Basics, innate receptors and complement Flashcards
E - Define innate immune system.
- active at initial exposure to pathogen
- immediate maximal response, rapid (min - h)
- non-antigen specific
- receptors are germline encoded
- cells: macrophages, neutrophils, NK cells, DCs
- no clonal expansion
- no immunological memory
E - Define adaptive immune system.
- response is antigen dependent and antigen specific and only after initial recognition of pathogen by innate immunity
- there is lag-time between exposure and maximal response
- receptors are specialized for each antigen (rearrangement of germline)
- recognition of pathogen by ABs and TCRs
- clonal expansion of T and B lymphocytes
- creates immunological memory
E - Name the typical cells of innate immune system.
macrophages mast cells NK cells DCs basophils, eosinophils, neutrophils
E - Name the typical receptors and molecules of the innate immune system.
Molecules: complement, antimicrobials (lysozyme, cathelicidin, ROS), type I IFNs, cytokines & chemokines
Receptors: PRRs and NKC receptors
- TLRs
- CLRs
- NLRs
- RIG-I like receptors
- DNA sensors like ALRs
E - What is the difference between humoral and cellular immunity?
Humoral: combats pathogens with antibodies (produced by B cells, can be transferred between individuals to provide passive immunization)
Cellular: primarily involves T cells which eradicate pathogens, clear infected self-cells and aid other cells in inducing immune response
E - Define pathogen and immunopathology.
pathogen = microorganism that typically causes disease when it infects a host
immunopathology = detrimental effect of immune response on host cells
E - Compare properties of macrophages vs neutrophils.
Origin: macrophages differentiate from monocytes or are tissue-resident/neutrophils are granulocytes
Phagocytic: both highly
Present in: macrophages are found in all tissues (e.g. Kupffer cells in the ilver, microglia in brain, alveolar macrophages in lungs)/neutrophils are abundant in blood, but normally not present in healthy tissue; but neutrophils ARE the first to be recruited to the site of infection
Neutrophils are short lived (dead neutrophils are a major component of pus, form extracellular NETs to trap pathogens)/ macrophages are long lived.
Macrophages produce pro-inflammatory lipids and cytokines that recruit other immune cells (IL-1B, IL-6, CXCL8, IL-12, TNF-a).
Neutrophils recognize and phagocytose microbes, destroy microbes, release enzymes and antimicrobial peptides from granules.
E - How are phagocytes activated?
- PRRs bind PAMP to activate the phagocyte
- Phagocyte ingests microbe and increases metabolic activity
- Activated phagocytes elevate antimicrobial activity
E - What is the role of TNF-a?
activates vascular endothelium
increases vascular permeability
-> enables entry of IgG, complement and immune cells to the site of infection
E - What happens during the inflammation upon infection?
- bacteria trigger macrophages to release cytokines and chemokines
- vasodilation and increased vascular permeability cause redness, heat and swelling
- inflammatory cells migrate into the tissue, release inflammatory mediators (cause pain)
E - Difference between thymus dependent and thymus independent antigen.
TD: require T cell help,
induce isotype switching and somatic hypermutation in germinal centers,
does not require repeating epitopes;
e.g. rhesus factor
TI: no T-cell help required for recognition by ABs (DCs can help via BAFF factor),
microbial Ag with repetitive epitopes,
limited isotype switching (stay IgM), no SHM
e.g. AB0 system
E - Who was the first person to discover a vaccine and how?
Edward Jenner: observed that maids who cought cowpox had protection from smallpox
inoculation with cowpox protects the recipient agains smallpox
E - What are PAMPs and PRRs?
Pathogen Associated Molecular Patterns = molecules specifically associated with groups of pathogens that are recognized by cells of the innate immune system
Pattern Recognition Receptor = receptors of the innate immune system that recognize common molecular patterns on pathogen surfaces
E - Name different types of PRRs.
Toll-like receptors NOD-like receptors C-type lectin receptors RIG-I-like receptors AIM2-like receptors
E - Name TLRs in the endosome and their ligands.
TLR3: dsRNA
TLR7/8: ssRNA, viral RNA
TLR9: CpG DNA
E - Dimerization of TLR leads to signaling in which IkB is degraded in the proteasome upon polyubiquitinilation. What follows?
NFkB becomes active, is transported in the nucleus where it acts as a TF and triggers cytokine genes expression.
E - What are systemic effects of LPS?
Triggering inflammation all over the body.
E - Name the 3 complement pathways.
Classical
Alternative
Lectin
E - Explain the 2 ways of how complement activates C1s protease.
2 molecules of C1s (and 2 molecules of C1r) are bound to C1q
C1q binding -> C1r activation -> C1s cleavage and activation
C1q can bind either:
a) one pentameric IgM bound to bacterial surface in the staple form
b) 2 IgG molecules bound to bacterial surface nearby
ALSO: binding of cell surface directly by recognizing repetitive epitopes
E - Describe how the complement is activated.
Classical pathway: C1q interacts with pathogen surface directly or ABs bound to it;
Lectin pathway: Mannose-binding lectin and ficolins recognize and bind carbohydrates on pathogen surface;
Alternative pathway: C3 undergoes spontaneous hydrolysis
All pathways then converge at the step of generating C3 convertase
C3 -> C3a (released) + C3b (bound to bacterial surface)
–> formation of C5 convertase
–> C5b binds C6 and C7; complex of those is bound by C8 (inserts into the membrane)
–> C9 bind this and polymerize to form a pore (membrane attack complex)
Also: byproducts ara anaphylatoxins (increase vascular permeability).
Ž - Describe first immune system barriers of the skin.
RNases and DNases microcidal molecules (defensines, cathelicidins) fatty acids keratinized epithelium commensal bacteria
Ž - What is Janeway’s hypothesis?
to activate lymphocytes, you need to activate them by costimulatory signal, which is inducible by conserved microbial products that get recognized by germline encoded PRRs and NOT the antigen receptors themselves
that means that the actual detection of infection by the adaptive immune system and determining the origin of the Ag is under control of innate immune system
= explains why you need adjuvant addition to antigen to get immune responses in experiments
Ž - What is C3 convertase made of in different complement pathways and how do you get C5 convertase from that?
classical and lectin pathway: C4b2a
alternative: C3bBb
to get C5: cleave C3 and add C3b to the complex
Ž - Describe formation of MAC.
After C5 convertase cleaves C5:
C5b + C6 + C7 bind membrane
+ C8 to insert the complex in the membrane
+ C9(s) to actually form the pore
