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Immunology > Immunodeficiencies > Flashcards

Immunodeficiencies Flashcards

1
Q

Lack of ab response results in

A

Recurrent sinopulmonary and gut infections

E.g. sinusitis, OM, bacterial pneumonia, bronchiectasis (long-term), infectious diarrhoea

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2
Q

How to investigate antibody deficiency?

A

1) Measure Immunoglobulin levels - IgG, IgA, IgM, and IgE

2) EPG
- To detect hypogammaglobulinemia (no immunoglobulins)
- Exclude paraproteinaemia (multiple myeloma - paraproteinemia interferes with production of other immunoglobulins)

3) Measure response to vaccine
- Ab to tetanus, diptheria, haemophilus

4) Lymphocyte count (B and T cells)
- Absent B cells = X linked agammaglobulinaemia
- Low B cells = CVID
- Low T cells = CVID

5) Serum and urine protein and albumin
- Exclude secondary causes of low Ig ?renal or GI loss

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3
Q

Common variable immunodeficiency (CVID) clinical features

A

Recurrent sinopulmonary infections –> bronchiectasis, amyloidosis in chronic infections

Gut infections - giardia, CVID enteropathy (gut symptoms)

Skin infections

Autoimmune conditions (20%) - thyroid disease, pernicious anaemia, immune cytopenias (ITP, AIHA)

Lymphoma, stomach cancers

Lymphoprolifefation - lymphadenopathy, splenomegaly

Allergic disease - food intolerance

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4
Q

Common variable immunodeficiency (CVID) diagnosis

A

Low IgG (most important) +/- Low IgA +/- low IgM

Poor response to vaccination

Low switched memory B cells

Must be after age 4

Exclude other causes of low immunoglobulin levels e.g. drugs (AEDs, captopril, sulfasalazine, steroids), lymphomas/myeloma, nephrotic syndrome (lose Ig through kidneys), GI protein loss

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5
Q

Do you get low B cells in Common variable immunodeficiency (CVID)?

A

Normally present but may be low

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6
Q

Treatment of Common variable immunodeficiency (CVID)

A

IVIG replacement
- Aim normal trough levels ~7g/L

Abx

  • Start early, treat for longer
  • Some may benefit from prophylactic abx

Monitor complications e.g. bronchiectasis (HRCT, annual RFTs), autoimmunity, cancer (lymphoma, gastric cancer)

Avoid live vaccines

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7
Q

IgA deficiency infections

A

Many patients asymptomatic (recruit IgM into the secretions instead)

Recurrent mucosa infections especially viral e.g. sinopulmonary and gut infections (giardia)

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8
Q

Disease associations with IgA deficiency

A 
Atopy (asthma)
Cow's milk allergy 
Nodular lymphoid hyperplasia 
IBD (lose protective layer, allow bacteria to invade and cause chronic inflammation)
Coeliac disease 
Autoimmune disorders  
Anaphylaxis on transfusion of IgA containing blood products due to anti-IgA abs 
Malignancy
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9
Q

How do we diagnose coeliac with serology?

A

tTG + IgA (tTG is an IgA so if you have absent IgA, then tTG is falsely negative; hence must check IgA at the same time)

Gliadin ab is an IgG - must be done if you have a falsely negative tTG

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10
Q

Treatment IgA deficiency

A

Ab for acute infection or prophylactic

Can’t replace with IVIG (this is a mucosal problem, not a systemic problem)

Should give transfusions that are IgA deficient or triple washed (risk of anaphylaxis) - let bloodbank know!

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11
Q 
IgG subclass deficiency 
Is this significant?
A

Not usually. Difficult to define as its not abnormal in the normal population to have absent subclasses.

Usually relevant to IgG2 or IgG3
May get mild infection like CVID
Not an indication for IVIG

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12
Q

Specific antibody deficiency (SAD) results in

A

Poor response to vaccines - pneumovax
Recurrent URTIs

Get normal Ig and B cell levels

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13
Q

What’s human anti-mouse ab (HAMA) response?

A

Immune response against the mAb (part mouse)
= Can block efficacy
= Trigger complement mediated anaphylaxis

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14
Q

How do we minimise human anti-mouse ab (HAMA) response?

A

Humanisation
Coadministration of immunosuppressant
E.g. infliximab + MTX

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15
Q

What do they following suffix mean in mAb?

