Immunology

Question 1

Function of IL-17

Answer 1

induction of epithelial cells and chemokines that attract neutrophils to sites of infection and (antimicrobial) B defensins

Question 2

The differentiation of CD4 T cells into TH17 cells is determined by what?

Answer 2

expression of transcription factor RORyT which is expressed by STAT3

Phosphorylated STAT3 dissociates from the receptor and forms homodimers that translocate the nucleus and induce expression of RORyT

Question 3

Hyper IgE triad

Answer 3

pneumonia, recurrent staphylococcal skin abscesses, and elevated IgE

Question 4

What is the mutational defect in hyperIgE

Answer 4

impaired TH17 differentiation

TH17 differentiation causes cells to express IL-17R to produce neutrophils, chemokines and macrophages like CXC8 which fight infection

Question 5

AR IgE syndrome is associated with which gene mutation

Answer 5

DOCK8

Question 6

AD IgE syndrome is associated with which gene mutation

Answer 6

STAT3

Question 7

Where does the thymus derive from

Answer 7

The third pharyngeal pouch

Question 8

Function of TBX1 gene

Answer 8

controls segmentation of the embryonic pharynx, growth, proper alignment and septation of the cardiac outflow tract

Question 9

Where is TBX1 gene located

Answer 9

ch 22q11.2

Question 10

heart defect, seizures, hypocalcemia and T cell lymphopenia

Answer 10

Digeorge syndrome

aka microdeletion of 22q11.2 region on ch. 22

Question 11

Function of the AIRE gene

Answer 11

regulation of self recognizing T cells, therefore del. in AIRE means ++ autoimmunity

Question 12

What is the ALPS mutation?

Answer 12

germ line mutation in TNFRSF6 (encodes Fas) which leads to increased survival of lymphocytes aka impaired apoptosis
(Autoimmunity lymphoproliferative Syndrome)
Note there are many mutations that can cause ALPS (ie. CTLA4)

Question 13

What are Cryopyrinopathies aka CAPS (Cryopyrin associated periodic fever syndromes)?

Answer 13

Autoinflammatories spectrum of disorders including

1. FCAS
2. MWS
3. CINCA/NOMID

Gain of function in NLRP3 gene results in hyper-activation of IL-1 beta
Occurs in an AD pattern

Question 14

HIES due to germline mutations

Answer 14

Type 1: Jobs syndrome
Due to STAT3 gene mutation loss of function (AD)
ZNF341 gene mutation (AR)
skeletal and bone abn.
delayed shedding of primary teeth, hyperext. joints, scoliosis

Type 2: PGME mutation, DOCK8 deficiency, Tyk2 def
recurrent viral skin infections like herpes
Atopy present - food and seasonal
normal bone and teeth

Question 15

HIES due to somatic mutation

Answer 15

STAT5b GOF mutation

presented with atopic derm, urticarial rash, resp infections, diarrhea

Question 16

What is MSMD?

Answer 16

Mycobacteria susceptible mendelian disease
IL-12 acts on T cells –> INF gamma released
INFg acts on macrophages to attack mycobacteria
In MSMD you get neutralizing anti INF gamma autoantibodies. This neutralizes INFg and halts the pathways of IL-12

Question 17

Disruption in thymus function - secondary

Answer 17

thymoma

Question 18

What is the effects of disruption in thymus function?

Answer 18

can cause neutralization antibodies to Th17, IL22 and IL12/23 . Impairment in these cytokines due to auto antibodies causes problems in defence against candida

Question 19

What is the effects of disruption in thymus function?

Answer 19

can cause neutralization antibodies to Th17, IL22 and IL12/23 . Impairment in these cytokines due to auto antibodies causes problems in defence against candida

Question 20

Name PID phenocopies due to auto antibodies (4)

Answer 20

1. AA against GM CSF –> causes pulmonary alveolar proteinosis
2. AA against CI inhibitor –> Acquired angioedema
3. AA against Factor H –> HUS
4. AA against various cytokines, Good syndrome –> thymoma and hypogamm.

Question 21

Features of ALPS (3)

Answer 21

with lymphadenopathy, splenomegaly, and autoimmunity.
Affected patients may also have AI hemolytic anemia, neutropenia and thrombocytopenia
They are at risk of developing lymphoma

Question 22

Management of ALPS

Answer 22

1. Immune suppression (Pred, cyclosporin A)
2. for ALPS- CTLA4 –> Abatacept (CTLA4 Ig)
3. Avoid splenectomy bc the risk of infections with encapsulated organisms

Question 23

What is the immune defect issue in WAS

Answer 23

there is an inability for the T cells to reorganize their actin cytoskeleton when required which has profound effects on their function. The T cells are unable to interact with B cell and other target cells.

