MII2 antibodies, mucosal immunity, malaria

which region of an Ab defines the function (class) of the antibody

Constant heavy chain (Fc) region

what defines whether an Ab is membrane bound or secreted

different forms of RNA processing resulting in different carboxyl terminals

does swapping Ab constant Fc region change the specificity for the Ag

no

what are the first Ab isotopes produced by a cell

IgM and IgD

which are the only Abs that can be produced simultaneously by a B cell

IgM and IgD

what Ab is the first response

IgM

how are IgM and IgD produced

differential RNA splicing

how are IgG, IgA, and IgE produced

irreversible change in DNA

can multiple isotopes (G, A or E) be produced at once

no

can a cell produce IgD or IgM after changing to IgG A or E

no

which Ig is responsible for allergies

IgE

which cell controls B cell isotype switching

Th cells

which Ig has the lowest affinity for Ag and why

IgM - produced prior to affinity maturation

what is IgM good at binding to and why

repeating epitopes , due to forming a pentamer

what is IgM good at activating

complement

which pathway do Ab activate the complement via

classical pathway

which region of antibodies activates complement molecules

Fc region

what is a complement fixer

an antibody capable of activating the complement

what makes IgM more effective at activating the complement than IgG

its pentameric structure

what environment is IgA best suited to

mucosal surfaces

which region of IgA facilitates transport across the intestinal epithelium

J chain

what is IgA resistant to (2)

low pH and digestive enzymes

How does IgA keep pathogens away from epithelium?

it clumps pathogens together for explulsion from the body

what makes IgA less likely to cause collateral damage

weak ADCC function and complement fixation

what is IgE suited for

helminth infections

which Ig can make innate cells into memory cells

IgE

how does IgE make innate cells into memory cells

- FceR has high affinity for IgE, and binds monomeric IgE.

- FceR becomes loaded with IgE

- This gives the cell an Ag-specific receptor

which FcR is specific for each Ig

which Igs can opsonise a cell (2)

IgG and IgA (and IgM via the complement)

why can't IgE opsonise

its meant for helminths which are too large to opsonise

how does IgG achieve ADCC

Directs innate cells to kill via interaction with FcR

how does IgE achieve ADCC

kills extracellular pathogens by firing anti-microbial molecules at them

what is the advantage of Ab having two Ag binding sites

Enhanced cross-linking: two binding sites allows a single Ab to bind two distinct epitopes (repeating or adjacent Ags) which is more easily recognised by immune cells

how does AgAb cross linking aid antibody mediated neutralisation (2)

clumps together toxins/pathogens, allowing clearance by immune complexes, and hindering pathogen mobility

why does IgE cause allergies and severe anaphylaxis

When exposed to an allergen Ag, the immune system produces IgE that binds to mast cells.

Upon re-exposure, the Ag cross-links these IgEs, causing mast cells to rapidly release inflammatory mediators (eg histamine), which produce allergic symptoms

what is affinity maturation in Ab

mutations to the V, D, J segments of the Ag binding site changes the affinity of the Ab for its Ag, or which Ag it recognises

is affinity maturation rare or common

common - 100,000 fold higher rate than normal human cells

what happens if the affinity maturation causes loss of affinity for Ag

the B cell dies

what happens if the affinity maturation causes reduced affinity for Ag

B cell survives but is outcompeted

what happens if the affinity maturation causes increased affinity for Ag

B cell outcompetes others

what is the process of affinity maturation called

somatic hypermutation

where does affinity maturation take place (2)

germinal centres of the lymph nodes and spleen

what do B cells require to undergo and survive affinity maturation

permission from T cells

what negative thing can occur from affinity maturation

B cells specific for self-Ag (autoimmune disease)

what usually prevents B cells producing Abs specific for self-Ags

B cell must present the Ag it recognises to a T cell.

- If the T cell recognises the Ag: B cell is still microbe specific and can survive

- If the T cell no longer recognises the Ag: B cell has lost specificity or is self-Ag specific so is deleted

do T cells undergo affinity maturation

no

How do clonal expansion, isotype switching and affinity maturation fit together? (picture to see)

what are the three mucosal surfaces of the body

respiratory tract, intestine, urogenital tract

self-reactive T cells can be deleted but what dangerous T cells aren't deleted

T cells that recognise non-self non-dangerous antigens

describe the structure of the intestinal epithelium from surface to mesentery

mucus layer, epthelial cells, lamina proria and peyers patches

what are peyers patches

the areas of lymphoid tissue in the wall of the intestine that are involved in the development of immunity

how do T cells know not to attack food Ags

they will not receive the second signal for danger (B7 upregulation)

what is the result of a T cell being shown a food Ag

it will die or deactivate

what is T cell deactivation called

anergy

receiving an Ag orally produces what effect. How does this compare to a second vaccination/pathogen occurrence

tolerance on second ingestion. As opposed to a heightened immune response on second infection.

