Primary immunodeficiency

Question 1

Briefly describe immune cell development

Answer 1

3 different types of immune cells that develop from pluriportent stem cells

• Pre-myeloid cells (precursors for neutrophils)
• Lymphocyte-committed stem cell (become T (develop in thymus) and B cells (develop in marrow)
  
  • Effector and suppressor T- cells
    
    • CD4 = Th1, Th2, Th17 and regulatory T cells
    • CD8 = regulatory ones too
  • B-cells are responsible for producing antibodies – once they start secreting antibodies they become plasma cells
• Pre-monocyte – become macrophages

Question 2

What is the adaptive/acquired immunity?

Answer 2

Immunity that occurs after exposure to an antigen either from a pathogen or a vaccination.

It involves 2 things:

• Antibodies produced by B cells and the cellular immunity through t-cells and antigen presenting cells
• Cellular immunity through T cells and antigen presenting cells

Question 3

What do antibodies mainly fight against?

Answer 3

• Pyogenic bacteria such as staphylococci, staph pneumoniae Haemophilus influenzae
• Some viruses such as enteroviruses

Question 4

What is the innate/non-specific immunity?

Answer 4

The body’s first line of defense against germs entering the body. It responds in the same way to all germs and foreign substances hence why it is termed ‘non-specific’

It does this through:

• the complement system
• phagocytes

Question 5

What do phagocytes fight mainly? (2)

Answer 5

• Bacteria - staphylococci, gram negative
• Fungi - aspergillus, candida

Question 6

What does the complement system fight mainly? (2)

Answer 6

Pyogenic bacteria

Neisseria - meningitis

Question 7

What bacteria do T-cells fight?

Answer 7

• Viruses - measles, herpes zoster
• Fungi - candida, aspergillus
• Bacteria - myobacteria, listeria
• Protozoa - cryptosporidium

Question 8

What is immunodeficiency?

It can be classified into 2 groups, what are these?

Answer 8

Defects in one or more components of the immune system can lead to serious and often fatal disorders, which are collectively called immunodeficiency diseases.

1. Primary, or congenital immunodeficiencies
2. Secondary, or acquired immunodeficiencies

Question 9

What is meant by the effector and suppressor parts of the immune system?

Answer 9

• Effector part of immune system – counteracts infectious organisms and cancers
• Suppressor/regulatory part of immune system – keeps immune system in check – if the immunodeficiency affects these regulatory systems then they could be associated with autoimmunity

Question 10

What is the main consequence of immunodeficiency?

Answer 10

Increased susceptibility to infection

• Patients with immunodeficiencies are also susceptible to certain types of cancer - failure of effector part of immune system
• Certain immunodeficiencies are associated with an increased incidence of autoimmunity - failure of suppressor part of immune system

Question 11

What is primary immunodeficiency?

Answer 11

• A group of genetic, congenital disorders
• Part of the immune system is either missing or functioning abnormally due to inherited mutations
• A smaller number of primary immunodeficiencies are caused by autoimmunity.
• It predisposes the person to infections (recurrent, unusal and difficult to treat) and tumours

Question 12

What abnormalities arise in the immune system as a result of primary immunodeficiency?

Answer 12

• Components of the innate immune system
• Stages of lymphocyte development
• Responses of mature lymphocytes to antigenic stimulation

Question 13

Does it matter at which stage of lymphocyte development a defect occurs?

Answer 13

Yes. Defects in development of lymphocytes can occur at any stage but the earlier the defect in the development process the more severe the disease is:

• If the defect happens very early on then it affects both B and T cell development
• Could be later when cells have committed to either becoming B or T cells, can affect one or the other
• Or even later, the defect could be in a cell’s function after normal development

Question 14

Look

Answer 14

Remember the increased susceptibility to infection depends on the component of the immune system that is defective.

• Different parts of the immune system fight different microorganisms
• The type of opportunist infection present also gives clues to the degree and cause of immunodeficiency

Question 15

What is one sign that a patient’s infection is being caused by defective antibody production?

Answer 15

Repeated infection with incapsulated bacteria

Question 16

Being deficient in IgG and IgA antibodies can lead to which infection?

Answer 16

Recurrent respiratory infection by pneumococcus or Haemophilus species (pyogenic bacteria)

Question 17

Infections with staphylococci, gram-negative bacteria, and fungi are associated with reduced number or function of which cell?

Answer 17

Phagocytes

Question 18

So we know that the type of disease can give some indication of which part of the immune system is affected but you can also determine the severity of T-cell immunodeficiency by the pattern of mycobacterial infection. Explain.

Answer 18

Mycobacterium tuberculosis is a virulent organism that causes lung infection in healthy/immunocompetent people.

• In mild T-cell immunodeficiency, the same organism is able to invade the body outside the lungs.
• More severe immunodeficiency predisposes to widespread infection with mycobacteria of low virulence normally found in the environment (e.g., M. avium intracellulare complex).

Question 19

Many viruses remain latent in the body and can become reactivated in periods of immunosuppression. What are the best examples of this?

Answer 19

Herpes simplex and herpes zoster infection - linked to T-cell immunodeficiency

In patients with mild to severe immunodeficiencies they get recurrent reactivation attacks of these viruses. They can get recurrent cold sores (herpes simplex) or shingles (herpes varicella zoster) for example.

Question 20

A recurrent Candida infection in immunodeficient patients suggest defects in which immune pathway?

Answer 20

Th17 pathway

Question 21

Uncontrolled HIV can lead to the development of which tumour?

Answer 21

Kaposi sarcoma - if a patient presents with this tumour and it is unexplained, you have to test for immunodeficiency

Question 22

EBV can cause which tumour if there is immunosuppression?

