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What are the two rare glomerular diseases linked to mutations in genes encoding proteins in the alternative pathway of complement?
What are the two rare glomerular diseases linked to mutations in genes encoding proteins in the alternative pathway of complement?
Atypical hemolytic uremic syndrome (aHUS) and membranoproliferative glomerulonephritis (MPGN)
What are the three major groups of effector molecules activated by complement?
What are the three major groups of effector molecules activated by complement?
Anaphylatoxins, opsonins, and the terminal C5b-9 complex
Which of these conditions is defined clinically by thrombocytopenia, non-immune microangiopathic hemolytic anemia, and acute kidney injury?
Which of these conditions is defined clinically by thrombocytopenia, non-immune microangiopathic hemolytic anemia, and acute kidney injury?
What protein is the most important regulator of the alternative pathway of complement and is composed of 20 short consensus repeats (SCRs)?
What protein is the most important regulator of the alternative pathway of complement and is composed of 20 short consensus repeats (SCRs)?
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Most mutations in the CFH gene associated with aHUS are homozygous mutations.
Most mutations in the CFH gene associated with aHUS are homozygous mutations.
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Which of the following is NOT a genetic defect associated with aHUS?
Which of the following is NOT a genetic defect associated with aHUS?
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What protein is the most important regulator of the alternative pathway of complement on cell surfaces and has cofactor activity for the cleavage of C3b and C4b by FI?
What protein is the most important regulator of the alternative pathway of complement on cell surfaces and has cofactor activity for the cleavage of C3b and C4b by FI?
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Which of the following genetic variations is the most frequent in aHUS?
Which of the following genetic variations is the most frequent in aHUS?
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Anti-FH autoantibodies are found in approximately 75% of aHUS patients.
Anti-FH autoantibodies are found in approximately 75% of aHUS patients.
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What protein is encoded by the THBD gene and functions as an endothelial anticoagulant protein that also regulates the alternative pathway of complement?
What protein is encoded by the THBD gene and functions as an endothelial anticoagulant protein that also regulates the alternative pathway of complement?
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Which of the following complement genes is most often associated with C3G?
Which of the following complement genes is most often associated with C3G?
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Mutations in the gene that encodes for C3 can result in gain-of-function mutations, which can lead to aHUS.
Mutations in the gene that encodes for C3 can result in gain-of-function mutations, which can lead to aHUS.
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The alternative and classic pathways of complement converge into a common terminal pathway resulting in the formation of the terminal complex C5b-9.
The alternative and classic pathways of complement converge into a common terminal pathway resulting in the formation of the terminal complex C5b-9.
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What is the most important regulator in fluid phase of the alternative pathway?
What is the most important regulator in fluid phase of the alternative pathway?
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What is the most usual type of mutation in CFH found in aHUS?
What is the most usual type of mutation in CFH found in aHUS?
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What complement component is the most important regulator of the alternative pathway in the fluid phase?
What complement component is the most important regulator of the alternative pathway in the fluid phase?
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Which of the following statements about the alternative pathway of complement is FALSE?
Which of the following statements about the alternative pathway of complement is FALSE?
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The alternative pathway of complement is finely regulated by a set of molecules that are either membrane-anchored or plasmatic.
The alternative pathway of complement is finely regulated by a set of molecules that are either membrane-anchored or plasmatic.
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What is the most common clinical feature of HUS?
What is the most common clinical feature of HUS?
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What is the name of the underlying histology lesion of thrombotic microangiopathy?
What is the name of the underlying histology lesion of thrombotic microangiopathy?
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Approximately 90% of cases of HUS are associated with infections by Shiga-like toxin-producing bacteria.
Approximately 90% of cases of HUS are associated with infections by Shiga-like toxin-producing bacteria.
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What is the name of the anti-C5 antibody used to induce disease remission in aHUS?
What is the name of the anti-C5 antibody used to induce disease remission in aHUS?
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What are the two main types of C3G?
What are the two main types of C3G?
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C3 glomerulopathy (C3G) is always associated with substantial Ig deposits.
C3 glomerulopathy (C3G) is always associated with substantial Ig deposits.
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What are two main patterns of glomerular injury typically seen in MPGN?
What are two main patterns of glomerular injury typically seen in MPGN?
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What are the two primary classifications of MPGN based on the composition of the deposits?
What are the two primary classifications of MPGN based on the composition of the deposits?
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What is the most common form of primary glomerulonephritis?
What is the most common form of primary glomerulonephritis?
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What is the name of the protein that is increased in IgAN patients with galactose-deficient IgA1 (Gd-IgA1) and is associated with immune complex formation and inflammation in the mesangium?
What is the name of the protein that is increased in IgAN patients with galactose-deficient IgA1 (Gd-IgA1) and is associated with immune complex formation and inflammation in the mesangium?
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What are two types of mutations in complement genes that may predispose to IgAN?
What are two types of mutations in complement genes that may predispose to IgAN?
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SLE, or systemic lupus erythematosus, usually affects only females.
SLE, or systemic lupus erythematosus, usually affects only females.
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What is the name of the autoimmune condition that affects the kidneys and is a common feature of Systemic Lupus Erythematosus (SLE)?
