Immunodeficiency and HIV

Question 1

What can the immune system be divided into?

Answer 1

Innate- the one that we are born with & our first response (e.g. phagocytes, complement, etc.)

Adaptive/acquired- changes throughout life (e.g. T cells, B cells, etc.)

Question 2

What does immunodeficiency result in & what is an indication of immunodeficiency?

Answer 2

Immunodeficiency results in increased susceptibility to infection by specific classes or types of microbes.

Repeated or unusual infections is an indication of immunodeficiency

Question 3

What is primary & secondary immunodeficiency?

Answer 3

Primary immunodeficiency:
Genetically determined or result of developmental anomalies
Inherited, congenital, and rare

Secondary immunodeficiency:
Acquired & caused by disease or an immunosuppressive treatment
More common

Question 4

What can primary immunodeficiencies be a result of?

Answer 4

it can be genetic so:
autosomal,
X-linked (sex chromosome),
gene deletions, rearrangements, polymorphisms (SNPs).

Or it can be biochemical or metabolic so:
adenosine deaminase deficiency (affects T cells), purine nucleoside phosphorylase deficiency (affects T cells),
developmental arrest (affects B cells, T cells, phagocytes)

Question 5

What are some examples of complement deficiencies that affect the classical pathway?

Answer 5

Defects that affect the classical pathway (C1qrs, C2 or C4) lead to:
Immune complex disease unable to remove Ag-Ab complexes (Type III hyper.)
Susceptibility to encapsulated organisms such as Streptococcus pneumoniae and Neisseria spp

Question 6

What are some examples of complement deficiencies such as C3 deficiency?

Answer 6

Opsonisation of microbes is defective hence:
removal by phagocytosis is compromised
susceptibility to encapsulated organisms i.e. Streptococcus, Neisseria, pyogenic organisms

Question 7

What are some examples of complement deficiencies such as Alternative pathway deficiencies (Factor B, Factor D and Properdin)?

Answer 7

Results in low C3b levels:
pneumococcal and meningococcal infections
no immune complex disease

Question 8

What are some examples of complement deficiencies such as MAC complex deficiency (C5-9)?

Answer 8

Inability to lyse bacterial cells hence:
recurrent infection with Neisseria meningitidis
humoral (antibody) immunity is unaffected

Question 9

Phagocytosis deficiencies - what are the consquences when there are defects in the stem cell differentiation?

Answer 9

Neutropaenia (low neutrophil numbers) Leukocyte adhesion disease - lack of adhesion molecules (CD18, that binds to ICAM-1) required for Neutrophil recruitment

Question 10

Phagocytosis deficiencies - what are the consquences when there are defects in phagocytosis?

Answer 10

Also known as Chediak-Higashi syndrome.

Lack of phagosome fusion with lysosomes:
-defect in lysosomal trafficking regulator (LYST)
-susceptibility to staphylococcus aureus

Question 11

Phagocytosis deficiencies - what are the consquences when there are defects in Defective intracellular Killing?

Answer 11

Also know as Chronic granulomatous Disease.
Defect in NADPH system:
-required for free radical formation (ROS)
-lack of oxygen-dependent killing
-increased bacterial and fungal infections

Question 12

What can phagocytosis deficiencies all lead to?

Answer 12

General increased susceptibility to bacterial and fungal infections of skin and mucosal tissues

Question 13

What is the treatment for Phagocytosis deficiencies?

Answer 13

Treatment: antibiotics or bone marrow transplant (gene therapy)

Question 14

Humoral / antibody deficiencies - what are the consequences of abnormal b cell development?

Answer 14

Abnormal b cell development can lead to Bruton’s agammaglobulinaemia (x-linked agammaglobulinaemia).

Few or no mature B cells / antibody leads to:
-Blockage in maturation of pre-B to B cells, while T cell maturation is normal
-Common in male infants; protected for 6-months, then recurrent bacterial infections

Question 15

Humoral / antibody deficiencies - what are the consequences of Failure of class switch from IgM?

Answer 15

Increased igM but little or no IgG
- Lack of igG antibody opsonization and phagocytosis (ex,defective CD40 on B cells or CD40L on T cells)

Question 16

Humoral / antibody deficiencies - what are the consequences Common variable immunodeficiency?

Answer 16

many potential causes but not completely known

IgG/IgM/IgA deficiency:
- either B cells do not undergo terminal differentiation (no IgG/IgA) or T cell signalling is defective
- adults of box sexes (late onset, 15-35 yrs)

Question 17

what can Humoral / antibody deficiencies lead to?

Answer 17

Recurrent extracellular bacterial infections (Pneumococcus, Streptococcus, Haemophilus, mainly encapsulated bacteria)

Question 18

What is the treatment for Humoral / antibody deficiencies?

