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Clinical Immunology and Haematology > Primary Immunodeficiency (PID) > Flashcards

Primary Immunodeficiency (PID) Flashcards

1
Q

What happens in normal infections?

A

1) Infectious agent triggers innate immune response
2) Antigens recognised as non-self and dangerous induce adaptive immune response
3) Ultimately clear infection and establishes state of protective immunity

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2
Q

What is PID?

A

Genetic immune deficiencys which cause part of the immune system to be eliminated or function abnormally

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3
Q

Why would you suspect someone has PID?

A

They get more infections particularly pathogens

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4
Q

What is secondary immunodeficiency?

A

Also known as acquired immunodeficiency (AIDS) which is caused by external sources

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5
Q

Are PIDs normally inherited?

A

Yes

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6
Q

What are the different ways PID can affect the body?

A

Lack of immune response
Inefficient immune response
Dysfunctional immune response

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7
Q

When is PID severe?

A

Is diagnosed in children rather than adult diagnosis as this would be mild.

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8
Q

Can PID be caused by a trigger?

A

Yes

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9
Q

Is there lots of different PIDs?

A

Yes over 350

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10
Q

What is the inheritance of PID?

A

Most single gene causes of PID is recessive (COMMON IF PARENTS ARE RELATED).

Majority are X-linked recessive and so generally only males show it e.g. IPEX, X-linked SCID

Often complete loss is not compatable with life.

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11
Q

What do CD4+ enhance?

A

The innate immune attack

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12
Q

What are the types of CD4+ cells and what do they trigger and fight?

A

Th1 = Macrophages = Extracellular bacteria, listeria, leishmania, pneumocystis, mycobacteria.

Th2 = Mast cells, eosinophils, basophils = helminth parasites

Th17 = Neutrophils = extracellular bacteria and fungi

Tfh = B cells - all microbes

Treg = T cells = self and microbiome derived

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13
Q

Can knowing type of oppertunistic infections give clue to type of PID?

A

Yes e.g. if they are getting lots of helminth parasite infections you would think they had an issue with their Th2 cells and no eosinophils, basophils would be produced

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14
Q

What type of PID would you think if someone had lots of intracellular bug infections e.g. mycobacterial TB?

A

Defect in macrophages or T cell immunity

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15
Q

What type of PID would you think someone would have is they had lots of extracellular encapsulated bacteria?

A

Defect in antibodies, complement or phagocytes

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16
Q

What type of PID dysfunction would you think someone would have is they had lots of fungal infections e.g. candida?

A

T cell dysfunction

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17
Q

What type of PID deficiency would you think someone would have is they had lots of herpes virus recurrance?

A

NK and CTL deficiency

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18
Q

What might viral susceptibility lead to?

A

Cancer

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19
Q

When would you think of PID as a diagnosis?

A

When someone is getting opportunistic pathogen infections that is usually mild bit life threatening in these cases. And either a high WBC count or low WBC cound

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20
Q

What infections in children is a concern for PID?

A

Continous, recurrent upper respiratory tract infections or pneumonia

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21
Q

When is infections in adults a concern for PIDs?

A

Repeated, unusual, difficult to treat infections leaving people in hospital.

22
Q

Other signs of PID?

A

Unexplained early infant deaths

Familial occurance e.g. if parents have it

23
Q

what do you want to know about in PID?

A

Haemoglobin level
Total WBC
Platelet count
Analysis of lymphocyte subsets for numbers of T,B and NK cells
Microbiology on organisms isolated
Check antibodies made to commonly used vaccinations.

24
Q

What would a test for SCID show?

A

Undetectable or very low levels of T cells receptor excision circles TRECs. TRECs should be present neonatally

25
Q

What would you see in a normal molecule testing blood sample?

A
  • IgG, IgM, and IgA all being present and IgE low
  • Specific antibodies expected due to vaccination (never give live vaccinations to someone with suspected PID).
  • Check RBC isohaemagglutinins.
26
Q

What other tests could you do in vitro for SCID?

A

B-cells - induce antibody production in response to pokeweed mitogen

T-cells - proliferation in response to phytohemagglutinin or tetanus

Phagocytes - nitro blue tetrazolium uptake - intracellular killing or bacteria.

27
Q

What would a clinnical immunologist do to diagnose SCID?

A

Immunophenotyping to sequence for mutations in any suspected genes.

28
Q

What are treatment of PID?

A

Treat symptoms - antimicrobial therapy e.g. antibiotics/ antivirals/ antifungals

Replace whats missing - antobody replacement and complement

29
Q

How do you replace antibodies and complement in PID?

A

Pooled donor IgG (this contains antibodies to many different pathogens. Intravenous immunoglobulin (IVIG) can be given in large doses and is fast acting (can be given every 3 - 4 weeks and self administered).

Complement is also replaced using donor material.

30
Q

What are longterm treatments of PID?