which cytokines does Th1 cells produce

IFN-gamma

which cytokines does Th2 cell producee

IL-4

In coeliac disease, what is activated and what do they produce (3)

Th1 cells produce IFN-y, activated macrophages, B cells

in normal food allergies, what is activated and what do they produce (3)

IL-4, mast cells, igE (from B cells)

where do intestinal commensals live

near the surface of the mucous layer

which type of gut cell produces antimicrobial peptides

paneth cells

which cells transport Ags to the lamina propria

M cells

what is the most prominent antibody in the intestines (reminder)

IgA

what is the special environment found in Peyer's patch

B cells in Peyer's patch have higher rates of somatic hypermutation, making IgA higher affinity for neutralising pathogens

what is the benefit of IgA poor ADCC and complement response

weak responses won't impair the epithelial barrier

comment on the action of these features of mucosal immunity:

1. tight junctions

2. mucus layer

3. anti-microbial peptides

4. IgA

1. tight junctions - prevent epithelium penetration

2. mucus layer - prevents microbes getting to the epithelium

3. anti-microbial peptides - in inner mucus layer, damages microbes that get too close

4. IgA - specialised for neutralising and blocking microbes

what is the result of having no commensals

immune system doesn't develop

how do commensals protect the intestine

they fill up the intestinal niche to prevent pathogenic bacteria surviving

do commensals trigger an immune response?

yes, just not an aggressive response

what causes Appendicitis

blockage in the appendix causing build up of mucus and microbial products and inducing inflammation

what is the result of inflammation in appendicitis

intestinal barrier loses integrity, commensals invade lamina propria, appendix bursts

what is inflammatory bowel disease linked to

over-enthusiastic immune responses against commensals

what is the difference between a normal gut commensal response and an IBD commensal response

normal: IgA release, then IL-10 and Treg cells for inhibition

IBD: IFN-y, TNF-a, IgG (ADCC and complement) activation

which two immune molecules regulate the immune response

Regulatory T cells and IL-10

what do Treg cells produce

IL-10

what is the inhibitory effect of Treg cells and IL-10 (5 targets)

inhibits:

helper T cells

B cells

macrophage activation

antigen presentation

cytokine production (TNF-a, IFN-y, IL-4)

allergies developed correlate with what childhood factor

interaction with different commensal communities

how long will plasmodium develop in humans

11-14 days

what stage of development does plasmodium enter the human skin

sporozoites

where in the human does plasmodium replication take place

liver

what cells does plasmodium invade

red blood cells

which stage of the plasmodium human cycle causes fever symptoms

erythrocytic cycle

how do the sporozoites reach the liver

carried by blood flow

what type of cell do the sporozoites infect in the liver

hepatocytes

what are hepatocytes

specialised epithelial cells important for protein synthesis and storage, production of bile, synthesis of blood clotting factors

are many hepatocytes infected

no, only about 100, but each cycle in the liver forms up to 90,000 merozoites

what do infected hepatocytes release

type I inferferon

what does type I IFN do in this environment and what effect does it have (2)

signals to neighbouring hepatocytes to reduce chance of infection and increase antigen presentation

reminder: what are the two mechanisms of CTL killing

FAS/FASL

perforin and granzyme B

what happens to the liver during infection and why

hepatomegaly - enlargement of the liver

due to infection and inflammation

what other organ is enlarged during malaria infection

spleen (splenomegaly)

what is the spleens role during malaria infection (3)

filtration of parasitised red blood cells

immune cell activation

haematopoiesis

what is severe malarial anaemia defined by and what causes it

in children mainly:

driven by both increased destruction of red blood cells (RBCs) and reduced production of new RBCs

defined by hemoglobin (Hb) concentrations <5 g/dL

what are the mechanisms that lead to reduced RBCs (4)

1. lysis of parasited RBCs

2. removal of parasited RBCs in the spleen

3. decreased/suppressed erythropoiesis

4. removal of uninfected RBCs

what is the process of RBC lysis

The parasitophorous vacuole membrane ruptures, freeing the merozoites in the RBC

The RBC will swell and the cytoplasm degrades. The lysis that occurs is explosive, scattering the merozoites.

what is also released by the RBC along with the parasite (4)

PAMPs and DAMPs, proteases, haemoglobin and haemozoin

what is haemozoin (Hz)

a product of haemoglobin metabolism by plasmodia.

a crystalline with a brown pigment

what is the purpose of Hz

free haem released by Hb digestion is toxic, so these crystalline byproducts are formed to help the parasites survive

how does haemozoin increase symptoms

it is immunostimulatory (produces lots of cytokines) - can cause chronic inflammation

what is the effect of removing phagocytes on malaria infection

decrease in anaemia, increase in parasitaemia