First Aid, Chapter 1 Immune Mechanisms, Complements and Kinins Flashcards
What is the function of the complement system?
Promote phagocytosis of microbes, to stimulate inflammation, and to induce lysis of these organisms.
Describe the steps of the complement alternative pathway. What regulates the pathway? What are cofactors in the pathway?
- C3 is continuously undergoing small-scale cleavage in the plasma (C3 tickover) to C3b → activates an internal thioester bond → covalent binding of C3b to hydroxyl groups on microbial cell surfaces.
- Bound C3b binds factor B to form C3bB.
- Factor D cleaves factor B to form the AP C3 convertase (C3bBb), stabilized by properdin.
- Regulation of this pathway occurs through factor I-mediated cleavage of C3b.
- Factor H, membrane cofactor protein (MCP/CD46) and decay-accelerating factor (DAF/CD55) serve as cofactors (only found on mammalian cells).
Which complement is the most potent mediator of basophil and cutaneous mast cell degranulation?
C5a
Describe the steps of the classical pathway. What inhibits the pathway?
- C1q binds to the Fc portion of an immunoglobulin cross-linked by antigen.
- Binding affinity of C1q for IgM > IgG3 > IgG1 > IgG2.
- C1q is associated with C1r serine proteases, which cleave and autoactivate C1s proteins.
- Activated C1s cleave C4 and C2 to yield C4b2a, which is the C3 convertase of the CP.
- C1 inhibitor inhibits C1r and C1s, thus regulating the pathway.
- C4b deposited on cell surfaces is bound by DAF, complement receptor type 1 (CR1) and C4-binding protein (C4BP), thus blocking further progression of the cascade.
- C4b bound to C4BP is inactivated to C4bi by factor I
What complement pathway does Factor H regulate?
alternative pathway
What is order of binding affinity of C1q to different immunoglobulins?
IgM > IgG3 > IgG1 or IgG2
Describe the lectin pathway (LP).
Activated in the absence of antibody. Mannose-binding lectin (MBL) binds to mannose residues on microbial polysaccharides, and also to MBL-associated protease-1 (MASP-1) and MBL-associated protease-2 (MASP2). MASP-2 cleaves C4 and C2 to form the C3 convertase C4b2a (Figure 1-12).
Describe the common pathway.
- C3 convertase cleaves C3 to C3b, which binds to the convertase and form C5 convertase: C3bBb3b in the AP, and C4b2a3b in the CP and LP.
- C5 convertase cleaves C5 and initiates the formation of the membrane attack complex (MAC), and C5a is released.
- MAC is formed by (C5b-8) polyC9 and it creates pores in the membrane and induces cell lysis.
- C9 is structurally homologous to perforin.
- S Protein and CD59 inhibit formation of the MAC.
- C5a is the most potent mediator of basophil and cutaneous mast cell degranulation; C5a > C3a > C4a.
- C5a is chemotactic for neutrophils, eosinophils, monocytes, and basophils.
- C3a is chemotactic for only eosinophils.
Which complement receptor is implicated in PNH (paroxysmal nocturnal hemoglobinuria)?
CD55 (DAF); CD59.
Describe the defect in LAD (Leukocyte adhesion deficiency) type 1.
Leukocyte adhesion deficiency (LAD) type 1 is observed in patients with CR3 or CR4 deficiency -> due to a rare mutation in the β chain (CD18) common to the CD11 or CD18 family of integrin molecules
What cell is CR4 a marker for?
Dendritic cells.
What does C3d bind to provide a second signal for B-lymphocyte activation by antigen?
CR2 (CD21).
What is the ligand for CR1? What is the CD name for it?
Ligand: C3b, C4b, iC3b
CD35
What is the function of CR1 (CD35)?
- Regulates complement activation
- Phagocytosis of C3b- and C4b-coated particles
- Clearance of immune complexes (CR1 on RBCs)
What microorganism/disease uses CR1 (CD35) to gain entry into the human cell?
HIV
What is another name for CR2?
CD21
What is the ligand for CR2 (CD21)?
C3D, iC3B, and C3dg
What is the function of CR2 (CD21)?
- Part of B lymphocyte coreceptor with CD19 and CD81 (TAPA)
- Trapping antigens in the germinal center
What microorganism/disease uses CR2 (CD21) to gain entry into the human cell?
EBV and HIV
What is the other name for CR3?
