Immunodeficiencies Flashcards
PIDs?
Primary inherited immunodeficiency - inheritance of mutation in either innate or adaptive immunity
Severity of mutation?
More than 300 defects associated so far, causing rare monogenic conditions
Severity depends on complete or partial LOF,
Paradoxical overactive immune response?
Caused by some IDs through regulation defects:
Autoinflammatory disorders Autoimmune disorders (Foxp3, AIRE, Fas gene defects)
Clinical phenotypes of PID?
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
Defects in innate immunity?
Phagocyte production, adhesion, activation and killing
LAD defects?
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
PRR sensing defects?
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
Phagocyte killing defects?
NADPH oxidase enzyme complex in the phagolysosome generates ROS to kill microbes in neutrophils
Defects in this, fusing, or phagolysosome formation = no phagocytosis
Chronic granulomatous disease?
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
Defects in adaptive immunity?
Genes at almost every stage of lymphocyte development
Combined immunodeficiencies?
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
SCIDs?
Severe combined immunodeficiencies - complete failure of T cell development, through:
- Defective cytokine signalling in T cell precursors
- Defective V(D)J rearrangement in developing lymphocytes
- Premature death of the lymphoid lineage as toxic metabolites accumulate
Lead to direct/indirect B cell deficiency, or NK cell development failure
Defective cytokine signalling SCIDs?
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
Defective V(D)J rearrangement in SCIDs?
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
Premature death of lymphoid lineage in SCIDs?
ADA SCID - adenosine deaminase (ADA) enzyme defect impairs purine synthesis salvage pathway causing progressive defect in lymphocytes = profound lymphopenia = T-B-NK- SCID
B cell effects causing PID?
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)
Absence of mature B cells disease?
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
Mature B cells with impaired function?
Most common form of PIDs
Generation of one or more Ig isotypes compromised
Mild recurrent infections in childhood
Deficient T/B and T/APC communication?
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
Treating PIDs
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
Secondary acquired immunodeficiency?
HIV/AIDS - therapeutic immune suppression/infection
Through defects acquired through life e.g. from malnutrition
Clinical course of HIV infection?
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
Structure of HIV?
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
Cell tropism of HIV?
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
