t cells)2. Binding of CO-STIMULATORY MOLECULES (e.g. CD80 to CTLA4 - don’t need to know name detail)3. A robust release of APPROPRIATE CYTOKINES
What happens if MHC binding to another immune cell occurs without any other stimulation
ANERGY- lack of response - form of PERIPHERAL TOLERENCE
What is the identifying co-stim molecule for all T cells. What is its main function
CD3 (protein complex - 1 gamma, 1 theta, 2 epsilon chains - probs don’t need this much detail)Intracellular signelling -> activates T cell
What co-stim type cells do T cells initaly start as? What do they change to in the thymus?
Initially NAIVE CD4+CD8+ double pos cells (have both).Undergo THYMIC EDUCATION so they only have EITHER one or the other.Also undergo VDJ recombination (also does same for Fab regions on Ab) to determine which EPITOPE their TCR (t cell receptor) will recognise - super specific to a certain antigen
Which antigens are an exception the very specific nature of TCRs
SUPERANTIGENS - bind to alpha/beta chains of any TCR- activates ~20% of T cell population (big response)
What is a naive lymphocytes
Never encountered antigen
How can Naive and Memory T cells be differentiated
nAive - has CD45RAmemOry - has CD45RO
\what is the general marker for T cell activation
CD25 expression
What are the 2 mechanisms by which Tc (CD8+) cells kill
- PERFORIN and GRANZYMES2. express Fas LIGAND - binds to Fas on target cells -> activates CASPASE CASCADE -> APOPTOSIS
Perforin
PORE forming CYTOLYTIC protein- alows SALT + WATER to enter cells -> CELL LYSIS
What are granzymes and what do they do?
Serine proteases- CLEAVE CASPASE PROTEIN (CPP-32) -> ACTIVATE a NUCLEASE (CAD) -> initiates DNA DEGRADATION + APOPTOSIS
Th1 vs Th2
Th1 CELL-MEDIATED; Th2 HUMORALTh1 regulate MONOCYTES/MACROPHAGES, Tc, NK- eliminate cellular antigensTh2 regulate EOSINOPHILS, BASOPHILS, MAST CELLS, B CELLS- increased IgE and IgGthey are ANTAGONISTIC to each other - T CELL POLARISATION
Types of T helper cells (CD4+)
Treg (regulatory cells)Th17
Treg vs Th17 cells
Treg - PERIPHERAL IMMUNE TOLERANCE; Th17 - MUCOSAL MEMBRANE (stimulates INFLAMMATION)Treg - principle cytokine = IL10 (mass ANTI-INFLAM action)Th17 - IL17 (induces INNATE cells to make IL8 -> stimulates NEUTROPHIL production/recruitment)
Which cytokine maintains Th17 populations
IL-23 (target for biologics)
How can B cells be activated? What kind of response does each produce?
- Th2 cells - produce LONG-LIVED plasma cells * typically make IgG, E or A+2. Can be activated directly by ANTIGEN in absence of T cell help- makes SHORT-LIVED plasma cells (+ response) * typically these plasma cells have LESS AFFINITY and produce IgM
What are the marker and the co-stimulatory molecule associated with mature B cells
Marker - CD20Co-stim - CD19
What processes do B cells undergo upon activation and where does activation occur
SOMATIC HYPERMUTATION and AFFINITY SELECTION (aided by dendritic + t cells) - mainly in CORTEX OF LYMPH NODES
What occurs in somatic hypermutation and affinity selection
somatic hypermutation:- activation-induced cysteine deaminase (AID) introduces RANDOM MUTATIONS in Fab Ab region geneAffinity selection:- Dendritic cells present same antigen (testing AVIDITY)- less avidity - neg selected- greater avidity = Positively selected -> undergo CLASS SWITCHING and clonal proliferation
What happens when B cells are activated in lymphoid follicles
They develop into germinal centres
Where does complement bind during opsonisation
Fc region of antibody
Which antibodies are in colostrum
IgA, M and G - but IgA is principle
Which cell type raised in bacterial infection
Neutrophils(esp if pyogenic)
Which cell type raised in viral infections
Lymphoctes(also raised in intracellular bacterial infections e.g. TB and some protozoa e.g. Toxoplasma)
Define hypersensitivity
Undesirable response to antigenic, allergenic or self material. This requires a pre-sensitized state of the host
Types of hypersensitivity reactions
Type 1 - AnaphylacticType 2 - Cell boundType 3 - Immune complexType 4 - Delayed HypersensitivityType 5 - Ab interferes with ligand binding (uncommon)
Type 1 hypersensitivity reaction
FAST - within minuitesCROSS-LINKING of ANTIGEN to IgE on MAST CELLS + BASOPHILS-> massive DEGRANULATION -> massive HISTAMINE RELEASE ** IL4 - KEY CYTOKINE - causes class switching to IgE, Th2 PolerisationANAPHYLAXIS + ATOPY (asthma, eczema)
Type 2 hypersensitivity reaction
IgG/IgM binds to SELF ANTIGEN -> CELL DESTRUCTION by membrane attack complex + cell mechanismaAUTOIMMUNE
Type 3 hypersensitivity reaction
IgG BINDS SOLUBLE ANTIGEN (free antigen + antibody combine) -> circulating IMMUNE COMPLEX- DEPOSIT in vessel walls esp in KIDNEYS-> inflam response - RBCs with COMPLEMENT RECEPTOR 1 bind to complement coated immune complexes and transport them to the liver and spleen for phagocytosis. E.g.- SLE- post-strp glomerular nephritis
Type 4 hypersensitivity reaction
Th1 mediated - ACTIVATED BY APCs-> forms memory T cells-> when reactivated -> activate macrophages -> tissue damageE.g.- TB- GvHD-MS- Guillain-Barre syndrome
Type 5 hypersesitivity reaction
IgM/IgG bind to CELL SURFACE RECEPTORS-> BLOCKS or STIMULATES ENDOGENOUS LIGAND BINDINGe.g.- Graves- Myasthenia gravis
Main ways autoimmunity can develop
- Incorrect THYMIC education- Tregs- CD4 activation against AUTOANTIGEN
Features of autoimmunity
- Often relapsing-remitting - Organ-specific vs Systemic- Damage to or destruction of tissues- Altered organ growth/function- Generation of autoantibodies
What is the defining factor for developing AIDS
< 200 cells/uL of CD4 cells
Which cytokine is the main activator of macrophages
IFN gamma
What triggers classical complement pathway
Antibodies
What triggers lectin pathway of complement system
when MANNOSE BINDING LECTIN (MBL - a protein which binds mannose sugars on pathogen surfaces) binds to mannose on bacteriatriggers cascade response