Mac-1m, CD11b/CD18
What is the ligand for CR3 (Mac-1, CD11b/CD18)?
iC3b and ICAM-1
What is the function of CR3(Mac-1, CD11b/CD18)?
Phagocytosis Leukocyte adhesion to endothelial cells
What is the associated pathology with CR3(Mac-1, CD11b/CD18)?
LAD type 1
What are the microorganism/diseases that use CR3(Mac-1, CD11b/CD18) to gain entry into the cell?
Mycobacterium TB, HIV, and West Nile Virus
What are the receptors of the complement system?
CR1 (CD35), CR2 (CD21), CR3 (Mac-1, CD11b/CD18), CR4 (gp 150/95, CD11c/CD18), CD46 (MCP), CD55 (DAF), CD59 (protectin)
What is the ligand for CR4 (gp150/95, CD11c/CD18)?
iC3b
What is the function of CR4 (gp150/95, CD11c/CD18?
Phagocytosis
What is the pathology associated with CR4 (gp150/95, CD11c/CD18?
LAD type 1
What disease/microorganism uses CD46 (MCP) to gain entry into the human cell?
measles virus
What is the other name for CD46?
MCP
What is the other name for DAF?
CD55
What is the ligand of CD55?
C4b and capsid
What is the function of CD55 (DAF)?
Regulates formation of C3 convertase
What is the pathology associated with CD55 (DAF)?
PNH
What is the diseae/microbe that uses CD55 (DAF) to gain entry into the human cell?
Echovirus and coxsackie virus
What is the other name for CD59?
Protectin
What is the ligand for CD59 (protectin)?
C5b-8 and monomeric C9
What is the function of CD59 (protectin)?
Disrupts formation of (C5b-8) poly C9
What is the associated pathology with CD59 (Protectin)?
PNH
What is the other name of CR4?
gp 150/95, CD11c/CD18
Which complement deficiency is inherited as X-linked?
Properdin.
What is C3 nephritic factor?
An autoantibody that binds and stabilizes C3bBb, and protects it from factor H-mediated dissociation and factor I cleavage, resulting in unregulated consumption of C3.
What diseases is C3 nephritic factor found in?
1) A few patients with SLE
2) Type II membranoproliferative glomerulonephritis (MPGN)
3) Partial lipodystrophy
What is the histology of MPGN? What pathologic complement factor is associated with it?
Mesangial proliferation, capillary wall thickening, and subendothelial deposits of Ig and C3. Associated with C3 nephritic factor.
What is partial lipodystrophy? What pathologic complement factor is associated with it?
Partial lipodystrophy, a disfiguring condition that affects the body from the waist upward but spares the legs. Associated with C3 nephritic factor.
Why is there a difference in fat loss between the upper body and lower body in partial lipodystrophy?
Adipose cells are the main source of factor D, which completes the formation of C3bBb
o There is a gradient in the concentration of factor D; more is present in the upper-half than the lower-half of the body, thus causing the distribution of fat loss observed in partial lipodystrophy. C3 nephritic factor stabilizes C3bBb that forms in the vicinity of adipocytes and cleaves C3 to allow assembly of membrane attack complex, which lyses the adipocytes.
What cell is the main source of Factor D?
adipose cells
What does Factor D do?
Completes the formation of C3bBb.
What is anti-c1q antibody?
Autoantibody to the collagen-like region of C1q
What disease is anti-C1q antibody found in?
Found in patients with hypocomplementemic urticarial vasculitis (HUVS)
What does anti-C1q result in?
Results in activation of creatine phosphate pathway with tissue deposition of immune complexes
What is the treatment of hypocomplementemic urticarial vasculitis?
hydroxychloroquine
Which complement deficiency is inherited as X-linked?
Properidin.
What does measuring CH50 do? What pathway does it assess?
- CH50: Assesses ability of serum to lyse sheep RBCs sensitized with rabbit IgM
- Classical Pathway
What pathway does AH50 assess? What does AH50 measure?
- Measures lysis of unsensitized rabbit RBCs
- Alternative pathway
What are C3 and C4 levels measured in in the lab?
C3 and C4 levels are measured in nephelometric immunoassays
What are C4a and C4d levels markers of?
Classical pathway or lectin pathway activation.
What is Bb a marker of?
Alternate pathway activation
What are markers of terminal pathway activation in the lab?
