Immunodeficiencies

Question 1

How can immunodeficiencies be classified?

Answer 1

Primary (congenital) = Immunodeficiency caused by defect in the component of the immune system

Secondary (acquired) = Immunodeficiency caused by another disease e.g infection (viral, bacterial), malignancy (myeloma, lymphoma, leukaemia), extremes of age, nutrition (anorexia, iron def), splenectomy

Question 2

What are the two basic clinical features of immunodeficiencies?

Answer 2

• Recurrent infections
• Severe infections, unusual pathogens (Aspergillus, Pneumocystis), infections will be in unusual sites for example liver abscesses or osteomyelitis (bone)

Question 3

What are warning signs of primary immunodeficiencies?

Answer 3

2 or more of the following symptoms can identify a primary immunodeficiency

• 8 or more new ear infections within 1 year
• 2 or more serious sinus infections within 1 year
• 2 or more months on antibiotics with little effect
• 2 or more pneumonias within 1 year
• Failure of an infant to gain weight or grow normally
• Recurrent, deep skin or organ abscesses
• Persistent thrush (mouth/ elsewhere on skin) after age 1
• Need for intravenous antibiotics to clear infections
• 2 or more deep-seated infections
• A family history

Question 4

Provide a general description of primary immunodeficiencies

Answer 4

• Usually genetic
• Infrequent but can be life threatening
  
  • Adaptive IS = Made up of B and T cells
  • Innate IS = Made up of phagocytes, complement, etc
• Frequency
  
  • 50% antibody; 30% T cell; 18% phagocytes, 2% complement

Question 5

List some defects in adaptive immunity

Answer 5

• Sub-classification; primary component affected
• E.g. B cells, T cells, combined (both B and T)
  
  • Often T cell defects will impair antibody production!!
    
    • This is because B-cells will require T-cell activation in order to undergo class switching and affinity maturation
      
      • Defects in T or B-cells can be either in lymphocyte development or in the activation stage later on

Question 6

What are some major B-lymphocyte disorders?

Answer 6

• X-linked agammaglobulinaemia (Bruton’s disease)
• Common variable immunodeficiency (CVID)
• Selective IgA deficiency
• IgG2 subclass deficiency
• Specific Ig deficiency with normal Igs

Question 7

Describe X-linked Agammaglobulinaemia

Answer 7

• First described primary immunodeficiency (Bruton’s disease)
  
  • Defect in btk gene
  • Encodes Bruton tyrosine kinase important for B-lymphocyte development
  • Block in B-cell development (stop at pre-B cells)
  • Subsequent stages are missing and no Ab production
    
    • Leads to recurrent severe bacterial infections
      
      • Presents in 2nd half of first year, as children have some immunity in first half from passive transfer of maternal IgG and IgA via breastfeeding

Question 8

How do we investigate and treat X-linked Agammaglobulinaemia?

Answer 8

Investigations

• B-cells absent/ low plasma cells absent
• All Igs absent/ very low
• T cells and T-cell mediated responses normal

Treatment

• IVIg; 200-600mg//kg/month at 2-3 wk intervals
• Or subcutaneous Ig weekly
• Prompt antibiotic therapy (URI/LRI)
• Do not give live vaccines!!

Question 9

Give an example of a disorder that affects both B and T cells (SCID)

Answer 9

Severe Combined ImmunoDeficiency (SCID)

Question 10

Describe the presentation and inheritance of SCID?

Answer 10

• Presentation = involves both T and B cells
• 50-60% X-linked, the rest is autosomal recessive
  
  • Presentation
    
    • Well at birth; problems occur > 1st month
    • Diarrhoea; weight loss; persistent candidiasis
    • Severe bacterial/ viral infections
    • Failure to clear vaccines (developing disease instead of Abs)
    • Unusual infections (such as pneumocystis, CMV)

Question 11

What are the causes of severe combined immunodeficiency?

