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RACP Written Exam 2015 > Immunology > Flashcards

Immunology Flashcards

0
Q

What conditions are associated with p-ANCA? (6)

A

“My Personal Computer Is Really Good! … So I permanently-ANCHORED (p-ANCA) it to my desk”

Microscopic Polyangiitis (MPA)
PAN
Churg-Strauss (EGPA/Eosinophilic GPA)
IBD - esp ULCERATIVE COLITIS
RPGN - Rapidly progressive Glomerulonephritis (necrotising / cresenteric GN)
Goodpastures Syndrome (= anti GBM disease)

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1
Q

6 points on Polyarteritis Nodosa (PAN).

A
  1. Medium vessel vasculitis, affects MALES > Females
  2. Renal involvement (60%), TESTICULAR (pain), GI, MSK manifestations, peripheral neuropathy, skin manifestations (livedo, purpura), constitutional symptoms
  3. ** NEVER INVOLVES THE LUNGS!!! **
  4. Associated with HEPATITIS B.
  5. Invx: Do a Mesenteric and Renal Angiography to look for vasculitis in renal or Mesenteric vessels. Hep B serology. complement c3/4 = normal. Biopsy affected tissues.
  6. Mx is with Steroids, CTX and treat Hep B
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2
Q

Mnemonic for Wegeners Granulomatosis.
What are the clinical features?
What is the Mx for acute disease, relapsed disease and maintenance?

A

(“WE CAN PASS this wRITTen exam!”
= WEgeners = cANCA (cytoplasmic) = pR3 = RITUXIMAB)

clinical manifestations:
E - ENT
L - Lungs
K - Kidney (haematuria, rapidly-progressive GN / PAUCI-immune)

PE/DVT (20x increased risk)

More likely to relapse than MIcroscopic Polyangiitis.

Diagnosis:
C- ANCA pos, PR3 Ab specificity on ELISA
Biopsy: necrotising GRANULOTMATOUS inflammation
Positive Urine sediment

MANAGEMENT:
1. Rituximab and Prednisone
(Rituximab as good as CTX, but less side effects)
2. IVIG if RPGN present

  1. Relapse –> CTX, then AZA.

Maintenance: AZA or MTX (only if CTX used)

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3
Q

What are the diagnostic features of Microscopic Polyangiitis?

A

MPA = p-ANCA (perinuclear staining) = MPO
A NECROTISING small vessel vasculitis.

Clinical features:
(“Malaysia Pacific Airlines flies to K.L.” = MPA –> Kidney > Lungs)

  • KIDNEY (Glomerulonephritis +/- RPGN)&raquo_space; Lung (alveolitis / haemoptysis)
  • Biopsy: NECROTISING Pauci-immune inflammation of small vessels
  • Positive urine Sediment
  • small percentage also anti-GBM antibody positive (Goodpastures)

Mx:

  1. Rituximab and Prednisone
  2. PLASMAPHERESIS improves renal outcomes
  3. Maintenance: AZA / MTX (only if CTX used)
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4
Q

What are the diagnostic features of Churg-Strauss?

What is the management?

A

Churg Strauss = EGPA = EOSINOPHILIC granulomatosis with Polyangiitis

(Strauss was an A-PLUS, Nazi composer)
(A = asthma, N= neuro)

** HLA DRB4 association **

Churg Strauss = An ASTHMA “plus” syndrome = Asthma + Neuro

Clinical features:

  • Churg Strauss = p-ANCA positive in 50%
  • Asthma & Eosinophilic pneumonia PLUS Neuropathy (peripheral neuropathy, mononeuritis multiplex)
  • Other “plus” features are: +/- Glomerulonephritis, cardiac/ coronary arteritis, myocarditis, dermatological features eg purpura.
  • BIOPSY = GRANULOMAS AND EOSINOPHILS / Eosinophilic infiltrates, thrombosis in small vessels, fibrinoid necrosis

MANAGEMENT IS PREDNISONE ONLY.

