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Flashcards in Immunodeficiencies Deck (36)
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1

How can immunodeficiencies be classified? 

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 

2

What are the two basic clinical features of immunodeficiencies? 

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

3

What are warning signs of primary immunodeficiencies? 

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

4

Provide a general description of primary immunodeficiencies 

  • 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

5

List some defects in adaptive immunity 

  • 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

6

What are some major B-lymphocyte disorders? 

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

7

Describe X-linked Agammaglobulinaemia 

  • 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 

8

How do we investigate and treat X-linked Agammaglobulinaemia? 

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!!

9

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

Severe Combined ImmunoDeficiency (SCID) 

10

Describe the presentation and inheritance of SCID? 

  • 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)

11

What are the causes of severe combined immunodeficiency? 

  • 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

12

How would be investigate for severe combined immunodeficiency syndrome? 

  • 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)

13

How can you treat severe combined immunodeficiency syndrome? 

  • 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)

14

What is the outcome of SCID? 

  • 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

15

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

  • DiGeorge Syndrome
  • Wiskott Aldrich Syndrome
  • Ataxia Telangiectasia

16

Describe Wiskott-Aldrich Syndrome 

  • 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)  

 

17

Describe DiGeorge Syndrome (22q11 deletion) 

  • Thymic hypoplasia 
  • 22q 11 deletion = failure development of 3+4th 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)

18

Describe ataxia telangiectasia

  • 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

19

What are symptoms of ataxia telangiectasia? 

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

20

What occurs as a consequence of ataxia telangiectasia? 

  • 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

21

What are the two defects in innate immunity? 

  • Phagocyte defects 
  • Complement defects 

22

Describe some phagocyte defects 

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

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

23

Describe chronic granulomatous disease 

  • 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.

24

Describe the oxygen dependant killing of pathogens 

  • 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 

25

How can you diagnose chronic granulomatous disease? 

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

26

Describe Chediak Higashi syndrome

  • 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

27

What is the diagnosis for chediak higashi syndrome

  • Decreased number of neutrophils
  • Neutrophils have giant granules

28

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

  • 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)

29

Describe complement deficiencies 

  • 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

30

List some examples of complement deficiencies 

  • 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

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