Immunology 4: integrated pathway and examples

Question 1

Whatt effects pathogen control?

Answer 1

Type of infection
- Is it a virus, bacteria or parasite (and subgroups)?

Where (location)
- Body surface: mucosal or skin
- Intracellular or extracellular
- Which tissue

When is it infecting host (age)
- Young and old tend to be less immune competent (when TCRyb>TCRab)

The nature of infection
o Innate = fast
o Adaptive = slower first time around

The condition of the hos
o Nutrition
o Age, genetics, sex
o Intercurrent infection
* Example: HIV takes out CD4 T cells, Therefore, the body cannot combat other infections.
o Prior infection or vaccination results in adaptive immune memory state and can prevent infection.

Question 2

Step by Step of a viral infection

Answer 2

1) Virus infects cells

• PRR
• Anti viral mechanisms within cell
• type I IFN released to signal infection -> induce anti viral state by stopping viral replication and increasing antigen presentation
• pro-inflammatry cytokines released (e.g. interleukine)
• NK recognise non-self as virus down regulate MHCI

2) cell lysis

• Local cells respond to PAMPs and DAMPS-> more type I IFN released
• Macrophage activation release more cytokines and chemokine
• initation and accelration of inflamation -> PMN migrate
• Cytokines stimulate NK
• Dendritic cells move to lymphs

5) Differentiation of niave CD4+ and CD8+ cells
- Dendritic cells present antigen to the niave T cells via MHCI and MHCII pathways and it is recognised by the TCR with cognate antigen -> clonal expansion and differentiation into sub types (dependent on cytokine profile from other immune cells)

6) Differentiation of naive B cells
- Dendritic cells present antigen to naive BCR and many secondary signals (e.g. cytokine release from T helper cells) lead to class switching of IgM to IgG, IgE or IgA and affinity maturation

7) Migration back to site of infection via thoratic duct
- B cells engulf antigens, become activated and present them waiting for T helper cell activation (Can occasionally clonally replicate on their own)

• T cells activate B cells
  (th1: bind to B cells presenting the correct antigen, release cytokines (IL-2, IFNy) causing clonal expansion and antibody production) -> neutralise, agglutinise, opsonise extracellular antigens

-T cells further activate resident innate cells (macrophage, neturophils, NK)
(th2: bind to macrophages presenting the correct antigen, realease IFNy to activate macrophages to kill more efficienty/ kill internal pathogen and produce TNFa (inflam cytokine escalating immune response)

• CD8 cytotoxicity -> targets cells that present antigens on their HCI complex (intracellular pathogens)

8) recovery
- macrophages switch to anti inflammatry due to influx of specific IL
- Regulatory T cells (Treg) become active)
- Memory B and T cells are stored
- Antibody production continues for a while

Question 3

Complex protist Example: Plasmodium falciparum

Answer 3

Disease: cerebral Malaria

Mosquito phase:
i. ingested
ii. gamete formation + ferilitsiaon in gut
iii. sporozoites move to salivary gland for biting

Mosquitos only have innate immune system
-> produce nitric oxide, enzymes / lysozymes, antimicrobial peptides, phagocytic cells, soluble pathogen binding factors

Human phase:

Local site of biting
- Sporocysts triggers PRR, complement and phagocytic cells
- Moves quickely through the blood to the liver

Liver stage:
- Upon Liver entry, B and T cell production is stimulated through the adaptive immune system.
- sporozoites enter hepatocytes in liver (to evade macrophages and antibodies as antibodies can’t enter cells)
- NK cells can kill hepatocyte states but is weak effect.
- hepatocytes only express MHC class I so only targeted by CD8+ T cells
- replicate + form schizont here in specialist vacuole to avoid MHCI presentation
- some molecules are translocated into the cytoplasm so that they can bind to MHCI and activate CD8+.
- By time CD8+ cells figure out how to access sporozoites they have left hepatocyte as merozoites w/ distinct antigens so antibodies are innefective

Blood phase:
- Parasite enters RBCs (RBC has no MCHs on surface so no recognition by T cells or antibody)
- Parasite eats haemoglobin
- Damaged RBCs cleared in spleen by macrophages normally but Parasite makes RBC avoid spleen by expressing erythrocyte membrane proteins Pf-EMPs (causes adherence to endothelial cells so don’t enter spleen)
- But Pf-EMPs can be targeted by antibodies
- But many (~60) Pf-EMPs in parasite genome so parasite switches them = antigenic variation

Subsequent infections are less sever as immunological memory for T cells and Ati-spz/ anti-PfEMP antibodies

Question 4

Bacteria example: Salmonella

Answer 4

Exists in many locations: gut lumen, systemic extracellular, intramacrophage (as macrophages live long + allow it to manipulate immune system)

Activation:
- Recognised by TLR4,5,9 and NLRs when Salmonella crosses the enterocyte cells of the intestine

Innate:
- Activates complement cascade
- when crosses enterocytes, Paneth cells produce defensins and goblet cells change the mucus leels
- NK activated and produced IFNy turning macrophages into super macrophages

Adaptive:
- B cells produce antibodies (they are stimulated but not necesary for clearnance as shown in chickens)

Living within macrophages weakens immnue response

Question 5

Extra cellular gut resident protozoa: Giardia

Answer 5

• Flagellated protozoan that colonises the small intestine
• attach to the intestinal epithelium using a specialized adhesive disc, causing localized damage to the epithelial cells.
• Impaires nutrients absorbtion

Both Innate and Adaptive involed
- > B cell production of IgA very important

Immunity is not strong or persistant
- Hard to protect outside of the body
- Immune cells must cross epithelial cells to reach pathogen

Question 6

Nematode: Trichuris

Answer 6

Immunity requires expulsion and reduction in egg produciton

Immunology
- Th2 response leading to antibody production (IgG)
- mast cells involved
- Epithelila cells as a physical barrier
- mucus + gut motility changes important

Nematodes are not evolving to evade the immune response

Question 7

intracellular protzoa: Cryptosporidium parvum

Answer 7

• Intracellular in vacuole to keep away from immune mechanisms in cytosol
• persistent in young animals and less in older animals

Immunolgy
- IFNy effectinve in early infection
- TCRγδ+ T cells for immunity in young and TCRαβ T cells in adults which are more effective