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5
Q

Patient with fever, haemoptysis and positive urine sediment. p-ANCA positive. What are the DDx?

A

DDx for p-ANCA positivity are: MPA, PAN, Churg, IBD, RPGN, Goodpastures.

DDx based on clinical features are: MPA or Goodpastures
Not PAN as PAN never involves the lungs.
Not Churg Strauss as no Asthma/eosinophilia
Not IBD or RPGN - doesn’t account for all of symptoms

NEED TO DIAGNOSE WITH A RENAL BIOPSY

  • -> anti GBM (linear staining) = Goodpastures
  • -> necrotising pauci-immune inflammation = MPA

Goodpastures = Pulmonary haemorrhages and RPGN
May be p-ANCA positive

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6
Q

What conditions are associated with Cryoglobulinaemia?

A

Cryoglobulinaemia associated with:

  • lymphoproliferative disorders (type I)
  • Hep C (type II / mixed CGA) - acute HepC
  • autoimmune syndromes (type III) - SLE, Sjogrens, PAN, RA
  • infections VIRAL - CMV, EBV, HIV, or BACTERIAL - endocarditis, Lyme, Syphilis
  • Renal transplants
  • idiopathic
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7
Q

What are the symptoms of Type II / Mixed Cryoglobulinaemia?

What tests would you order?

A

Note - Type II / Mixed CG is the most common CG (accounts for 50-60%)

Symptoms: ("This is a MIXED up, PUGLy CHAP")
Palpable purpura
Urticaria
GN
LYmphadenopathy
CHRONIC RENAL DISEASE in the long run
Hepatosplenomegaly
Arthralgias
Palpable purpura (repeated for emphasis!)

( –> an Immune complex vasculitis with MULTI-ORGAN involvement)

TESTS:
1. C3/4 = LOW C4 (c3 is variable) / HYPOCOMPLEMENTAEMIA
2. Hep C serology (80% have HCV RNA positive / anti Hep
C antibody neg = ie.acute HepC)
3. IgM and IgG = MIXED monoclonal IgM and polyclonal IgG
4. Cryoglobulin titre = positive, RF = positive, ESR = positive (point 4 is found in all the Cryos)
5. LFTs (elevated)
6. WCC / Platelets - Falsely elevated due to cryoprecipitation
7. Biopsy of the affected tissue

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8
Q

What tests are positive in Cryoglobulinaemia?

What is the management of Cryoglobulinaemia?

A

Cryoprecipitate
Hypocomplemetaemia - consumed C4
RF
ESR
LFTs - elevated
WCC - falsely elevated due to cryoprecipitation
Platelets - falsely elevated due to cryoprecipitation

MANAGEMENT:

  1. Treat underlying disease eg. Hep C for Mixed CGA, Cancer for type I etc.
  2. NSAIDS NSAIDS NSAIDS for symptoms
  3. Prednisone + CTX (+/- Plasmapheresis)
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9
Q

Don’t confuse cryoglobulins with cold agglutinins.

What are the differences?

A

Cryoglobulins are PROTEINS in serum or plasma that precipitate on exposure to cold.
(note cryofibrinogens only present in plasma)

Cold Agglutinins are IgM ANTIBODIES to RBCs.

Cold Agglutinins are associated with "MMMM cold ice cream"
Measles
Mumps
Mono (EBV / infectious mononucleosis)
Mycoplasma
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10
Q

What defines Type I and Type III Cryoglobulinaemia?

A

Type I (10%)

  • MONOCLONAL IgM (the only monoclonal Cryoglobulinaemia)
  • associated with Waldenstroms, Multiple myeloma, lymphoproliferative disease
  • Hyperviscosity and thrombosis

Type III (25-30%)

  • POLYCLONAL IgG
  • may be asymptomatic
  • associated with Autoimmune syndromes - SLE, sjogrens, inflammatory Bowel disease, PAN, RA

= Type II (mixed) and Type III are immune complex vasculidities with multi-organ involvement

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11
Q

What is Icatibant?

