Immunology Flashcards
BTK
Bruton’s Tyrosine Kinase
Crucial in B Cell maturation
Deficiencies cause X-linked agammaglobulinemia (no mature B cells)
TDT
Terminal Deoxynucleotidyl Transferace
Responsible for junctional diversity (during VDJ recombination)
AID
Activation Induced (Cytidine) Deaminase Involved in Somatic Hypermutation Class switching (IgM -> IgG)
RAG
Recombination Activating Genes
Enzyme for rearrangement of receptors (VDJ recombination) during developmental stages.
Th1
SIGNAL & FUNCTION
SIGNAL:
IL-12
PRODUCES:
IL-2
IFN-γ
LT/TNF
FUNCTION :
Macrophage Activation (IFN- γ)
B Cell activation – IgG antibody (IFN- γ)
Neutrophil Activation (LT/TNF)
Th2
SIGNAL & FUNCTION
SIGNAL:
IL-4
PRODUCES:
IL-4
IL-5
IL-13
FUNCTION:
Macrophage activation (IL-4/IL-13)
Mast Cell / Eosinophil activation (IL-5)
B Cell activation - IgE (IL-4)
Th17
SIGNAL & FUNCTION
SIGNAL: IL-6 IL-21 IL-23 TGFβ
PRODUCES: IL-17A IL-17F IL-6 IL-21 IL-22
FUNCTION:
Neutrophil recruitment
Treg
SIGNAL & FUNCTION
SIGNAL:
TGFβ
PRODUCES:
TGFβ
IL-10
FUNCTION
Dampen immune response and maintain tolerance, regulation of anti-self responses
nTregs - derived from thymus during T cell development
iTregs - derived following activation of naiive CD4 T cells in presence of TGFb
TFH
SIGNAL & FUNCTION
SIGNAL:
IL-6
PRODUCES:
IL-21
CXCR5
FUNCTION
Combine necessary signals to get B cells activated (proliferation and differentiation) - maintenance of germinal centres
Complement - Alternative
C3 tickover, Factor B, Factor D
C3bBb = C3 convertase
Complement - Classical
Antibody Mediated, C1, C4, C2
C4bC2b = C3 Convertase
Complement - Mannose Binding Lectin
MASP-2, C4, C2
C4bC2b = C3 Convertase
B Cell stimulation (stimulated by cytokines from CD4 T Cells)
SIGNAL: CD40L & CD40 TCR & MHC II + pathogen (peptide) IFN-γ IL-4 TGFβ
EFFECT: IFN-γ - IgG IL-4 - IgE TGFβ - IgA Affinity Maturation Memory Cell Production
CD4 T Cell Activation (by APC following ICAM-1 & LFA-2 adhesion)
SIGNAL:
MHC II + pathogen (peptide) & TCR
CD80/86 & CD28
(cytokine signal)
EFFECT: Express CD40L Express IL-2R Secrete IL-2 Express CTLA-4 (higher affinity for CD80/86 than CD28)
TNFα / LTα
Inflammatory & Pyrogenic
Principal Source: Macrophages, T Cells
Endothelial Cells: activation (inflammation, coagulation)
Neutrophils: Activation & Migration
Hypothalamus: Fever, Prostaglandin Synthesis
Liver: synthesis of acute phase proteins
Muscle & Fat: catabolism (Cachexia)
Many cell types: Apoptosis
Increase cell migration, expression of adhesion molecules, collagen synthesis
TGFβ
Regulatory & Suppressive Principal Source: T Cells (Treg), Many Cell Types Inhibition of inflammation Fibroblast migration, Treg & Th17 differentiation, IsoType switch to IgA
IL-1
Inflammatory & Pyrogenic
Principal Source : Monocytes/macrophages, DCs, endothelial cells, some epithelial cells, fibroblasts, keratinocytes, hepatocytes
Endothelial Cells : activation (inflammation, coagulation)
Hypothalamus : Fever, Prostaglandin syhtnesis
Liver : synthesis of acute phase proteins (CRP, complement, fibrinogen)
Vasodilation expression of adhesion molecules, collagen synthesis
Increases Bradykinin-1 receptors
Increases COX-2 and PLA2
IL-2
Survival Signal
Principal Source : T Cells
CD8 T cell activation
T cells: proliferation and differentiation into effector and memory cells; promotes regulatory T cell development, survival, and function NK cells: proliferation, activation
IL-4
Principal Source : T Cells (Th2), Mast Cells
