Immunology Flashcards
Components of Innate Immunity:
5
- physical and chemical barriers
- inflammation
- fever
- cells
- chemicals
antimicrobial peptides (AMPs), key points (4)
- mostly short peptides
- broad spectrum, less specific (target gram positive, gram negative, fungi)
- kill microbes
- interact with adaptive immune system (recruit T cells…)
AMP examples (4)
- Cathelicidins (LL-37)
- Defensins
- Lysozyme
- RNase 7
Defensins, key points (3)
- short, disulfide-rich peptides
- amphipathic (accumulate in cell membranes, form and defend pores)
- induced by presence of pathogen on a surface
General diseases associated with AMPs
up or down-regulation of AMPs associated with inflammatory skin and inflammatory bowel diseases
Bacterial Lipopolysaccharide
virulence factor, initiator of inflammation, target of innate immune system
Complement System, key points (3)
- biosynthesized in the liver
- ~20 soluble proteins circulating in blood and extracellular fluid
- mostly inactive precursors, activated by proteolytic cascade
Classical Pathway
- C1 binds IgG/IgM (part of acquired immunity)
Alternative Pathway
- C3 binds microbial lipopolysaccharide
- direct lysis of pathogens
- induce inflammation
- promote phagocytosis
Mannose Binding
- Mannan-binding lectin (MBL) binds microbial mannose
Complement System, components
- C1 binds IgM/IgG (classical pathway activation)
- C3 binds microbial lipopolysaccharide (alternative pathway activation)
- C3 products can contribute to B cell activation
- C3b is a strong opsonization signal
- C5a is a potent chemotactic factor
- C3a, C4a and C5a contract smooth muscle and increase vascular permeability (this produces local swelling and “walls off” sites of infection. These factors also participate in anaphylactic reactions)
- C5,6,7,8 and 9n create membrane attack complex that can lyse targeted cells by breaking their cell walls
Pattern Recognition Receptors (PRRs)
recognize pathogen-associated molecular patterns (PAMPs): unique, vital, conserved products of pathogens;
stimulate chemical defenses (interferons, AMPs…), inflammation, cytokines, adaptive immune system…
Toll-Like Receptors (TLRs)
intra and extracellular pattern recognition receptors, ‘alarm system’ for both innate and adaptive immune systems
NOD-Like Receptors (NLRs)
intracellular pattern recognition receptors
Inflammation is…
a localized protective response to tissue damage (injury, infection, irritation, allergy)
Inflammation, key points
Coordinated, multi-stage response by cellular and non-cellular components
Stages of Inflammation (5)
- clotting, complement (platelets release clotting factors)
- mast cells degranulate, vasodilation, WBC migration (mast cells release factors (vasodilation, vasoconstriction, permeability–deliver troops))
- neutrophils degranulate (neutrophils release factors to kill pathogens)
- neutrophils and macrophages phagocytose pathogens
- macrophages release cytokines to recruit immune cells and tissue repair
Symptoms of Inflammation (4+1)
- rubor (blood flow)
- calor (blood flow)
- tumor (exudate)
- dolor (exudate, bradykinin)
- loss of function
Functions of Inflammation (3)
- confine pathogens
- destroy pathogens
- repair tissue
Inflammation can progress from acute to chronic to granuloma formation (wall off site)
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Kinin system
in long-term inflammation, cause endothelial cell retraction to increase vascular permeability
Functions of Complement System (5)
- opsonization (C3b)
- chemotaxis (C5a)
- anaphylatoxins (C3a, C4a, C5a)
- cytotoxins (C5,6,7,8,9n form membrane attack complex)
- initiate inflammation
Clotting system activated by:
collagen, proteases, kinins, bacterial endotoxins
Clotting system is balanced by:
fibrinolysis (plasminogen being converted to plasmin)
Kinin system, cascade and effects (5)
activated by first step in clotting cascade, ultimately produces bradykinin, which:
- vasodilation
- smooth muscle contraction
- vascular permeability
- WBC chemotaxis
- pain
Mast cell component of cellular response
mast cells release histamine, neutrophil and eosinophil chemotactic factors, and leukotrienes (smooth muscle contraction, increase vascular permeability), prostaglandins, cytokines;
important in trauma
Resident macrophages component of cellular response
phagocytosis;
toll-like receptor activation, release TNF-a and IL-1, important in chronic inflammation
Exudate
any fluid that filters from circulatory system into lesions/areas of inflammation
Exudate functions (3)
- dilutes toxins (from bacteria and dying cells)
- carries away toxins, dead cells, inflammatory products
- brings in plasma proteins (antibodies, leukocytes)
Types of Exudate (3)
- early (watery)
- severe inflammation (pus, leukocytes)
- hemorrhagic (bleeding, erythrocytes)
WBC migration into tissue
coordinated response: need signal to activate both WBC and endothelial cell
important WBCs from acute to chronic inflammation (4)
(acute inflammation) 1. neutrophils 2. eosinophils 3. macrophages 4. T-cells (chronic inflammation)
platelets component of cellular response
activated by damaged tissue, release histamine and serotonin, aggregation
neutrophils component of cellular response
activated by invaders or mast cells, phagocytosis, secrete factors to kill pathogens
Margination
movement from blood into tissue
oxygen dependent killing
phagocytes generate toxic oxygen-containing molecules and radicals
Types of Lesions (5)
- granulomas (TB, leprosy, syphilis)
- fibrinous inflammation (vascular permeability allowing fibrin to pass through; cancer)
- purulent inflammation (pyogenic bacteria)
- serous inflammation (copious effusion of serous fluid; skin blisters)
- ulcerative (necrotic loss of tissue from the surface exposing lower layers; ulcer)
Resolution (5)
- Termination of inflammation
- Regeneration (proliferation of cells)
- Resolution (restoration of normal tissue structure and function)
- Repair (scar tissue replaces damaged tissue)
- Maturation (wound contraction, remodeling of scar tissue)
Chronic Inflammation
Duration of two weeks or longer
Antibody Effects:
- opsonization
- complement activation (IgG/IgM C3)
- neutralization, agglutination, precipitation
What are antibodies?
