Immunodeficiencies

Question 1

PIDs?

Answer 1

Primary inherited immunodeficiency - inheritance of mutation in either innate or adaptive immunity

Question 2

Severity of mutation?

Answer 2

More than 300 defects associated so far, causing rare monogenic conditions
Severity depends on complete or partial LOF,

Question 3

Paradoxical overactive immune response?

Answer 3

Caused by some IDs through regulation defects:

Autoinflammatory disorders 
Autoimmune disorders (Foxp3, AIRE, Fas gene defects)

Question 4

Clinical phenotypes of PID?

Answer 4

Increased susceptibility to infection, especially opportunistic ones that would not normally cause disease

Mutations may affect:
immune cell development
activation
effector mechanisms

Mostly affect adaptive humoral response of B cells

Question 5

Defects in innate immunity?

Answer 5

Phagocyte production, adhesion, activation and killing

Question 6

LAD defects?

Answer 6

LAD1 - CD18 subunit, normally pairs with CD11a to form LFA1 for leukocyte extravasation
ALSO CD11b and CD11c for complement receptors CR3 and 4
= compromised neutrophil recruitment and phagocytosis
Bacterial and fungal severe infections early on

LAD2 - needed to synthesis sialyl-Lewis C ligand on neutrophils for rolling phase of leukocyte extravasation, with same effect as above

Question 7

PRR sensing defects?

Answer 7

ALL TLRs except TLR3 need MYD88 and IRAK4 to recognise MAMPs
(IRAK4 also on IL1 and 18 receptors)
Defects in either = recurrent pyogenic bacterial infections with little inflammation

Affects leukocyte activation

Question 8

Phagocyte killing defects?

Answer 8

NADPH oxidase enzyme complex in the phagolysosome generates ROS to kill microbes in neutrophils
Defects in this, fusing, or phagolysosome formation = no phagocytosis

Question 9

Chronic granulomatous disease?

Answer 9

Defects in NADPH complex for phagocytosis
= T cell mediated chronic inflammation and granuloma formation
Severity varies e.g. one X-linked variant still expresses some protein, treated with IFNy

Recurrent intracellular fungi and bacterial infections

Question 10

Defects in adaptive immunity?

Answer 10

Genes at almost every stage of lymphocyte development

Question 11

Combined immunodeficiencies?

Answer 11

T helpers needed for complete B cell activation, so T cell deficiencies also affect the humoral response
T cells and NK cells also overlap in development, so NK cells also affected

Question 12

SCIDs?

Answer 12

Severe combined immunodeficiencies - complete failure of T cell development, through:

1. Defective cytokine signalling in T cell precursors
2. Defective V(D)J rearrangement in developing lymphocytes
3. Premature death of the lymphoid lineage as toxic metabolites accumulate

Lead to direct/indirect B cell deficiency, or NK cell development failure

Question 13

Defective cytokine signalling SCIDs?

Answer 13

X-linked SCID, most commonly due to mutation in common y chain shared in IL2 cytokines (2,4,7,9,15 and 21)
(IL15 - NK cell development, IL7 - T cell)
B cells not affected - T-B+NK- SCID

Disproportionately affects males as X-linked

JAK-3 SCID (same as above but caused by autosomal recessive mutation)

IL7R SCID - only T cells through deletion of alpha chain = T-B+NK+ SCID

Question 14

Defective V(D)J rearrangement in SCIDs?

Answer 14

In developing lymphocytes

RAG SCID - mutation of RAG1/2 = no formation of V exons, stopping B and T development = T-B-NK+ SCID

Artemis SCID - artermis gene mutation = impaired DNA repair of dsDNA cuts from RAG1/2 =T-B-NK+ SCID and increased radiation sensitivity

Question 15

Premature death of lymphoid lineage in SCIDs?

Answer 15

ADA SCID - adenosine deaminase (ADA) enzyme defect impairs purine synthesis salvage pathway causing progressive defect in lymphocytes = profound lymphopenia = T-B-NK- SCID

Question 16

B cell effects causing PID?

Answer 16

Specific B cell targeting or absence of Th = indirectly
Most common form, occurs about 7-9months old when maternal antibodies decline
Recurrent bacterial infections
(fungal/viral fine as T cells intact)

Question 17

Absence of mature B cells disease?

Answer 17

X linked agammaglobulineia (XLA)
Pre-B cell stage, mutations in Burton’s tyrosine kinase for downstream signalling of preB cell receptors
Don’t pass pre-BCR quality control = profound deficiency

Question 18

Mature B cells with impaired function?

