Immunodeficiencies Flashcards by Jenny Yiu

Lack of ab response results in

Recurrent sinopulmonary and gut infections

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

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How to investigate antibody deficiency?

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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Common variable immunodeficiency (CVID) clinical features

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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Common variable immunodeficiency (CVID) diagnosis

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

Normally present but may be low

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Treatment of Common variable immunodeficiency (CVID)

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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IgA deficiency infections

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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Disease associations with IgA deficiency

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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How do we diagnose coeliac with serology?

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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Treatment IgA deficiency

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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IgG subclass deficiency 
Is this significant?

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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Specific antibody deficiency (SAD) results in

Poor response to vaccines - pneumovax
Recurrent URTIs

Get normal Ig and B cell levels

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

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

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

Humanisation
Coadministration of immunosuppressant
E.g. infliximab + MTX

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What do they following suffix mean in mAb?

1) ximab
2) zumab
3) umab

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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X linked agammaglobulinemia (XLA)

Age of onset

6 months

When maternal IgG declines

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X linked agammaglobulinemia (XLA) clinical features

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

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X linked agammaglobulinemia (XLA) defect occurs where?

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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X linked agammaglobulinemia (XLA) diagnosis

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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X linked agammaglobulinemia (XLA) treatment

As per CVID

IVIG
Abx
Avoid live vaccines

Monitor for complications - bronchiectasis, cancer, autoimmunity

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Ibrutinib MOA

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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Ibrutinib use

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

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Hyper IgM syndrome has a defect where?

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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Hyper IgM syndrome diagnosis

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

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Hyper IgM syndrome clinical features

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

Hyper IgM syndrome treatment

IVIG Abx for infections Bactrim prophylaxis G-CSF for neutropenia ??bone marrow transplant

Which cells do you find CD20?

Mature B cells

Which cells do you find CD19?

Pan B cells

Where is the defect in SCID?

Defective T cell function

Clinical features in SCID

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

Ipilimumab MOA

Blocks CTLA4 = blocks T cell inhibition | wake up T cells so they can kill tumour cells

Abatacept MOA

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

Nivolumab, pembrolizumab MOA

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.

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

Autoimmunity | Due to overactive T cells (loss of inhibition)

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

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

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

``` 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) ```

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

TGF-beta TGF-beta and IL10 Regulate T cells

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

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

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

IL21 | Activate B cells to produce ab

Overactive Th17 cell leads to

Psoriasis | Overproduction of IL17 (can block this for treatment)

Underactive Th17 cell leads to

Chronic mucocutaneous candidiasis | Affects skin, nails, mucosa, oesophagus, pulmonary

Ustekinumab MOA

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

Ustekinumab uses

Psoriasis, Crohn's, AS

Th2 response leads to type .... hypersensitivity

Type 1 | IgE mediated

Causes of elevated IgE

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)

Mepolizumab MOA and uses

IL5 blocker | Severe refractory eosinophilic asthma

Omalizumab MOA

Anti-IgE | Severe allergic asthma, chronic spontaneous urticaria

Explain 2 phases of allergy

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

What do the following T cell surface molecules do? 1) CD3 2) CD4 3) CD8 4) CD40L 5) CD28 6) CTLA-4

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.

Digeorge syndrome | What 2 things do they present with?

T cell deficiency (lack of thymus) | Hypocalcaemia (lack of parathyroid)

Mechanism of common variable immunodeficiency (CVID)

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

Antibody deficiency typically causes what kind of infections?

Bacterial

T cell defects typically causes what kind of infections?

Fungal, viral HPV

Phagocyte defects typically causes what kind of infections?

Fungal, staph | Deep seated infections

Complement deficiency or splenectomy typically causes what kind of infections?

Encapsulated organisms

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

SLE-like autoimmunity (failure to clear self antigen) C2 deficiency = recurrent sinopulmonary infections; Rx prophylactic penicillin, vaccinate for meningococcus, haemophilus, pneumococcus

C5-C9 deficiency (late complement pathway) results in

Neisseria meningitidis

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

Neisseria and bacterial infections

What happens in familial mediterranean fever?

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

Familial mediterranean fever attack presentation

``` Fever Abdominal pain (peritonitic) Serositis involving the joints and pleura ``` Self-limiting. Lasts 24-48 hours Eventually can get renal amyloidosis --> ESKD

Treatment familial mediterranean fever

Colchicine - treatment and prevention of FMF attacks and prevention of renal amyloidosis/ESKD Anakinra (IL1 antagonist)