Immunology Flashcards
Function of IL-17
induction of epithelial cells and chemokines that attract neutrophils to sites of infection and (antimicrobial) B defensins
The differentiation of CD4 T cells into TH17 cells is determined by what?
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
Hyper IgE triad
pneumonia, recurrent staphylococcal skin abscesses, and elevated IgE
What is the mutational defect in hyperIgE
impaired TH17 differentiation
TH17 differentiation causes cells to express IL-17R to produce neutrophils, chemokines and macrophages like CXC8 which fight infection
AR IgE syndrome is associated with which gene mutation
DOCK8
AD IgE syndrome is associated with which gene mutation
STAT3
Where does the thymus derive from
The third pharyngeal pouch
Function of TBX1 gene
controls segmentation of the embryonic pharynx, growth, proper alignment and septation of the cardiac outflow tract
Where is TBX1 gene located
ch 22q11.2
heart defect, seizures, hypocalcemia and T cell lymphopenia
Digeorge syndrome
aka microdeletion of 22q11.2 region on ch. 22
Function of the AIRE gene
regulation of self recognizing T cells, therefore del. in AIRE means ++ autoimmunity
What is the ALPS mutation?
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)
What are Cryopyrinopathies aka CAPS (Cryopyrin associated periodic fever syndromes)?
Autoinflammatories spectrum of disorders including
- FCAS
- MWS
- CINCA/NOMID
Gain of function in NLRP3 gene results in hyper-activation of IL-1 beta
Occurs in an AD pattern
HIES due to germline mutations
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
HIES due to somatic mutation
STAT5b GOF mutation
presented with atopic derm, urticarial rash, resp infections, diarrhea
What is MSMD?
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
Disruption in thymus function - secondary
thymoma
What is the effects of disruption in thymus function?
can cause neutralization antibodies to Th17, IL22 and IL12/23 . Impairment in these cytokines due to auto antibodies causes problems in defence against candida
What is the effects of disruption in thymus function?
can cause neutralization antibodies to Th17, IL22 and IL12/23 . Impairment in these cytokines due to auto antibodies causes problems in defence against candida
Name PID phenocopies due to auto antibodies (4)
- AA against GM CSF –> causes pulmonary alveolar proteinosis
- AA against CI inhibitor –> Acquired angioedema
- AA against Factor H –> HUS
- AA against various cytokines, Good syndrome –> thymoma and hypogamm.
Features of ALPS (3)
with lymphadenopathy, splenomegaly, and autoimmunity.
Affected patients may also have AI hemolytic anemia, neutropenia and thrombocytopenia
They are at risk of developing lymphoma
Management of ALPS
- Immune suppression (Pred, cyclosporin A)
- for ALPS- CTLA4 –> Abatacept (CTLA4 Ig)
- Avoid splenectomy bc the risk of infections with encapsulated organisms
What is the immune defect issue in WAS
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.
WAS triad
thrombocytopenia, recurrent infections, eczema
Rituxumab MOA
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
Name some periodic fever syndromes associated with urticaria
- CAPS - CIAS1 associated periodic syndrome
- FCAS - fam. cold autoinflammatory syndrome
- Muckel wells
- NOMID/ CINCA
Criteria for Dupilumab therapy for atopic dermatitis
- Moderate to severe AD not adequately controlled with topical therapies, or those therapies are not advisable
- Age 6 +
Name the Major and Minor Criteria for FMF
Major:
- recurrent fevers with serositis
- AA amyloidosis without other disease
- Favourable responses to regular colchicine
Minor:
- Family history in first degree relative
- recurrent fevers
- erysipelas- erythematous rash
3 advantages of SCIG vs IVIG
- Home infusion
- Venous access not required
- Less systemic side effects
- Gradual absorption maintains more consistent IgG levels
3 disadvantages of SCIG
- requires frequent dosing due to small volume per infusion
- home infusions require a reliable and adherent patient
- some equipment may be complicated
- loss of dexterity in the elderly
- multiple infusion sites may be needed
3 defining features of T regs and diseases associated with it
- Maintain tolerance by suppressing CD4 and CD8 T cells
- Anti-inflammatory production occurs with Treg activation like IL-10, TGF-B
- 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
MOA of Cyclophosphamide
- 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
3 side effects of cyclophosphamide
- hemorrhagic cystitis
- bladder neoplasia
- gonad toxicity
- bone marrow suppression
5 signs of adult PID
- 2 + new ear infections in 1 year
- 2 + sinus infections in 1 year
- One pneumonia per year for more than 1 year
- Chronic diarrhea and weight loss
- recurrent viral infections
- recurrent need for IV antibiotics to clear infections
- recurrent deep seated abscesses of the skin or internal organs
- persistent thrush or fungal infection on the skin or elsewhere
- infection with normally harmless TB like bacteria
- Family history of PID
4 ways B cells diversify
- VDJ recombination (combinational diversity)
- junctional diversity
- somatic hypermutation
- heavy and light chain combinations
4 mechanisms of IVIG
- neutralizations of antibodies: example ITP
IVIG binds the Fc receptors which prevents the destruction of antibodies - passive immunity: IV delivery of antibody protection
- anti inflammatory effects
HLH proteins involved
What cytokine is elevated in serum in HLH
- Increased IL-2R in serum
2. Proteins involved are perforin, granzyme B, and granulysin
name 3 immunological changes that occurs after measles infection
- t cell lymphopenia
- decrease t cell response to mitogens
- decreased antibody responses
patient has cold induced urticaria, arthritis, uveitis and fever, no deafness, what do they have?
