The Innate System II: Interferon and the Complement Cascade Flashcards
summarize the antimicrobial serum agents
describe interferon alpha and interferon beta (type I)
- type I interferons can be produced by almost any cell upon stimulation by a virus
- act on neighboring uninfected cells
- inhibit transcription and translation of viral proteins
describe interferon gamma (type II)
- produced by: TH1, CTLs (CD8+), NK cells
- promotes NK cell activity
- increases activity of macrophages
-
activates inducible nitric oxide synthase (iNOS):
- relaxes smooth muscle, vasodilation
- induces the production of antibodies
- causes normal cells to increase expression of MHCI and MHCII
- promotes adhesion and binding required for leukocyte migration
- induces the expression of intrinsic defense factors with direct antiviral effects
- respond to cancerous growth
describe granuloma formation by IFN-γ
- body’s way of dealing with a substance it cannot remove
- infectious causes: tuberculosis, leprosy, histoplasmosis, cryptococcosis, blastomycosis, coccidiodomycosis and cat scratch disease
- non-infectious causes: sarcoidosis, Crohn’s disease
- association between IFNγ and granulomas: IFNγ activates macrophages to kill intracellular organisms
- IFNγ-induced granuloma formation:
- activation of Th1 helper cells by macrophages
- IL-1 and IL-12 by macrophages
- Th1 helper cells aggregate around the macrophages
- IFNγ release, which activates the macrophages
- repetitive action
- activation of Th1 helper cells by macrophages
- finally, macrophages surround the Th1 helper cells and become fibroblast-like cells walling off the infection
describe the complement system (series of pro-enzymes)
- 5% of serum globulin
- consists of >20 serum glycoproteins synthesized principally by hepatocytes, but also monocytes, macrophages and epithelial cells
- the complement system is important for the recruitment of inflammatory cells and the killing or opsonization of pathogens
- many components ciruclate in the seurm as proenzymes (inactive); complement proteins are activated by cleavage (cascade reaction)
- inactive precursors in blood: C2, C3, C4
name the 3 mechanisms that can enzymatically trigger the complement components, and what they all lead to
all lead to production of C3b
- antibody-antigen (classical pathway)
- microbial or non microbial foreign substances (alternative pathway)
- mannose-binding lectin, MBL (lectin pathway)
describe the classical pathway
adaptive immunity
- C1 binds to Ag-Ab complex
- activated C1 cleaves C4 and C2
- formation of C3 convertase
- C3 is cleaved
- C5 is cleaved
- sequential binding of C5b, C6-C9
describe the alternative pathway
innate immunity
- spontaneous cleavage of C3 based on multiple initiators
- requires Factors B and D
- formation of C3 convertase (less stable)
- requires Properdin
describe the MBL pathway
innate immunity
- mannan-binding lectin (MBL), an acute phase protein found in serum binds to carbohydrate residues on cells or pathogen surfaces
- MBL-associated serine protease (MASP) binds to MBL
- this complex cleaves C4 and C2 much like activated C1 (classical pathway)
summarize the 3 activation pathways (activator, C3-convertase, C5-convertase, MAC development)
describe the development of MAC
- three pathways converge with activation of C5 convertase
- C5b binds antigenic surface
- MAC is formed on surface
- C5 components: C5b, C6, C7, C8, C9
- poly-C9: perforin-like molecule
summarize the functions of complement
complement has a role in both innate and adaptive immunity
- cell lysis (C5b-C9)
- Ab-dependent
- Ab-independent
- opsonization (C3b)
- inflammation (C3a, C5a)
- clearance of immune complexes (C3b)
- viral neutralization (C3b, C5b-C9)
describe the CR1 complement cell receptor
describe the selected inhibitors of complement cascade
summarize the complement cascade inhibitors of the different pathways
-
inhibitors of alternative pathway:
- factor H, factor I, DAF, MCP
-
inhibitors of classical/lectin pathways
- Factor I, DAF, MCP, CR1, C1inh, C4bp
-
inhibitors of terminal common pathway
- S protein, Clusterin, Factor J, HRF, CD59
describe the 2 types of complement deficiences
- activator disorders: under-reactive system; more susceptible to infxns
- inhibitor disorders: overreactive system
describe classical pathway component deficiencies (complement deficiencies of activators)
-
classical pathway component deficiencies (C1, C4, C2)
- individuals are prone to immune complex disease
- inability to clear circulating immune complexes
- deposition in tissues and an associated inflammatory response
- example: SLE, glomerulonephritis, vasculitis
- individuals are prone to immune complex disease
describe MBL deficiency (complement deficiency of activator)
-
MBL deficiency
- classically presents with recurrent pyogenic infxn in childhood
- susceptibility to Saccharomyces cerevisiae, pneumococcal and Neisseria infxns
describe alternative pathway component deficiencies (complement deficiencies of activators)
-
alternative pathway component deficiencies (Properdin, factor B and factor D)
- affected individuals are prone to pneumococcal and meningococcal infxns
- Properdin deficiency: risk of overwhelming Neisseria infxn
describe C3 deficiency (complement deficiencies of activators)
-
C3 deficiency
- C3 is required for opsonization
- primary C3 deficiency tends to present in early life with overwhelming infxn with encapsulated organisms
- there is also a tendency to connective tissue disease
describe MAC deficiences (complement deficiences of activators)
-
MAC deficiencies (C5-C9)
- recurrent infxns
- common infxn with Neisseria meningitidis
- recurrent infxns
describe deficiency of C1-inhibitor (complement deficiences of inhibitors)
- C1-inhibitor (C1-INH) regulates the classical pathway
- deficiency results in angioedema (hereditary or acquired)
- C2b accumulation: vasoactive
- deficiency results in angioedema (hereditary or acquired)
describe deficiency of DAF (complement deficiences of inhibitors)
- DAF (decay acceleration factor)/CD55 and CD59
- paroxysmal nocturnal hemoglobinuria (lysis of red blood cells)
- caused by “continuous drilling”
summarize the diseases associated with complement deficiencies
describe complement genetics
- most complement deficiencies follow AR inheritance
- Properdin deficiency may be inherited as an X-linked trait
- MBL deficiency can be both AD and AR
- complement deficiencies can also be acquired
- post-infxn
describe hereditary angioedema
- rare syndrome characterized by episodic, nonpruritic, localized subcutaneous and submucosal swelling
- laryngeal edema can precipitate fatal resp. obstruction
- dysregulation of 3 different systems:
- complement - classic (C1) and MBL (MASP-2) pathways
- excessive activation of the complement due to mutation on C1inh results in high concentration of anaphylatoxins: C3a and C5a
- coagulation: factor XI and XII leading to fibrin buildup
- contact cascade: resulting in increased bradykinin levels leading to inflammation, coagulation and other body effects
- complement - classic (C1) and MBL (MASP-2) pathways
- there is an absence of urticaria (rash) that distinguishes HAE from an allergic reaction
summarize the problem in hereditary angioedema
describe assays for the classic pathway (laboratory testing)
- assays for the classical pathway:
- the hemolytic titration (CH50) assay: amount of patient serum required to lyse 50% of antibody-sensitized sheep erythrocytes
- needs all complement molecules (C1-9) to function
- ELISA
- the hemolytic titration (CH50) assay: amount of patient serum required to lyse 50% of antibody-sensitized sheep erythrocytes
- AH50 for the alternative pathway
describe the cascade defects/expected results for individuals components
list the diseases associated with decreased complement activity
list the diseases associated with increased complement activity
