Immunodeficiencies Flashcards
Immunodeficiency
Classification: - describe
Primary (congenital): defect in immune system
Secondary (acquired): caused by another disease
Immunodeficiency
Clinical features: for recurrent/severe infections
recurrent infections (normal: <6-8 URI/year for the 1st 10 years; 6 otitis media and 2 gastroenteritis/year for the 1st 2-3 years)
severe infections, unusual pathogens (Aspergillus, Pneumocystis), unusual sites (liver abscess, osteomyelitis)
Warning signs of PID
2 or more of the following:
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 of primary immunodeficiency
Primary Immunodeficiencies - cause and prevalence
Usually genetic
Infrequent but can be life-threatening
Primary Immunodeficiencies - describe their sub classification
sub-classification: primary component affected
e.g. B cells, T cells, combined (both B & T)
often T cell defects impair antibody production
defects in lymphocyte development or activation
Major B lymphocyte disorders: - list
X-linked agammaglobulinaemia (Bruton’s disease) Common variable immunodeficiency (CVID) Selective IgA deficiency IgG2 subclass deficiency Specific Ig deficiency with normal Igs
X-linked Agammaglobulinaemia - define and describe effects
Bruton’s disease defect in btk gene (X chromosome) encodes Bruton’s tyrosine kinase block in B-cell development (stop at pre-B cells) recurrent severe bacterial infections
Btk - function
Btk needed for pre-B cell receptor signalling
X-linked Agammaglobulinaemia - investigations
- B cells absent / low; plasma cells absent
- all Igs absent / very low
- T cells and T cell-mediated responses normal
X-linked Agammaglobulinaemia - treatment
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
Predominant T cell disorders:
DiGeorge syndrome
Wiskott-Aldrich syndrome
Ataxia-telagiectasia
SCID - define
Combined immunodeficiencies:
Severe Combined ImmunoDeficiency (SCID)
- involves both T and B
- 50-60% X-linked; rest - autosomal recessive
SCID - Presentation:
well at birth; problems > 1st month diarrhoea; weight loss; persistent candidiasis severe bacterial/viral infections failure to clear vaccines unusual infections (Pneumocystis, CMV)
SCID - causes
common cytokine 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 & deoxy-ATP => toxic for rapidly dividing thymocytes
SCID - investigations
Lymphocyte subsets: T, B, NK (% and numbers) => low total lymphocyte count => SCID sign!
Pattern: very low/absent T; normal/absent B, sometimes also absent NK (γ-chain defect affecting IL-15 receptor)
Igs low
T cell function ↓ (proliferation, cytokines)
SCID - treatment
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)
SCID - outcome
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
DiGeorge syndrome (thymic hypoplasia): - define and describe effects
22q11 deletion => failure development 3+4th pharyngeal pouches
complex array of developmental defects
dysmorphic face: cleft palate, low-set ears, fish-shaped mouth
hypocalcaemia, cardiac abnormalities
variable immunodeficiency (absent/reduced thymus => affects T cell development)
Wiskott-Aldrich syndrome (WAS): - define and describe effects
X-linked
defect in WASP (protein involved in actin polymerisation => defect in signalling)
thrombocytopaenia, eczema, infections
progressive immunodeficiency (T cell loss)
progressive ↓ T cells; ↓ T cell proliferation
Ab production (↓ IgM, IgG; high IgE, IgA)
Ataxia-Telangiectasia (AT): - define
autosomal recessive
defect in cell cycle checkpoint gene (ATM) => sensor of DNA damage => activates p53 => apoptosis of cells with damaged DNA
ATM gene stabilises DNA double strand break complexes during V(D)J recombination => defect in generation of lymphocyte antigen receptors & lymphocyte development
Ataxia-Telangiectasia (AT): - describe effects
progressive cerebellar ataxia (abnormal gait)
typical telangiectasia (ear lobes, conjunctivae)
immunodeficiency
increased incidence of tumours later in life
defects in production of switched Abs (IgA/G2)
T cell defects (less pronounced) <= thymic hypoplasia
upper & lower respiratory tract infections
autoimmune phenomena, cancer
Phagocyte defects: - describe types and list examples
quantitative (↓ number) qualitative Chronic granulomatous disease Chediak-Higashi syndrome Leucocyte adhesion defects (LADs)
Chronic granulomatous disease - define
Defective oxidative killing of phagocytosed microbes; mutation in phagocyte oxidase (NADPH) components
as assembly of NADPH oxidase = superoxide anion in the activated phagocyte
CGD - define
Phagocyte defects - CGD
formation of granulomas (wall off microbes)
CGD - diagnosis
Diagnosis:
Tests that measure oxidative burst: NBT test (nitroblue tetrazolium reduction) Flow cytometry assay dihydrorhodamine
Chediak-Higashi syndrome - define
rare genetic disease
defect in LYST gene (regulates lysosome traffic)
neutrophils have defective phagocytosis
repetitive, severe infections
Chediak-Higashi syndrome - explain the cause of recurrent infections
Defect phagosome-lysosome fusion => defective killing of phagocytosed microbes => recurrent infections
Chediak-Higashi syndrome - diagnosis
decreased number neutrophils
neutrophils have giant granules
LAD (leucocyte adhesion deficiency) - define
defect in β2-chain integrins (LFA-1, Mac-1)
defect in sialyl-Lewis X (selectin ligand)
delayed umbilical cord separation => diagnosis defect in β2-chain integrins (LFA-1, Mac-1)
LAD (leucocyte adhesion deficiency) - presentation
Presentation:
=> skin infections, intestinal + perianal ulcers
LAD (leucocyte adhesion deficiency) - investigations
↓ neutrophil chemotaxis
↓ integrins on phagocytes (flow cytometry)
Complement deficiencies - effect and symptoms
can affect different complement factors severe/fatal pyogenic infections (C3 deficiency)
predisposition to infection with different pathogens
symptoms differ depending on C factor affected
Complement deficiencies - describe examples
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) hereditary angioneurotic oedema: failure to inactivate complement (deficiency in C1 inhibitor); intermittent acute oedema skin/mucosa => vomiting, diarrhoea, airway obstruction
Complement deficiencies - investigations
complement function: CH50 (haemolysis)
measure individual components
PID: treatment principles - aims
Aims:
- replace defective/absent component of IS
- minimise/control infection
prompt treatment of infection
prevention of infection: isolation, antibiotic prophylaxis, vaccination (not live vaccines!)
good nutrition
PID: treatment principles - examples
Immunoglobulin replacement therapy
Bone marrow transplantation
Gene therapy
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
Secondary Immunodeficiency - list types of infections with examples for each
viral: HIV, CMV, EBV, measles, influenza
chronic bacterial: TB, leprosy
chronic parasitic: malaria, leishmaniasis
acute bacterial: septicaemia
Secondary Immunodeficiency - list examples of malignancies
Myeloma
Lymphoma (Hodgkin’s, non-Hodgkin’s)
Leukaemia (acute or chronic)
Secondary Immunodeficiency - explain the effect of extremes of age
Prematurity
- infants < 6 months => maternal IgG
- premature delivery: interrupts placental transfer of IgG => infant Ig deficient
Old age
- decline in normal immune function
