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

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

Lower than normal

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 and antibody responses 

CD46 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 activation in patients with RA causes what?

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

• Lack of IFN-gamma+ IL-10- induced 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 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 are associated with autoantibody binding

• Autoantibody binding can then cause the renal damage due to complement activation 

What is the normal role of FHR proteins?

Prevent pathogen binding to factor H

• Otherwise, pathogens can protect themselves using factor H

What is the folded back model of factor H?

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