SLE- the role of inherited and acquired complement deficiencies Flashcards
How does complement act as a bridge between humoral adaptive immune system and innate immunity?
many of the effector activities of antibody are mediated by the activation of complement to immune complexes; augments antibody responses
What are the function of the classica complement pathway?
immune complexes; apoptotic cells; certain viruses and bacteria; CRP
What is the C3 inhibitor?
factor I
What are the functions of C3?
opsonin; anaphylatoxin; leucocyte activation; natural dajuvant
What is the result of C3 deficiency?
recurrent pyogenic infections
What is the result of deficiencies in the terminal complement pathway (C5-9)
meningococcal infection
What inhibits MAC?
CD59
What is the traditional view of inflammation in SLE?
autoantibodies form immune complexes with autoantigens which fix complement which causes tissue injury
Why doesn’t the traditional view of the pathogenesis of inflammation in SLE fit?
complement deficiencies would protect rather than predispose to SLE
What % of patients with a C1q deficiency get SLE?
93%
What is the sibling concordancy of SLE in C1q deficiency?
90%
What do the figures about C1q deficiency indicate about the role of complement in SLE?
a physiological activity of the early part of hte classical pathway protects against the devleopmnet of SLE
What are the actions of C1q?
helps clear apoptotic cells; downregulates autoreactive B cell function; acts as adjuvant and increases humoral immune repsonse
Where are lupus autoantigens concentrated?
surface of apoptotic blebls and bodies
What is the waste disposal hypothesis in SLE?
SLE associated wtih C1q deficiency may be caused by an impairment of the clearance of dying cells and/or immune complexes which cause inflammation and provide a source of autoantigens
What supports that there is defective waste disposal in C1q deficiency?
in C1q -/- mice you can see apoptotic cells in kidney biopsy- which normally wouldn’t as cleared. % of macrophages ingesting apoptotic bodies is lower- not as effective
What happens when there is impaired clearance of apoptotic cells?
develop secondary necrosis- lose membrane integrity and release of intracellular contents
How does C1q regulate cytokine expression?
suppresses IFN-a responses to ICs directly on pDCs and monocytes
What indicates that IFNa is upregulated in SLE?
SLE patietns have lots of expression of genes induced by IFNa
What suggests that increased IFNa in C1q deficiency is not solely responsible?
C4 and C2 deficiency are associated with increased SLE risk but do not inhibit IFNa
What are the unconventional complement activation independent actions of C1q
pro-angiogenesis; carinogenesis; trophoblast invasion; role in neurodegeneration and ageing
What effect does C1q have on CD8 T cells?
acts through the mitochondria to act on the metabolism and result in uncontrolled proliferation and lots of granzyme production–tissue damage–epitope spreadign
What are the acquired complement deficiencies of SLE?
consumption :decreased C4 and C3
How does complement relate to disease activity in SLE?
reflects sever disease; increase after treatment; bippsies show deposits of C3 and C4
What are the difficulties with complement assays?
serum levels vary widely in heatlhy individuals; rise with acute phase response (infection); loca activation may not be reflected in circulating components
What is the SLE paradox with C1q?
genetic deficiency of C1q is associated with SLE and patients with SLE develop antibodies to C1q
How were the anti-C1q antibodies in SLE first detected?
when trying to create an assay to detect immune complexes, by having plate bound C1q which then bound antibody
Why do anti-C1q antibodies only bind C1q in solid phase?
neoepitope when C1q is in its bound form
What does the fact that the anti-C1q antibodies are high affinity suggest?
they are the result of an antigen-driven response
What type of antibody are nati-C1q antibodies?
mainly IgG2
What part of the C1q molecule do the antibodies recognise?
the collagenous part
How many pateints have anti-c1q antibodies?
around 30%
What do the anti-C1q antibodies highly correlate with?
lupus nephritis; hypocomplementaemia
What other diseases are anti-C1q antibodies found in?
rheumatoid vasculitis; Felty’s sydnrome
What is the thought to be the reason for devleopment of anti-C1q antibodies?
C1q binds to dying cells and beomces part of autoantigenic complexes
What was the initial question posed by the finding of anti-C1q antibodies in SLE?
are they pathogenic or an epiphenomenon
What was the effect of administering anti-C1q mAb to naive mice?
mouse didn’t develop albuminuria
What was the effect of administration of anti-C1q mAb to anti-GBM pretreated mice?
developed proteinuris
What did the effect of anti-C1q antibodies in context of goodpastures suggest about their role in SLe?
amplify damage if there are immune complexes already present- cause increased inflammation, increased complement fixation and influx of immune cells
Give an example of complement therapeutic effective in SLE?
anti-C5a
What are the 3 type of complement deficiency that can cause increased susceptibility to pyogenic infections?
deficiency of the opsonic activities of the complement system; any deficiency that compromises the lytic activity of complement and deficiency function of the MBL pathway
What type of infection is increased with deficient opsonic activity of complement?
general susceptibility topyogenic organsims
What type of infection is increased with compromised lytic activity of complement?
neisserial infections
Give examples of pyogenic bacteria?
h.influenzae and strep. pneumoniae
What is the normal pathway of defense against pyogenic bacteria?
opsonisation with antibody activation of copmlement; phagocytosis; intracellular killing
What are the most important complement opsonins in the defense against bacterial infection?
C3b and iC3b- the covalently bound cleavage fragments of C3
What is extracellular lysis a major mechanism of killing neisseria?
they are capable of intracellular survival
What MBL homologos in structure to?