A

Icatibant is a Bradykinin receptor antagonist (renders bradykinin less effective)

Used in Bradykinin-mediated angioedema.

other Mx is supportive, Intubation etc, stop OCP

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12
Q

What is Felty’s Syndrome?

A

RA with unexplained splenomegaly and neutropaenia.

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13
Q

Where can you find PAMPs and DAMPs?

A

PAMPs- viruses and bacteria only.

DAMPs (Danger associated molecular patterns) are released by dying cells. 
Examples of DAMPs are:
ATP
Heat shock proteins
Uric acid/ Monosodium urate crystals (= NOD like receptor on inflammasones)
DNA
Hyaluronan fragments
Heparin
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14
Q

What are the contraindications to anti TNF biologic therapy?

If someone is found to have TB, what is the management prior to starting anti TNF?

A

Contraindications:

  • active infections
  • chronic infections such as chronic Osteomyelitis, Bronchiectasis, optic neuritis
  • heart failure (as anti-TNFs worsen heart failure in patient with CCF)

If someone is found to be positive for TB screening (Q Gold, CXR), can still have anti-TNF but need TB treatment first.

LATENT TB:
9 MONTHS of ISONIAZID MONOTHERAPY.
commenced 4-6weeks prior to anti-TNF agent, then continue course.

ACTIVE TB:
NEEDS FOUR-DRUG TB REGIMEN (R.I.P.E)
Commenced at least 2 months prior to anti-TNF agent.

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15
Q

Side effects of anti-TNF agents?

A 
Lupus
Lymphomas
Infections
MS
TB reactivation
Teratogenic
* NON-melanoma skin cancers
* Heart failure - worsening of HF in those with pre-existing HF
16
Q

What are the ENCAPSULATED organisms?

A

“SHiNKS”

Streptococcus pneumoniae
Haemophilus influenzae B (HiB)
Nisseria Meningitidis 
Klebsiella pneumoniae
Salmonella
  • these are susceptible to antibodies rather than the cell-mediated response
  • patients with asplenia (sickle cell disease or functional asplenia) and complement deficiency are more susceptible to sepsis from these organisms due to impaired opsonisation.
17
Q

What is the most important warning sign that a patient has a primary immunodeficiency?

A

Family history of a primary immunodeficiency is the most important!

Most commonly caused by antibody deficiency, and CVID is the most common primary immunodeficiency in adults.
10% familIal.
Likely polygenic.
CD19 and 20 deficiency (B cell surface markers)
Occurs in the YOUNG, 2 peaks: Childhood and age 20’s

18
Q

How does CVID manifest? (4 main points)

A

CVID = a lack of antibody response (B cell deficiency –> Ab deficiency)

  1. Recurrent sinopulmonary infections
    - sinusitis, bronchitis
    - bronchiectasis
    - otitis, tonsillitis
    - pneumonia
  2. Recurrent GI infections
    - infective diarrhoea - Giardia, Campy
    - malabsorption (mimics Coeliac)
  3. Increased RISK OF NON-HODGKINS LYMPHOMAS by 400x!!!
  4. Autoimmunity in 20%
    - AIHA, Pernicious, ITP
    - AI thyroiditis
    - Rheum- RA, vitiligo, Polymyositis
19
Q

What are the investigations you would order to make a diagnosis of CVID?

What is the MANAGEMENT of CVID?

