Immunodeficiency Flashcards
define immunodeficiency
there are 2 types: primary and secondary
Primary (congenital): defect in immune system
Secondary (acquired): caused by another disease
Clinical features:
- recurrent infections, severe infections
- unusual pathogens, unusual sites
describe the warning signs and symptoms of PID?
sometimes patient has a family history of primary immunodeficiency
Symptoms aren’t clear cut
Infections often affect the upper respiratory infection
Primary Immunodeficiencies
- Usually genetic (defect in genes required for proper functioning of the immune system)
- Infrequent but can be life-threatening
Adaptive immune system: T and B cells - often T cell defects impair antibody production, also defects in lymphocyte development or activation
Innate immune system: phagocytes, complement
50% of primary cases are related to antibody defects
T cell defects impair antibody production – why?
Because for certain Ig classes, B cells need signals from T helper cells to produce antibodies
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
describe X-linked Agammaglobulinaemia (major B lymphocyte disorder)
defect in btk gene (X chromosome) that encodes Bruton’s tyrosine kinase
- needed for pre-B cell receptor signalling, so defect blocks B cell development so they stop at pre-B cells
recurrent severe bacterial infections autoimmune diseases (35% of patients)
Investigations:
- B cells absent / low; plasma cells absent
- all Igs absent / very low
- T cells and T cell-mediated responses normal
Treatment:
- subcutaneous Ig weekly
- prompt antibiotic therapy (URI /LRI) - can’t produce any or sufficient amounts of antibodies, so need Ig replenishment as part of the treatment
- Do not give live vaccines - patients antibody levels are absent or very low, so giving a live vaccine will mean the patient will actually contract the disease
IgG and IgA
IgG can transfer from the mother to the fetus during pregnancy, and IgA can transfer from the mother to the fetus during breastfeeding
types of Primary Immunodeficiencies
Combined immunodeficiencies:
Severe Combined ImmunoDeficiency (SCID)
Predominant T cell disorders:
DiGeorge syndrome
Wiskott-Aldrich syndrome
Ataxia-telagiectasia
Severe Combined ImmunoDeficiency (SCID)
Survival is above 80% with an early diagnosis
involves both T and B
- 50-60% X-linked; rest - autosomal recessive
Presentation:
well at birth; problems > 1st month diarrhoea; weight loss severe bacterial/viral infections failure to clear vaccines unusual infections (Pneumocystis, CMV)
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 causes?
common cytokine receptor γ-chain defect (signal transducing component of receptors for IL-2, IL-4, IL-7, 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 ( immune cell present in the thymus, before it undergoes transformation into a T cell)
SCID - treatment
isolation => to prevent further infections
Do not give live vaccines !
Blood products from CMV-negative donors - CMV-negative donors – if the donor is CMV positive the patient can then contract the virus - dangerous
IVIg replacement
Treat infections
Bone marrow/haematopoietic stem cell transplant
Gene therapy (for ADA and γ-chain genes)
DiGeorge syndrome
22q11 deletion, thymic hypoplasia - T cells mature in the thymus but here the thymus is not developing properly
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):
defect in a gene located on X chromosome, encodes the Wiskott-Aldrich (WASP) protein, involved in cytoskeletal remodelling via actin polymerisation.
Not just a defect in this protein, there are defects in other pathways – for example the generation of platelets, leading to thrombocytopaenia
progressive immunodeficiency, decreased T cell and T cell production
Ab production (↓ IgM, IgG; high IgE, IgA)
high IgE = eczema
Ataxia-Telangiectasia (AT):
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
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
symptoms:
progressive cerebellar ataxia (abnormal gait)
typical telangiectasia (ear lobes, conjunctivae)
immunodeficiency
increased incidence of tumours later in life
(primary immunodeficiencies)
Defects in innate immunity:
- phagocyte defects - decrease in phagocyte number or phagocyte “quality”
Chronic granulomatous disease
Chediak-Higashi syndrome
Leucocyte adhesion defects (LADs)
- complement defects
(Phagocyte defects)
Chronic granulomatous disease
impaired generation of oxidation reactive species which kill phagocytosed microbes
mutation in phagocyte oxidase (NADPH) components
assembly of NADPH doesn’t occur, generation of superoxide anion doesn’t happen - so certain pathogens cannot be destroyed properly by macrophages and neutrophils
formation of granulomas (wall off microbes)
TEST - NBT test (nitroblue tetrazolium reduction)
Take some neutrophils and incubate them with nitroblue tetrazolium and activate them and see if they will produce reactive oxygen species.
The ROS will cleave this dye, producing a blue colour – so patients who have the deficiency won’t produce the blue.
TEST -Dihydrorhodamine assay
dihydrohodamine cleaved and fluorescence occurs – doesn’t happen in someone with a deficiency
(Phagocyte defects)
Chediak-Higashi syndrome
rare genetic disease
defect in LYST gene (regulates lysosome traffic)
neutrophils have defective phagocytosis
Phagosomes won’t be able to fuse with lysosomes so the enzymes from the lysosomes won’t have access to the pathogens so they can’t be eliminated and the patient will get repetitive, severe infections
decreased number neutrophils
neutrophils have giant granules
(Phagocyte defects)
Leucocyte adhesion defects (LADs)
delayed umbilical cord separation => diagnosis defect in β2-chain integrins (LFA-1, Mac-1)
Presentation:
=> skin infections, intestinal + perianal ulcers
↓ neutrophil chemotaxis
↓ integrins on phagocytes (flow cytometry)
Complement deficiencies:
can affect different complement factors severe/fatal pyogenic infections (C3 deficiency)
predisposition to infection with different pathogens, symptoms differ depending on C factor affected
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
Deficiency in c1 inhibitor means the classical pathway is activated and will cause inflammation when its not needed
PID: treatment principles
Aims:
- minimise/control infection
- replace defective/absent component of IS
prompt treatment of infection
prevention of infection: isolation, antibiotic prophylaxis, vaccination (not live vaccines!)
good nutrition
Immunoglobulin replacement therapy
Bone marrow transplantation
Gene therapy
Secondary Immunodeficiency
Infections: viral, bacterial Malignancy Extremes of age Nutrition (anorexia, iron deficiencies) Chronic renal disease Splenectomy Trauma/surgery, burns, smoking, alcohol Immunosuppressive drugs
infections:
viral: HIV, CMV, EBV, measles, influenza
chronic bacterial: TB, leprosy
chronic parasitic: malaria, leishmaniasis
acute bacterial: septicaemia
Malignancy:
Myeloma
Lymphoma (Hodgkin’s, non-Hodgkin’s)
Leukaemia (acute or chronic)
Extremes of age:
Prematurity - premature delivery: interrupts placental transfer of IgG => infant Ig deficient
Old age - decline in normal immune function
