Primary Immunodeficiencies Flashcards
name the 4 main components of the immune system and their immune mechanism
B cells and antibodies (humoral, specific immunity)
T cells (cellular, specific immunity)
Phagocytes (innate immunity)
complement system (innate immunity)
what are primary immunodeficiencies?
- Group of > 300 rare, chronic disorders in which part of the body’s immune system is missing or functions improperly
- Caused by single genetic defects
- May affect a single part of the immune system or more components of the immune system
main causes of primary immunodeficiencies in europe
predominately antibody disorders predominantely T cell disorders phagocyte disorders other well defined PIDs complement deficiencies auto-immune and immune dysregulation syndromes auto-inflammatory syndromes unclassified
what are secondary immunodeficiences
- Components of the immune system itself are all present and functional.
- Acquired diseases affecting the immune system and/or treatments negatively influencing the immune system.
- Caused by environmental/iatrogenic insults.
- Most well-known examples are HIV infection and patients treated for malignancies.
- Much more common than primary immunodeficiencies.
causes of secondary immunodeficiencies: environmental
malnutrition
trauma
burns
causes of secondary immunodeficiencies: disease
infection diabetes renal failure asplenia malignancies (leukaemia, lymphoma)
causes of secondary immunodeficiencies: iatrogenic
surgery
splenectomy
drugs (immunosuppressive, antirheumatic, antiepileptic)
3 categories of primary immunodeficiencies
antibodies deficiencies
cellular immunodeficiencies
innate immune disorders
primary immunodeficiencies: antibody deficiency
characterised by a deficiency of one or more (sub)classes of antibodies e.g. IgG, IgA, IgM, IgG2 due to defective B cells
or
absence of mature B cells
primary immunodeficiencies: cellular immunodeficinces
characterised by impaired T cell funciton or the absence of normal t cells
primary immunodeficiencies: innate immune disorders
defects in phagocyte function
complement deficiencies
absence or polymorphisms in pathogen recognition receptors
infections in primary immunodeficiencies: antibody deficiencies
recurrent bacterial infections of the upper and/or lower RT
s. pneumoniae, H. influenzae
infections in primary immunodeficiencies: cellular immunodeficiencies
unisal or opportunistic infections often combined with failure to thrive
pneumocystic jirovecii, CMV pneumonia
infections in primary immunodeficiencies: innate immune disorders
defects in phagocyte function: s. aureus (sepsis, skin lesions, abscesses internal organs) aspergillus infections (lung, bones, brain)
complement deficiencies
n. miningitidis
consequences of neutrophil defects
- Absence of neutrophils > congenital neutropenia
- Adhesion > leucocyte adhesion defect
- Recognition and Phagocytosis > deficiencies of PRR
- Intracellular Killing > chronic granulomatous disease
describe hereditary angioedema
• C1-inhibitor deficiency (autosomal dominant)
• Recurrent episodes of painless, non-pitting, non-pruritic, non erythematous swellings
• Subcutaneous tissues, intestines, oropharynx
•
Acute emergency management of:
•
Pharyngeal/laryngeal obstruction
•
Acute abdominal pain
•
C1-inhibitor infusion OR fresh frozen plasma
•
(steroids, antihistamines ineffective)
disorders of adaptive immunity: B cells
- Absence of mature B-cells due to maturation stop in the bone marrow (BTK mutation)
- Absence of immunoglobulin production
- Absence of specific immunoglobulins and/or subclasses
- IgG, IgA, IgM, IgG1, IgG2, IgG3, IgG4
- Absence of functional antibodies (upon immunisations
disorders of adaptive immunity: T cells
- Isolated T-cell subset deficiencies (CD3, CD4, CD8)
- Combined deficiencies (severe combined immunodeficiency)
- Syndromal immunodeficiencies
describe with a diagram b cell maturation and defects
see notes
what is 22q11 deletion syndrome aka
diGeorge
what is 22q11 deletion syndrome
• Hemizygous 22q11.2 deletion • Most common microdeletion syndrome • de novomutations (10% deletion identified in a parent) • Highly variable expression • 1:4000 (Down syndrome 1:1200) • UK/Ireland: 10,000-15,000 affected • 2ndmost common cause of developmental delay and major congenital heart disease (after DS)
clinical presentation of 22q11 deletion syndrome
• Congenital cardiac anomalies • Palatal defects (affecting feeding and speech) • Characteristic facial features • Immunodeficiency –Thymus a-/hypo-plasia • Hypocalcaemia • Developmental disabilities • Learning disabilities • Behavioralproblems • Psychiatric illness • Structural abnormalities (renal, eye, dental, skeletal, brain, GI-tract) • Haematological & AI disorders
physical appearance in 22q11 deletion syndrome
- Short forehead
- Hooded eyelids with upslanting palpebral fissures
- Malar flatness
- Bulbous nasal tip with hypoplastic alea nasi
- Protuberant ears
immune deficiency in 22q11 deletion syndrome
• Recurrent RTI’s during infancy • low T-cell numbers (+ qualitative defects) • low IgA and IgM • reduced antibody responses • Autoimmune phenomena (30%) • anaemia/thrombocytopenia • juvenile chronic arthritis (JIA; low IgA) • Raynaud’s • thyroid disease
complete diGeorge anomaly
diGeorge + thymus aplasia
fatal < 2
atypical complete diGeorge anomaly
oligoclonal t cells, rash, lymphadenopathy
t cells can reject transplant
typical complete diGeorge anomaly
very low t cell numbers, no rash
may develop into atypical phenotype
infections in: adaptive CD4 def
pneumocystitis spp
ophthalmic pneumocystosis pneumocystitis pneumonia hepatosplenic infiltrates renal pneumocystosis bone marrow infiltrates
infections in: innate neutrophil disorders
aspergillus spp
cerebral aspergillosis kerattis sinusitis allergic and invasive pulmonary aspergillosis aspergilloma invasive aspergillosis osteomyelitis cutaneous aspergillosis
infections in: systemic innate (phagocytic disorders)/mucosal addaptice (IL-17 response)
candida spp
cerebral abscess endopthalmitis thrush oesphagitis endocarditis candidemia hepatic abscess urinary candidiasis vilvovaginal candidiasis osteomyelitis cutaneous candidiasis onychomycosis
infections in: adaptive CD4 def cryptococcus spp
meningitis cerebral abscess endophthalmitis pulmonary infiltrates endocardititis crpytococcemia renal abscess subcut abscess
invasive fungal infections in PID
- Presenting symptom of primary immunodeficiency
- In children with neutropenia due to leukaemia and/or chemotherapy
- Invasive candidiasis in premature neonates due to immature (but physiological) immune system
- In children admitted to PICU and treated with broad spectrum antibiotics and/or abdominal surgery
management of PID
• Symptomatic treatment = prevention of infections • Causative • Immunoglobulin substitution • Gene therapy (ADA-SCID) • Stem cell transplant (CGD) • Thymus transplant (diGeorge) • Genetic counselling & prenatal diagnosis
