Immunodeficiency

Question 1

What is immunodeficiency ?

Answer 1

A congenital or acquired state where the immune response has:
-Missing components- genes missing or mutated so no protein is made.
-Non functioning components- mutated gene makes protein but it doesn’t function.
-Incorrectly functioning components- mutated gene makes component but it either works partially or works too well e.g. mutation alters binding affinity with target in singalling pathway so signal is too big or small etc

Question 2

What does immunodeficiency lead to ?

Answer 2

Leads to a deficiency in the function of the immune response and therefore increases susceptibility to infection, malignancy and autoimmunity.

The immunodeficiency is the increased susceptibility to infection

Question 3

What are causes of acquired immunodeficiency ?

Answer 3

In prematurity: babies dont have antibodies from placenta

Question 4

What are primary and secondary immunodeficiencies ?

Answer 4

Primary immunodeficiency: Genetic/congenital → often single-gene defects.
Secondary immunodeficiency: Acquired → due to infection, drugs, or disease; not inherited.

Question 5

What can give indications of the arm of the immune system which is deficient ?

Answer 5

The type of infection

Question 6

What do oppurtunistic infections suggest ?

Answer 6

Deficiency in T cells
e.g. Candida, Pneumocystis jiroveci and Mycobacterium avium complex.

Question 7

What are SCIDs ?

Answer 7

Severe Combined Immunodeficiencies
-A genetic condition causing severe impairment of both T-cell and B-cell immunity, leading to life-threatening infections early in life, often with opportunistic organisms.

Question 8

What do deficiencies in antibodies and B cells lead to ?

Answer 8

Recurrent bacterial infections of the respiratory and gastrointestinal tract.
-These are normally encapsulated bacterial that cause fevers and are pyogenic
-e.g pneumococcus, haemophilus and campylobacter

Question 9

What do deficiencies in neutrophils lead to ?

Answer 9

Recurrent and unresolving bacterial and fungal infections with granuloma/ulcers and very poor wound healing.

Question 10

What do deficiencies in the compliment system lead to ?

Answer 10

Neisserial infections if it is terminal components (C5-C9)
Immune complex mediated disease if it is classical pathway (C4)
Recurrent bacterial infections if C3 (early pathway)

Question 11

How can primary immunodeficincies (PID) be inhereted ?

Answer 11

Autosomal dominant
Autosomal recessive
X linked

These diseases are all very rare are the prevalence of these gene mutations in the human population is very low therefore autosomal recessive conditions are the rarest

Autosomal recessive more common with consanguinuity

Question 12

What is an autosomal dominant PID ?

Answer 12

1 normal functioning allele and one defective allele.
-The defective allele dominates the function of the normal product
-e.g. ALPS, hyper IgE, C1inhibitor

Question 13

What is an autosomal recessive PID ?

Answer 13

Defective allele from both parents, both parents are carriers
-e.g. SCID caused by RAG1/2 deficiency

Question 14

What is an X-linked PID ?

Answer 14

Recessive defect on the X chromosome.
-Males inherit defective gene from their mothers who are carriers
-X linked disease is a common mode of inheritance in primary immunodeficiency
-e.g. XLA, WAS, XLP, X linked hyper IgM, NEMO, Properdin
-Mothers are carriers and may be symptomatic due to inactivation of the normal X chromosome

Question 15

What are neutrophils ?

Answer 15

Polymorphonuclear (PMN) leukocytes - lobed or segmented nucleus
-Characteristic of acute inflammation
-Most abundant white blood cell
-Bone marrow derived; Myeloid lineage
-Very rapid turnover; Die in tissues after phagocytosing target bacteria or fungi
-Rapidly mobilised from marrow

lobated nucleus lets it squish between cells and be good at moving

Question 16

What are examples of primary immunodeficiencies ?