C1q
What does the low levels of MBL in young children with recurrent infections suggest?
the MBL pathway is important during the interval between the loss of maternal antibody and acquisition of a mature immunologic repertoire
Why may low levels of MBL partially protect against mycobacterial infection?
opsoinsation of intracellular organisms eg mycobacteria enhances entry of such pathogens into cells
How do mycobacteria manipulate the complement system?
synthesise a C4-like molecule that binds the serine esterase fragment of C2, C2a, leading to cleavage of C3 and deposition of C3b on mycobacterial-cell membranes enhancing uptake into macraophges
Give an example of a virus that uses complement to gain entry into the cell?
uses CD21 (CR2) as a cellular receptor for its envelope glycoprotein gp350/220- trposim for B cells with CR2
How do group A streptococci manipulate complement?
use the M protein to bind factor H which increases catabolism of C3b and reduces formation of C3 convertase enzymes
How does vaccinia virus evade complement?
has complement-control protein which acts as a cofactor to factor I which cleaves C4b and C3b inhibiting activation of complement
How does HIV evade complement?
incorporates complement regulatory proteins into the viral env
What does activation of the internal thioester bond of C3 bind to?
hydroxyl groups on carbohydrates and proteins
How is C3b which doesn’t bind inactivated?
binding to water molecules
What does the amplification step of C3 deposition require?
facto B
What activates factor B bound to C3b ?
factor D to form C3bBb
What does binding of factor H to C3b allow?
degradation of C3b by factor I into iC3b and C3f
What determines the relative affinity of C3b for factor H or factor B?
the carbohydrate environment of the surface on which teh C3b is deposited
What type of carbohydrate environemnt favours factor H binding to C3b rather than factor B?
sialic acids
What disease is defective regulation of C3 typically associated with?
glomerulonephritis
What causes the defective regulation of C3 in GN?
C3 nephritic factor
What is the function of C3 nephritic factor?
increases the stability of the C3 convertase enzymes or reduced function of factor H or I
What is C3 nephritic factor?
autoantibody that binds to and stbailises C3 convertase C3Bb
What disease does C1 inhibitor deficiency result in?
recurrent angioedema
What is the function of C1 inhibitor in copmlement?
inactivates serine esterases C1r and C1s
Give an example of a disease related to a failure to regulate the formation of MAC?
paroxysmal nocturnal haemoglobinuria
What causes the failure of regulation of MAC in PNH?
lack proteins which prevent anchoring CD55 and CD59
What is the function of CD55?
regulates the formation of C3 convertase
What is the principal way of activating hte classical pathway of the complement system?
formation of immune complex
what demonstrated that complement plays a role in the induction of antibody responses?
formation of antibodies against T-cell-dependent antigens was reduced in animals in which C3 had been depleted
Why could copmlement be used as an adjuvant?
binding to C3dg to complement receptors reduces the threshold for activation of the B cell
What type of antibody is important for binding complement intiially?
natural IgM antibodies
What indicates the importance for natural IgM antibodies in stimulating an antibody response?
mice lacking serum IgM have suboptimal responses of IgG antibody to low doses of antigen
What are hte 2 ways by which complement is actiated in tissues?
through immune complexes and through tissues ischaemia and reperfusion which exposes phospholipids and mitochondrial proteins which bind C1q or MBL; natural IgM or CRP
How is hereditary angioedema linked to SLE?
excessive cleavage of C4 and C2 by C1s caused by a deficiency of C1INH leads to acquired deficiency of C4 and C2 resulting increased risk of SLE
What od macrophages secrete in response to engulding apoptotic cells?
TGFb
What animal models support the waste disposal hypothesis?
mice lacking serum amyloid P component which binds to extracellular chromatin and apoptotic cells develop SLE; also mice lacking DNase1 which digests extracellular DNa
Why is IFa particularly produced in SLE?
in absence of C1q, instead of Ics binding to monocytes that preferentially engage pDC generating IFN; lack of C1q increases NET degradation which promote type I IFN production and source of antigen for formation of ICs
How do complement proteins protect against infeciton?
promote phagocytosis; direct pathogen lysis; promoting chemotaxis; stimulating antibody production
What is the paradox of complement in SLE?
complete activation of the complement pathway promotes tissue injury, yet deficiency of classical complement components predisposes to SLE
How does IFNa contribute to autoimmunity?
autoantigens taken up by DCs- DC activated by IFNa- activation of T and B cells
What part of C1q binds to phagocytic receptors?
collagenous
What may explain why C4 and C2 deficiency predisposes to SLE?
C1q activation of apoptotic cells rpomotes apoptotic cell clearance by activating the classical pathway with deposition of C3b
What supports the C3 model of SLE?
C1q did not enhance ingestion of apoptotic cells in the absence of fresh serum
What is efferocytosis?
ingestion of apototic cells
How may NETosis be induced in SLE?
by ICs and/or IFNa
Why may SLE patients be less able to degrade NETs?
lower DNase1 levels
Describe the C1q molecule?
collagen-like region that sprouts in 6 globular heads
What are anti-C1q antibodies directed against?
neoepitopes- epitopes not accessible in the native protine but when bound - collagen-like region
What type of IgG is the most potent activator of C1q?
IgG3
How can the types of autoantibody in SLE be divided?
thos directed against nuclear components; those against membrane phospholipids (anticardiolipin); antibodies against serum proteins (b2-glycoprotein)
How can anti-C1q antibodies be used in SLE?
predict a renal relapse better than dsDNA; will not develop severe lupus nephritis if don’t have anti-C1q antibodies
