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Veterinary Medicine

Additional Veterinary Medicine Flashcards




What is the complement system?

-Complement system is part of the immune system that enhances complements or the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammation and attack the pathogen's cell membrane.

-Complement system takes part in innate and acquired pathways. The first-time immediate action of complement (innate)- blood transfusion. Delayed blood transfusion- 2 weeks later rxn- acquired arm.

How is C3 affected in a person with cirrhosis of the liver?

-Pro-enzymes are present all the time and produced by the liver.

-A person with cirrhosis of the liver will produce fewer proteins (including less complement, ie C3 deficiency) and develop a recurrent infection.

How does malnutrition affect complement production?

-Malnutrition will affect complement production and cause recurrent infections because pathogens will not be handled properly.

-Complement proteins are also produced by macrophages and dendritic cells locally, however, the contribution of that complement is insignificant because the amount is less.

What is the membrane attack complex (MAC)?

-Membrane attack complex (MAC) or terminal complement complex (TCC) is a complex of proteins typically formed on the surface of pathogen cell membranes as a result of the activation of the host's complement system, and such is an effector of the immune system.

-Antibody-mediated complement activation leads to MAC deposition on the surface of infected cells. Assembly of the MAC leads to pores that disrupt the cell membrane of target cells and leads to lysis and death.

-C1 and 6,7,8,9 are not cleaved or broken out. (C1 saw 7 eat 9). 7, 8,9 are not enzymes because when they assemble together they make a pore (MAC).

-MAC is inserted into a membrane and whatever cell it is inserted into causes the cell to lyse and substances to spill out.

What is the purpose of the proenzymes of the complement system?

-Proenzymes (C2, 3, 4, 5 ) when activated cleave one or more other complement proteins and initiate an amplifying cascade of further cleavages.

-Proenzymes will normally break into small and big pieces.

-Small pieces are called 'a' and 'b'.

-The hero of the complement system is C3.

-It is all about C3 activation. Once C3 is active then a lot of functions occur.

-The mission of all 3 pathways (classical, lectin, and alternative) is to activate C3.

What are the primary functions of complement?

-The primary function of complement is to clear the infection by opsonization.

-The second role is to clump up the pathogens (complement can fixate to the surface of pathogens to neutralize them and remove them).

-Lastly, complement plays a role as anaphylatoxins and increases inflammation in an area (so the immune system can clean it up).

Classical pathway basics

-Initiated by IgM and IgG Ag/Ab complexes binding to C1q (first protein in cascade) leading to activation of C1r, which in turn cleaves C1s.

-The classical pathway is normally triggered by Ag/Ab complexes that bind to the C1 complex (C1q, C1r, C1s) through C1q component which is able to cleave the C4 complement protein into C4a and C4b.

-The classic pathway needs antibodies to be present, therefore, the first time the infection is brought into the body, this pathway is not activated- it takes time to activate (unlike the alternative and lectin pathways).

-Classic antigen and antibody pathway activates C1. C1 has a component called C1q that has about 18 polypeptides (these attach with immunoglobulins- it attaches to the Fc portion of immunoglobulin).

-Complement binding portions on antibodies are usually hidden but once antigen binds immunoglobulin, the site for C1q attachment opens on the antibody. When C1s become active, it causes the cleavage of C1 and C2.

Alternative pathway basics

-This pathway becomes activated when they see pathogen, do not need antibody help- part of the innate arm).

-Endotoxins/LPS released by pathogen bind to proenzyme C3 (H2O) and factor B which causes cleavage into 2 pieces C3a and C3b.

-This releases C3a and C3b which settle on the surface of the pathogen. When the complement has to attach to the surface of the pathogen, Factor H binds to C3b, and Factor I comes and destroys them.

-Normally, when complement is activated, the factors become overwhelmed. Factor H and I are down regulators (Factor C3b has to overwhelm these factors to move on).

-The important thing is to convert is C3. All anaphylatoxins come towards blood vessels and do something to endothelial cells and act on mast cells. C3bBbC3b (C5 convertase) is formed and all of the rest of the pathways are common from this point. The b pieces stay in the pathways and the pieces keep separating.

Anaphylatoxins purpose in the complement system

-Anaphylatoxins (or complement peptides) are fragments (C3a, C4a and C5a) that are produced as part of the activation of the complement system.

-Complement components (C3a, C4a, and C5a) of the complement system are large glycoproteins that have important functions in the immune response and host defense.

-They act on mast cells and cause degranulation and histamine release which acts on endothelial cells and causes bronchoconstriction and respiratory difficulty, also results in endothelial cell shrinkage and fluids leak out ('edema').

-The bradykinins are released which results in edema, pain, and swelling. C3a and C5a are potent chemotactic factors- neutrophils are attracted and result in local inflammatory reaction and results in damage to tissue cells. These are the actions of the activated complement system.

Lectin pathway basics

-Lectin pathway (become activated when they see pathogen, do not need antibody help- part of the innate arm).

