Sickness Behavior

� Signs of systemic innate immune response
� Malaise, lassitude, fatigue, loss of appetite, muscle
and joint pain, fever
� Microbial PAMP through PRR on sentinel cells stimulate production of IL-1, IL-6 and TNF-? - which all signal to brain
�IL-1 promotes

Cytokine Signals to the Brain (2 Routes)

�1. Neurons that serve damaged tissue
�IL-1 receptors expressed, especially vagus nerve
� LPS and TLR4 can also use vagal signals
� Trigger fever, nausea, other sickness response
�2.Cytokines diffuse into brain from bloodstream or produced in the brain

Bacterial Septic Shock

�Systemic inflammatory response syndrome
caused by severe bacterial infection
� 9% of human deaths, about the same in animals
�Severe infections may cause excessive triggering of TLR = massive and uncontrolled release of HMGB1
�Other cytokines involved TN

Bacterial Toxic Shock

�Occurs most commonly in Staphylococcus aureus
infections, sometimes in Streptococcal infections
�Enterotoxins produced by Staph bind and
stimulate T-cell antigen receptors
�Up to 20% of the T-cells can be stimulated at once:
�Huge release of IL-2 and IFN

Complement Jobs

�Major innate defense system
� Protect against infections
� Regulate inflammatory process
� Remove damaged cells
� Send 'danger' signals to body
� Regulate adaptive immune response

Complement Proteins

�30 + proteins
�Labeled numerically with letter prefix (ie C1, C2)
or designated by letters (B, D, P, etc.)
�Some free in serum, others membrane bound
�Proteins can be stored in various organs in the body or in neutrophil granules where they are readily a

Complement System

�This system is inactive in healthy animals
�System is made up of sets of inactive proteins
that get activated in stepwise manner
�3 major steps
1. Complement system gets activated
2. Key protein, C3b generated****
3. Terminal complement complex assembled

Complement Activation

�3 pathways: alternative, lectin and classical pathways
�Alternative and lectin pathways are triggered by microbial carbohydrates
�Classical pathway triggered by antibody (part of the adaptive immune response - happens later in timeline)

The Alternative Pathway

�Triggered by microbial cell wall interaction with
complement components in blood
�C3 protein important because it has highly reactive side chain that can bind to surface of microbes and mark them for destruction
�C3 made in the liver and by macrophages,

Substrate Modulation

� Happens throughout many complement pathways
� In the alternative pathway, C3 splits creating C3a and
C3b, if on surface of microbe, C3b binds factor B = C3bB
� Bound factor B is cleaved by protease (factor D), C3bBb
attached to bacteria
� Factor D can o

The Lectin Pathway

�Lectin - a protein that can bind to carbohydrates
�Ficolin - a family of lectins produced by liver and some lung cells, soluble PRR specific to carbohydrates on microbes
�Triggered by soluble pattern-recognition
molecules that recognize microbial carbohy

The Classical Pathway

� Triggered by clusters of antibody molecules on surface of invading microorganism
�(as late as 7 to 10 days after infection)
� C1 (3 component protein)
� C1q activated when at least two of its strands bind
to clustered antibody
�IgM better than IgG at ac

Amplification Pathway

�Once C5 binds to C3b, substrate modulation, C5 cleaved by C3bBb
� Leaves site on C5b that can bind C6 and C7 = C5b67
� C5b67 can insert into microbial cell membrane
�Once inserted, complex binds C8
� 12-18 molecules of C9 then join the C5b678 complex for