FCAS - familial cold urticaria syndrome
AD pattern
tx is Anakinra (anti IL1R antag)
What is cryoglobinemia, name the 3 types.
- 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
mechanism of HIV
- 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
what infection is associated with TNF inhibitors
mycobaterial infections
Mgmt of Digeorge
- partial digeorge - monitor, live viral vaccines are ok if CD8>300, normal ab response to killed vaccines and normal PHA
- complete digeorge - SCID precautions, HSCT, thymic transplant
Monogenic causes of CVID
- TACI deficiency - a receptor for BAFF and APRIL which is needed in T cell independant class switching in B cells
- ICOS def
- CD19 def
- BAFF R def
What is Goods Syndrome?
- 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
causes of Hyper IgM
- CD40L def
- CD40 def
- AID/UNG def
- NEMO
- T-B+NK- SCID (XLinked)
- AT
what is unique about AID/UNG def in Hyper IgM?
- AID and UNG def do not affect T cells
- so there is no oppurtunistic infections
pathogenesis of AID and UNG mutation
- 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
most common cause of Agam
XLA (accounts for 85% of agam)
pathogenesis of XLA
- 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
AR agamm causes
- mutation in BCR
- Mu heavy chain mutation
- Lambda 5 mutation
- IgAlpha and IgBeta
- BLNK mutation
when does transient hypogamm of infancy occur?
at age 3-6 months of life
low IgG levels
most pts asymptomatic
improvement by 18 months, some up to 5 years
causes of HIES
- Dock 8 (AR)
- STAT 3 (AD)
- Tyk2 (AR)
APECED
- pathogenesis
- mgmt
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
- manage endocrine comps and CMC
HSCT is NOT indicated will not correct the thymic issue
which PID is associated with fulminant EBV
XLP
pathogenesis of XLP
- SAP def
- XIAP def
these muts leads to uncontrolled T cell activation, especially in response to EBV
ALPS pathogenesis
- mutation in fas-fas L pathways leads to proliferation of activated lymphocytes, leading to autoimmune inflammation and malignant transformation
- increased risk of lymphoma
Pathogenesis of HLH
- 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
HLH gene mutations
FHL1 - uknonw FHL2 - perforin FHL3- Munc13-4 FHL4 - syntaxin 11 FHL5 - Munc 18-2
Chediak Higashi Syndrome mutation
LYST gene in charge of lysosomal traficking
leads to rec. infection with pyogenic and fungal bugs
giant cytoplasmic granules, low plts, seizures
Griselli syndrome mut
Rab27a
granule docking problem
name SCID like syndromes
- MHC class 1 def (bare lymphocyte syndrome)
- MHC class 2 def (bare lymphocytes syndrome type 2)
- ZAP70 def
- def in CD8 T cells - CD25 def: IL2R def needed for proper T cell differentiation and Treg cells
- STAT5b def
T-B-NK- SCID muts
- ADA def
- Reticular dysgeneis
- PNP deficiency
T-B+NK- SCID muts
- gamma chain def (XLinked SCID)
2. jak3 def
T-B+NK+ SCID muts
ILR7-a def
CD45 def
T-B-NK+ SCID muts
rag1
rag2
artemis
Omenn syndrome features
- 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
WHIM mutation
CXCR4 GOF mut causing retaining mature neutrophils in the bone marrow
Warts, hypogamm, infections, myelokathexis
function of INF-y
macrophage activation especially in killing pathogens like listeria, mycobacteria, salmonella
LAD type 1 mutation
- b2 integrin family CD18 - issue with firm adhesion
NEMO and IKBA def mutation
- TLR sig defect causing inability to form IKK complex needed for NFkB
- NEMO is XL and IKBA is AD