-Mannose-binding protein or lectin combine with MBP produced by the liver.

-It is similar to the classical complement pathway, in that, after activation, it proceeds through the action of C4 and C2 to produce activated complement proteins further down the cascade.

-It is activated by the binding of the complex of mannose-binding lectin (MBL), CL-K1 or ficolins, and MBL-associated serine proteases 1 and 2 (MASP-1 and 2) to various carbohydrates or acetylated residues on the surface of the pathogen (PAMPs).

-This pathway serves a major protective role during the vulnerability window experienced by infants between the tapering of maternal antibodies and the establishment of an effective adaptive immune system.

-Activation of the complement via the lectin pathway occurs when the proenzyme forms of MASPs are activated.

C3 deficiency clinical signs

-Main clinical manifestation of primary C3 deficiency is childhood-onset of recurrent bacterial infections, mainly caused by gram negative bacteria (such as Neisseria meningitidis, Enterobacter aerogenes, Haemophilus influenza, and E.coli). However, infections with gram positive bacteria may also occur.

-Patients may develop recurrent infections with severe sequelae and high morbidity and mortality or overwhelming sepsis early in life. Deficiencies of the MAC (C5-C9) tend to lead to less severe infections and have a better prognosis with careful management.

-C3 is responsible for the opsonization of encapsulated bacteria and making membrane attack complex.

-C3 deficient patients will develop recurrent upper respiratory infections.

MAC deficiency clinical signs

-Terminal complement pathway deficiency is a genetic condition affecting the complement membrane attack complex (MAC).

-MAC deficiency involves deficiencies in C5, C6, C7 and C8 (while C9 is part of the MAC, and deficiencies have been identified, it is not required for cell lysis)

-Membrane attack complex (C5b6789) not formed correctly in Neisseria infections.

-MAC punches a hole into pathogens and causes pathogens to leak out 'lyse' and die.

-Complement deficiency is a form of primary immunodeficiency disorder and these patients develop immunocompromise and overwhelming infection and sepsis.

C3b deficiency will result in what?

-C3b augments actions of plasma cells

-C3b is deficient then plasma cell activity is decreased (less production of immunoglobulins and more susceptible to infection)

-In innate immunity, a pathogen is coated in C3b binds to complement receptor 1 (CR1) expressed on the surface of phagocytes (including APCs). These cells are then easily engulfed and the invader is destroyed.

-C3b is said to be acting as an opsonin and enhances the ability of an entity to be phagocytosed

How do Splenectomy patients develop immunocompromise?

-The Spleen reduces blood flow by 4000x and as macrophages pass through then they can grab onto C3 coated pathogens and phagocytose and destroy them.

-This is why splenectomy patients have issues with encapsulated pathogens because they are unable to clear with the spleen.

How do C3 deficient patients develop recurrent pyogenic infections?

-C3 deficiency would cause recurrent sinus and pulmonary infections

-C3 activation is the primary player in the activation for the MAC complex.

How does C3b affect immunoglobulins?

-C3b can act on plasma cells (not on the B cells) which will cause increased release of immunoglobulins.

-Plasma cell antibody release becomes decreased (cannot produce enough antibodies to handle infections and have recurrent infections)

How is C1 autoactivation controlled in a patient?

-C1 has a tendency to become autoactivated (C1 esterase inhibits it when it becomes activated).

-C1-inhibitor is a protease inhibitor belonging to the serpin superfamily.

-Its main function is the inhibition of the complement system to prevent spontaneous activation but also as the major regulator of the complement system.

-This prevents things like "a" factors causing mast cell degranulation and angioedema.

-In paroxysmal hemoglobinuria: The people with a lack of decay-accelerating factor, cannot remove MAC, RBC's burst at night when oxygen levels are decreased- results in brown-colored urine in the morning (e.g. paroxysmal hemoglobinuria)

What is the function of complement proteins?

1) participate in the construction of membrane attack complexes

2) tag pathogens for ingestion by professional phagocytes

3) act as chemoattractants to recruit phagocytic cells to the battle site

What is the difference between the activation of the alternative complement pathway vs. activation of the lectin-activated pathway?
  • The alternative pathway is spontaneous with MAC grenades
  • Lectin activation via complement produces smart bombs that are targeted by MBL. MBL acts as a guidance system that targets the complement bombs to invaders that have distinct carbohydrates on their surface
What are the 4 major functions of complement activation and what breed of dog has a known complement deficiency?

1) Lysis of infectious organisms

2) activation of inflammation

3) opsonization 

4) immune clearance


***Brittany Spaniels have a known C3 deficiency which affects all parts of the pathways (they get a lot of infections, short life and immune complex kidney disease)

What are the main actions of the 3 complement pathways?



3) Alternate: SPONTANEOUS CLEAVAGE AT ANY TIME, but only get going if stimulus present (eg. bacteria, etc)

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