The Innate Immune System Part II Flashcards
Explain The Complement System ?
- Group of >30+ plasma proteins circulating in blood & body fluids in inactive form.
- Cells of the liver and macrophages synthesize complement proteins continuously
- These proteins are abundant in the blood serum and are capable of responding immediately to infecting microorganisms
Why is it called The Complement System ?
The complement system is so named because it is complementary to the antibody response of the adaptive immune system
How do the binding of complement proteins occur ?
In a specific and highly regulated sequence, with each successive protein being activated by cleavage and/or
structural changes induced upon binding of the preceding protein(s)
Once activated, multiple possible outcomes that ultimately destroy extracellular pathogens ?
- Opsonisation to enhance phagocytosis:
- The proteins serve as a marker to indicate the presence of a pathogen to
phagocytic cells, such as macrophages and B cells, and enhance engulfment; this process is called opsonisation
- Opsonisation refers to an immune process where particles such as bacteria
are targeted for destruction by an immune cell known as a phagocyte - Target pathogen cell membrane leading to lysis:
- Certain complement proteins can combine to form attack complexes that open pores in microbial cell membranes
- These structures destroy pathogens by causing their contents to leak - Perpetuate inflammation:
- Recruits inflammatory cells and perpetuates inflammation via liberation of small fragments known as anaphylatoxin
The complement system can be activated through three major pathways:
- Classical
- Lectin
- Alternative
How is the Classical pathway initiated ?
- Initiation of the classical pathway occurs when C1q complexes with two other molecules - C1r and C1s which are serine proteases.
- This is called the C1 complex. - The C1 complex can bind to the Fc region of antibodies (this is the bottom of the Y shape) when they are attached to pathogenic surfaces
Steps of the Classical pathway?
- First, Antibody binds to a multivalent antigen on pathogen
- Then this allows the binding of C1q, beginning the process of complement deposition on the surface of the pathogen
- Next, C1q undergoes a conformational change upon binding generating a C1
complex composed of C1q (pathogen sensor) & serine proteases C1r & C1s - This ‘C1 complex’ cleaves other complement components called C4 and C2 into their
constituent parts (C4a and C4bb and C2a and C2b) - C4b and C2a combine to C4b2a known as classical complement C3 convertase
- C3 convertase cleaves many C3 proteins into C3a and C3b
- The C5 convertase makes holes in the pathogen surface, known as membrane attack
complex
What are C3a and C3b ?
- C3a - is an anaphylatoxin driving inflammation
- C3b – combines with the C3 convertase (C4b2a) to make the C5 convertase (C4b2a3b)
How is the lectin pathway different to the classical pathway ?
It doesn’t rely on antibodies
How is the Lectin pathway initiated ?
It is initiated when a protein called mannose-binding lectin (MBL an acute phase protein from the liver) binds to a pathogen
What has MBL have a similar conformation to ?
The C1 complex
What does MBL on a pathogen surface lead to ?
MBL-associated serine proteases (MASPs) attaching
What do MASPs cleave ?
C4 and C2 to form the C3 convertase
- and the rest of the steps are the same as the classical pathway
What does the alternative ‘tickover’ pathway involve ? and why is the pathway sometimes called ‘the amplification loop’ ?
This pathway involves various factors, B, D, H & I, which interact with each other, and with C3b, to form a C3 convertase, C3bBb, that can activate more C3, hence the pathway is sometimes called ‘the amplification loop’
What are the three ways to the alternative pathway being activated ?
1. Spontaneous hydrolysis allows altered conformation to bind factor B rendering it susceptible to cleavage by factor D 2. Some of the C3b molecules bind to cell membrane 3. Membrane bound C3bBb is stabilised by properdin. Addition of another C3b generates the C5 convertase
What does C5 initiate ?
The generation of the Membrane Attack Complex (MAC)
- Membrane attack complex is the result of deposition of C5b, C6, C7, C8, and C9 in target cell membranes
- This pore structure disrupts osmotic integrity, resulting in cell death
How does the complement enhance the host defence against infection ?
- MAC-induced cell death
- Promotion of inflammation
- Promotion of opsonisation
- Opsonised microbes easier to ingest/destroy
- Opsonised immune complexes easier to clear
How does the complement system aid in contraction of immune response ?
- As inflammation is no longer required, complement aids in disposal of cellular debris formed during responses
- These responses avoid damaging inflammation induction in the absence of antigens following clearance of an infection
Explain the regulation of complement ?
- Short half-life of C3 convertase unless stabilised
- Self-cells possess different carbohydrate structures that are more effectively bound by fluid-phase proteases
- These more readily inactivate C3b through hydrolysis, protecting self-cells
- Numerous regulatory proteins help to prevent the complement system from harming self-cells
The complement system might play a role in disease such as?
- Barraquer-Simons Syndrome
- Asthma
- Autoimmune heart disease
- Multiple sclerosis
- Inflammatory bowel disease
What do deficiencies in complement proteins produce in the liver ?
Can lead to a form of primary (congenital) immunodeficiency, in which the body is more susceptible to disease, particularly autoimmune diseases and severe bacterial infections
