Innate Immunity

Question 1

Describe the pathway during inflammation that produces pain?

Answer 1

Nocioreceptors- pain receptors that are located in interstitial area.
Bradykinins stimulate nocioreceptors.
Plasma leaks out from endothelial gaps and causes interstitial edema which in turn pushes down on and activates nocioreceptors.

Question 2

How is swelling produced in inflammation?

Answer 2

Pathogen causes cellular damage which stimulates mast cells.
Mast cells release leukotrienes, bradykinins, prostaglandins and histamine which all act on vascular endothelial cells to create spaces between the cells.
With this, plasma leaks out of the intravascular space to the interstitial space which causes edema/swelling.

Question 3

Describe the vascular response during inflammation?

Answer 3

Increased vascular permeability to allow plasma to leak into interstitial area.
Smooth muscle cells are stimulated by leukotrienes, prostaglandins, bradykinins and histamine to relax which causes vasodilation.
Vasodilation allows more blood to get to the affected area which in turn causes redness and heat (2 cardinal signs of inflammation).

Question 4

Signs of Inflammation

Answer 4

1) Pain
2) Redness
3) Swelling
4) Heat
5) Joint immobility

Question 5

What is diapedesis?

Answer 5

When the monocytes in the bloodstream squeeze through the capillary gaps of arterial vessels to enter the site affected by inflammation and injury.

Question 6

What is positive chemotaxis in inflammation?

Answer 6

When macrophages and neutrophils enter the interstitial space ready for battle with the pathogen and are signalled via the cytokines (bradykinin, prostaglandins, leukotrienes and histamine) to the direction of where that pathogen is.
WBC’s are attracted to the target pathogen.

Question 7

What do macrophages release and what does that do?

Answer 7

Macrophages release: IL-1, TNF alpha and IL-8.
IL-1 & TNF-alpha stimulate the production of selectins on endothelial cells of the intravascular space. These attach to monocytes and neutrophils floating through the bloodstream so that they stay in the site of inflammation and can work their magic.
IL-8 stimulates the production of ICAM/VCAM which facilitates diapedesis of the neutrophils and monocytes which contributes to positive chemotaxis.

IL-1 & TNF-alpha also play a major role in generating a fever. They signal to the hypothalamus to adjust the temp of the body. This creates a harsher environment for a pathogen molecule to thrive in, speeds up cellular metabolism and sequesters iron and zinc which bacteria needs to multiply.
- also stimulate the liver to produce acute phase reactant proteins such as CRP (c-reactive peptides)

• stimulate the bone marrow to pump out WBCs (leukocytosis)

Question 8

What is margination?

Answer 8

Margination is when p-selectins on the endothelial cells of the intravascular space grasp on to WBC’s which cause them to “roll” along the cell membrane to guide them towards the endothelial gaps and cause diapedesis.

Question 9

What is phagocytosis?

Answer 9

When macrophages and neutrophils extend their “arms” and encompass the bacteria. A phagosome is the vesicle that is formed inside of the WBC that contains the bacteria with its antigens.

Question 10

What is a lysosome?

Answer 10

A vessel/molecule within the WBC that contains hydrolytic enzymes which are going to break down the bacteria in the phagosome. Lysosome and phagosomes fuse together = phagolysosome. The enzymes break down the cell wall of the pathogen, as well as its intracellular structures, leaving just the pathogen’s antigens.

Question 11

What is exocytosis?

Answer 11

When neutrophils have broken down the pathogen- leaving just the antigens left. They spit out the antigens that then migrate from the interstitial space to the lymphatic system.

Question 12

What is an antigen-presenting cell?

Answer 12

B-cells, macrophages and dendritic cells that use antigens of pathogens to stimulate the adaptive immune system via the lymphatic system. Utilize MHC-2 molecules to present the antigen on the cell surface.

Question 13

What is a membrane attack complex?

Answer 13

Following the binds of compliment proteins to the antibody of a pathogen- half the proteins break off of that complex to form a cylinder type formation that acts as an entrance into the bacteria cell wall. This allows water and sodium to enter the cell and cause bacterial cell lysis.

Question 14

What is opsonization?

Answer 14

The end of the complement cascade that easily binds to macrophages and neutrophils via receptors to initiate phagocytosis of the bacteria.

Question 15

What are C3a and C5a/what do they do?

Answer 15

They are proteins made from the complement cascade that allow for positive chemotaxis to the area of injury.