A 
Firstly need to exclude any other causes of hypogammaglobulinaemia:
Drugs (CMZ, Valproate, SZP, CAPTOPRIL)
NSAIDS --> low IgA
Myeloma
Lymphoma
Nephrotic syndrome
GI protein loss

Investigations:

  • Immunoglobulin levels = hypogammaglobulinaemia
  • B Cell count = low or normal
  • EPG/IEPG and Serum free light chains — to exclude myeloma (as myeloma may mimic hypogammaglobulinaemia)

Management:

  • IVIG MONTHLY (SC, dosage 0.4g/kg)
  • CHRONIC BACTRIM (Sulfamethoxazole plus trimethoprim = sulfonamide plus DHFR inhibitor = ANTIFOLATE agents) or chronic Amoxicillin
  • Yearly flu vaccine
  • avoid live vaccines
20
Q

What is the function of CD40 ligand?

What is the condition defined by CD40 Ligand deficiency?

A

CD40 ligand deficiency = Hyper IgM Syndrome!!!

CD40 LIGAND is expressed on T cells.
CD40 RECEPTOR is expressed on B cells
–> Important in B and T cell INTERACTION

In Hyper IgM Syndrome,
a deficiency in T Cell CD40 ligand –> Results in failure of B and T cells to “talk” –> No isotope switching –> NO PLASMA CELLS, NO MEMORY B CELLS

–> Results in HYPER/ HIGH (or normal) IgM but verrrry LOW IgA/G/E.

–> Results in impaired response to T cell infections
(Recurrent bacterial infections, candidiasis, PJP)

Diagnosis:
Flow cytometry

Mx:
IVIG
Chronic BACTRIM
G-CSF a

21
Q

How does IgA deficiency present and what is the management?

A 
IgA def is common - 1 in 700.
Due to a dysregulation in Ig class switching.
Associated with IgG deficiency.
IgM PROTECTS patient from infections.
May present with:
Coeliac disease (tTG is an IgA)
Sinopulmonary infections and giardiasis
Atopy 
Autoimmune diseases - Haem & Rheum

Management:
Give Antibiotics when needed only.
(Not for IVIG)
If patient ever requires transfusion, needs IgA deficient blood.

22
Q

What causes X-linked (Bruton’s) Agammaglobulinaemia and how does it present?

A 
Early onset < 6 months
Caused by an absence or mutation of "BTK" tyrosine kinase
 --> No B cell development
--> NO antibodies
--> No lymphoid tissues
Positive family history in 50%

Clinical features as per CVID but also CHRONIC ECHOVIRUS MENINGIENCEOHALITIS

Investigations:
**Genetic analysis for BTK gene
B Cell count = 0

Mx: (as per CVID)
IVIG monthly
chronic Bactrim or Amoxycillin
Flu vaccine, avoid live vaccines

23
Q

Lack of T cells. How do these patients present?

A

= Infections of INTRACELLULAR organisms

Fungi - Candidiasis, Pneumocystis

Viruses - CMV, VZV, HSV, Protozoa, Listeria

Mycoplasma - MAC, M.Tub

24
Q

What are the causes of T cell deficiencies?

A

Primary T cell deficiency-

  1. Idiopathic CD4 T cell lymphopaenia
    - no specific treatment
    - clinically looks like AIDS but HIV negative
  2. Chronic Mucocutaneous Candidiasis
    - often lack Th17 cells
    - chronic nail and oesophageal candidiasis
  3. **SCID - Severe Combined Immunodeficiency **
    - Paeds population
    - T cells unable to mature
    - due to ABSENCE OF GAMMA COMMON CHAIN
    –> can’t develop any T cells
    –> lack of IL2 (T cells can’t self-proliferate),
    IL21 (can’t activate NK cells),
    IL7 (can’t stimulate development of T and NK cells)
  4. Chronic granulomatous disease
    - X-linked, Paeds population
    - deficiency of NADPH oxidase (produces ROS to kill bacteria), responsible for “respiratory burst” in neutrophils necessary for killing intracellular organisms
    - Present with recurrent coag-neg Staph and Fungi infections, skin infections, bronchopneumonia, HEPATIC ABSCESSES
    - Invx: “Nitro-blue” test (Nitroblue Tetrazolium)
    - Mx: Chronic Abx, Immunise, IFN gamma
25
Q

** What is the mechanism of action of CTLA4? **

What are some Biologic agents that act on CTLA4 and how do they work?

