complement system and diseases

2. HISTORY
Jules Bordet at the Institut Pasteur in Paris.
He named those substances as
Alexins.
Paul Ehrlich coined the term
complement.

3. INTRODUCTION
Consists of serum and cell surface proteins involved in defense
against pathogens and tissue damage mediated by antibodies
The Complement system is the major effector of cellular and
humoral branch of immune system.
Plays major role in both innate and adaptive immunity.

4. Complement system represents more than 30
proteins
Most of these proteins are found in serum or on cell surfaces.
Synthesized in liver as inative precursors
activated by proteolysis durig their interaction

5.  Three main effects of complement are:
1. Lysis of cells (bacteria, allografts, tumor cells)
2. Generation of mediators of inflammation
3. Opsonization – enhancement of phagocytosis

6. Complement Pathway
Three pathway of complement activation
1. Classical pathway:- antibody dependent pathway
- triggered by formation of soluble antigen-antibody complex
- binding of the antibody to the antigen present on the target cell
surface.
2. Alternative pathway:-
Is antibody independent pathway stimulated by antigen directly
3. Lectin Pathway:-
Also antibody independent but resembles classical pathway.

7. Stages of complement Activation
Three main stages in the activation of complement by
any pathway are
 Formation of C3 convertase
 Formation C5 convertase
 Formation of membrane attack complec(MAC)

9. Classical Pathway
Generation of C3-convertase

10. C4b2a is C3
convertase
C4b

11. Classical Pathway
Generation of C5-convertase
C4b
C3
b
C4b2a3b is C5
convertase; it leads
into the Membrane
Attack Pathway

12.  C4b-2a-3b functions as the classical
C5 convertase:

13. Lytic pathway
assembly of the lytic complex
b
C6
C7

14. Lytic pathway:
insertion of lytic complex into cell
membrane
b
C6
C7
CCCC
C9999C
9CCC9
9 9 9

16. Ab independnt pathway.
In the alternative pathway, many unrelated cell surface
initiate the process by binding C3 and factor B.
This complex is cleaved by a protease, factor D, to
produce C3bBb.
This acts as a C3 convertase to generate more C3b.
Alternative pathway

18. Lectin pathway
Also known as the MBL Pathway
In the lectin pathway, mannan-binding lectin (MBL)
(also known as mannose-binding protein)
Binding causes activation of MASP (MBP- associated
serine proteases) cleave C2 and C4 and activate
the classic pathway.

22. Role of complement in
renal disease

23. aHUS (Atypical Hemolytic Uremic
Syndrome)
 HUS -hemolysis, thrombocytopenia, and acute kidney
injury.
 HUS - Shiga-toxin producing bacteria.
 The remaining cases are referred to as “atypical HUS”
 40–60% of patients with aHUS have mutations in
complement proteins,
 10% of patients have autoantibodies to factor H that
impair its function.

24.  All complement defects -enhance alternative pathway
activation
 The mutations in factor B and C3 are gain of function
mutations.
 factor H mutations cluster in the region of the protein
that mediates binding to endothelial cells.

25.  The mutant proteins control alternative pathway
activation-
 binding to endothelial cells and other surfaces is
impaired.
 Autoantibodies to factor H bind this same region of the
protein and have a similar functional effect.

26.  Plasma exchange is beneficial in some patients with aHUS.
 This removes autoantibodies or dysfunctional complement proteins,
 replacement of patient plasma with fresh frozen plasma can restore
deficient proteins (factor H and factor I).
 patients who did not respond to plasma exchange -responded to
eculizumab

27. C3 Glomerulopathy
 a disease of dysregulated alternative pathway activation.
 presence of electron dense deposits within glomerular
basement membrane
 C3 glomerulopathy (and DDD) is associated with mutations
in the genes for
 C3,
 factor H,
 factor B
 complement factor H related proteins 1, 2 and 5 (CFHR1,
CFHR2, and CFHR5).

28.  70% of patients with DDD
 40% of patients C3 glomerulopathy have a circulating
auto-antibody,
 as C3 nephritic factor (C3Nef) that stabilizes the
alternative pathway C3-convertase and protects it from
inactivation by factor H.
 autoantibodies to factor H, C3, and factor B present
 Rituximab could potentially ameliorate disease in those
with autoantibodies

29. Membranoproliferative
Glomerulonephritis
 In MPGN type 1, immune-complexes in the mesangium and
subendothelial space activate the classical pathway of
complement.
 deposits of complement proteins in the glomeruli and
consumption of plasma C3 and C4
 40% of patients have circulating C3nef
 Heterozygous mutations in factor H or factor I – alternate
pathways

30. Cryoglobulinemia
 Associated with a MPGN pattern of injury.
 Immune-complexes within capillary loops and in the
subendothelial space
 C1q, C3, and C4 are usually detected

31. Lupus nephritis
 Deficiencies in components of classical pathway are
strong risk factors lupus
 due to defective clearance of nuclear antigens released
by injured and apoptotic cells.
 Complement activation mediates glomerular injury in
lupus nephritis.
 C3 and C4 levels are depressed in >90% of patients with
diffuse proliferative lupus nephritis,
 and a fall in these proteins reflects an increase in
disease activity

32. Membranous nephropathy
 Immune complexes in the subepithelial space of the
glomerular capillary wall.
 M-type phospholipase A2 receptor (PLA2R) are the target
antigen in idiopathic membranous nephropathy.
 Most of the IgG in the glomeruli and most of the anti-
PLA2R antibody in the serum is of the IgG4 subclass,
 IgG4 is a poor activator of the classical pathway of
complement.

33.  Mannose binding lectin detected in the glomeruli
 secondary membranous nephropathy, glomerular
immune deposits usually contain IgG1 and IgG3 -->
 effective activators of the classical pathway

34. Antibody-Mediated
Rejection
 Detection of C4d deposition in the peri-tubular capillaries
reflects classical pathway activation by donor specific
antibodies against HLA.
 Treatment aims at reducing the levels of donor specific
antibodies, such as plasmapheresis, IV Ig, and rituximab
 Eculizumab has been used to prevent antibody-mediated
rejection in sensitized patients

35. IgA Nephropathy
 Aberrant glycosylation of IgA1 molecules,
 the development of autoantibodies specific for the altered
IgA1.
 IgA1 containing immune complexes deposit within the
mesangium, and initiate glomerular injury.
 plasma C3 levels are usually normal,
 plasma C3a is elevated in some patients and glomerular C3
deposits are detected in 85% of biopsies.

36.  IgA activates complement system through either the
alternative or mannose binding lectin pathway.
 Complement factor H related proteins can compete
with factor H, positively activating the alternative
pathway.
 deficiency of the complement factor H related proteins
may make factor H more effective

37. Antineutrophil Cytoplasmic
Antibody (ANCA)-Associated
Vasculitis
 Complement activation through alternative pathway
contributes to the pathogenesis of this disease.
 Active disease is associated with elevations in plasma
levels of C3a, Bb, C5a, and sC5b-9,
 not with elevations in plasma C4d, consistent with
alternative pathway activation

40. Refernces
 Cellular and molecular immunology – Abbas et al
 Role of complements in kidney disease –Jamie willows
 Complement in kidney disease – core curriculum 2015
Joshua m thurman