B Cells : Isotype switch to IgE
T Cells : Th2 differentiation
Macrophages : Alternative activation and inhibition of IFN-γ classical activation
IL-5
Principal Source : T Cells (Th2)
Eosinophiles : Activation, increased generation
IL-6
Principal Source: Macrophages, Endothelial Cells. T Cells (Th17)
Liver: synthesis of acute phase proteins
B cells: proliferation of antibody producing cells
Marrow: stimulation of megakaryocytes
Fever, prostaglandin synthesis by hypothalymus,
IL- 8 (CXCL8)
Released by macrophages/epithelial cells/endothelial cells
Chemotactic gradient for recruitment of WBCs (primarily neutrophils)
CCR5
Chemokine receptor Important in HIV infection - CCR-5 delta32 mutation confers resistance to infection - Moderately pathogenic - used early in phase of infection
CCR7
Chemotactic towards lymph
IL-9
Source: CD4 T Cells
Mast cells, B cells, T cells, and tissue cells: survival and activation
IL-10
Regulatory & Suppressive
Principal Source: Macrophages, DCs, T Cells (Treg)
Macrophages & DCs: Inhibition of IL-12 production, reduced expression of co-stimulators and MHC Class II
Suppression of Th1 proliferation, reduction in inflammation
IL-12
Stimulatory
Principal Source: Macrophages, Dendritic Cells
Stimulate T-Cells and NK Cells: IFN- γ production, increased cytotoxic activity
T cells: Th1 differentiation
IL-13
Principal Source: Th2, NKT Cells, Mast Cells
B cells: isotype switching to IgE Epithelial cells: increased mucus production Fibroblasts: increased collagen synthesis Macrophages: alternative activation
IL-15
Principal Source: Macrophages
NK cells: Proliferation
T Cells: Proliferation and survival
IL-18
Principal Source: Macrophages
NK & T Cells: IFN- γ
IL-17
Principal Source: T Cells, other cells
T Cell: Differentiation to Th17
Endothelial cells: increased chemokine production Macrophages: increased chemokine and cytokine production Epithelial cells: increased defensin GM-CSF and G-CSF production
IL-21
Principal Source: T Cells (Th17)
B cells: activation, proliferation, differentiation Th17 cells: increased generation TFH cells: development
IL-22
Principal Source T Cells (Th17)
Epithelial cells: production of defensins, increased barrier function Hepatocytes: survival
Enhances antimicrobial defence and epithelial repair and barrier entegrity - important in GI immune response
IL-23
Principal Source: Macrophages, CDs
T cells: increased stability and inflammatory activity of IL-17 producing T cells
IL-27
Principal Source: Macrophages, CDs
T cells: inhibition of Th1 cells NK cells: IFN-γ synthesis
IL-33
Principal Source: DCs, Epithelial cells, Endothelial Cells Stimulation of basophils (release IL-4) T cells: IL-5, IL-13 expression Mast cells: activation Eosinophils: activation
INF-α/β
Antiviral
Principal Source α : DCs & Macrophages, β : fibroblasts
Cause antiviral state, increased MHC Class I expression
Activation of NK Cells
Bind neighbouring cell and block translation of viral mRNA
IFN-γ
Principal Source : NK Cells, T Lymphocytes (Th1, CD8)
Stimulates macrophage pathogen killing (classical activation)
Stimulation of some antibody responses
B Cell Isotype switching to IgG
Increased expression of MHC class I and II
Increased antigen processing and presentation to T Cells
LT
Lymphotoxin, neutrophil activation
PECAM-1 (CD31)
Platelet Endothelial Cell Adhesion Molecule for leukocyte diapedesis
Hypersensitivities
I - IMMEDIATE
IgE, Mast Cells, IL-4, Th2, low dose Ag
Asthma & anaphalaxis.
