Immunology Flashcards
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innate vs adaptive immune system
Innate:
- Physical barriers: epithelium (e.g., skin, mucous membranes)
- Secreted effector proteins and complement system
- Antigen-presenting cells, Natural killer cells, Granulocytes
- toll-like receptors (TLR): pattern recognition receptors that recognize pathogen-associated molecular patterns (PAMPs) and lead to activation of NF-kB
Adaptive:
- B cells, T cells (helper T cells, cytotoxic T cells)
- Immunoglobulins (IgA, IgM, IgG, IgD, IgE)
immune cell terminology
granulocytes:
mast cell, eosinophil, basophil, neutrophil
agranulocytes:
lymphocytes (NK cells, T-cells, B-cells), monocytes (–> macrophages)
immune cell lineage (from multipotential hematopoietic stem cell AKA hemocytoblast)
Common myeloid progenitor:
- megakaryocyte ==> thrombocytes
- erythrocytes
- myeloblasts ==> basophil, neutrophil, eosinophil, monocyte (–> macrophage)
Common lymphoid progenitor:
- natural killer cell (large granular lymphocyte)
- small lymphocyte ==> T-lymphocyte, B-lymphocyte (–> plasma cell)
cells of the innate immune system
monocytes/macrophages:
- monocytes (blood stream) become macrophages (tissues)
- phagocytosis, cytokine production, antigen presentation
- secrete pro-inflammatory cytokines: IL-1, TNF-a
neutrophils:
- provide extra support to macrophages
- phagocytosis only
- attracted by chemotaxins: IL-8, C5a
natural killer (NK) cells:
- kill infected human cells, produce IFN-y to activate macrophages
- destroy human cells with reduced MHC I
eosinophils, mast cells, basophils:
- contain granules with destructive enyzmes
- activated by IgE antibodies
- release of toxic substances to kill parasites
- mast cells in tissue, basophils in blood stream
respiratory burst (oxidative burst)
- part of innate immune system
- activation of the NADPH oxidase complex generates and releases ROS (free radicals) that destroy the pathogens in phagosomes
Pattern recognition receptors (PRRs)
- part of innate immune system
- recognize PAMPS (pathogen-associated moelcular patterns) and activate immune response
- Toll-like receptors (TLRs): activate the NF-κB pathway (proinflammatory cytokines, adhesion molecules) or IRFs (interferon regulatory factors, antiviral)
- Nucleotide-binding oligomerization domain-like receptors (NLRs): activation of NOD-like receptors → upregulation of NF-κB → ↑ transcription of proinflammatory cytokines (e.g., IL-1β, IL-18)
complement system
- can be activated by innate OR adaptive immune system
- amplifying cascade
-
alternative pathway, classical pathway, lectin pathway:
C3 ==> C3a (inflammation) ==> C3b (opsonization, phagocytosis) ==> C5a (inflammation) ==> C6-9 (MAC formation, lysis of microbe)
major functions of complement:
1. opsonization and phagocytosis
2. complement-mediated cytolysis (MAC)
3. stimulation of inflammatory reactions, destruction of microbes by leukocytes
cardinal signs of inflammation
- heat
- redness
- swelling
- pain
- loss of function
caused by a combination of vasodilation, vascular leakage, tissue damage
leukocyte extravasation (innate)
neutrophils
- rolling: leukocyte rolls along inner surface of vessel via binding of E-/P-selectin on endothelial cells
- crawling/arrest: tight binding of integrins with intercellular adhesion molecules (ICAM) on endothelial cells
- extravasation: diapedesis (passage of cell through blood vessel wall), transendothelial migration via binding of PECAM-1 between endothelial cells
- migration: leukocyte travels through interstitium to phagocytose foreign material
cytokines
- cell signaling proteins that stimulate inflammatory response
- chemokine: attracts immune cells (chemotaxis)
- interleukins (IL-1, IL-2): travel between leukocytes
- tumor necrosis factor (TNF): can cause tumor death
- transforming growth factor (TGF): repair
- interferons (Type I and II): Type I (alpha/beta) IFN interfere with viral replication, Type II (gamma) IFN activates macrophages
steps of phagocytosis
- engulfment
- phagosome acidification
- phagosome-lysosome fusion ==> phagolysosomes
- killing and digestion (ROS, NO, lysosomal enzymes)
MHC I and MCH II expressed by
MHC I: all nucleated cells
MHC II: only professional antigen-presenting cells (APCs)
- dendritic cells
- B lymphocytes
- macrophages
- thymic epithelial cells
MHC molecules bind only peptides
MHC molecules are membrane-bound
MHC I vs. MHC II
MHC I:
- originate from cytoplasmic proteins (Inside of cell)
- viral proteins ubiquitinated into peptides ==> peptides transported from cytoplasm into ER (TAP) where they are edited and loaded on MHC I ==> completed complex migrates to cell surface
- cross-presentation: endosomal antigens (usually MHC II) are secreted to cytoplasm –> MHC I pathway
MHC II:
- originate from extracellular proteins (phagocytosis by macrophages)
- lysosomal proteases degrade phagocytosed microbes into short papetides in phagolysosome ==> MHC II fuses with phagolysosome ==> completed complex migrates to cell surface
MHC and T cell relationship
CD8+ (cytotoxic) T cells = MHC I
CD4+ (helper) T cells = MHC II
1 x 8 = 2 x 4
- CD8+ T cells have 1 antigen-binding chain, have 1 letter after HLA (A, B, C)
