What characterizes Acute inflammation?
Edema and Neutrophils
What causes acute inflammation?
Infection and tissue necrossis
What are the five main mediators of acute inflammation?
- Toll-like receptors
- Arachidonic acid metabolites
- Mast cells
- Hageman factor
What is CD14 recognizing a lipopolysacharide (LPS) an example of?
A TLR (toll-like receptor) recognizing a PAMP (Pathogen-associated molecular pattern).
LPS is found on the outer membrane of gram-negative bacteria.
On what type of immune cells are there TLRs? (Innate vs adaptive)
Both innate and adaptive cells.
What happens when a TLR is activated?
It upregulates NF-kB ("on" button) which activates immune response genes which produces multiple immune mediators.
Which two pathways act upon arachidonic acid after it has been released from the cell membrane, and what releases it?
- Cyclooxygenase pathway which produces prostaglandins.
- 5-lipoxygenase pathway which produces leukotrines.
- Phospholipase A2
Which prostaglandin mediates fever and pain?
PGE2 mediates fEver and pain
Which physiological responses are mediated by both PGI2, PGD2, and PGE2?
Vasodilation of the arterioles and increase of vascular permeability in the post capillary venules.
Which mediators attracts and activates neutrophils?
LTB4, C5a, IL-8, and bacterial products.
What is mediated through the leukotrines LTC4, LTD4, and LTE4?
They cause smooth muscle contraction: vasoconstriction of the arterioles, bronchospasm, and increased vascular permeability through the pericytes.
What are the 3 methods of mast cell activation?
- Tissue trauma
- Complement proteins; C3a and C5a
- Cross linking cell-surface IgE by antigen
Which mediator is released from the mast cells and what does it cause?
Histamin, causes vasodilation of arterioles and increased vascular permeability.
Which three individual pathways are able activate the complement cascade, and how do they work?
- Classical pathway: C1 binds to IgG or IgM (general motors makes classic cars) that is already bound to an antigen, creating C3 convertase.
- Alternative pathway: Microbial products directly bind complement, creating C3 convertase.
- Lectin pathway: Mannose-binding lectin (MLB) binds to mannose on icroorganisms and activate complement, creating C3 convertase.
What is the sequence of the activated complement cascade, and what do the mediators produce?
C3 convertase mediates C3 → C3a and C3b. C3b produce C5 convertase which mediates C5 → C5a and C5b.
- C5b complexes with membrane attack complex (MAC) and lyse the microbes
- C3a and C5a trigger mast cells.
- C5a is chemotactic for neutrophils, together with LTB4, IL-8, and bacterial products.
- C3b is an opsonin for phagocytes
Hageman factor takes part in the activation of three major systems, which?
- Coagulation and fibrinolytic system (factor XII)
- Complement system
- Kinin system: plays a role in creating bradykinin which mediates vasodilation, increased vascular permeability and pain.
What are the 5 signs of inflammation and what mediates them?
- Rubor and Calor: are both caused by increased blood flow through smooth muscle relaxation. Key mediators are histamine, prostaglandines, and bradykinin.
- Tumor: caused by leakage of fluid from the post capillary venules (histamin, PG, LT, or tissue trauma)
- Dolor: Sensitization of nerve endings by bradykinin and PGE2.
- Fever: is mediated through Pyrogens mediated increase in cyclooxygenase activity in the thalamus or through PGE2 mediation.
What are the seven steps of Neutrophil arrival and function?
4. Transmigration and chemotaxis
6. Destruction of phagocytosed material
Which mediators take part in Margination?
Margination occurs through the change in flow during vasodilation. Mediators of vasodilation are bradykinin, histamin, and the prostaglandins.
Which mediators take part in Rolling?
Rolling is the decrease in speed, achived by the selectin "speed bumps". P-selectin is released from Weibel-Palade bodies (Von Willebrandt factor) which is mediated by Histamins. E-selectin is induced by TNF and IL-1.
Which mediators take part in Adhesion?
Interaction between CAMs and Integrins are what causes adhesion. CAMs are upregulated by TNF and IL-1, while integrins are upregulated by C5b and LTB4.
Case: An 18 month old patient presents with it's third E. coli mediated UTI in four months.
The family history does not indicate a significant risk of UTIs.
Tests show a high circulating neutrophil count.
In the patient notes it is documented that the umbillical cord was slow to detach.
Leukocyte adhesion deficiency is an autosomal recessive defect of integrins. It effects the bodies ability to adhere neutrophils to the blood vessel walls. This causes a dysfunction of the acute inflammation state (destroys the dead tissue in the umbillical cord), and depleation of the marginated pool (does not attach), as well as an inability to form pus (dead neutrophils+fluids).
