Complement Pathways

And then there were 3.

3 pathways to rule them all – destroying microbes, clearance of cellular debris/apoptotic cells and promote inflammation.

The classical, lectin and alternative pathways.

Each pathway is activated by a different mechanism. The major goal of all three cascades is the deposition of large quantities of C3b on a target (opsonization), which marks it for elimination. Engagement of each pathway also leads to the release of proinflammatory anaphylatoxins (C3a and C5a) and assembly of the membrane attack complex (MAC).

complement_pathwaysFrom uptodate.com

But I mean, let’s face it. What we really want to know is how to interpret the tests and what they mean right?

So let’s make it simple.

Classical pathway is represented by C3 and C4 levels.

Generally:

Low C3/C4 or Low C3 only can represent:

  1. Antiphospholipid syndrome
  2. Mixed cryoglobulinemia
  3. Sjögren’s syndrome
  4. MPGN
  5. Any causes of circulating immune complexes – IE, hepatitis, mononucleosis, shunt nephritis

Low C4 but normal C3

  1. Hereditary angioedema
  2. Acquired C1 inhibitor deficiency
  3. Genetic partial deficiency of C4

But sometimes SLE too as C3 is 6x higher in concentration than C4 and while it falls, the level might still remain in the ‘normal limit’ whereas C4 levels will have dropped below the lab limit.

Things to note : The complement system is designed to work onthe biological membrane. In diseases like angioedema, C3 convertase works poorly in the plasma (fluid) phase, hence C3 levels appear normal (but they are also consumed) as they are not broken down whereas C4 levels are low.

But in syndromes involving excessive soluble immune complexes, such as mixed cryoglobulinemia, SLE, and MPGN can also lead to ‘normal’ C3 but low C4. Hence, screen for all the above if complement is low!

Alternative pathway activation is indicated by low levels of factor B, low C3 with normal C4 and is a pathway that is constantly working at a low level behind the scenes (like how your heart beats all the time!)

complement-pathway

Now, sometimes I feel certain things are easier to be explained using layman terms. Too much medical jargon makes one’s head go round and round.

Especially explaining things that are just LETTERS. I mean H, I, B … they are just that. Alphabets.

So I’m going to say there are accelerators and brakes in the alternative pathway system.

Complement Factor H (CFH), Factor I (CFI) and Membrane cofactor protein (MCP) are all BRAKES.

Complement Factor B (CFB) and D (CFD) are ACCELERATORS.

So something comes along and activates our dear old alternative pathway. C3 generates C3b which binds indiscriminately to pathogens and host cells. On a foreign surface, such as a bacterium, C3b binds CFB, which is then cleaved by Factor D to form the C3 convertase C3bBb. This amplifies the C3 convertase loop leading to formation of the MAC that kills of the bacteria.

Now if this continues to go into overdrive (i.e. the accelerators are being stepped on all the time) pretty soon we will be attacking all cell surfaces which leads to all sorts of problems. Our brakes CFH, CFI and MCP are there to police this. Competition between CFH (which is the main player) binding to C3b limits the binding of CFB instead hence reducing C3 convertases and reducing MAC formation.

Got it?

In summary (but not exclusively)

lowc3c4

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MPGN

Membranoproliferative glomerulonephritis, i.e. mesangiocapillary glomerulonephritis.

What a bloody mouthful.

Again, one of the GNs that just sound difficult in medical school and needs some thinking into it. The problem is that the definitions and classifications have been changed multiple times throughout the years and what I learned 10 years ago is probably not relevant anymore now.

Anyhow, I digress.

Firstly – MPGN has characteristic changes on LIGHT MICROSCOPY.

  • Immune complex/complement factors deposit onto the GBM, leading to thickening of the GBM. This then leads to inter positioning of the mesangium & endothelial cells  with the GBM leading to laying down of new GBM; hence double contouring of the glomerular capillary walls.
  •  This also leads to mesangial hypercellularity and endocapillary proliferation, causing a lobular appearance of the glomerular tuft.

