Basics of Immunology - Innate Immune System Flashcards
1
Q
Host components of the innate immune system
A
- Physical barriers - tight junctions, epithelial and mucous membranes surface, mucus
- Antimicrobial enzymes in epithelial and phagocytic cells (e.g. lysozyme)
- Inflammation-related serum proteins e.g. complement components, CRP, lectins (carbohydrate-binding proteins)
- Antimicrobial peptides (AMPs) e.g. defensins, cathelicidins, on the surface of cells and within phagocyte granules
- Cell receptors that sense micro-organisms and signal a defensive response e.g. toll-like receptors (TLRs)
- Cells that release cytokines and other mediators of inflammatory response e.g. macrophages, mast cells, natural killer (NK) cells, innate lymphoid cells
- Cytokines, cell-cell communicating and signalling proteins that mediate and regulate immunity, inflammation and haematopoiesis including chemokines, interferons (IFNs), interleukins (ILs), lymphokines and tumour necrosis factor (TNF)
- Phagocytes (neutrophils, monocytes, macrophages)
- The inflammasome - a central signalling system that regulates the innate inflammatory response
- The microbiome
2
Q
Functions of the innate immune system:
A
- Detection of micro-organisms and first-line defence against invasion and infection
- Maintainence of “immunologic homeostasis” - balance between pro-inflammatory mechanisms of host defence and anti-inflammatory responses that return host to healthy baseline
- Activation and instruction of adaptive immune responses
3
Q
Principles of microbial detection through pattern recognition:
A
- Pathogen recognition receptors recognise pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) → expressed on “sensor” cells e.g. macrophages, dendritic cells
PAMPs
- Produced only by microbes
- Structures shared by entire classes of pathogens
- Usually fundamental to integrity and pathogenicity of pathogen such that a microbe can’t mutate its PAMPs to avoid host defence
- E.g. → lipopolysaccharide on the outer membrane of gram-negative bacteria
DAMPs
- Nuclear, mitochondrial or cytosolic molecules released from host cells as a result of infection, tissue injury or cell necrosis
- E.g. HMGB1, S100 proteins, heat-shock proteins, ATP
4
Q
Broad classification of PRRs (Pattern Recognition Receptors)
A
- Secreted and circulating pattern recognition molecules - antimicrobial peptides (AMPs), collectins, lectins (MBL), pentraxins, C1q of the complement system → mediate direct microbial killing, act as helper proteins for transmembrane receptors, enhancers of phagocytosis by immune effector cells
- Surface membrane - C type lectin receptors, TLRs (activate inflammatory pathways in innate cells)
- Intracellular - TLRs, NOD like receptors, RIG like receptors, AIM like receptors
5
Q
Examples of secreted and circulating pattern recognition receptors
A
- The complement system
- C1q (PRR) → binds to antibody fixed to microbe, damaged cells/tissues, immune complexes → complement cascade → attachment of C3b promotes phagocytosis of the microbe, generates chemotactic factors, triggers fixation of the membrane-attack complex which can directly lyse some cells
- Antimicrobial peptides (AMPs) - form pores through outer membranes of a microbe that disrupt the membrane integrity and lead to death → examples include defensins
- Lectins e.g. mannose binding lectin - produced by liver, recognises terminal mannose residues of carbohydrates on some gram +ve and -ve organisms, fungi, some viruses and can opsonise them for phagocytosis
- Pentraxins - e.g. CRP → secreted by liver, acute phase reactant, secreted in response to toll-like receptor activation or pro-inflammatory cytokines. Can fix C1q and activate the complement system
6
Q
Cell associated pattern recognition receptors - toll like receptors
A
- Transmembrane associated PPRs within cells of innate immune system (monocytes, macrophages, neutrophils). Recognise PAMPs and DAMPs. Signalling results in changes in tanscription factors that regulate genes, including those encoding proinflammatory cytokines
- 5/10 - TLRs 3,4,7,8,9 → trigger production of interfones (IFN a,b,gamma) → essential for antiviral immunity
- Deficiency of TLR3 → severe viral infections, particularly HSV 1 encephalitis
7
Q
Notes on phagocytic cells in the innate immune system:
A
Neutrophils
- Most abundant, first cell recruited into tissues by inflammatory chemicals released by other cells e.g. macrophages, attracted by (1) N-formyl bacterial oligopeptide, C5a, leukotreine B4, IL-8. Some AMPs also chemotactic for neutrophils.