Answer 11

• Causes (syndrome as the causes can be different)
  
  • Common cytokines receptor γ-chain defect (signal transducing component of receptors for IL-2, IL-4, IL-7, IL-9, IL-11, IL-15, IL-21); IL-7 needed for survival T cell precursors → Defective T cell development → Lack in B cell help (low Ab)
  • RAG-1/RAG-2 defect = No T and B cells
  • ADA (adenosine deaminase deficiency); = accumulation of deoxyadenosine and deoxy-ATP à toxic for rapidly dividing thymocytes

Question 12

How would be investigate for severe combined immunodeficiency syndrome?

Answer 12

• Low total lymphocyte count
• Pattern: very low/ absent T; normal/ absent B, sometimes also absent NK (γ-chain defect affecting IL-15 receptor)
• Igs low
• Decrease in T cell function (proliferation, cytokines)

Question 13

How can you treat severe combined immunodeficiency syndrome?

Answer 13

• Isolation (to prevent further infections)
• Do not give live vaccines
• Blood products from CMV-negative donors
• IVIg replacement
• Treat infections
• Bone marrow/ haematopoietic stem cell transplant
• Gene therapy (for ADA and γ-chain genes)

Question 14

What is the outcome of SCID?

Answer 14

• Dependant on promptness of diagnosis
• Survival > 80% (early diagnosis, good donor match, no infections pre-transplant)
• Survival <40% (late diagnosis, chronic infections, poorly matched donors)
• Regular monitoring post BMT -à engraftment

Question 15

Give examples of predominant T-cell disorders that can lead to immunodeficiency?

Answer 15

• DiGeorge Syndrome
• Wiskott Aldrich Syndrome
• Ataxia Telangiectasia

Question 16

Describe Wiskott-Aldrich Syndrome

Answer 16

• X-linked
• Also known as eczema thrombocytopenia immunodeficiency syndrome
• Defect in WASP protein (involved in actin polymerisation of cytoskeleton) = defect in signalling
  
  • (T cells will form psuedopods + immunological synapses with other cells so they can interact)
    
    • Progressive immunodeficiency (T cell loss)
    • Progressive decreased T cells, decreased T cell proliferation
    • Ab production (low IgM, IgG, high IgE, IgA)
      
      • Will produce high IgE and IgA which contributes to the development of eczema
        
        • https://youtu.be/R5ADKNVc6t4

Question 17

Describe DiGeorge Syndrome (22q11 deletion)

Answer 17

• Thymic hypoplasia
• 22q 11 deletion = failure development of 3+4^th pharyngeal pouches
  
  • 3rd pharyngeal pouch goes on to develop into the thymus hence underdevloped = thymic hypoplasia ​
    
    • Complex array of developmental defects
    • Dysmorphic face: cleft palate, low-set ears, fish-shaped mouth
    • Hypocalcaemia (as it also affects parathyroid gland),cardiac abnormalities
    • Variable immunodeficiency (absent/ reduced thymus à affects T cell development)
      
      • https://youtu.be/YdDs92gaWl8

Question 18

Describe ataxia telangiectasia

Answer 18

• Autosomal recessive
• Defect in cell cycle checkpoint (ATM) à sensor of DNA damage = activates p53 = apoptosis of cells with damaged DNA
• ATM gene stabilises DNA double break complexes during V(D)J recombination = defect in generation of lymphocyte antigen receptors and lymphocyte development

Question 19

What are symptoms of ataxia telangiectasia?

Answer 19

• Progressive cerebellar ataxia (abnormal gait(walking)
• Typical telangiectasia (ear lobes, conjunctivae)
• Immunodeficiency
• Increased incidence of tumours later in life

Question 20

What occurs as a consequence of ataxia telangiectasia?

Answer 20

• Combined immunodeficiency (B + T)
• Defects in production of switched Abs (IgA/G2)
• T cell defects (less pronounces) ß thymic hypoplasia
• Upper and lower respiratory tract infections
• Higher risk of Autoimmune phenomena, cancer

Question 21

What are the two defects in innate immunity?

Answer 21

• Phagocyte defects
• Complement defects

Question 22

Describe some phagocyte defects

Answer 22

Phagocyte defects can affect the number of phagocytes, function or both

• Chronic granulomatous disease
• Chediak-Higashi Syndrome
• Leucocyte adhesion defects (LADs)

Question 23

Describe chronic granulomatous disease

Answer 23

• Defective oxidative killing of phagocytosed microbes; mutation in phagocyte oxidative (NADPH) components
• This means pathogens cant be eliminated properly
• There will be granuloma formation preventing the spreading of the infection to other areas.