Question 24

WAS triad

Answer 24

thrombocytopenia, recurrent infections, eczema

Question 25

Rituxumab MOA

Answer 25

IgG1 CD20 specific monoclonal antibody targets B cells from the pre- B cell stage, causing down regulation of the B cells making them less likely to be activated

Question 26

Name some periodic fever syndromes associated with urticaria

Answer 26

1. CAPS - CIAS1 associated periodic syndrome 2. FCAS - fam. cold autoinflammatory syndrome 3. Muckel wells 4. NOMID/ CINCA

Question 27

Criteria for Dupilumab therapy for atopic dermatitis

Answer 27

1. Moderate to severe AD not adequately controlled with topical therapies, or those therapies are not advisable 2. Age 6 +

Question 28

Name the Major and Minor Criteria for FMF

Answer 28

Major: 1. recurrent fevers with serositis 2. AA amyloidosis without other disease 3. Favourable responses to regular colchicine Minor: 1. Family history in first degree relative 2. recurrent fevers 3. erysipelas- erythematous rash

Question 29

3 advantages of SCIG vs IVIG

Answer 29

1. Home infusion 2. Venous access not required 3. Less systemic side effects 4. Gradual absorption maintains more consistent IgG levels

Question 30

3 disadvantages of SCIG

Answer 30

1. requires frequent dosing due to small volume per infusion 2. home infusions require a reliable and adherent patient 3. some equipment may be complicated 4. loss of dexterity in the elderly 5. multiple infusion sites may be needed

Question 31

3 defining features of T regs and diseases associated with it

Answer 31

1. Maintain tolerance by suppressing CD4 and CD8 T cells 2. Anti-inflammatory production occurs with Treg activation like IL-10, TGF-B 3. Express cell surface markers like CD3, CD25, CD4 and transcription factor FOXP3 Disease association - IPEX with is a FOXP3 mutation which leads to Treg dysfunction and autoimmunity

Question 32

MOA of Cyclophosphamide

Answer 32

- alkylating agent which inhibits cell division - activated cyclophosphamide is phosphoramide mustard which binds, alkylates and inhibits protein synthesis by cross linking of DNA and RNA

Question 33

3 side effects of cyclophosphamide

Answer 33

1. hemorrhagic cystitis 2. bladder neoplasia 3. gonad toxicity 4. bone marrow suppression

Question 34

5 signs of adult PID

Answer 34

1. 2 + new ear infections in 1 year 2. 2 + sinus infections in 1 year 3. One pneumonia per year for more than 1 year 4. Chronic diarrhea and weight loss 5. recurrent viral infections 6. recurrent need for IV antibiotics to clear infections 7. recurrent deep seated abscesses of the skin or internal organs 8. persistent thrush or fungal infection on the skin or elsewhere 9. infection with normally harmless TB like bacteria 10. Family history of PID

Question 35

4 ways B cells diversify

Answer 35

1. VDJ recombination (combinational diversity) 2. junctional diversity 3. somatic hypermutation 3. heavy and light chain combinations

Question 36

4 mechanisms of IVIG

Answer 36

1. neutralizations of antibodies: example ITP IVIG binds the Fc receptors which prevents the destruction of antibodies 2. passive immunity: IV delivery of antibody protection 3. anti inflammatory effects

Question 37

HLH proteins involved | What cytokine is elevated in serum in HLH

Answer 37

1. Increased IL-2R in serum | 2. Proteins involved are perforin, granzyme B, and granulysin

Question 38

name 3 immunological changes that occurs after measles infection

Answer 38

1. t cell lymphopenia 2. decrease t cell response to mitogens 3. decreased antibody responses

Question 39

patient has cold induced urticaria, arthritis, uveitis and fever, no deafness, what do they have?

Answer 39

FCAS - familial cold urticaria syndrome AD pattern tx is Anakinra (anti IL1R antag)

Question 40

What is cryoglobinemia, name the 3 types.

Answer 40

- condition in which blood contains large amount of cold sens. antibodies (cryoglobulins) Type 1: monoclonal IgG, IgM -> MGUS, CLL, MM Type 2: monoclonal IgG, IgM, and IgG with RF activity --> SLE, HIV, HBC, HBV Type 3: polyclonal IgG and IgM --> HBV, HCV, SLE, Sjogrens

Question 41

mechanism of HIV

Answer 41

- retrovirus/lentivirus - HIV binds CD4 via GP120 and GP41 - GP 120 binds CCR5 then CXCR4 later - GP41 mediates fusion with the cell leading to insertion of the viral core into the CD4 cytoplasm

Question 42

what infection is associated with TNF inhibitors

Answer 42

mycobaterial infections

Question 43

Mgmt of Digeorge

Answer 43

1. partial digeorge - monitor, live viral vaccines are ok if CD8>300, normal ab response to killed vaccines and normal PHA 2. complete digeorge - SCID precautions, HSCT, thymic transplant

Question 44

Monogenic causes of CVID

Answer 44

1. TACI deficiency - a receptor for BAFF and APRIL which is needed in T cell independant class switching in B cells 2. ICOS def 3. CD19 def 4. BAFF R def

Question 45

What is Goods Syndrome?