Which mediators aid in migration and chemotaxis?
Bradykinin, histamin, leukotrines, and prostaglandins causes increased permeability of the blood vessel walls. Bacterial products, IL-8, C5b, and LTB4 are chemotaxins, they attract neutrophils.
Which mediators facillitate phagocytosis?
IgG and C3b work as opsonins, tagging organisms for phagocytosis.
Case: Patient presents with impetigo. On blood test you find a low neutrphil count and giant granules in the leukocytes on histology. The patient also suffers from albinism. What is the underlying condition?
Chediak-Higashi syndrome, protein tracking deffect leading to impairment of phagolysosome formation.
Which two methods of destruction of phagocytosed material is used by leukocytes?
1. O2 dependent killing (most effective) uses free radicals
2. O2 independent killing uses enzymes present in the lekocytes.
Case: Patient presents with recurrent Pseudomonas cepacia infections. You perform a Nitroblue tetrazolium test which does not have a color change. What is the underlying condition?
Chronic granulomatose disease caused by a defect in NADPH oxidase. This means the cells are unable to produce oxidative bursts which eventually creates the important HOCl. used to destroy phagolysied material. It leads to recurrent catalase positive infections because the catalase impairs the bacterias own H2O2 stores that the leukocytes can use to create HOCl..
What happens to the neutrophils after they have finshed their job? And which mediators are part of the healing phase of acute inflammation?
They undergo apoptosis. The healing phase is mediated by IL-10 and TGF-ß.
What are the three "phases" of acute inflammation marked by?
1. Fluid phase (starts imidiately) mediators cause vasodilation and increased permeability.
2. Neutrophil phase (peaks after 24h)
3. Machrophage phase (peaks after 2-3 days)
What characterizes chronic inflammation?
Lymphocytes and plasma cells.
It is a delayed, but specific response.
What stimulates chronic inflammation?
1. Persistent infection
2. Virus, mycobacterium, parasites, fungi
3. Auto immune disorders
4. Foreign bodies
5. Some cancers
Which MHC class binds to which T-cell?
MHC I + CD8+ = 8
MHC II + CD4+ = 8
How are CD4+ T-cells activated?
1. Binds to antigen presented on MHC II
2. Binds CD28 to B7 on APC.
4*2=8 , 28/7=4
What is the function of the CD4+ T-cells?
TH1 secretes IL-2 (T-cell growth, CD8+ activator) and IFN-y (machrophage activator - Epithelioid histiocytes)
TH2 secretes IL-4 (B-cell class switching),
IL-5 (eosinophil chemotaxis and activation), and
IL-10 (Inhibits TH1 and initiates healing)
How are CD8+ T-cells activated?
1. Binds to antigen presented on MHC I
2. IL-2 from TH1 CD4+.
1*8=8 , 2*4=8
How do CD8+ cells kill?
1. Secretion of perforins and granzymes which activate caspases leading to apoptosis.
2. FasLigand binds to Fas which acivates caspaces leading to apoptosis.
How are B-cells activated?
1. Antigen binding to IgD or IgM
2. Antigen presentation to TH2 CD4+ T-cells.
- CD40 receptor (B-cell) binds to CD40L (T-cell).
- T-cell secretes IL-4 and IL-5 causing maturation of B-cell
What defines a granuloma?
Giant cells and a rim of leukocytes may also be present, but is not necessary.
What is the histological difference and the ethiological difference between a caseating and a noncaseating granuloma.
Caseating: Has central necrosis and indicates TB or fungal infection.
Noncaseating: Lacks central necrosis and indicates foreign material, sarcoidosis, beryllium exposure, chron's disease, and cat scratch disease, etc.
Which mediator turns Machrophages into epithelioid histiocytes?
Case: Newborn baby presents with abnormalites of the face, heart and great vessels, hypercalcemia and T-cell defiency. Where did the developmental failure occure and what is the name of the syndrome?
Third and fourth pharyngeal pouch. causing the abnormalities pluss a lack of parathyroids and thymus.
Case: Your patient has Severe combined immunodeficency characterized by susceptibility to all kinds of infections. Treatment is sterile isolation "bubble baby" and stem cell transplant. In which three pathways may the defect be?
It is caused by either a cytokine receptor deficency (affects signaling necessary for proliferation and maturation), adenosine deaminase deficency (failure to remove toxic waste which is fatal to lymphoctes), or MHC class II deficency (No CD4+ activation or subsequent cytokine production)
Case: 7 month old male presents with Giardia Lambia infection. Which primary immunodeficency disorder is most likely the cause?
Complete lack of immunoglobulin due to a mutation in the Bruton tyrosin kinase which is essential for turning B-cells into plasma cells. Most common in males. Causes increased risk of bacterial, enterovirus and giardia infections.
