Lecture 21 – Complement deficiencies and autoimmunity links

What is SLE?

Systemic Lupus Erythematosus

• Several complement deficiencies associated with SLE

What is C1q deficiency?

Deficiency in the complement protein C1q

• Restoring C1q levels restores normal complement function

• C1q-deficiency SLE patient cured with bone marrow transplant

What is the tolerance hypothesis of C1q deficiency in SLE?

• C1q isn’t present in the bone marrow

• This prevents apoptotic blebs from being displayed in the bone marrow

• This causes maturing T-cells to not be educated on what self antigens look like

  • This can result in autoimmunity

What is the clearance hypothesis of C1q deficiency in SLE?

• C1q interacts with apoptotic blebs produced from apoptotic cells

• C1q binding plays a key role in the clearance of the blebs

• Without C1q, there will be an excess of waste material

  • Leads to inflammation and lack of B-cell tolerance

In SLE, CR1 and CR2 expression levels on B-cells are….

Lower than normal

• Suggests a reduction in signalling

In SLE mice, what B-cell phenotypes were observed?

• Abnormal B-cell morphology

• Abnormal B-cell receptor editing

• Larger marginal zone B-cell population

How are CD8+ T-cells associated with C1q-deficiency mediated SLE?

Response to viral infections in C1q KO mice was greatly increased 

• Hyperactive CD8+ T-cells

C1q KO mice had reprogrammed CD8+ metabolism which affected their function.

C3 is important for what?

Known to be important for germinal centre formation, antibody responses and B-cell memory

What is CD46 (MCP)?

• Important for Th1 T-cell phenotype

  • Via binding with C3b

  • Drives IFN-y production and Th1 phenotype

CD46 (MCP) deficiency causes T-cells to not do what?

T-cells don’t assume a Th1 phenotype (Th2 not affected)

• This results in recurrent viral infections in patients 

CD46 (MCP) overexpression on T-cells causes what?

• T-cells are more likely to be inflamed and can lead to autoimmunity

CD46-C3b signalling results in what in T-cells?

• Modulate TCR function

• Intracellular activation of internal complement system

  • Drives Th1 response

CD46 activation in patients with RA causes what?

T-cells produce lots of IFN-gamma upon CD46 activation

• Lack of IFN-gamma- IL-10+ T-cells (Tregs)

What is the internal complement system?

Internal production and binding of complement proteins to receptors. 

• Not a well understood system but is clearly important for the immune systems function

• Can alter metabolism and gene transcription 

What is the complosome?

The intracellular complement system

What is factor H?

Regulator protein of C3

• Without factor H, C3 is quickly consumed and cleaved 

• This causes C3 deficiency as a result 

What does factor H deficiency/induced C3 deficiency cause?

• Down-regulation of PD1

  • Usually a protector against autoimmunity

• Less Treg cells

How does PD1 protect against autoimmunity?

• Inhibits immune responses

• Promotes self tolerance by modulating T-cell activity 

• Activates apoptosis of antigen specific T-cells

• Inhibits apoptosis of Treg cells

What is C3G?

C3 glomerulopathy

• Rare kidney disease caused by damage to the glomeruli because of abnormal C3 activity 

How can C3G be caused?

C3Nef auto-antibody production

• Stabilises the C3 convertase enzyme which allows for constant cleavage of C3 to C3b

Anti-Factor B antibody

• Also stabilises the convertase enzyme but is much rarer 

What is Haemolytic Uraemic Syndrome?

Recognised as

• Acute renal failure

• Thrombocytopenia 

• Microangiopathic haemolytic anaemia 

Caused by shiga-toxin producing E. coli 

What is Atypical Haemolytic Uraemic Syndrome?

Frequent occurrence and poor renal prognosis

Factor H mutations are associated with aHUS

• Genetic condition which often occurs in families 

How do factor H mutations cause aHUS?

Deficiency of FHR3 and FHR1 which is associated with autoantibody binding

• Autoantibody binding can then inhibit factor H and cause renal damage due to uncontrolled complement activation 

What is the normal role of FHR proteins?

Prevent pathogen binding to factor H

• Otherwise, pathogens can protect themselves by recruiting factor H to their surfaces

What is the folded back model of factor H?

Suggests factor H exists as a folded molecule which prevents it from constantly binding C3