Immunodeficiencies Flashcards
How is immunodeficiency classified?
Primary (congenital)
- defect in immune system
Secondary (acquired)
- caused by another disease
What are the clinical features of immunodeficiencies
Recurrent infections
- <6-8 URI/year for 1st 10 yrs
- 6 otitis media
- 2 gastroenteritis/year for 1st 2-3 years
Severe infections, unusual pathogens (Aspergillus, Pneumocystis), unusual sites (liver abscess, osteomyelitis)
Outline the warning signs of Primary immunodeficiency
- 8+ new ear infections within 1 year
- 2+ serious sinus infections within 1 year
- 2+ months on antibiotics w/ little effect
- 2+ pneumonias in 1 year
- Infant fails to gain weight / grow normally
- Recurrent, deep skin or organ abscesses
- Persistent thrush (mouth/elsewhere on skin) after age 1
- Need for IV antibiotics to clear infections
- 2+ deep-seated infections
- Family history of primary immunodeficiency
What is the main cause of PID?
Usually genetic
- Infrequent but can be life-threatening
What are the major consequences of Primary immunodeficiency (PID)?
Adaptive immune system defects: T and B cell
Innate immune system lacks; phagocytes, complement
Describe the frequency of primary immunodeficiency of immune cells
50% antibody
30% T Cell
18% phagocytes
2% complement
How are defects in adaptive immunity classified?
Sub-classification: primary component affected e.g.
- B cells
- T cells
- Combined (both B & T)
What cellular defects occuring adaptive immunity during primary immunodeficiency?
T cell defects impair antibody production
Defects in lymphocyte development or activation
Name the major B-lymphocyte immunodeficiency disorders
- X-linked agammaglobulinemia (Bruton’s disease)
- Common variable immunodeficiency (CVID)
- Selective IgA deficiency
- IgG2 subclass deficiency
- Specific Ig deficiency with normal Igs
What is the first described immunodeficiency?
X-linked Agammaglobulinemia
What causes Bruton’s disease?
Defect in btk gene (X chromosome)
form of agammaglobulinemia
What is the role of the btk gene?
Encodes Bruton’s tyrosine kinase
What is the effect of btk gene defect?
Btk needed for pre-B cell receptor signalling
Blocks in B-cell development (stop at pre-B cells)
What is the consequence of Bruton’s disease?
Recurrent severe bacterial infections
- 2nd half of first year (lung, ears, GI)
- autoimmune diseases (35% of patients)
How do we investigate Brutons disease?
- B cells absent / low;
- Plasma cells absent
- All Igs absent / very low
- T cells + T cell-mediated responses normal
How is brutons disease treated?
- IVIg: 200-600mg/kg/month at 2-3 wk intervals
- or subcutaneous Ig weekly
- prompt antibiotic therapy (URI /LRI)
- Do not give live vaccines
What is SCID?
Severe Combined ImmunoDeficiency (SCID)
A form of Combined immunodeficiencies
Outline the predominant T cell disorders
- DiGeorge syndrome
- Wiskott-Aldrich syndrome
- Ataxia-telangiectasia
Which lymphocyte disorder is SCID a form of?
- involves both T and B
- 50-60% X-linked; rest - autosomal recessive
Describe the presentation of SCID
- well at birth; problems > 1st month
- diarrhoea; weight loss; persistent candidiasis
- severe bacterial/viral infections
- failure to clear vaccines
- unusual infections (Pneumocystis, CMV)
What are the different causes of SCID?
Different causes; affect T & B cell development e.g.
- Cytokine receptor defects
- RAG defects
- Adenosine Deaminase Deficiency
How do cytokine receptor defects effect T and B cell development?
Common cytokine receptor γ-chain defect
(signal transducing component of receptors for IL-2, 4, 7, 9, 11, 15, 21)
IL-7 needed for survival T cell precursors => defective T cell development => lack in B cell help (low Ab)
What is the effect of RAG enzyme defects?
RAG-1/RAG-2 defect => no T and B cells
What is the effect of adenosine deaminase deficiency?
Accumulation of deoxyadenosine & deoxy-ATP => toxic for rapidly dividing thymocytes
How is SCID investigated?
Lymphocyte subsets
- T, B, NK (% and numbers)
=> low total lymphocyte count
Pattern:
- T very low/absent
- B normal/absent
sometimes NK also absent (γ-chain defect affecting IL-15 receptor)
- Igs low
- T cell function ↓ (proliferation, cytokines)
How is SCID treated?
- Isolation
- Do not give live vaccines !
- Blood products from CMV -ve donors
- IVIg replacement
- Treat infections
- Bone marrow/ HSCT
- Gene therapy (for ADA and γ-chain genes)
Describe SCID prognosis and survival
Dependent 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 => engraftment
What is DiGeorge syndrome?
Complex array of developmental defects
What are the physical signs of DiGeorge syndrome?
Dysmorphic face: cleft palate, low-set ears, fish-shaped mouth
What are the clinical symptoms of DiGeorge syndrome?
Hypocalcaemia, cardiac abnormalities
Variable immunodeficiency (absent/reduced thymus => affects T cell development)
What is Wiskott-Aldrich SYndrome (WAS)?
X-linked
Defect in WASP (protein involved in actin polymerisation => defect in signalling)
What are the clinical signs of Wiskott-aldrich syndrome?
