Immunodeficiency Flashcards
What are the 4 elements in the process of immunity?
- Recognition
- Interaction
- Elimination
- Control and regulation
What are the contributors to out immune defences?
- Barriers
- Innate immunity
- Adaptive immunity
What cells are involved in innate immunity?
- Macrophages
- Monocytes
- Neutrophils
- Mast cells
- NK cells
- APCs
What receptors are involved in innate immunity?
- Fc
- Complement -Mannose
- Toll-like
- C-type lectins
- Cytokine
What molecules are involved in innate immunity?
- Complement
- Acute phase proteins
- Chemokines
- Cytokines
What cells are involved in adaptive immunity?
- B cells
- T cells
What receptors are involved in adaptive immunity?
- Ig
- TCR
- HLA
- Cytokine
- Complement
- Toll-like
What molecules are involved in adaptive immunity?
- Immunoglobulins
- Cytokines
What are the 4 main components of immune defence mechanisms?
- B-cells and antibodies (humoral, specific immunity)
- T-cells (cellular, specific immunity)
- Phagocytes (innate immunity)
- Complement system (innate immunity)
What are primary immunodeficiencies?
- A group of >300 rare chronic diorders in which part of the body’s immune system is missing or functions improperly
- Caused by a single gene defect
- May affect a single part of the immune system or more components
What is the most common subtype of PID in Europe?
Antibody disorders
What are secondary immunodeficiencies?
- Components of the immune system are all present and functional but acquired disease affects the immune system and/or treatments negatively influence the immune system
- Much more common than PID
What causes SID?
- Caused by environmental/iatrogenic insults.
- Most well-known examples are HIV infection and patients treated for malignancies.
Give examples of causes of SID.
Environmental
- Malnutrition
- Trauma
- Burns
Disease
- Infection
- Diabetes
- Renal failure
- Asplenia
- Malignancy (leukaemia/lymphoma)
Iatrogenic
- Surgery
- Splenectomy
- Drugs (immunosuppressant’s, antiepileptic’s and antirhematics)
What are antibody deficiencies due to?
- Deficiency of 1 or more (sub)classes of antibodies (e.g. IgG, IgM, IgA, IgG2) due to defective B cell function
- Absence of mature B cells
What are cellular immunodefiencies due to?
Impaired T cell function or the absence of normal T cells
What are innate immune disorders due to?
- Defects in phagocyte function
- Complement deficiencies
- Absence of polymorphisms in pathogen recognition receptors
What infections are common in antibody deficiencies?
- Recurrent bacterial infections of the upper and/or lower respiratory tract
- S. pneumoniae, H. influenzae
What infections are common in cellular immunodeficiencies?
- Unusual or opportunistic infections often combined with failure to thrive
- Pneumocystic jirovecii, CMV (pneumonia)
What infections are common in defects of phagocyte function?
- S. aureus (sepsis, skin lesions, abscesses internal organs
- Aspergillus infections (lung, bones, brain)
What infection is common in complement deficiencies?
N. menigitidis
How can PID be recognised?
- Severe: requires hospitalisation or IV antibiotics
- Persistent: won’t completely clear up or clears very slowly
- Unusual: caused by an uncommon organism
- Recurrent: keeps coming back
- Runs in the family: others in your family have had similar susceptibility to infection
What are the warning signs for PID in children and adults?
2 or more= see GP
- 4 or more (children) or 2 or more (adults) new ear infections in 1 year
- 2 or more serious sinus infections within 1 year
- 2 or more bouts of pneumonia in 1 year (children) or recurrent (adults)
- Chronic diarrhoea with weight loss, and failure to grow normally or weight gain in children
- Recurrent viral infections
- Persistent thrush or fungal infection
- Recurrent deep skin or organ abscesses
- Need for IV antibiotics to clear infections
- 2 or more deep-seated infections
- Family history
What is the key role of innate immunity?
Phagocytosis
What neutrophil defects may occur?
- Absence of neutrophils > congenital neutropenia
- Adhesion > leucocyte adhesion defect
- Recognition and Phagocytosis > deficiencies of PRR
- Intracellular Killing > chronic granulomatous disease
What integrin complex is required for neutrophil adhesion?
CD11/CD18
What is necessary for neutrophil intracellular killing to take place?
NADPH-oxidase complex
What are the key components of the complement cascade?
- Chemotaxis of phagocytes to sites of inflammation (C3a, C5a)
- Opsonisation (C3b, C4b)
- Lysis of micro-organisms without cell wall (C5b-C9 complex)
What is hereditary angioedema caused by?
Autosomal dominant C1-inhibitor deficiency
What is hereditary angioedema characterised by?
- Recurrent episodes of painless, non-pitting, non-pruritic, nonerythematous swellings
- Can affect the subcutaneous tissues, intestines, oropharynx
How is hereditary angioedema treated?
- Acute emergency management of pharyngeal/laryngeal obstruction and acute abdominal pain
- C1-inhibitor infusion OR FFP
Give examples of disorders in 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
- Absence of functional antibodies (upon immunisations)
Give examples of disorders of T cells
- Isolated T-cell subset deficiencies (CD3, CD4, CD8)
- Combined deficiencies (severe combined immunodeficiency)
- Syndromal immunodeficiencies
What is the genetics of 22q11 deletion syndrome
- Hemizygous 22q11.2 deletion
- Most common microdeletion syndrome
- De novo mutations (10% deletion identified in a parent)
- Highly variable expression
What is the epidemiology of 22q11 deletion syndrome?
- 1:4000 (Down syndrome 1:1200)
- UK/Ireland: 10,000-15,000 affected
- 2nd most common cause of developmental delay and major congenital heart disease (after DS)
What is the 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
- Behavioral problems
- Psychiatric illness
- Structural abnormalities (renal, eye, dental, skeletal, brain, GI-tract)
- Haematological & AI disorders
What are facial characteristics of 22q11 deletion syndrome?
- Short forehead
- Hooded eyelids with upslanting palpebral fissures
- Malar flatness
- Bulbous nasal tip with hypoplastic alea nasi
- Protuberant ear
What immune system disorders are associate with 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
What are the subtypes of 22q11 deletion syndrome?
Complete DiGeorge anomaly
- = DiGeorge + thymus aplasia
- Fatal < age of 2 years
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
What immunodeficiency is pneumocystis spp. associated with?
Adaptive CD4 deficiency
What immunodeficiency is aspergillus spp. associated with?
Innate neutrophil disorders
What immunodeficiency is candida spp. associated with?
- Systemic: innate phagocytic disorders
- Mucosal: adaptive IL-17 response
What immunodeficiency is Cryptococcus spp. associated with?
Adaptive CD4 deficiency
Who are invasive fungal infections seen in?
- Presenting symptom of PID
- 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 broadspectrum antibiotics and/or abdominal surgery
How is PID managed?
Symptomatic treatment= prevention of infections
Causative
- Immunoglobulin substitution
- Gene therapy (ADA-SCID)
- Stem cell transplant (CGD)
- Thymus transplant (diGeorge)
Genetic counselling and prenatal diagnosis