- Short lived - 1 day, continuously generated in bone marrow → migrate to blood
- Kill by generating toxic O2 metabolites
Monocytes and macrophages
- Monocytes develop in bone marrow → differentiate into macrophages or dendritic cells in tissues (alveolar macrophages in lung, Kupffer cells in liver, osteoclasts in bone, cardiac macrophages, microglia in brain/retina)
- Differ from neutrophils in that:
- Present microbial antigens to lymphocytes to initiate adaptive immunity
- Secrete proteins that mediate host defence including cytokines
8
Q
Notes on eosinophils, basophils, mast cells:
A
Eosinophils
- Kill pathogens too large to be ingested by macrophages - attempt to kill extracellularly
- Release extracellular traps carrying attached eosinophil granules that secrete their contents when secreted - role in parasitic infection but also antibacterial and antiviral activity. Also role in allergic reactions
- Live mostly in the lamina propria of GI tract → “nutured” by IL-5, IL-3, cytokines
Basophils
- Only in blood, express IgE receptors - participate in allergic response and resistance to parasitic infections
Mast cells
- Generated in marrow from HSC → leave marrow in immature form, migrate and mature in tissues → esp. muscosal gut, lung, skin
- Reside in the interstitium of peripheral tissues.
- Express TLRs 1,2,4,6 for the complement C5a and receptors for MBL
- Activation → release of TNF-alpha and IL-8. Also inflammatory mediators → histamine, heparin, leukotreines etc.
- Role in helminth protection and ?envenomation
9
Q
Notes on natural killer cells
A
- Lymphoid origin in bone marrow, do not express antigen specific receptors derived from exposure to specific antigens (like T and B cells) but can alter behaviour based on prior exposure to particular antigens
- Express receptors inc. TLRs - particularly important in response to viral infections (herpesvirus infections) and malignant cells
- NK cells avoid healthy host cells by recognising MHC Class I molecules expressed on all normal healthy cells - inhibits NK mediated cell lysis and cytokine secretion
- Virus infection and malignant cells that downregulate MHC class I molecules → becomesusceptible to attack by NK cells
Helper innate lymphoid cell
- Localise to surfaces
- Respond quickly to danger signals released by the pathogen or local cells
- Release cytokines that govern local responses
10
Q
Notes on dendritic cells
A
- Major antigen presenting cells, key link between innate and adaptive immunity
- Capture, process, and present antigens to unprogrammed T cells to induce adaptive immunity or tolerance to self-antigens
- As they mature → develop antigen specificity → become part of the adaptive immune response
- Internalise microbial products (LPS, PAMPS, DAMPS released by damaged tissue) → induces maturation → upregulation of cytokine receptors, MHC Class II, and costimulatory molecules CD80 and CD86 → presentation to unprogrammed T cell to induce their proliferation
11
Q
Significance of chronic granulomatous disease and the innate immune system:
A
- Defective NADPH oxidase in neutrophils and macrophages
- Patients suffer from severe bacterial and fungal infection and inflammatory disorders e.g. IBD
- Severe infections due to defective production of microbicidal O2 metabolites (dependent on NADPH-oxidase)
- Excess inflammation → NADPH-oxidase also involved in regulation of inflammation, macrophages in this disorder also do ingest apoptotic neutrophils normally
- Exposing macrophages to IFN-gamma (activator of macrophages) → used in treatment
12
Q
Basic notes on the complement system:
A
- Innate and adaptive immunity - opsinizes and lyses bacteria
- Promotes local acute inflammatory response → influences the adaptive immune response
- Consists of plasma proteins of the activating cascades and membrane regulators and receptors
- 3 major cascades → classical, alternative, lectin pathways
Biological functions of complement:
- Deposition of C3b on a target → opsonization
- C3a and C5a → promotion of inflammatory response → bind to their receptors to promote vasodilation, chemotaxis
- Note: b = bind to cell surface, a = released
13
Q
Notes on classical complement pathway:
A
- Triggered by antibodies binding to antigens
- C1q (part of the C1 complex) binds to Fc portion of antibody (IgM, IgG)
- Autoactivation of C1 complex which leads to cleavage of C4 and C2 → C4b and C2b → assemble on target to form C3 convertase (C4b2b)
- C3 converstase activates C3 (via proteolytic cleavage). Ultimately leads to formation of:
- C3a → inflammation (anaphylatoxin)
- C3b → opsonization, also activates C5 convertase
- C5 convertase cleaves C5 to:
- C5a anaphylatoxin
- C5b - begins formation of the MAC (composed of C5b, C6, C7, C8,C9) → forms transmembrane channels → osmotic lysis
14
Q
Notes on the lectin complement pathway
A
- MASP 2 mediated cleavage of C4 and C2 on recognition of 2 major protein families:
- Ficolins
- Collectins - including mannose binding lectin
- Otherwise the same as the classical pathway
15
Q
Notes on the alternative complement pathway
A
- Small amount of autoactivated C3 always present (“tickover”).
- Activated C3 binds factor B → factor B cleaves → Bb and Ba → form alternative pathway C3 convertase
- C3 convertase cleaves C3 → C3b (C3b produced in classical and lectin pathway also amplifies the alternative pathway)
- C3b binding to C3 convertase → activates MAC in usual way