II - ANTIBODY MEDIATED
IgM and IgG against cell-bound or ECM Ag
Myasthenia Gravis, Rheumatic Heart Disease, Graves,
Drugs bound to RBCs, Rh newborn, Goodpastures
III - IMMUNE COMPLEX
IgM and IgG immune complex deposition
Systemic Lupus Erythematosus, Vasculitis, Glomerulonephritis, Arthritis
IV - DELAYED
CD4(Th1) mediated, CD8, persistant antigenic stimulation
TB / Mantoux, Celiac
Mast Cell Secrections
IMEMDIATE: 30-45seconds Histamine Heparin Tryptase +- chymase TNF-alpha
RAPID: 10-30 minutes
Prostaglandins
Leukotrienes
SLOW (transcriptional)
IL-3, IL-4, IL-5, IL-13, TNF-alpha
Goodpasture’s Syndrome (basic immuno)
Type II Hypersensitivity
Antibodies to Collagen type IV (basement membranes)
Cause glomerular disease
Graves Disease (basic immuno)
Type II Hypersensitivity
Antibodies bind to TSH Rc on thyroid cells stimulating thyroid hormones
(negative feedback to pituitary is circumvented)
Hyperthyroidism
Type III Hypersensitivity Factors
Excessive production of immune complexes
Inefficient clearance
Size (larger are better at activating complement and binding to RBCs -> spleen)
Low affinity antibodies (don’t form large complexes)
Excessive antigens
MadCAM1
Mucosal Cell Adhesion Molecule 1
Exists on endothelial cells in mucosal tissue
Allows lymphocytes to home to vascular endothelium of mucosal surfaces
GI immunity
Commensals IL-22 &TGFb Treg MALT TLR5 basolateral (so only invasive pathogens stimulate response)
Obesity & inflammation
Chronic Low Grade Inflammation TNFalpha, IL-1, IL-6, IL-17 decrease in Tregs desensitisation of insulin receptor and leptin receptor increased epithelial permeability
Inflammasome
SIGNAL 1
TLR -> NF-kb -> pro-IL-1b
SIGNAL 2
potassium efflux, membrane perturbation, viral RNA, etc.
Formation of inflammasome (active caspase-1)
cleavage of pro-IL-1b and pro-IL-18 and secretion
ICE
Interleukin-1-converting enzyme
A.K.A active caspase-1
CD40L
Expressed on activated T Cells
Required for B Cell isotype switching, affinity maturation, differentiation to memory cells (w/o get hyper-IgM)
Required for Macrophage activation (and respiratory burst)
Required for CD8 activation
Multiple Sclerosis
Degeneration of CNS leading to paralysis
CD4 cells specific for myelin promote inflammatory response
Th1 and Th17 responses are detrimental (IFN gamma, IL-17)
Th2 associated with remission
Dysregulation of Tregs
HLA-DR15, HLA-DQ6
Eamples of T cell mediated Autoimmunity
Insulin dependent diabetes mellitus (IDDM) Multiple Sclerosis (MS)
Examples of B Cell mediated Autoimmunity
Graves Disease (stimulating Ab) Myasthenia Gravis (inhibitory Ab) SLE (immune complex deposition)
CTLA4
binds CD80/86 more avidly than CD28 and delivers inhibitory signals to activated T cells
Important in suppressing autoimmunity
AIRE
Autoimmune Regulator of Expression
Ectopic expression of peripheral tissue proteins in thymic medulla
People without AIRE get multiple organ systemic autoimmune disease
B-Cell maturation & receptor
BONE MARROW
Heavy D-J rearrangements on both chromosomes
Heavy V-DJ rearrangement on first chromosome (second if failure)
* RAG - cleavage
* TDT - junctional diversity
Light κ rearrangement on first chromosome
Light κ rearrangement on second chromosome
Light λ rearrangement on first chromosome
Light λ rearrangement on second chromosome
Express μκ or μλ
BTK required for maturation