Question 16

What is the classical pathway?

Answer 16

Compliment cascade proteins bind together and then bind to the antibody that has attached to the antigen of the bacteria. The complement cascade works to kill the bacteria via positive chemotaxis, forming the MAC and initiating opsonization.
Starts with protein C1, antibody-mediated effect

Question 17

What is the alternative pathway?

Answer 17

When protein C3b can attach to the antigen of the bacteria and this produces the MAC which causes cell lysis, contribute to positive chemotaxis via C3a and C5a and initiate opsonization.
Starts with protein C3b, no antibody-mediated effect

Question 18

What is the lectin pathway?

Answer 18

Mamose-binding lectin binds to a mamose sugar on the bacterial cell surface which in turn produces all the effects on the compliment cascade: MAC = cell lysis, positive chemotaxis and opsonization.

Question 19

What do interferons do in innate immunity?

Answer 19

3 types of interferons: alpha, beta and gamma.
Alpha & beta interferons-
When a cell is infected by a virus, IRF comes and transcribes some of the infected DNA to become interferons which are used in protection against infection of other cells. Alpha and beta are secreted by lots of different tissues, specific to beta are platelets. Alpha and beta interferons allow other cells to cleave viruses (via protein kinase R) upon entering the cell because they have been given the secret to destruction (interferons).

Gamma- stimulates natural killer cells, as well as produced when macrophages are infected with viruses. Gamma interferons can stimulate nearby macrophages to amp up an inflammatory response.

Used to treat: herpes, genital warts, MS.

Question 20

What are toll-like receptors?

Answer 20

Toll-like receptors are located on the cell membrane of in the intra-cellular space and they are activated by different pathogens to stimulate DNA transcription. This produces IFN, protein signalling and interleukins (IL-1, TNF alpha, IL 18) that all help aid the inflammatory response.

Question 21

What are the diagnostics involved in RA?

Answer 21

• If the patient has signs/symptoms of RA and an elevated rheumatoid factor, it is likely that they have RA.
• A negative rheumatoid factor does not rule out RA. As well, it can be negative in about 30% of patients and this is where ordering an Anti-CCP antibody (cyclic citrullinated peptide antibody) may be quite useful. -
• Rheumatoid factor can also be positive in other disease states such as SLE, scleroderma, hepatitis, multiple myeloma, leukemia and bacterial/viral infections
• ESR and CRP are inflammatory markers and can be useful in support of an underlying inflammatory disorder. They are most useful in monitoring the course/treatment of RA (i.e., higher levels indicate greater inflammation).

Question 22

What are the signs and symptoms of RA?

Answer 22

• multiple symmetrical joint involvement/pain (i.e. wrist, hands, proximal interphalangeal joints (PIP), feet)
• presence of joint deformity
• pain is worse in the morning and may improve throughout the day warmth/redness over affected joints (underlying inflammation)
• fatigue, weight loss/anorexia (RA is a systemic disease)

Other extra-articular findings in RA include:

• small vessel vasculitis (chronic leg ulcers)
• eye involvement (scleritis)
• cardiovascular (increased risk of CAD/MI, Heart Failure)
• peripheral neuropathy
• hematological issues (anemia of chronic disease, thrombocytopenia - causes for this are multifactorial and may be due to nutritional issues, drug treatment, underlying ineffective erythropoiesis).

Question 23

What are the risk factors for RA?

Answer 23

• exact etiology of RA remains unknown
• several gene-environmental interactions that can increase the risk of developing RA: tobacco use is one of the most important environmental factors, infections, such as Epstein-Barr and cytomegalovirus, have also been linked with RA.
• well-established genetic susceptibility associated with RA (in 1st degree relatives). There is a higher prevalence of RA in females vs. males. Studies have also looked at a possible hormonal role - there are mixed results however with regards to if oral contraceptives and early menarche decrease the risk of developing RA.

Question 24

What is the management for RA?

Answer 24

• early referral to a rheumatologist
• NSAIDs are used for symptom and short-term management.
• You could consider initiating a DMARD (i.e., nonbiologic agent such as methotrexate PO) to prevent destruction of joints and improve her overall function (need to take it on the same day of each week)
• You would want to order initial baseline electrolytes/Cr and LFTs given this drug’s side effect profile (i.e., abnormalities in LFTs). You also need to educate on avoidance of ETOH. If you did order methotrexate, folic acid would be important to add. As well, order and review CXR and PPD before starting- to rule out TB!!!