Innate Immunity Flashcards
the innate immune response recognizes three sorts of things
Foreign molecular structures call pathogen-associated molecular patterns (PAMPs)
Stress or damage indicators expressed by body cells, referred to as damage-associated molecular patterns (DAMPs)
The absence of certain “self” marker molecules.
This is done by NK cells.
Defensins and cathelicidins.
Major families of antimicrobial peptides.
Widely expressed in a variety of epithelial cells and sometimes in leukocytes.
Role in the innate immune system through antimicrobial, chemotactic, and regulatory activities.
Protect against bacteria, fungi, viruses, and parasites.
Ancient arm of the innate immune system that evolved to directly neutralize invading microbes.
100s of defensin proteins have been identified from amoeba, plants, birds, mammals, etc.
Classified based on their secondary structural features.
Cathelicidins (CATionic HELIcal bacteriCIDal proteIN) are α-helical peptides
Human cathelicidin LL37 is highly expressed by PMNs and numerous mucosal and epithelial cell types.
Defensins are β-strand peptides connected by disulfide bonds
Most are short peptides (<100 amino acids) and carry a positive charge
AKA – “cationic antimicrobial peptides”
Interact with microbial cell membrane components to increase cellular permeability resulting in cell death. They also act to modulate the inflammatory response.
Defensins.
Two main classes – α and β (based on the linking pattern of the cysteines).
α: 29-35 amino acids long, highly concentrated in the granules of PMNs and Paneth cells of the small intestine. Production is regulated by pro-inflammatory cytokines. There are 6 types of human α-defensins. Human neutrophil peptide (HNP) 1-4 are primarily expressed in PMNs, monocytes, and lymphocytes. Human defensin (HD) 5-6 are mainly expressed in Paneth cells.
β: 38-42 amino acids long, secreted by mucosal surface epithelia, including cells of the eye, skin, oral mucosa, urogenital and respiratory systems. There are 4 types of human β-defensins.
Human beta defensin (HBD) 1-4 are mainly expressed by various epithelial tissues (HBD4 is more limited to the testes and epididymis) but can also be expressed by monocytes, macrophages, and dendritic cells.
TLR
TLRs are transmembrane proteins that are evolutionarily conserved receptors related to the Toll protein found in fruit flies. The Toll protein controls innate immunity in invertebrates, as well as anterior/posterior differentiation.
TLRs bind to, and are activated by, pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) – sometimes called damage-associated molecular patterns.
NF-κB
“the Mother of all immune system transcription factors”
Signaling results in the production of interferons (IFNs), pro-inflammatory cytokines, and effector cytokines that direct the adaptive immune response.
Cellular Responses to TLR Signaling
causes Activation of NF-κB which causes:
Expression of pro-inflammatory genes
Production of prostaglandins and other leukotrienes
Production of interleukins and other cytokines
Increased phagocytosis and synthesis of reactive oxygen and nitrogen molecules in macrophages and neutrophils
Increased efficiency of antigen presentation
DAMPs
DAMPs include intracellular proteins and protein fragments from the extracellular matrix.
Stimulation of TLRs by PAMPs and DAMPs initiates signaling cascades that lead to the activation of AP-1, NF-κB, and interferon regulatory factors (IRFs).
Classical pathway (adaptive immunity)
C1q binds to antigen:antibody complex. Cleaves and activates downstream complement components.
C5b binds to the membrane associated with the antigen:antibody complex which leads to the formation of the membrane attack complex.
Lectin pathway (innate immunity)
Mannose binding protein bound to bacterial carbohydrates mimics C1q. Leads to the cleavage and activation of downstream complement components.
C5b binds to the membrane which leads to the formation of the membrane attack complex.
Alternative pathway (innate immunity)
C3 is spontaneously cleaved or cleaved by C3b by serum proteases activated by bacteria.
C3b binds to bacterial and yeast cell walls and viral envelopes.
Bound C3b leads to the downstream activation of the complement components.
C3a, C4a, and C5a
Chemotactic factors that increase directional migration of PMNs and macrophages
Activate PMN and macrophage degranulation
Release digestive enzymes and adhesion factors
Cause mast cells and basophils to degranulate releasing large quantities of histamine
Potency: C5a»_space;> C3a»_space;> C4a
C3b and C4b
Deposited on any surface with an exposed amine or hydroxyl, such as a bacteria cell
Act as opsonins
Further cleave C3
When bound to host cells they are inactivated by decay-accelerating factor (DAF)
C5b
Binds to microorganisms or host body cells
Acts as a focal point for the deposition of the membrane attack complex.
Body cells have protectin (CD59) and homologous restriction factor (HRF) to prevent the formation of the membrane attack complex.
Histamine
increased vascular permeability
Prostaglandin E2
vasodilation, increased vascular permeability
Leukotriene D2
neutrophil chemotaxis, increased vascular permeability