What is the name of the autoimmune condition that affects the kidneys and is a common feature of Systemic Lupus Erythematosus (SLE)?
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The HLA DR3 allele is a SLE risk allele and is associated with the risk of developing LN.
The HLA DR3 allele is a SLE risk allele and is associated with the risk of developing LN.
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Complement deficiency is the most common cause of SLE.
Complement deficiency is the most common cause of SLE.
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The C4AQ0 allele is associated with a higher risk of SLE.
The C4AQ0 allele is associated with a higher risk of SLE.
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Complement deficiency is a rare condition, but the majority of homozygous C2 carriers are asymptomatic.
Complement deficiency is a rare condition, but the majority of homozygous C2 carriers are asymptomatic.
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Study Notes
Genetics of Immune-Mediated Glomerular Diseases
- Immune-mediated damage to glomerular structures is a key factor in many glomerular diseases.
- Diseases include aHUS, MPGN, IgAN, LN, acute poststreptococcal GN, and anti-GBM antibody disease.
- Immune-mediated glomerular injury involves both innate and adaptive immune systems.
- Studies have identified genetic determinants in some diseases, including complement pathway abnormalities.
- Mutations in complement genes are linked to atypical hemolytic uremic syndrome (aHUS) and membranoproliferative glomerulonephritis (MPGN).
- aHUS-associated complement gene abnormalities often cause complement dysregulation restricted to cell surfaces.
- Complement activation in the fluid phase is more prevalent in some MPGN cases.
- Genetic variations in complement genes may influence predisposition to common, multifactorial kidney diseases (i.e. IgA nephropathy and lupus nephritis).
- Genetics of disease is complex and involves a balance between protective and harmful functions of the complement system.
The Complement System
- The complement system is part of the innate immune system and plays a key role in pathogen clearance.
- It has three pathways: classic, lectin, and alternative.
- These pathways converge to form C3 convertases, which cleave C3 into C3a and C3b.
- C3b further contributes to C5 convertase formation.
- The complement system generates effector molecules: anaphylatoxins (C3a, C5a), opsonins (C3b, iC3b, C3d) and the terminal C5b-9 complex.
- Regulation proteins protect cells to avoid damage (e.g. C1 inhibitor, FB, DAF, FH, MCP, FI, CD59, vitronectin and clusterin).
- Dysregulation of complement proteins can lead to disease.
Atypical Hemolytic Uremic Syndrome (aHUS)
- Clinical features: thrombocytopenia, non-immune microangiopathic hemolytic anemia, and acute kidney injury.
- Histology: thrombotic microangiopathy in arterioles and capillaries; vascular wall thickening with endothelial swelling and protein accumulation.
- Pathogenesis: often linked to infections by Shiga-toxin-producing bacteria, but sometimes other factors are involved.
- Complement pathway activation: C3 deposits are observed along glomerular capillaries and on endothelium. Often reduced serum C3 levels, which can be normal.
- Genetic factors: mutations in genes encoding complement proteins (CFH, CFHRs, MCP, CFI).
- Mutations mainly result in complement dysregulation impacting cell surfaces.
Membranoproliferative Glomerulonephritis (MPGN)
- Clinical features include varying degrees of renal impairment, often including isolated hematuria and proteinuria, with some cases developing into nephrotic or nephritic syndrome or rapidly progressive glomerulonephritis.
- Histology: mesangial hypercellularity, matrix expansion, capillary thickening with double contours, interposition of leukocytes and mesangial cells, and new GBM formation.
- Types are defined based on electron microscopy: sub-endothelial deposits (Type I), intra-membranous deposits (Type II), and combined sub-endothelial/subepithelial deposits (Type III).
- Classification based on immune complex deposition.
- Complement activation is implicated.
- Genetic factors: mutations in complement genes (CFH, CFHRs , and MCP).
IgA Nephropathy (IgAN)
- Common primary glomerulonephritis.
- Affects mainly individuals in East Asia.
- Clinical symptoms: asymptomatic microhematuria through severe renal deterioration.
- Histologic features: mild to severe mesangial changes, including cells/matrix expansion, and sometimes proliferation/necrosis.
- Genetics: complex model with multiple gene variations.
- Complement and IgA1 deposition play a role.
Lupus Nephritis (LN)
- Immune-complex-mediated glomerulonephritis which is a severe feature of systemic lupus erythematosus (SLE).
- 40% of SLE patients experience LN, contributing to SLE-related morbidity and mortality.
- Histology: vascular, glomerular and tubulointerstitial lesions.
- Classified by degree of glomerular involvement (I-VI).
- Autoantibodies against DNA, Sm, and nucleosomes are implicated.
- Genetic polymorphisms affect susceptibility to SLE and LN.
- Complement pathway activation is implicated; with complement gene mutations implicated in some cases.
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Description
Explore the genetic determinants involved in immune-mediated glomerular diseases such as aHUS, MPGN, and IgAN. This quiz delves into the role of complement genes and their impact on kidney disease susceptibility and pathology. Test your knowledge of the interplay between genetics and immune function in these complex conditions.