A

Replace - stem cell therapy and/or gene therapy

Activate - phagocytes can be activated with injections of interferon gamma

Stimulate proliferation - if neutrophils no produced in normal numbers - granulocyte colony stimulating factor (G-CSF), raises levels of white cells including granulocytes (neutrophils).

31
Q

Types of PID - What causes SCID and what are the symptoms?

A

Defects in T-cell development due to X-linked mutations of the IL-2RG gene which causes patients to be susceptable to a broad range of infectious agents, central to adaptive immune responses.

32
Q

How does the IL-7R mutations cause SCID?

A

They cannot become T-cells they remain as common myeloid progenitors.

33
Q

Do you have any T or B cells in SCID omenn syndrome?

A

No

34
Q

Can SCID be caused by MHC class 1 deficiency?

A

Yes and this means no CD8 t-cells.

35
Q

How to treat SCID?

A

Hematopoietic cell transplantation - this needs to be done early (first 3.5 months of life) and hopefully before any infections the survival rate is 80 - 90% (its higher in HLA-matched family donors)

36
Q

How does autologous Bone Marrow Transplant work?

A

After gene therapy (which is only allowed in certain cases) you take HSPCs from patient and sort the CD34+ cells which would then be activated and harvested.

These are then transduced with the vectors containing a corrected copy of the IL2RG transgene.

The gene corrected CD34+ genes are re-introduced into the patients and the patient is cured.

37
Q

When is using gene therapy to treat PID only allowed?

A

If there is no bone marrow match or the patients is too ill to get one.
And the patient has a life threatening infection unresponsive to conventional treatment including steroids.

38
Q

Types of SCID - Antibody deficiency - what does this affect and what might cause it?

A

This affects B cells and is caused by an IgA deficiency.

39
Q

What causes agammaglobulinaemia? (Antibody deficient SCID)

A

No Igs due to bruton tyrosine kinase (BTK) which can a crucial role in B cell development being mutated (stop codon found where it shouldnt be).

40
Q

Why does a lack of BTK cause no antibodies?

A

B cell receptor signalling is insufficient to induce differentiation into mature peripheral B cells without BTK.

If BTK is overexpressed B cells get uncontrolled antibody production and sytemic lupus like diseases.

An effective BTK inhibitor is ibrutinib.

41
Q

What are some PIDs whihc influence antibody production?

A

X-linked agamma-globulinemia (deficiency in B cells)
Hyper IgM syndrome (deficiency in Th)
Hyper IgM syndrome - B cell intrinsic (deficiency in B cells)
Hyper-IgR syndrome (deficiency of Th)

42
Q

Types of SCID - Phagocyte defects and innate immune defects infuence what cells and cause what type of common infections?

A

Phagocytic defects can influence neutrophils, monocytes and DC cells making people more likely to get bacterial infections, leukemia, HPV etc.

Innate immune defects influence DCs, monocytes and macrophages but stop their IFN-gamma secretion. People with this are more likely to get mycobacterial and salmonella infections.

43
Q

What are some examples of PID?

A
  • Leukocyte adhesion deficiency (widespread bacrerial infections)
  • Chronic granulomatous disease (intracellular and extracellular, granulomas)
44
Q

What are soem diseases caused by phagocytes or complement deficiences?

A

Salmonella, Staphylococcus, Escherichia coli, strep pneumonia, klebsiella phenomiae, pseudomonas aeruginosa, neisseria gonorrhoeae, actinomyces, burkholderia cepacia, mycobacterium TB.

45
Q

What is chronic granulomatous disease (CGD)?

A

Phagocytes need NADPH oxidase (PHOX) to digest bacteria have eaten. This is a repiratory burst and is critical for killing bacteria. However, defects in subunits of PHOX can cause CGD in varying severity.

46
Q

What diseases are common in those with CGD?

A

Bacterial and fungal infections - salmonella, klebsiella, pseudomonas cepacia, staphylococcus aureus, klebsiella species etc.

Both gram negative and gram positive

47
Q

Is CGD x-linked or autosomal recessive?

A

Both depending on what subunit is missing.

48
Q

How would you diagnose CGD?

A

Nitroblue tetrazolium tests - neutrophils are stimulated and placed in yellow dye. If there is normal phagocytosis the dye turns blue. Carriers have a mix.

49
Q

CGD treatments?

A

Antibiotic therapy to help prevent bacterial infections and intraconazole for anti-fungal protection

Infections require additional antibiotics

Corticosteroid drugs for treating granulomatous complications

IFN gamma

Bone marrow transplants have proven to be successful in some cases.

50
Q

What happens in catalase negative and positive bacteria?

A

Catalase positive bacteria break down hydrogen peroxide the pathogen produces causing deleterious infections within the host.

Whereas, negative bacteria lack catalase and so the H2O2 can be hijacked by phagocytes to effectively kill the bugs.

51
Q

What type of PID would be involved if someone had many neisseria infections?

A

Complement

Clinical Immunology and Haematology (25 decks)

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