Answer 18

Treatment: life-long or periodic gamma globulin injections

Question 19

T cell deficiencies - what are the consequences of undeveloped thymus?

Answer 19

Also known as DiGeorge’s syndrome.

Lack of T cells:
- susceptibility to many infections, abnormal B cell immunity
- hypoparathyroidism (resulting in hypocalcemia and congenital heart disease)

Question 20

T cell deficiencies - what are the consequences of Stem cell defect or death of developing T cells?

Answer 20

Severe combined deficiency syndrome (SCID):
- Defect in the common gamma chain used by cytokine receptors (IL2/4/7/9/15/21) in 50% of cases

• Adenosine deaminase deficiency or purine nucleoside phosphorylase deficiency in 25% of cases (metabolite build up inhibiting DNA synthesis)

Question 21

T cell deficiencies - what are the consequences of MHC II deficiency?

Answer 21

No mature CD4+ T cells:
- Low antigen presenting cell function, reduced B/T cell activation (no antibodies)
- Death by yr 5 due to bacterial and viral infections

Question 22

What can T cell deficiencies lead to?

Answer 22

Opportunistic infections (viruses, fungi, parasites, bacteria). Often fatal in early years of life.

Question 23

What is the treatment for T cell deficiencies?

Answer 23

Treatment: bone marrow transplant (gene therapy)

Question 24

What are some clinical features of immunodeficiencies?

Answer 24

• Chronic and recurrent infections
• Unusual microbial agents
• Incomplete responses to treatment
• Skin lesions, warts
• Diarrhoea
• Recurrent abscesses
• Autoimmunity
• Failure to thrive

Question 25

What are some examples of causes of secondary immunodeficiencies?

Answer 25

Therapeutic drugs (cancer chemotherapy, radiation therapy, post-transplant immunosuppression)

Infection (HIV/AIDS)

Metabolic / chronic disorders (eg: diabetes)

Malnutrition, aging

Burns/trauma (loss of immunoglobulin via damaged skin)

Question 26

Describe the human immunodeficiency virus.

Answer 26

Group VI of Baltimore virus classification (ssRNA virus with a DNA intermediate).

Question 27

what are the hallmarks of the HIV?

Answer 27

Hallmarks of this virus are its ability to reverse transcribe (RNA–>DNA) & chromosomal integration.

its ability to integrate ensures the virus is copied and maintained into the host.

Question 28

What 3 main genes are in the proviral DNA of HIV?

Answer 28

gag- codes for structural proteins
pol- codes for viral enzymes
env- codes for the viral protein

Question 29

What are the steps of the HIV life cycle & cell entry?

Answer 29

1. Receptor binding - the virus recognises a target cell via its envelope. The viral envelope protein interacts with host protein CD4
2. After engagement there is membrane fusion and entry of the virus.
3. This is followed by uncoating and reverse transcription where the viral rna is reverse transcribed into DNA by viral rt enzyme.
4. nuclear uptake
5. integration this is where the viral DNA intergrates with a host chromosome.
6. viral DNA can transcript viral rna this is exported to the cytoplasm for translated into viral proteins
7. assembly of the viral proteins to the cell membrane
8. the viral particle buds from the host cell and matures and will effects a new cell.

Question 30

How do HIV enter cells?

Answer 30

Receptor CD4 can only enter cells that have this receptor.
Sometime Attachment factors are involved in entry such as:
Heparan Sulphate Proteoglycans
Galactosylceramide
a3b7 integrin
DC-SIGN
however these are not essential.

Co-Receptors are also sometimes involved in entry:
CCR5 (macrophages and DCs)
CXCR4 (T cells)

Question 31

Explain the course of HIV infection?

Answer 31

4-8 weeks is the acute stage: HIV multiply rapidly and speeds throughout the body. greater risk of HIV transmission.

5-15 years chronic stage: continues to multiply but at very low levels. may not have any symptoms but antibodies can be detected.

2-3 years develop into AIDS:THE MOST SEVERE STAGE AND THE CD4T-CELLS HAVE BEEN DEPLETED.. Immune system compromised.

Question 32

When is AIDS diagnosed?

Answer 32

At CD4 <200 cells and/or presence of opportunistic infection

Question 33

What happens once an individual is diagnosed with AIDS?

Answer 33

The host will not be able to mount a proper immune response against other infectious agents such as parasites, bacteria, fungi, viruses

Question 34

Which malignancies are common in people with AIDS?

Answer 34

Kaposi’s sarcoma - a type of cancer that forms in the lining of blood vessels and lymph vessels
Non-Hodgkin’s lymphoma (including Burkitt’s lymphoma)
Primary CNS lymphoma
Invasive cervical cancer
Increased rates of other cancers