Answer 16

Leukocyte adhesion deficiencies I, II and III (innate immune issue)
Chronic granulomatous disease (innate immune issue)
SCID/Omenn Syndrome (RAG1/2) (adaptive immune issue)
X linked agammaglobulinaemia (adaptive immune issue)

Question 17

What is Leukocyte adhesion deficiency (LAD)

Answer 17

Autosomal recessive condition

4 types:
LAD type 1- CD18 deficiency resulting in no tethering to endothelium
LAD type 2- Deficiency of fucose transport leading to Sialyl lewis X (CD15 deficiency)- no rolling
LAD Type 3 - Kindlin-3 deficiency → leukocytes can’t migrate through endothelium.
Rac2 deficiency → ↓L-selectin → impaired adhesion/migration (autosomal dominant)

Question 18

What is LAD type 1 ?

Answer 18

CD18 (part of LFA-1) is missing → neutrophils cannot firmly bind ICAM-1 on endothelium → impaired adhesion → neutrophils fail to migrate to infection sites → bacterial clearance is defective.

Question 19

What is LAD type 2

Answer 19

Defective sialyl Lewis X → neutrophils cannot bind E-selectin → rolling on endothelium is impaired → neutrophils fail to slow down and migrate into tissues → infection is not cleared.

Question 20

What is LAD type 3 ?

Answer 20

Kindlin-3 mutation → neutrophils cannot change shape → cannot squeeze between endothelial cells → neutrophils fail to reach infection sites → bacteria are not cleared.

Question 21

What are consequences of LAD ?

Answer 21

Inability to recruit neutrophils to site of infection
Delayed umbilical cord detachment as lesser healing
Omphalitis- inflammation of umbilical cord, leads
Overwhelming bacterial infections with no pus- no neutrophils means no pus
Poor wound healing
Death without bone marrow/stem cell transplant
These are very rare diseases as the prevelance of the mutated genes is very rare

Question 22

What causes Chronic granulomatous disease (CGD) ?

Answer 22

Mutation in one of the proteins that make up NADPH oxidase of the neutrophil respiratory burst
-Inheritance X linked or autosomal recessive
-Most common on X linked gene therefore 70% of cases are boys!

resp burst = rapid oxygen consumption → generates reactive oxygen species (ROS) → kills ingested microbes.

Question 23

How does CGD work ?

Answer 23

The NADPH oxidase is missing a component therefore there is no respiratory burst and no super oxide produced;
-Phagocytosed bacteria or fungi is not killed
-Granuloma formed of immune cells to isolate pathogen
-Chronic production of small granuloma in sites of infection

CGD and IBSs can get mixed up as have similar symptoms and can both cause granulomas

Question 24

What are consequences of CGD

Answer 24

-Recurrent infections with catalase positive bacteria leading to pneumonia, abscesses of skin and infection of lymph nodes.
-Lung disease with aspergillus
-Inflammatory bowel disease like condition
-Granulomas- failure to clear phagocytosed bacteria

Question 25

How is CGD treated ?

Answer 25

Stem cell transplant (bone marrow) advised, gene therapy has been tried with limited success

Question 26

What is RAG SCID

Answer 26

Mutogenic RAG1 or RAG2 (recombinase activating genes) deficiency -Makes up 20% of total SCID identified -Is autosomal recessive; rare -Usually presents before 1 month Presents from birth but usually detected at 3-6 months as it takes time for baby to fail through infection -NK cells but no T or B; T-B-NK+ -T and B cell death due to developmental failure to assemble rearranged gene segments for T/B cell receptors; no adaptive immune response ## Footnote RAG deletion means - Complete loss of gene product- null alleles, no RAG protein is made

Question 27

How can RAG SCID be found in babies ?

Answer 27

Seccesful rearrangement of genes in T/B cell receptors excise DNA produced cells and small circle of DNA called TREC -TREC in blood detectable by PCR -TREC detectible in card; no TREC mean RAG SCID -Screening done in babies as blood spot on guthrie card; early detection important as will die without it | TRECs from T cells, KREC from B cells ## Footnote TREC- T cell receptor excision circle

Question 28

How does RAG deletion present ?

Answer 28

Baby presents with: -Failure to thrive (FTT) -Recurrent severe opportunistic infections: Pneumocystis jiroveci, Mycobacterium avium complex, Epstein–Barr virus Cytomegalovirus (herpesvirus species are common and extremely severe) Invasive Candida. Fatal- Human Stem Cell Transplant is only treatment ## Footnote At 3-6 months baby has lots of damage and infection - harder for transplant and survival so screening is v important

Question 29

What is Omenn syndrome ?