- CD4+ T cells have 2 antigen-binding chains, have 2 letters after HLA (DP, DQ, DR)
diversity of antibodies and TCR
- DNA rearrangement/recombination of variable (V), diversity (D), joining (J) genes
–> recombinase activated gene (RAG) -
junction diversity: enzymes semi-randomly add and remove nucleotides at the ends of different gene segments
–> terminal deoxynucleotidyl transferase (TdT)
these genetically diverse regions encode the complementary determining region (CDR) loops involved in antigen recognition
CDR loops bind both MNC and peptide residues to TCR
maturation/selection of T and B cells
T-cells:
- mature in the thymus
- T cell selection occurs through interacting with thymic epithelial cells
- positive selection = mature naive T cell development + MHC restriction
- negative selection = central T cell tolerance
- no receptor editing for self-reactive T cells, only apoptosis
B-cells
- develop in the bone marrow
- self-reactive B cells undergo receptor editing or apoptosis (negative selection/central tolerance)
overview of effector T-cell generation/responses
- dentritic cell phagocytoses microbe and activates
- DC migrates to lymph node
- naive T-cell activation, differentiation, expansion (CD4+ <-> MHC II, CD8+ <-> MHC I)
- effector T-cells migrate to infected area via chemokine/cytokine signaling
- effector T-cells encounter antigens on cells w/ intracellular microbes
- effector T-cell activation/function:
CD4+ cells release cytokines to tell other cells what to do (inflammation, phagocytosis, killing of microbes);
CD8+ cells directly kill infected cells
naive T-cell activation requires what molecular interactions
2 structural signals:
1. MHC/antigen + TCR
2. costimulators: B7 (on APC) + CD28 (on T-cell)
1 cytokine signal:
tells T-cell what to differentiate into
what cytokines promote differentiation of CD4+ T-cells: Th1, Th2, Th17, Tfh
Th1: IL-12, IFN-y
intracellular microbes
- dentritic cell secretes IL-12
- natural killer cell secretes IFN-y
Th2: IL-4
parasites
- mast cells, eosinophils secrete IL-4
Th17: IL-1, IL-6, IL-23, TGF-b
extracellular pathogens
- dentritic cell secretes IL-1, IL-6, IL-23, TGF-b
differentiated CD4+ T-cells (Th1, Th2, Th17, Tfh) secrete which cytokines to target which cells/reactions
Th1: IFN-y
- IFN-y: macrophage activation
–> respiratory burst, cytokine secretion, increased expression of B7 costimulators and MHC molecules
- also CD40L (Th1) + CD40 (M) costimulator binding with macrophage
Th2: IL-4, IL-13, IL-5
- IL-4: B cell antibody production (IgE Ab) –> mast cell degranulation
- IL-4, IL-13: intestinal mucus scretion/peristalsis AND alternative macrophage activation (tissue repair)
- IL-5: eosinophil activation
Th17: IL-17, Il-22
- IL-17: neutrophil activation + leukocytes and tissue cell chemokines –> inflammation
- IL-22: epithelial cells –> increased barrier integrity
Tfh: IL-21
- IL-21: help B cells (plasma cells) produce high-affinity antibodies
CD4+ T-cell cytokines
- IL-2: T cell proliferation
- Interferon-gamma (IFN-y): activation of macrophages (classical pathway)
- IL-4: B cell switching to IgE
- IL-5: activation of eosinophils
- IL-13: B cell switching to IgE
- IL-17: stimulation of acute inflammation
- IL-21: B cell activation; Tfh differentiation
- IL-22: maintenance of epithelial barrier function
skewed T cell reaction: cells that are activated by cytokines also produce same cytokines; forward feedback loop
CD8+ cytotoxic T-cell mechanism of killing infected cells
- antigen recognition and binding to target cell
–> CD4+ helper T-cells promote licensing of CD8+ T-cells via:
1) cytokine production to stimulate CTL differentiation
2) upregulation of APC costimulators/ cytokines to help CTL differentiation - CTL activation, granule exocytosis: granzymes (activate apoptosis) and perforin (facilitates entry of granzymes into cytosol)
- apoptosis of target cell
Antibody isotypes
IgM - located on B-cells as BCR, main/largest Ig, not specific (low affinity), first response to antigen, complement activation
IgG - found in blood serum, main Ig during secondary/memory response, opsonization of bacteria, complement activation
- opsonized microbe binds to phagocyte Fc receptors –> phagocytosis of microbe
- opsonized infected cell binds to NK cell –> killing of antibody-coated cell (cytotoxicity)
IgA - mucosal surfaces and bodily fluids (breastmilk), prevention of infection
IgE - bind to mast cells which release histamine, bind to basophils, allergic response
IgD - lets leave (not as important)
humoral vs cell-mediated immunity
Humoral: B-cells, helper T-cells (CD4+)
- secretion of antibodies
- complement system
Cell-mediated: CD8+, NK cells
- direct killing of cells
3 major types of B-cells
- B2: follicular B-cells (IgG, IgA, IgE), T-cell dependent (needs protein antigen)
- marginal zone B-cells (IgM)
- B1 cells: fetal development (IgM)
Vaccine types
Live attenuated:
- Measles/mumps/rubella, varicella, rotavirus, influenza
Inactivated/killed: cell mediated response only with adjuvant
- Polio, hepatitis A, influenza
Subunit: cell mediated response only with adjuvant
- HPV, pertussis,, pneumococcal, meningococcal, zoster, influenza
Toxoid:
- Tetanus, diphtheria
Conjugate:
- Haemophilus influenzae, pneumococcal, meningococcal
RNA:
- COVID-19