glycoproteins that specifically bind target antigens
What is an antigen?
molecules that induce an immune response
Fab
fragment of antibody including heavy and light chain with variable regions
Fc
fragment of antibody including just heavy chain constant region
The hypervariable loop of an antibody is the complementarity determining region
:)
Why is glycosylation of antibodies important?
affects pharmacokinetic profile (half-life)
How do we generate more unique antibodies than genes in our genome, short answer?
somatic recombination
How do we generate light chain diversity?
VJ somatic recombination:
short repetitive sequences (germ line DNA) –> rearranged B lymphocyte DNA –> transcription (primary transcript) –> alternative mRNA splicing (immunoglobulin mRNA)
end with one V (variable) and one J (joining) region
How do we generate heavy chain diversity?
VDJ somatic recombination
RAG protein
responsible for cutting and splicing performed in somatic recombination; recognizes specific sequences
purpose of somatic hypermutation
improve antibody affinity on subsequent encounters; activation-induced deaminase (AID) purposefully introduces mutation
How do we increase antibody diversity? (4)
- V(D)J recombination of heavy chain and light chain
- diversity due to heavy and light chain joining
- junctional diversity (imperfect joining of V and J/D segments)
- somatic mutations
Encounter with self-antigen results in:
clonal deletion/apoptosis (multivalent self-antigen) or anergy/unresponsiveness (soluble self-antigen)
Receptors/surface proteins on antigen-presenting cells (2)
- MHC-II
2. B7
Receptors/surface proteins on mature B cells (3)
- IgM
- IgD
- MHC-II
Receptors/surface proteins on helper T cells
with APC:
- TCR (with MHC-II of APC)
- CD4+ co-receptor (with MHC-II of APC)
- CD28 co-receptor (with B7 of APC)
with B cell:
T cells release IL to activate B cells after they match
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main players in humoral and cell-mediated immunity
humoral: B cells/plasma cells
cell-mediated: T cells/CTLs
A few functions of T cells:
- cytokines to activate macrophages
- IL to activate B cells
- able to detect pathogens hiding in a host cell (unlike antibodies)
T cell positive vs. negative selection
positive: must react to self MHC carrying peptides (otherwise apoptosis)
negative: do not react strongly to self-antigens on MHC
(2-5%)
T cells defined by:
development in thymus, T cell receptors (TCR), specific MHC
cytotoxic T lymphocytes (CTL)
CD8+ co-receptor
recognize MHC-I (infected self cell)
helper T cells
TH1: inflammatory (activate macrophages, CTLs)
TH2: helper (activate B cells)
CD4+ co-receptor recognizes MHC-II (antigen presentation)
CD28 receptor with B7 of APC
T cell receptor vs. B cell receptor
T cell receptor: univalent, similar to single Fab fragment
B cell receptor: bivalent, surface immunoglobulin (IgG/IgM)
T cell receptor (TCR)
univalent
similar to single Fab fragment (alpha and beta chain)
unlike immunoglobulins, TCRs have no secreted form and do not recognize free antigens (must be presented on MHC)
MHC-I
self
MHC-II
antigen
antigen presenting cells
MHC-I vs MHC-II differences in presenting peptide length
MHC-I: shorter (8-10 aa) peptides
MHC-II: longer (13+ aa) peptides
MHC - T cell interactions
MHC interacts with TCR and CD8+/CD4+ co-receptor
antigen presenting cells (APC)
- dendritic cells (MHC-I, MHC-II, B7)
- macrophages (PRR –> MHC-II, B7)
- B cells (MHC-II, CD40?)
CD4+ T cell activation
- TCR/CD4+ interacts with MHC-II/antigen
- CD28 interacts with B7
- T cell stimulated by its own IL-2
Cyclosporin
inhibits IL-2, preventing CD4+ T cell activation, resulting in immunosuppression and preventing rejection of transplant organs
CD8+ T cell activation
- TCR/CD8+ interacts with MHC-I/antigen
- CD28 interacts with B7
- T cell stimulated by its own IL-2
CTL killing mechanisms (2)
- perforins (form channels)
2. granzymes (signal apoptosis)