SECONDARY LYMPHOID Express μκ & δκ or μλ & δλ Antigen binding Isotype Switching Somatic hypermutation (AID) Clonal Selection (for antigen based on affinity)
T-Cell maturation & receptor
Encoded by rearranging TCR α and TCRβ genes
α - VJC region
β - VDJC region
Pro-T cell Double Negative T Cell (β rearrangement) Double Positive (α rearrangement) Single Positive Thymocyte (based on MHC recognition & positive/negative selection)
Autoimmune Polyglandular Syndrome 1
Loss of thymic tolerance to peripheral antigens
Results from mutations to AIRE gene
Multiple immune disorders (addison’s, hypoparathyroidism, mucocutaneous candidasis, type 1 diabetes)
IPEX (Immune Dysfunction, Polyendocrinopathy, Enteropathy, X-Linked)
Mutation of FoxP3 (controls Tregs)
Approx 80% with syndrome develop diabetes
Bone marrow transplant can reverse
Passive Immunisation
Passive immunisation with Ig antibodies from blood plasma
Short lived
Potentially hazardous (can cause serum sickness w/ repeat injections)
Living Immunising Agents
- Unattenuated (different host or route)
Cow pox to prevent smallpox (vaccinia)
Rotavirus (monkey and bovine)
Respiratory adenovirus given by mouth
Living Immunising Agents
- Empirically attenuated
Don’t know why they are less virulent
Grown under conditions they don’t like, causes adaptation, hopefully no longer grow well in humans
polio (Sabin OPV), measles, mumps, rubella, varicella-zoster, rotavirus (Rotarix), yellow fever*
BCG, Typhoid (Ty21a - doesn’t have vi antigen due to attenuation)
*Need to give to mother BEFORE she becomes pregnant
Living Immunising Agents
- Rationally attenuated
no current vaccines avaiable
CVD 103-HgR
Live oral cholera vaccine w/ deleted gene for cholera toxin and mercury label
Living Immunising Agents
- Reassortants
Take existing living vaccine (e.g. typhoid), and clone genes that are virulence factors for other pathogens (e.g. E. Coli adhesins, ETEC colonisation factors)
Rotavirus (RotaTeq)
Influenza
Non-Replicating Immunising agents
- Inactivated pathogen
Polio (Salk IPV), influenza, Hep A, Jap Encephalitis, Rabies
Oral cholera, thyphoid, pertusses (whole cell), Q fever
Non-Replicating Immunising agents
- Component
Hepatitis B (recombinant DNA of surface antigen)
HPV
acellular pertussis (3 or 5 components - less sides than whole cell, less effective)
toxoids: diptheria, tetanus
capsular polysaccharide:
- unmodified: 23vPPV (pnemococcal), Vi (S. typhi)
- modified: Hib, 10vPCV, 13vPCV, MenCCV, 4vMenCV
CXCR4
Chemokine receptor
Important in HIV infection
- highly pathogenic
- used late in phase of infection
TRIM5a
Cellular Enzyme
Causes destabilization of viral capsid
Prevents uncoating and interferes with the reverse transcription
Degrades virus&capsid through proteasome
Possible medical use to inhibit HIV infection
APOBEC3G
Cellular Enzyme
Assembles within virus
during step of reverse transcription it interacts with ssDNA and causes deamination of cytosine to uracil = lethal hyper-mutation of virus
(HIV-Vif binds APOBEC3G and targets it for death through proteosome)
Tetherin
Cellular Enzyme
Inhibits virus release
(HIV-Vpu antagonises tetherin and allows virus to excape)
Interferon α/β
Type I Interferons
Produced by infected epithelial cells and macrophages
Induces influx and activation of NK
Enhances MHC-I expression
Bind neighbouring cells and block translation of RNA (antiviral state)
Induces Protein Kinase R (dsRNA dimerises and this causes deactivation of eIF2α, thereby halting protein translation)
