Innate immunology – receptors and cellular processes Flashcards
(24 cards)
Where do innate immune cells arise from
Comes from the common myeloid progenitor cell
Where do NK cells come from
Arise from a common lymphoid progenitor instead
What is different about innate immune cells compared to T and B cells
Innate immune cells do not express antigen specific receptors but can distinguish between self and non-self
What is the invertebrate immune system
Insects have innate immune cell responses; phagocytosis & proteins
They have an open circulatory system (haemocoel), contains cells (haemocytes) –> 3 classes: lamellocytes , crystal cells and plasmatocytes (control the phagocytic removal of microbes)
Evolutionary conserved Pattern Recognition Receptors - toll-like receptors
What are innate immune cells in humans similar to
drosophila
Human granulocyte repertoire
Cytoplasm full of granules – vesicles containing various innate immune cell function proteins
Hypermorphic multilobed or bilobed nuceli
Differentiated via haematoxylin / eiosin staining (or Giemsa)
What is the function of neutrophils
Indiscriminately kill microbes by recognising non-self components
Does this through phagocytosis
How do neutrophils move through the body
Neutrophil passage through the blood is slow due to transient integrations with neutrophil cell surface receptors
They roll through the vasculature
What does vascular damage do
increase in proinflammatory cytokines release by macrophages (TNFα, IL-1) causes neutrophil attraction
What are key receptors involved in neutrophil activation
A key mechanism for this involves toll-like receptor-4 (TLR4)
TLRs are pathogen associated molecular patterns (PAMP) receptors which function as a dimer
TLR4 recognise bacteria endotoxin lipopolysaccharide on a gram negative bacteria
What do TLR4 do during activation
Engagement of TLR4 with LPS triggers a conformational change which is transmitted through the membrane to the cytoplasmic TIR domain
Downstream signalling involves the activation of IL-4 receptor associated kinase (IRAK) and subsequent MAP-kinase activation - TAK1 –> MKK4 –> JNK
Or in the activation and nuclear
translocation of NF-kB which leads to
the transcription of pro-inflammatory
cytokines
What are the characteristics of toll-like receptors
Function as a dimer
Each monomer has :
Leucine rich repeat extracellular domain and forms a horseshoe shape
Are alpha-helical transmembrane domains
A cytoplasmic Toll/IL-1R (TIR) signalling domain
There are 12 human TLRs which are expressed on a wide variety of innate immune cells
What is the topology of toll-like receptors
Leucine rich repeat extracellular domain
Conserved intracellular TIR domain
Can form heterodimers (TLR2/TLR6) - diversifies the PAMP recognition
What are C-type lectin receptors
CLRs are a family of cell surface and soluble receptors with an affinity to carbohydrates in a calcium dependent manner
What else does C-type lectin receptors include
Include receptors with PAMP recognition as well as “self” glycoprotein (cell:cell) communication
Conserved CHO recognition domain
What are the 2 membrane types for C-lectin receptors
Type-I have multiple CRDs e.g. DEC-205 and the macrophage mannose receptor (MMR)
Type-II have a single CRD e.g. Dectin-1, Dectin-2 and DC-SIGN
Important for fungal recognition and innate immune response modulation
What are Fc receptors
Immunoglobulin Fc receptors (opsonising)
Igs have an opsonising function
Fc-gamma receptors bind to IgG (gamma-heavy chain)
Fc receptors can be activating or inhibitory
Tissue mast cells express Fce receptors that bind to IgE – the basis of hypersensitivity responses
What is phagocytosis
A key function of innate immune cells
Fc gamma receptor mediated - the Fc region of IgG interacts with the FcγR
on innate immune cell
IP3 signalling and Ca2+ release (PKC involvement)
Rac (GTPase) involvement cytoskeletal
remodelling
What is the function of clathrin
Endosome vesicle formation
What does NADPH oxidase do
Generate reactive oxygen species (ROS)
These cause damage to pathogen molecules like proteins etc
NOX is a multi-subunit membrane complex
Activation through PKC phosphorylation
Rac1 (GTPase) translocation is central to NOX activation
Electrons from NADPH required for free radical generation
What do monocytes do
After phagocytosis, pathogen molecules are coupled to MHC-II molecules and are presented at the cell surface
Monocytes are an important cell for antigen presentation —> differentiate into dendritic cells (DC)
What do dendritic cells do
Present antigens on their MHC and activate T cells
How does antigen presentation occur
In ER the MHC-II molecule is complexed with the ‘invariant chain’ in the
peptide binding cleft (MHC-II li) prevents binding of endogenous peptide
Invariant chain is cleaved creating MHC-II CLIP complex
Fusing with phagosome –> HLA-DM/DO mediates release of CLIP –>
binding of peptide to MHC-II
How do pro-inflammatory cytokines stimulate the immune system
engagement with cognate receptors which are expressed on a wide
variety of cells
What do anti-inflammatory cytokines do
suppress the immune system
(IL-4 in involved in antibody class switching to IgE)