A

CTLA4 BLOCKS SIGNAL 2 / COSTIMULATION –> T CELL SUPRESION.

CTLA4 is a T cell receptor that is expressed on Treg’s to limit T cell expansion.

It binds to B7 on the APC and blocks its interaction with CD28 on the T cell
–> thereby INHIBITS T cell proliferation and activation.

BIOLOGICS THAT TARGET CTLA4:
NOTE THESE 2 DRUGS have OPPOSITE MECHANISMS!!

  1. IPILIMUMAB - for Prostate Ca, metastaticMelanomas
    - CTLA4 BLOCK
    - inhibits/blocks CTLA4
    - STIMULATES Tcell activation and proliferation (by inhibiting the inhibition)
  2. ABATACEPT - for Rheumatoid Arthritis
    - acts as a fusion Ig for CTLA4 (binds to reCEPTor and acts as a ligand –> potentiates the regulatory action of CTLA4
    - INHIBITS / stops T cell proliferation and activation
26
Q

** Apart from CTLA4 receptor on Treg’s, what are the other mechanisms of T cell suppression? **

A
  1. IL10 (“We STOP at AILSE 10, our shop is so small”)
  2. TGF-beta
  3. FoxP3
  4. other inhibitory cytokines - IL35, IL9

IL10 and TGF-beta = INHIBITORY CYTOKINES
(Upstream of Treg’s & CTLA4)

–> promotes induction of Treg’s –> CTLA4
PLUS
–> BLOCKS IL-2 –> blocks T cell proliferation

(As an aside - Steroids and Calcineurin inhibitors block IL2)

FoxP3
- is a transcription factor which is the “master regulator” of Treg’s
that is responsible for the development and function of Treg’s
- promotes CTLA4 receptor expression on Treg’s
- promotes IL10 (inhibitory cytokines)
- blocks IL 2 (blocks T cell proliferation)

27
Q

Grab a piece of paper and draw all the important pathways of the immune system, including important cytokines (David Fulcher diagram)

A

must include:

CD4 T cell (4 pathways)

  • Th17 (promoted by TGFbeta, IL1, IL6) –> produces IL17, IL23
  • Th2 (promoted by IL4) –> produces IL5, IL4, IL13
  • Th1 (promoted by IL12) –> produces IFN gamma –> NK cells, macrophages
  • Treg’s - (promoted by TGFbeta and IL10) –> CTLA4 receptor expression, IL10, block IL2

B and T cell interaction

complement

  • c3b activation
  • C5b + C6-9 = MAC ATTACK
28
Q

What is APECED?

A

Autoimmune PolyEndocrinopathy with Candidiasis and Ectodermal Dystrophy

  • caused by mutated AIRE gene, auto recessive
  • failure to delete T cells that have high affinity for self antigen
  • -> lots of autoimmunity
  • produce antibodies to IL17

3 Cardinal manifestations

  • Candidiasis - chronic, Mucocutaneous
  • Autoimmune hypOparathyroidism
  • Autoimmune Addisons
29
Q 
Which cell is responsible for periodic fever syndrome?
A. Neutrophil
B. Inflammasome
C. NK cell
D. B cell
E. T cell
A

Inflammasome

30
Q

Angioedema without rash, no identifiable triggers.

What is the diagnosis and what investigation is most important to identify the cause?

A

Angioedema without rash = Hereditary Angioedema

Best test is C4.

(“C4 explosives blow things up” = angioedema)

31
Q

What is the mechanism behind Stephen-Johnson syndrome?

A

T cell mediated Cytotoxicity.

  • -> Fas-fas ligand apoptosis
  • -> desquamation

RACP Written Exam 2015 (14 decks)

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