Applied Clinical Immunology

Front 1

Describe the functions of the complement system

Back 1

Hint 1

Front 2

Describe why there are 3 ways to initiate the complement pathway

Back 2

Of the three pathways two are innate (meaning that they do not require the participation of antibody). The innate pathways are the Mannose-Binding Lectin pathway and the Alternative pathway. The Classical pathway is initiated by either IgM or IgG antibody and is, thus, an acquired pathway. The above slide shows the major functions of the three pathways. The thing to remember is that the pathways differ only in the initiation steps. They converge at the C3 convertase and from there to the termination there is a single, common pathway. The five functions of the cascade are shown at the bottom of the slide, chemotaxis, opsonization, killing, immune complex removal and B and T cell activation.

Hint 2

C3b is our OPSONIN

C3a, C5a, C4a= very powerful chemokines

Front 3

Back 3

(IgA--Don't want complement activation at mucosal surfaces)

IgE-- attatched to mast cells,

Front 4

What two molecules are super important for providing the "handles" to grab the pathogen? Why is crosslinking required??

Back 4

Deposition of both C3b and IgG on the pathogen surface provide the most important trigger fro uptake by phagocytes.

IgG the most powerful

Crosslinking = safety mechanisim to prevent unwanted activation

Hint 4

IgG antibody is a powerful opsonin in the adaptive immune system. When IgG antibodies specific for pathogen surface antigens bind to the pathogen they provide the phagocyte with ‘handles’ with which to grasp the pathogen. This is accomplished by IgG Fc receptors on the cell membrane of the phagocyte ligating the Fc region of the pathogen-bound IgG. In order to trigger uptake of the pathogen Fc receptors of the phagocyte must be cross-linked. This is a safety mechanism to prevent unwanted activation of phagocytic cells.

Front 5

What role does C5a and C3a have in the complenet system?

Back 5

VERY POWERFUKL CHEMOKINES

Front 6

How do we get rid of immune complexes onces were done with complement cascade

Back 6

Hint 6

During an immune response immune complexes are formed that consist of pathogen antigens and pathogen-specific IgG antibodies. These complexes activate the Complement cascade with the generation of C3b. Large complexes need to be removed from the circulation otherwise they may deposit in capillary beds with high blood flow, such as the renal glomerulus and cause tissue damage. The erythrocyte (RBC) serves to remove these immune complexes because it has numerous receptors for C3b on its surface which can capture the immune complexes. When the RBC enters the liver or spleen these immune complexes are plucked off the RBC surface by resident macrophages and are destroyed. In addition the complement cascade, particularly the Alternative pathway, can soluble these large immune complexes to prevent them from falling out of solution. Complement, particularly, C!qrs and C3 but also the Alternative pathway, also inhibit precipitation of antigen-antibody immune complexes. Interestingly, solubilization occurs more effectively for complexes where antigen is in excess, whereas inhibition of precipitation is more effective in complexes formed in antibody excess.

Front 7

Deficiencies in the complement system is bad, and can be different whether it is earlier or later complement deficiencies. Which one leades to lupus like symptoms because of poor immune complex removal? which leads to more nisserial infections (gonnerrehia, menengial)?

Back 7

Front 8

Complement system is TIGHLY regulated... What could happen if one of these regulatory proteins is not working? (abherrant complement activation)

Back 8

Front 9

descrive the role of complement in adaptive immunity

Back 9

The Complement receptor CR2 is part of the B cell co-receptor complex. CR2 on mature B cells form a complex with two other membrane proteins, CD19 and CD81. The CR2-CD19-CD81 complex is often called the B cell co-receptor complex because CR2 binds to antigens through attached C3d (or iC3b or C3dg) when membrane IgM binds to the antigen. This results in the B cell having greatly enhanced response to the antigen. Follicular dendritic cells (FDC) also express CR2 and it enables FDC to retain antigen on their surface so that they maximize the interaction with B cells.

Hint 9

Initiation Phase: activation of complement (the generation of the chemotactic factors C3a and C5a facilitates antigen recognition and the maturation of antigen-presenting cells (APCs).
Effector Phase: Antigen-experienced mature APCs induce effector T cell responses to produce interleukin-2 (IL-2), which is necessary for the induction of complement (CD46)-induced regulatory T cells (CD46 is a surface receptor for C3b and C4b). Ligands for CD46, such as opsonized immune complexes (ICs), are also generated at this time. Clonal expansion of antigen-specific effector T cells leads to the clearance of the pathogen, and the balance between effector T cells and CD46-induced regulatory T cells prevents excessive immunopathology.
Contraction Phase: Continuing expansion of CD46-induced regulatory T cells (which proliferate more strongly than effector T cells, IL-10 secretion and granzyme B-expressing regulatory T cells assist in shutting down the successful effector T -cell response. The inactivation of effector T cells leads to the simultaneous contraction of the regulatory T-cell pool - as these cells are dependent on IL-2 produced by effector T cells - and the generation of an effector T cell and regulatory T cell memory pool.

Front 10

What is a very duh thing that all NSAIDs have in common? How does this help them get to where they need to be?

Back 10

Better pharmacokinetics... NSAID is retained LONGER in synovial fluid compared to serum

Hint 10

Front 11

When a patient asks you the difference between Tylenol (acetaminophen) and ibuprofen, what do you tell them? Why does Tylenol suck as an anti-inflammatory?

Back 11

Tylenol has POOR ANTIINFLAMMITORY activity...

if the patient really wants to know why.... here ya go!

Hint 11

Front 12

Why can we not use potencies in inhibiting cox-1 or cox-2 as a way to predict the efficacy of a drug?? And how does the therapeutic effectiveness of ASPRIN for inflammation compare with other NSAIDs?

Back 12

Rank order of COX-1 inhibition usually corresponds to antiinflammmitory _______(potency), but not EFFICACY.

Hint 12

Front 13

Which NSAIDS should you use on your period?

Back 13

Hint 13

Front 14

Key concept: How does the potency of COX inhibition correlate with antiinflammitory and analgesic effectiveness of the drug?

Back 14

Hint 14

Front 15

What causes INFLAMMATION after injury? What should drugs target?

Back 15

Hint 15

Front 16

What causes PAIN after injury? what should drugs target to reduce pain (analgesic)?

Back 16

Hint 16

Don't forget to go for the comboz!

Front 17

What causes a FEVER? What can drugs target to prevent fever (antipyretics)?

Back 17

FYI: BE CAREFUL NOT TO GIVE KIDS ASPIRIN (REYE'S SYNDROME)

Hint 17

Front 18

Why do we tell people to take a BABY aspirin for post MI propholactically?

Back 18

Aspirin is an IRREVERIBLE INHIBITOR of Cyclooxygenase

Hint 18

Front 19

Which drugs should we be really be careful about when prescribing NSAIDs for a patient?

Back 19