Answer 45

- adult onset hypogamm with thymoma - presents with sinopulmonary infections and opp. infections - investigations show low/absent B cells, low CD4 T cells and increased CD8 T cell

Question 46

causes of Hyper IgM

Answer 46

1. CD40L def 2. CD40 def 3. AID/UNG def 4. NEMO 5. T-B+NK- SCID (XLinked) 6. AT

Question 47

what is unique about AID/UNG def in Hyper IgM?

Answer 47

- AID and UNG def do not affect T cells | - so there is no oppurtunistic infections

Question 48

pathogenesis of AID and UNG mutation

Answer 48

- AID converts cytidine to uridine which triggers DNA to break and repair which is important in class switching - the uracil is removed by UNG, leading to DNA breaks and class switching occurs

Question 49

most common cause of Agam

Answer 49

XLA (accounts for 85% of agam)

Question 50

pathogenesis of XLA

Answer 50

- mutation in Btk gene (brutons tryrosine kinase) - required for survival and maturation of progenitor B cells - mut leads to arrest in pre B cell stage

Question 51

AR agamm causes

Answer 51

1. mutation in BCR 2. Mu heavy chain mutation 3. Lambda 5 mutation 4. IgAlpha and IgBeta 5. BLNK mutation

Question 52

when does transient hypogamm of infancy occur?

Answer 52

at age 3-6 months of life low IgG levels most pts asymptomatic improvement by 18 months, some up to 5 years

Question 53

causes of HIES

Answer 53

1. Dock 8 (AR) 2. STAT 3 (AD) 3. Tyk2 (AR)

Question 54

APECED 1. pathogenesis 2. mgmt

Answer 54

autoimmune polyendocrinopathy w candidiasis and ectodermal dystrophy aka APS1 1. mutation in AIRE gene, expressed in medulla of the thymus, lack of AIRE leads to self reactive T cells escape deletion and cause autoimmunity abs to IL-17 and IL-22 causes candidiasis 2. manage endocrine comps and CMC HSCT is NOT indicated will not correct the thymic issue

Question 55

which PID is associated with fulminant EBV

Answer 55

XLP

Question 56

pathogenesis of XLP

Answer 56

1. SAP def 2. XIAP def these muts leads to uncontrolled T cell activation, especially in response to EBV

Question 57

ALPS pathogenesis

Answer 57

- mutation in fas-fas L pathways leads to proliferation of activated lymphocytes, leading to autoimmune inflammation and malignant transformation - increased risk of lymphoma

Question 58

Pathogenesis of HLH

Answer 58

- defect in the transport of granules that lead cause lymphocyte toxicity and carry lytic enzymes (perforin and granzyme) - CD8 and NK cells which make these enzyme are active but not effective and they release high amounts of INF which activates macrophages, leads to phagocytosis of cells like RBS, plts causing pancytopenia

Question 59

HLH gene mutations

Answer 59

``` FHL1 - uknonw FHL2 - perforin FHL3- Munc13-4 FHL4 - syntaxin 11 FHL5 - Munc 18-2 ```

Question 60

Chediak Higashi Syndrome mutation

Answer 60

LYST gene in charge of lysosomal traficking leads to rec. infection with pyogenic and fungal bugs giant cytoplasmic granules, low plts, seizures

Question 61

Griselli syndrome mut

Answer 61

Rab27a | granule docking problem

Question 62

name SCID like syndromes

Answer 62

1. MHC class 1 def (bare lymphocyte syndrome) 2. MHC class 2 def (bare lymphocytes syndrome type 2) 3. ZAP70 def - def in CD8 T cells 4. CD25 def: IL2R def needed for proper T cell differentiation and Treg cells 5. STAT5b def

Question 63

T-B-NK- SCID muts

Answer 63

1. ADA def 2. Reticular dysgeneis 3. PNP deficiency

Question 64

T-B+NK- SCID muts

Answer 64

1. gamma chain def (XLinked SCID) | 2. jak3 def

Question 65

T-B+NK+ SCID muts

Answer 65

ILR7-a def | CD45 def

Question 66

T-B-NK+ SCID muts

Answer 66

rag1 rag2 artemis

Question 67

Omenn syndrome features

Answer 67

- FTT, erythroderma, and diarrhea - HSM and lymphadenopathy - oligoclonal T cell expansion - "leaky SCID" bc not all T cells abolish, some develop - seen in ADA, RAG1, RAG2, artemix, XL SCID, ZAP70 and IL-7Ra

Question 68

WHIM mutation

Answer 68

CXCR4 GOF mut causing retaining mature neutrophils in the bone marrow Warts, hypogamm, infections, myelokathexis

Question 69

function of INF-y

Answer 69

macrophage activation especially in killing pathogens like listeria, mycobacteria, salmonella

Question 70

LAD type 1 mutation

Answer 70

- b2 integrin family CD18 - issue with firm adhesion

Question 71

NEMO and IKBA def mutation

Answer 71

- TLR sig defect causing inability to form IKK complex needed for NFkB - NEMO is XL and IKBA is AD