Answer 22

Non-hodgkin lymphoma

Question 23

What are the 3 main causes of genetic primary immunodeficiency disorders?

Answer 23

• Mutations
• Polymorphism
• Polygenic disorders

Question 24

What is polymorphism?

Answer 24

Genetic polymorphisms are alleles (different forms) of the same gene occurring at a single locus in at least 1% of the population.

• The gene could still be functional but is sometimes dysfunctional.
• It could be a difference in a single base pair of DNA or much larger in size and involve long stretches of DNA.
• Polymorphisms are more common in the immune system than mutations
• They affect any part of the immune system causing a moderately increased risk of infection (not as severe as mutations)

Question 25

What are polygenic disorders?

Answer 25

* Disorders that are associated with the combined function of several genes * Polygenic disorders of the immune system are relatively common and affect mainly antibodies * Some may be caused by autoimmunity

Question 26

What is severe combined immunodeficiency (SCID)?

Answer 26

A group of rare but severe disorders caused by mutations in the early development of T and B cells. Together, T and B cells counteract a vast array of organisms hence why these disorders result in severe infections/recurrent infections that can sometimes be fatal * Infants with SCID die in the first few months of life unless treatment is given. * Some are autosomally inherited and there may be a history of incest * Others are X-linked * Stem cell transplant can cure SCID but it has to be done quickly. If it is performed very soon after birth, 90% infants survive; if it is delayed for a few months, only 50% infants survive the transplant procedure. * Many countries screen for SCID in newborns.

Question 27

Give an example of polymorphism?

Answer 27

1. Mannan-binding lectin (MBL) - binds sugars in bacterial cell walls and activates the classic complement pathway. Polymorphisms in MBL and complement affect the risk for infections. 2. Human leukocyte antigen (HLA) alleles are polymorphic and affect the outcome of infections. Individuals with HLA alleles that are unable to bind viral peptides have a worse outcome.

Question 28

Give examples of common polygenic disorders (3)

Answer 28

Common polygenic disorders that affect antibody production: * **Common variable immunodeficiency (CVID)** * **IgA deficiency** * **Specific antibody deficiency**

Question 29

Discuss common variable immunodeficiency (CVID)

Answer 29

* CVID = a group of diseases * It is the most common primary immunodeficiency requiring treatment and occurs in about 1 in 20,000 young people * Patients with CVID have low levels of total IgG. Their levels of IgA and IgM and numbers of B and T cells are variable * CVID causes recurrent respiratory tract infections * Infections that involve the gut, skin, and nervous system also occur * Autoimmunity is common in CVID * Autosomal-recessive inheritance - FH

Question 30

What is autoimmune polyendocrinopathy candidiasis ectodermal dysplasia (APECED)?

Answer 30

* A polygenic disorder * _Frequently experience **severe recurrent** candida infection_ * This can be due to deficiency in IL-17 as some produce autoantibodies against it * Or it can just be a failure of production

Question 31

Deficiency of Interferon gamma can result in recurrent problems with which infection?

Answer 31

Mycobacterial infection

Question 32

Summary of Primary immunodeficiencies

Answer 32

**Monogenic** = mutation in single gene. If they affect T and C cells you have multiple types of infections. All of the pathogens are a risk for these patients. * SCID - T and B cells affected * Wiskott-Aldrich - '' * X-linked SCID - '' * DiGeorge syndrome - only affects T cells - these patients don't have an active thymus so T cell imunity is affected **Autoantibodies** - against certain parts of the immune system * Against IL-17 - affects Th17 responses - results in severe candida infections * IFN gamma - affects Th1 responses - results in mycobacteria infections

Question 33

Summary of Primary immunodeficiencies 2.0

Answer 33

Question 34

How do you diagnose Severe combined immunodeficiency? (SCID)

Answer 34

Clinical presentation - Children with SCID have defective T cells and B cells and therefore develop infections in the first few weeks of life: * Unusual or recurrent infection * Diarrhoea * Unusual rashes Take a family history: * Family history of neonatal death * Family history of incest Lymphocyte count: * Very low total lymphocyte count (less than 1 × 109/L [106/mL]) * Lymphocyte numbers should be measured by flow cytometry If SCID is confirmed, definitive treatment should be given. Until definitive treatment need to avoid serious infection - avoid live vaccines + prophylaxis against opportunistic infections. In SCID and most T-cell deficiencies stem cell transplantation may be required

Question 35

How do you diagnose antibody deficiency?

Answer 35

* Measure antibody levels i.e IgG, IgA, and IgM * With low levels of immunoglobulins, causes of secondary immunodeficiency should be excluded. * If total Igs are normal, specific antibodies against Haemophilus spp. and pneumococcus should be measured. * If these tests are all normal, it is important to check no problems are apparent with complement or neutrophil function.

Question 36

How is primary immunodeficiency treated?

Answer 36

The aim of treatment is to prevent infection. * In mild immunodeficiency - prophylactic antibiotics may be adequate * In more severe antibody deficiency - immunoglobulin replacement therapy: * Antibodies against a wide range of pathogens * Ig pooled from thousands of normal donors * Ig replacement can be given IV or subcutaneously * Plasma screened for HIV and hep B and C antibodies

Question 37

How is SCID treated?

Question 38

How is gene therapy used in the treatment of primary immunodeficiency

Answer 38

Gene therapy uses recombinant technology to correct the genetic defect in the patient’s own stem cells, which can then reconstitute the immune system. * It is used in patients with SCID for whom no suitable stem cell donor was available.