C3a, iC3b, C5a, and soluble C5b-9
CH50 absent + AH50 OK =
Deficiency: C1q, C1r, C1s, C2, C4
CH50 OK + AH50 absent =
Deficiency Factor B or D, properdin
CH50 absent + AH50 absent =
Deficiency: C3, C5, C6, C7, C8, C9
C3 absent =
Deficiency: Factor H, Factor I
What diseases are associated with C1q, C1r, C1s, C4, and C2 deficiency?
SLE and MPGN
What infections are associated with C1q, C1r, C1s, C4, and C2 deficiency?
Recurrent pyogenic bacterial infections: Streptococcus pneumonia and Haemophilus influenzae type b.
What disease is C3 deficiency associate with?
MPGN
What infections are increased in C3 deficiency?
Severe, recurrent pyogenic infections beginning shortly after birth
What disease is MBL deficiency associated with?
SLE
What type of infections is MBL deficiency associate with?
pyogenic infections
What complement deficiencies are associated with increased Neisseria infections?
C5-C9, Factor D, Fact B, and Proerdin, Factor H, Factor I, CD46 (MCP).
What diseases are associated with Factor H deficiency?
HUS, MPGN, and ARMD (Age-related macular degeneration)
What disease is associated with Factor I deficiency?
MPGN
What disease is associated with CD46 (MCP) deficiency?
MPGN
What disease is associated with C1 inhibitor deficiency?
HAE
What complement deficiencies is PNH associated with?
CD59 (MAC) and CD55 (DAF)
What inheritance are most complement deficiencies? Which complement deficiency is inherited as X-linked?
Autosomal recessive.
Properdin is x-linked recessive (all male).
What is the most frequent complement deficiency seen with SLE?
SLE is seen much more frequently with deficiency of C1q than any other complement deficiency. Also caused by C1r/C1s, C4 (1% whites C4A), and C2 deficiency.
Describe the simpler pathway of bradykinin generation.
Tissue kallikrein cleaves low-molecular-weight kininogen to yield lys-bradykinin, which is further cleaved by an aminopeptidase to bradykinin.
Describe the contact activation pathway of generating bradykinin.
Initiated when circulating factor XII (Hageman factor) binds to a negatively charged surface and autoactivates (contact activates) to form factor XIIa. Prekallikrein (PK) circulates as a complex with highmolecular-weight kininogen (HK), and HK binds to the initiating cell surface. Factor XIIa then cleaves PK to kallikrein, 10–20% of which dissociates into the fluid phase, and kallikrein digests HK to liberate the vasoactive peptide bradykinin (Figure 1-14). A positive feedback loop is shown in which kallikrein cleaves and activates factor XII at a rate at least 50-fold faster than the factor XII autoactivation. Factor XIIa also cleaves XI to form factor Xia, which initiates the intrinsic coagulation pathway
What is C1 inhibitor the sole inhibitor of? What else does it inhibit? What is C1 inhibitor consumed by?
C1 inhibitor is the sole plasma inhibitor of factor XIIa and factor XIIf, a cleavage product derived from factor XIIa by digestion with kallikrein or plasmin. C1 inhibitor is also one of the major inhibitors of kallikrein and factor XIa as well as C1r and C1s. C1 inhibitor is consumed by plasmin.
What is bradykinin? What receptor does it act via?
The mediator of swelling during angioedema episodes, via the B-2 receptor on endothelial cells.
What happens to bradykinin in HAE? Where is activation most pronounced and where else is it detected?
Hereditary angioedema (HAE) is characterized by bradykinin overproduction caused by lack of C1 inhibitor function; activation is most pronounced at the site of swelling although enzyme activation is detectable throughout the plasma
Why do ACE I lead to bradykinin accumulation?
Angiotensin-converting enzyme (ACE) is identical to kininase II, which is the major enzyme responsible for bradykinin degradation. Thus treatment with ACE inhibitors leads to bradykinin accumulation caused by inhibition of degradation.
What does Factor XII bind to on the endothelial cell membrane? In the presence of what molecule?
Bind to cell-surface complexes of urokinase plasminogen activator receptor (u-PAR), cytokeratin 1 in the presence of zinc.
What does HK bind to on the endothelial cell surface? In the presence of what molecule?
Receptor for the globular head of C1q (gC1qR), cytokeratin 1, in the presence of zinc.
What are the ways that the cascade to generate bradykinin can be activated?
- Cell-bound factor XII
- Cell-derived heat shock protein (HSP) 90 or prolylcarboxypeptidase can activate the PK-HK complex stoichiometrically (but not unbound PK) to generate kallikrien which then can activate factor XII