Answer 29

A variant of RAG SCID; Hypomorphic mis-sense mutation with partial RAG 1/2 enzyme activity -T+B-NK+, -T cells saved by partially functioning RAG protein. B cells absent in the blood but present in tissue. -T cells not normal; oligoclonal -Very characteristic presentation indicative of a highly activated uncontrolled T cell immune response to self. | Aka “leaky SCID" ## Footnote Autoimmune like

Question 30

Describe T cells in Ommen syndrome

Answer 30

T cells not normal; oligoclonal: -Very limited numbers of different TCR -Highly activated → chronically “switched on,” produce cytokines, autoreactive → cause autoimmune-like symptoms (rash, eosinophilia, high IgE). | Most T cells target self

Question 31

Descrie the characteristic presentation of Ommen syndrome

Answer 31

-Generalised red rash (erythroderma/scalded skin syndrome) -Oedema (swelling due to fluid moving into tissues) -Failure to thirive (FTT) with protracted diarrhoea (malnutrition), hepatosplenomegally, lymphadenopathy, high eosinophils and IgE levels (low IgG, IgA and IgM) -Recurrent infection from opportunistic infections -Features of a dysfunctional hyperactivated immune response with self reactive T cells and cytokine production (Th2- IL-4, IL-5) -T cells are present through homeostatic expansion there is NO control, NO regulatory T cells -Rapidly fatal- HSCT is only treatment but it is very difficult due to activated phenotype of T cells which need to be ablated prior to Transplant.

Question 32

What are antibodies essential for ?

Answer 32

Removal of extracellular pathogens, especially bacteria in respiratory and GI tracts.

Question 33

What do antibodies do ?

Answer 33

1. Neutralise toxins 2. Opsonise bacteria for efficient phagocytosis by neutrophils and macrophages 3. Activate classical complement cascade → opsonization & lysis

Question 34

Why are specific antibodies critical for encapsulated bacteria?

Answer 34

Bind capsular carbohydrates, trigger complement, opsonize bacteria → neutrophils can phagocytose (e.g., pneumococcus, H. influenzae)

Question 35

What is the role of IgA in the respiratory tract?

Answer 35

Prevents bacterial colonization by binding surface → blocks attachment → reduces infections

Question 36

What is a consequence of absent specific antibodies in lungs?

Answer 36

Bacteria attach → recurrent infections → irreversible damage → bronchiectasis

Question 37

Which antibody do babies get from the placenta ?

Answer 37

IgG crosses the placenta in the third trimester; baby born with mother’s IgG circulating in blood -New-born babies usually have none of their own antibody until 3-6 months and some antibodies can take longer to appear e.g. IgA. -Half life of IgG in vivo is 21 days. | IgG from mother completely gone in 3 months

Question 38

What is X linked Agammaglobulinaemia (XLA) ?

Answer 38

No B lymphocytes so no antibodies -X linked so only boys, mothers usually asymptomatic -B cells normally produced in bone marrow continuously -In XLA all B cells die at the pre-B cell stage due to failure to produce Bruton type kinase protein (BTK) -BTK essential in signalling that BCR has been correctly formed - No signal and B cell undergoes programmed cell death. | serine kinase is a mistake, BTK is a tyrosine kinase

Question 39

Describe clinical consequences of XLA

Answer 39

Presents around 6 months of age; maternal antibody has fallen and none of own antibody made; -Present with recurrent infections primarily of pyogenic (fever initiating, pus forming) bacteria in respiratory tract often leading to recurrent pneumonia (HIB, Strep pneumococcus and pyrogenes and Staphlococcus) -Increased susceptibility to enterovirus induced meningo-encephalitis which can be fatal Therapy- Immunoglobulin replacement which is highly effective and life long - chill is caught early and not much damage already done | Recurrent pneumonia in babies/kids is sus

Question 40

Describe neonatal screening for SCID

Answer 40

Guthrie Cards -Measures TREC levels now also able to do same for B cell deficiencies by measuring excision circles for immunoglobulin gene rearrangement | Pilot in UK, used abroad