Electron microscopy (EM) in immunoglobulin-positive MPGN typically demonstrates subendothelial and mesangial deposits. EM does not differentiate immune complex or complement mediated MPGN.

MPGN can be classified into 2 separate entities:

Immune complex mediated – c3 and Ig staining along capillary wall in a granular pattern vs linear pattern in anti GBM  :

Causes:

i)chronic infections (HCV : shows granular deposition of IgM, C3, and both kappa and lambda light chains +/- IgG; HBV, TB, coxiella, brucella, nocardia) or carrier state (mycoplasma, Neisseria, strep) -> this causes chronic low grade Ab production.

ii)Monoclonal gammopathies like MGUS (deposition of monotypic kappa or lambda light chains but not both), and less likely, myeloma, Non Hodgkin’s lymphoma and CLL.

iii) Autoimmune diseases :  typically characterized by the “full house” pattern of immunoglobulin deposition, including IgG, IgM, IgA, C1q, C3, and kappa and lambda light chains. Most common is SLE, followed by Sjogren’s and then RA

Recurrence of MPGN with monoclonal IgG deposits has been described in transplanted kidneys (idiopathic immune complex mediated MPGN)

Complement mediated – dysregulation and persistent activation of the alternative complement pathway. Immunoflorescence demonstrates bright c3 staining (No Ig in the mesangium and capillary walls). Complement can be low or not, especially in the chronic phase of DDD and C3GN

Causes:

Dense Deposit Disease – activation of the alternative complement pathway (negative staining for C1q and C4 which is the classical complement pathway)

EM shows characteristic sausage-shaped, wavy, densely osmophilic deposits along the glomerular basement membranes (GBM) and mesangium.

Aetiology is likely due to an absence of a constitutive inhibitor of the alternative complement pathway (factor H) or the presence of a circulating autoantibody (C3 nephritic factor; CNefs) that binds to and prevents inactivation of the alternative pathway C3 convertase (80% have elevated levels). External manifestations:drusen in Bruch’s membrane of the retina (like macular deposits in age related macular degeneration, however, drusen in DDD occurs at a much younger age). Acquired partial lipodystrophy characterized by loss of subcutaneous fat in the upper half of the body

DDD is also occasionally diagnosed in older adults, some of whom have been found to have an underlying monoclonal gammopathy

C3 glomerulonephritis

C3GN has also been reported in association with monoclonal gammopathies and anti-factor H activity, as well as with inherited disease due to mutations in the CFHR5 gene (CFHR5 nephropathy) and a mutation producing a CFHR1-CFHR3 hybrid gene.

Similar appearances in light microscopy and immunoflorescence BUT EM demonstrates deposits that are similar to those seen with immune complex-mediated MPGN but does not show the typical sausage-shaped intramembranous and mesangial deposits observed in DDD

CFHR5 nephropathy – a familial form of C3GN, in cypriot families  due to a mutation in the gene for complement factor H-related protein 5. Autosomal dominant with 90% penetrance. Can reoccur in transplanted kidney.

What if one gets sub epithelial deposits and sub endothelial deposits too ? If they are both complement + and Ig + , post infections GN is what is happening. What if its complement + but Ig – ? It could be resolving post infections GN, OR undiagnosed C3GN – check their complement pathway!!

And finally, MPGN features but negative for complement or immunoglobulins?

  • TMA : TTP, HUS, drug induced
  • Antiphospholipid Ab Syndrome
  • Nephropathy associated with bone marrow transplantation
  • Chronic renal allograft nephropathy
  • Radiation nephritis
  • Malignant hypertension

mpgn

Treatment

  1. Non nephrotic range proteinuria & normal GFR – ACEi
  2. Nephrotic syndrome – Prednisolone, ACEi, CNIs if steroid intolerant
  3. Reduced GFR +/- nephrotic syndrome +/- hypertension with no crescents – Prednisolone first, if no better trial cyclophosphamide. If persistent – RTX
  4. RPGN +/- crescents – prednisolone and cyclophosphamide