13. When Immunity Fails

Question 1

What are the types of immunodeficiencies?

Answer 1

Primary: Inherited gene defect or mutation - quite rare

Secondary: effects of external agents/breakdown of other body systems which affect immune system (more common)

Question 2

Give 3 examples of a primary immunodeficiency affecting the innate immune response

Answer 2

Chronic granulomatous disease (CGD): NADPH oxidase defect affecting phagocytic cells

Leukocyte adhesion deficiency: beta2 integrin defect affecting neutrophils and monocytes

Complement deficiencies: complement gene defects

Question 3

What are the 5 components of the NADPH oxidase?

Answer 3

p22phox (transmembrane - sub), p47phox, gp91phox (transmembrane, X chromosome), p67phox, p40phox

Question 4

What does gp47 mean?

Answer 4

glycoprotein with a molecular weight of 47kDa

Question 5

What chromosome are most primary immunodeficiencies gene mutations at?

Answer 5

X - hence many more boys have

Question 6

Give 3 examples of a primary immunodeficiency affecting the ADAPTIVE immune response

Answer 6

1. B cell problems - Selective IgA deficiency (reduced IgA levels - no symptoms), Hyper-IgM syndrome (CD154 defect, class switching cannot take place so can’t make IgG/A/E), X-linked agammaglobulinaemia (Bruton’s tyrosine kinase defect, no Ig at all)
2. T cell problems - Wiskott-Aldrich syndrome (WASP defect), DiGeorge syndrome (TBX1 gene defect)
3. Severe combined immunodeficiency (SCID) - affect T and B cells - gamma chain, RAG, ADA, Artemis problems

Question 7

How does Hyper-IgM syndrome occur?

Answer 7

Mutation in gene encoding CD40L or CD40 on Th cells so no class switching as no interaction between Th and B cells (obligatory for class switching) so can’t activate certain antibodies

Question 8

How does DiGeorge syndrome occur?

Answer 8

Humans have defect in TBX1 (same as defect in nude mice) which leads to lack of thymus and overwhelming recurrent infections

Question 9

What is significant about the nude mouse?

Answer 9

They are athymic (have no thymus) due to TBX1 gene defect - so have no T cells

Question 10

There are a variety of immunodeficiencies on the X chromosome

Answer 10

Yep

Question 11

How does SCID occur?

Answer 11

Defect in gamma-chain so no signalling between cytokine receptors - may be T- B- but NK+
Jak3 also important

If there is no T cells present (even if there are B cells) then B cells cannot be activated at all

Question 12

What are some secondary immunodeficiencies?

Answer 12

1. Malnutrition - won’t respond well to infections or vaccines - so give dietary supplements
2. Loss of cellular/humoral components - lymphocytes passively lost into intestines (intestinal lymphangiectasia) and proteins lost to urine (nephrotic syndrome)
3. Tumours - tumours of the immune system can produce T/B cell leukaemia or lymphomas, myeloma (plasma cell tumour), acute myeloid leukaemia (myeloid cells)
4. Cytotoxic drugs/irradiation - prevents cell dividing rapidly
5. Infections - dampen down immune response (e.g. malaria, HIV)

Question 13

How does HIV occur?

Answer 13

HIV infects cells with CD4 on surface, T cells that recognise MHCII (helper and regulatory, macrophages, monocytes, dendritic cells) have CD4 so are infected. Also needs chemokine coreceptor (CCR5 on macrophage, or CXCR5 on T’s) will enter cells.

Question 14

How does the CD4 count vary on HIV infection?

Answer 14

Decreases rapidly immediately after infection as HIV plasma virus increases, but then plasma virus decreases and CD4 cells increase (do not peak as high as before), then years later plasma cells increase again and the CD4 could drops to ~0 (AIDS)

Question 15

What kills AIDS patients?

Answer 15

Opportunistic infections e.g. Virus (cytomegalovirus), Bacteria (TB), Fungi (pneumocystis), Protozoa (toxoplasma)

Question 16

How do you treat immunodeficicies?

Answer 16

Antibiotics -
Gammaglobulins - for antibody deficiencies
Cell replacement -
Gene therapy - gamma-c & ADA deficiencies