Question 24

Describe the oxygen dependant killing of pathogens

Answer 24

• After the microbe is taken up by the phagocyte, then you have the assembly of the NADPH complex by recruitment of subunits from the cytosol.
  
  • This will convert oxygen into the superoxide anion that is used to generate the ROS
• In chronic granulomatous disease = defects in various components that lead to the formation of the complex, cannot create the superoxide anion and generate ROS

Question 25

How can you diagnose chronic granulomatous disease?

Answer 25

* Use tests that measure the oxidative burst * NBT test (nitroblue tetrazolium reduction) * Flow cytometry assay dihyrorhodamine

Question 26

Describe Chediak Higashi syndrome

Answer 26

* Rare genetic disease * Defect in the LYST gene (involved in trafficking of lysosomes) * Phagosome is unable to fuse with the lysosome; enzymes cannot access the pathogen to break it down * Neutrophils have defective phagocytosis killing * Repetitive, severe infections

Question 27

What is the diagnosis for chediak higashi syndrome

Answer 27

* Decreased number of neutrophils * Neutrophils have giant granules

Question 28

Describe leukocyte adhesion deficiency, how it presents and how you would investigate?

Answer 28

* Defect in **β2-chain integrins** (LFA-1, Mac-1) * **Defect in sialyl-Lewis** X (selectin ligand) * Delayed umbilical cord separation à Diagnosis defect in β2-chain integrins (LFA-1, Mac-1) * Presentation * Skin infections, intestinal + perianal ulcers * Investigations * Decreased neutrophil chemotaxis * Decreased integrins on phagocytes (flow cytometry)

Question 29

Describe complement deficiencies

Answer 29

* Can affect different complement factors * Severe/ fatal pyogenic infections (C3 deficiency) * Predisposition to infection with different pathogens * Symptoms/ particular illness can present and be associated with a C factor affected

Question 30

List some examples of complement deficiencies

Answer 30

* **Deficiency in the terminal complex (C5, C6, C7, C8 and C9)** à can get recurrent infections with **Neisseria** * **C3 deficiency** = Severe/ fatal pyogenic infections * **C1q, C2, C4 deficiency** = SLE-like syndrome * **Deficiency in C1 inhibitor** = this results in the failure to inactivate complement leading to **hereditary angioneurotic oedema** (inflammation is activated when it is not needed), intermittent acute oedema skin/mucosa = vomiting, diarrhoea, airway obstruction

Question 31

How do you investigate complement deficiencies?

Answer 31

* Complement function: Ch50 (haemolysis) * Measure individual components

Question 32

What are some treatment principles of primary immunodeficiencies?

Answer 32

1. We minimise/ control infection of a patient 2. We then try to replace defective or absent component of the immune system 1. This can be carried out by either 1. Immunoglobulin replacement therapy 2. Bone marrow transplantation 3. Gene therapy

Question 33

What are some examples of secondary immunodeficiencies

Answer 33

* Infections: viral, bacterial * Malignancy * Extremes of age * Nutrition (anorexia, iron deficiencies) * Chronic renal disease * Splenectomy * Trauma/ surgery, burns, smoking, alcohol * Immunosuppressive drugs

Question 34

What are some infections associated with secondary immunodeficiency?

Answer 34

* Viral: HIV, CMV, EBV, measels, influenza * Chronic bacterial: TB, leprosy * Chronic parasitic: malaria, leishmaniasis * Acute bacterial: septicaemia

Question 35

What are some malignancies that occur due to secondary immunodeficiency

Answer 35

* Myeloma * Lymphoma (Hodgkin’s, non-Hodgkin’s) * Leukaemia (acute or chronic)

Question 36

How does secondary immunodeficiency link with extremes of age?

Answer 36

**PREMATURITY** * Infants \<6 months still have maternal IgG * A premature delivery interrupts the placental transfer of IgG which make the infant Ig deficienct **OLD AGE** * There is a decline in normal immune function as you age