1) ximab
2) zumab
3) umab

A

1) Chimeric (mouse variable region; human fixed constant region)
2) Humanised (mouse CDRs, human Fc and framework regions)
3) Fully human

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16
Q

X linked agammaglobulinemia (XLA)

Age of onset

A

6 months

When maternal IgG declines

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17
Q

X linked agammaglobulinemia (XLA) clinical features

A

Recurrent sinopulmonary and GI infections
Similar to CVID
- OM, pharyngitis, pneumonia, sinusitis –> bronchiectasis
- Giardia (normally neutralised by IgA)

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18
Q

X linked agammaglobulinemia (XLA) defect occurs where?

A

Mutation in Bruton’s TYR kinase (Btk) = important enzyme involved in the maturation of B cells in the BM (B cell maturation is stopped at the pre B cell stage)

Hence no mature B cell leaves the BM –> no formation of plasma cells –> no ab production

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19
Q

X linked agammaglobulinemia (XLA) diagnosis

A

EPG - hypogammaglobulinemia
Ig levels - undetectable
B cell count - 0

B cell precursors in the BM
No plasma cells or germinal centres in tissue biopsies

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20
Q

X linked agammaglobulinemia (XLA) treatment

A

As per CVID

IVIG
Abx
Avoid live vaccines

Monitor for complications - bronchiectasis, cancer, autoimmunity

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21
Q

Ibrutinib MOA

A

Bruton tyrosine kinase inhibitor
= Stops B cell maturation at the pre B cell stage in BM
= No mature B cell leaves the BM

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22
Q

Ibrutinib use

A

CLL
Waldenstrom’s
B cell lymphoma - mantle cell, DLBCL

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23
Q

Hyper IgM syndrome has a defect where?

A

CD40L
= Absent CD40-CD40L signal
= No costimulation signal in the T cell B cell interaction when the T cell presents the antigen to the B cell (occurs in lymph node) –> B cell doesn’t undergo class switching or form memory B cells
= High IgM, low everything else

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24
Q

Hyper IgM syndrome diagnosis

A

High IgM
Low IgG, IgA, IgE
Normal circulating B cells (express IgM, IgD). No class switched B cells.

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25
Q

Hyper IgM syndrome clinical features

A

Recurrent bacterial infections due to poor opsonisation - respiratory +++, PJP
Acute/chronic diarrhoea e.g. cryptosporidium
Neutropenia

26
Q

Hyper IgM syndrome treatment

A

IVIG
Abx for infections
Bactrim prophylaxis
G-CSF for neutropenia

??bone marrow transplant

27
Q

Which cells do you find CD20?

A

Mature B cells

28
Q

Which cells do you find CD19?

A

Pan B cells

29
Q

Where is the defect in SCID?

A

Defective T cell function

30
Q

Clinical features in SCID

A 
Paediatric problem
Failure to thrive
Chronic diarrhoea
Recurrent opportunistic infection - fungal, viral, protozoa esp PJP
\+/- malignancy, autoimmunity
31
Q

Ipilimumab MOA

A

Blocks CTLA4 = blocks T cell inhibition

wake up T cells so they can kill tumour cells

32
Q

Abatacept MOA

A

Binds to CD86 (aka B7) on APC, so it can’t bind to CD28 on T cell (co-stimulation) –> without costimulation, T cell can’t be activated

33
Q

Nivolumab, pembrolizumab MOA

A

Anti-PD1

PD1 receptors are located on T cells. Tumour cells express PD1 ligand which can bind to this receptor, and cause inhibition of the T cell.

By using anti-PD1 and blocking this receptor first, tumour cell can’t bind and switch off the T cell.

34
Q

Side effects of checkpoint inhibitors (anti-PD1 or CTLA4)

A

Autoimmunity

Due to overactive T cells (loss of inhibition)

35
Q

Th0 (naive cell) gets exposed to …. to become Th1 –> Th1 releases …. to attack ….

A

IL12
IFNy + TNF-alpha
Intracellular pathogens such as bacteria and viruses

36
Q

Th0 (naive cell) gets exposed to …. to become Th2 –> Th2 releases …. to attack …. and also drive ….

A 
IL4
IL4, IL5, IL13
Helminths
Allergy
= IL4 pushes for more production of Th2
= Make B cells class switch to IgE (IL4, IL13)
= Attract eosinophils (IL5)
37
Q

Th0 (naive cell) gets exposed to …. to become Treg –> Treg releases …. to ….

A

TGF-beta
TGF-beta and IL10
Regulate T cells

38
Q

Th0 (naive cell) gets exposed to …. to become Th17 –> Th17 releases …. to attack ….