Answer 18

Most common form of PIDs
Generation of one or more Ig isotypes compromised
Mild recurrent infections in childhood

Question 19

Deficient T/B and T/APC communication?

Answer 19

Leads to hyper IgM syndromes
X-linked form-mutation in CD40 ligand gene, so failure of T cells to interact with receptor on B cells and APCs
No isotype switching = impaired macrophage and DC activation
Type 1 immunity impaired as less IL12

Question 20

Treating PIDs

Answer 20

Early intervention with antibiotics and antifungals
Replace missing component:
Protein replacement
Cell replacement with bone marrow/haemopoietic stem cell transplants
MORE SAFE:
Gene replacement
CRISP/Cas

Question 21

Secondary acquired immunodeficiency?

Answer 21

HIV/AIDS - therapeutic immune suppression/infection

Through defects acquired through life e.g. from malnutrition

Question 22

Clinical course of HIV infection?

Answer 22

2-6 weeks
Flu-like disease, spike and then dip in viral load as initial infection controlled
Then on: seroconversion, asymptomatic phase while CD4 T cells deplete and viral RNA increases
About 10 years later: symptomatic phase
Then AIDS = death

Question 23

Structure of HIV?

Answer 23

Retrovirus
Has reverse transcriptase for dsDNA integration to host DNA
Host-derived outermembrane to avoid immune recognition
Gp120 and gp41 = spike proteins (very few) for cell entry

Question 24

Cell tropism of HIV?

Answer 24

Infects CD4+ cells - T cells, monocytes/macrophages. DCs
Gp120 undergos conformational change for binding site for co-receptors:

CCR5-tropic = binds activated effector/memory T cells, immature DCs, monocytes/macrophages

CXCR4-tropic
Bind naive T cells, mature DCs

Question 25

Transmission of HIV?

Answer 25

Bodily fluid, usually mucosal surfaces of genital and GI tract
Local propagation in small amount of cells at entry site occurs, then transferred to draining LNs:
Kills CD4+ memory T cells, peak viral load in plasma
Also produces latent reservoirs for a self-sustaining infection in follicular DCs, lymph nodes

Question 26

Founder virus?

Answer 26

Responsible for initial small infection, takes about a week to reach high enough numbers for lymph node drainage

R5-tropic

Question 27

Role of DCs in infection?

Answer 27

Transfers virus from periphery to notes by binding surface lectin molecules
Retains virus on follicular DCs as source of virus throughout course

Question 28

Replication cycle?

Answer 28

Attachment with gp120 to CD4
Fusion - gp41
Viral proteins enter cell, reverse transcriptase acts in error-prone way to avoid immune recognition
Provirus active or latent in cell
Activation - binds host machinery, move to surface and releases new HIV proteins in host-derived membrane

Transfer also through cell:cell interaction at viral synapse

Question 29

Why can’t the immune system clear HIV?

Answer 29

High replication and mutation rate
Latent reservoir = hide for long periods
Camouflage

Question 30

Anteretroviral drugs?

Answer 30

Viral protease inhibitors
Reverse transcriptase inhibitors
Integrase inhibitor
Fusion inhibitors
Co-receptor binding inhibitors

Drug combos needed to cope with rapid mutation rates - HAART

Question 31

Drawbacks of drug treatments?

Answer 31

Cost
Availability
Only works on replicating virus
Compliance - taken for life
Side-effects; becomes chronic inflammatory condition

Question 32

Sterilising cure?

Answer 32

Complete removal, very rare (London and Berlin patients)

HIV+ with leukaemia - got transplant with mutation in CCR5 gene, blocking HIV entry to cells

Question 33

Issues with sterilising cure?

Answer 33

Transplantation risk
Rarity of donors with CCR5delat32/delta32 mutation
Second attempts caused switch in tropism to X4 so did not help

Question 34

Problem with latency?

Answer 34

Key challenge to overcome, as drugs do not act on these viral molecules
Early intervention needed to stop formation of the reservoir

Question 35

Functional cure?

Answer 35

Aims to reduce viral load to that which the immune system can cope with, so drugs do not have to be taken for like

Question 36

Current cure efforts?

Answer 36

Eliminate latency - shock/kick and kill
Activate latent cells so hidden virus is exposed to treatment

Lock down reservoir - inhibit HIV protein Tat to suppress activation if latent infected cells (functional cure)

Make cells resistant to infection - gene therapy to remove CCR5, cut out integrated virus (sterilising)

Develop antibody and cel-mediated vaccines e.g. broadly neutralising antibodies