OBS! avoid live vaccines!
Case: 12 year old patient presents with recurring Giardia Lambia infections. Which two types of illnesses is the patient at a higher risk for developing later in life?
Common variable immunodeficency
Deficency due to either B-cell or helper T-cell defects.
Icreases the risk for autoimmune disorders and lymphoma
Case: Your patient presents with recurrent mucosal infections, and symptoms of malnutrition. Tests show low mucosal and serum levels of IgA. Which autoimmune disorder should you test for?
IgA deficiency is the most common immunoglobulin deficency. Most patients are asymptomatic. High correlation with autoimmune diseases such as rheumatoid arthritis and celiac disease. Infants born with it are at increased risk of developing infections, allergies, and asthma.
Case: Patient presents with recurrent pyogenic infections of the mucosa, elevated IgM and low IgA, IgG and IgE count on blood tests. Which ligand/receptor couple is most likely mutated?
Hyper IgM syndrome
CD40L/CD40 is mutated causing no second signal for B-cell activation and class switching.
Case: Patient suffering from thrombocytopenia, eczema, and recurrent infections is diagnosed with Wiskott-Aldrich syndrome. Where does the mutation lie?
In the WASP (Wiskott-Aldrich Syndrome Protein) gene.
Case: This patient walks into your office. Tests shows a deficency of an inhibitor. Which inhibitor?
C1 inhibitor deficency
Case: 30 year old female comes to the clinic to test for STIs. She has recently been experiencing fever and weight loss as well as joint pain. She tests positive for syphilis. What else should you suspect?
SLE and antiphospholipid syndrome
Lupus can present in many ways, among the most important are fever, weight loss, malar rash, arthritis, pleuritis and pericarditis, psychosis, diffuse proliferative glomerularnephritis, endocarditis, anemia, etc.
Antiphospholipid syndrome is associated with Lupus in 30% of cases. It leads to false positive syphilis test and falsely-elevated PTT.
Case: 28 year old female presents with a history of several miscarriages. She has recently developed edema in the lower left leg. Standard tests are quite normal except a low platelet count and a prolonged PTT time. Which further testing should you perform? And given a positive test, how should you treat?
Lupus anticoagulant assay
Treatment is lifelong anticoagulation.
Case: During Echocardiography you notice small deposits on both sides of the mitral valve in a 45 year old female. What could cause this type of deposits and what test should you perform to be most sure?
Characteristic for Libman-Sacks endocarditis which is strongly associated with SLE. The most sensitive test is anti-dsDNA andtibodies.
What is the classical presentation of Sjogren syndrome?
Dry eyes, dry mouth, and recurrent dental carries.
Which autoimmune disease is associated with an increased risk of B-cell lymphoma?
Which antibody is associated with sjogren syndrome?
anti-ribonucleoprotein antibodies (anta-SS-A/Ro, anti-SS-B/La)
How is the visceral organs connected to the distinction between diffuse and localized scleroderma?
Diffuse = early envolvment
Localized = slow envolvment
Case: Female patient presents with difficulty swallowing both solids and liquids, thightening of the skin on the hands, and visible blood vessels on the skin. Which test should you perform?
Test for anti-DNA topoisomerase I (Scl-70)
Which condition is associated with U1 ribonucleoprotein?
Mixed Connective Tissue Disease
What are the three different types of tissue?
Labile: continously regenerate (small bowel, skin, bone marrow, lungs)
Stable: In the G0phase, but can be reenter the cell cycle (e.g., liver)
Permanent: lack significant regenerative potential (myocardium, skeletal muscle, neurons)
What are the three components of granulation tissue?
1. Fibroblasts: deposits collagen type III.
2. Capillaries: provide nutrients.
3. Myofibroblasts: contract the wound.
What is the characteristic location of the first four types of collagen based on their abilities?
Type I: Strong: bone, skin, organs, tendons.
Type II: Shock absorbent: cartilage
Type III: Pliable: granulation tissue and embryonic tissue.
Type IV: basement membrane
Which cofactors are necesarry in wound healing, and where do they work?
- Zinc: cofactor of collagenase whch converts TIII to TI
- Vitamin C: cofactor in the hydroxylation of proline and lysine (important for cross-linking)
- Copper: cofactor for lysyl oxidase, cross-links lysine and hydroxylysin.
What is the difference between primary and secondary intention with wound healing?
Primary = proxymation, the edges are brought together.
Secondary = Scar, granulation tissue fills the wound and myofibroblasts contract the wound.
What might cause delayed healing?
- Cofactor deficency
- foreign body
What is a keloid?
Excess production of scar tissue, mainly collagen TIII. More common in Africans.