A

TGF-beta + proinflammatory cytokines such as IL1, IL6
IL17, 22, 23
Fungi, general inflammation

39
Q

Th0 (naive cell) becomes T follicular helper cell –> T follicular helper cell releases …. to …

A

IL21

Activate B cells to produce ab

40
Q

Overactive Th17 cell leads to

A

Psoriasis

Overproduction of IL17 (can block this for treatment)

41
Q

Underactive Th17 cell leads to

A

Chronic mucocutaneous candidiasis

Affects skin, nails, mucosa, oesophagus, pulmonary

42
Q

Ustekinumab MOA

A

Anti-p40 (chain shared by IL12 and IL23)
IL23 is important for Th17 differentiation
IL12 is important for Th1 differentiation

Hence it is a
Th1 and Th17 blocker

43
Q

Ustekinumab uses

A

Psoriasis, Crohn’s, AS

44
Q

Th2 response leads to type …. hypersensitivity

A

Type 1

IgE mediated

45
Q

Causes of elevated IgE

A

Atopy - atopic dermatitis, atopic eczema, allergic rhinitis, atopic asthma, food allergy

ABPA - levels correlate with disease activity

Parasites

Lymphoma esp HL

Hyper-IgE syndrome

IgE myeloma (rare)

46
Q

Mepolizumab MOA and uses

A

IL5 blocker

Severe refractory eosinophilic asthma

47
Q

Omalizumab MOA

A

Anti-IgE

Severe allergic asthma, chronic spontaneous urticaria

48
Q

Explain 2 phases of allergy

A

Early

  • Mast cell degranulation
  • Effects caused by vasoactive mediators
  • Resistant to steroids

Late

  • Mast cells release proinflammatory granules –> attract inflammatory cells e.g. leukocytes, eosinophils
  • Steroids responsive
49
Q

What do the following T cell surface molecules do?

1) CD3
2) CD4
3) CD8
4) CD40L
5) CD28
6) CTLA-4

A

1) CD3 - part of TCR
2) CD4 - binds MHC II on APC
3) CD8 - binds MCH I on APC
4) CD40L - binds CD40 (B cells) to mediate class switching. Costimulation between T and B cells.
5) CD28 - binds to B7. Costimulation between T cell and APC.
6) CTLA-4 - inhibitor molecule to switch off T cells. Binds to B7.

50
Q

Digeorge syndrome

What 2 things do they present with?

A

T cell deficiency (lack of thymus)

Hypocalcaemia (lack of parathyroid)

51
Q

Mechanism of common variable immunodeficiency (CVID)

A

Most people with CVID have normal numbers of B cells. However, these B cells do not mature normally to produce effective antibodies or they don’t receive the help needed from T cells to develop normal antibody responses.
= Low immunoglobulin is hallmark, usually IgG +/- others

52
Q

Antibody deficiency typically causes what kind of infections?

A

Bacterial

53
Q

T cell defects typically causes what kind of infections?

A

Fungal, viral HPV

54
Q

Phagocyte defects typically causes what kind of infections?

A

Fungal, staph

Deep seated infections

55
Q

Complement deficiency or splenectomy typically causes what kind of infections?

A

Encapsulated organisms

56
Q

C1, C4 and C2 deficiency (early complement pathway) typically results in …

A

SLE-like autoimmunity (failure to clear self antigen)

C2 deficiency = recurrent sinopulmonary infections; Rx prophylactic penicillin, vaccinate for meningococcus, haemophilus, pneumococcus

57
Q

C5-C9 deficiency (late complement pathway) results in

A

Neisseria meningitidis

58
Q

Alternative pathway defect (factor B, factor D, properdin) results in …

A

Neisseria and bacterial infections

59
Q

What happens in familial mediterranean fever?

A

Insignificant trigger (e.g. emotional stress) –> active pyrin (lack of phosphorylation secondary to MEFV gene mutation) generates pyrin inflammasomes –> secretes IL1, IL18 –> FMF attack

60
Q

Familial mediterranean fever attack presentation

A 
Fever
Abdominal pain (peritonitic)
Serositis involving the joints and pleura

Self-limiting. Lasts 24-48 hours

Eventually can get renal amyloidosis –> ESKD

61
Q

Treatment familial mediterranean fever

A

Colchicine - treatment and prevention of FMF attacks and prevention of renal amyloidosis/ESKD

Anakinra (IL1 antagonist)

Immunology (6 decks)

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