Thrombocytopaenia, eczema, infections
Describe the progression of wiskott aldrich syndrome?
Progressive immunodeficiency (T cell loss)
Progressive ↓ T cells; ↓ T cell proliferation
Ab production (↓ IgM, IgG; high IgE, IgA)
What is ataxia telangiectasia?
Autosomal recessive
Defect in cell cycle checkpoint gene (ATM) => sensor of DNA damage => activates p53 => apoptosis of cells with damaged DNA
What is the role of the ATM gene?
ATM gene stabilises DNA double strand break complexes during V(D)J recombination => defect in generation of lymphocyte antigen receptors & lymphocyte development
What are the consequences of ataxia telangiectasia?
Progressive cerebellar ataxia (abnormal gait)
Typical telangiectasia (ear lobes, conjunctivae)
Immunodeficiency
Increased incidence of tumours later in life
What are the causes of ataxia telangiectasia?
- Combined immunodeficiency (B & T)
- Defects in production of switched Abs (IgA/G2)
- T cell defects (less pronounced) => thymic hypoplasia
- Upper & lower respiratory tract infections
- Autoimmune phenomena, cancer
What are the 2 types of innate immunity defects?
- Phagocyte defects
- Complement defects
What are the types of phagocyte defects?
Quantitative (↓ number)
Qualitative
- Chronic granulomatous disease
- Chediak-Higashi syndrome
- Leukocyte adhesion defects (LADs)
What is chronic granulomatous disease?
Defective oxidative killing of phagocytosed microbes; mutation in phagocyte oxidase (NADPH) components
- Formation of granulomas (wall off microbes)
How is chronic granulomatous disease?
Diagnosis: Tests that measure oxidative burst:
- NBT test (nitroblue tetrazolium reduction)
- Flow cytometry assay dihydrorhodamine
Outline how an NBT reduction test is carried out?
- Control neutrophils + Patient neutrophils
- Incubate in nitroblue tetrazolium
- Activate using microbe / cytokines
- Checks production of active oxygen species
- If oxygen species produced; cells cleave active dye
= blue - Deficient patients have no colour as they are defective
How is a dihydrorhodamine assay used to diagnose chronic granulomatous disease?
Dihydrorhodamine assay used in similar manner
Cells producing active oxygen species will cleave the dye making the cells fluoresce, if deficient no fluorescence will occur
Takes ~30 mins
What is Chediak-Higashi Syndrome?
- rare genetic disease
- defect in LYST gene
- neutrophils have defective phagocytosis
- repetitive, severe infections
What is the role of the LYST gene?
Regulates lysosome traffic
What causes recurrent infections in chediak-higashi syndrome?
Defect phagosome-lysosome fusion => defective killing of phagocytosed microbes => recurrent infections
How is Cjhediak-Higashi Syndrome diagnosed?
- Necreased number neutrophils
- Neutrophils have giant granules
What defects cause LAD (Leukocyte Adhesion Deficiency)?
- Defect in β2-chain integrins (LFA-1, Mac-1)
- Defect in sialyl-Lewis X (selectin ligand)
Describe the presentation of leukocyte adhesion deficiency
Skin infections, intestinal + perianal ulcers
How is leukocyte adhesion deficiency investigated?
↓ neutrophil chemotaxis
↓ integrins on phagocytes (flow cytometry)
What is the effect of complement deficiencies?
Can affect different complement factors severe/fatal pyogenic infections (C3 deficiency)
Predisposition to infection with different pathogens
What are the symptoms of complement deficiencies?
Symptoms differ depending on C factor affected
What recurrent infections occur in complement deficiencies?
Recurrent infections (Neisseria) - deficiency terminal complex (MAC): C5, C6, C7, C8 & C9
Severe/fatal pyogenic infections (C3 deficiency)
SLE-like syndrome (C1q, C2, C4 deficiency)
What is Hereditary angioneurotic oedema?
Failure to inactivate complement (deficiency in C1 inhibitor); intermittent acute oedema skin/mucosa => vomiting, diarrhoea, airway obstruction
How are complement deficiencies investigated?
- measure individual components
- complement function: CH50 (haemolysis)
What are the aims of primary immunodeficiency treatments?
- Ig replacement therapy
- Bone marrow transplantation
- Gene therapy
- Prompt infection treatment
- Prevention of infection: isolation, antibiotic prophylaxis, vaccination
(not live vaccines!) - Good nutrition
What are the secondary immunodeficiency causes?
Infections: viral, bacterial Malignancy Extremes of age Nutrition (anorexia, iron deficiencies) Chronic renal disease Splenectomy Trauma/surgery, burns, smoking, alcohol Immunosuppressive drugs
Outline common secondary immunodeficiency infections
Viral:
- HIV, CMV, EBV,
- Measles
- Influenza
Chronic bacterial:
- TB
- Leprosy
Chronic parasitic:
- Malaria
- Leishmaniasis
Acute bacterial
- Septicaemia
What malignancies cause immunodeficiency?
- Myeloma
- Lymphoma (Hodgkin’s, non-Hodgkin’s)
- Leukaemia (acute or chronic)
What are the age extremities causing immunodeficiency?
prematurity
old age
How does prematurity cause immune vulnerability?
- infants < 6 months => maternal IgG
- premature delivery: interrupts placental transfer of IgG => infant Ig deficient
How does old age affect the immune system?
Decline in normal immune function
