Immunodeficiencies Flashcards
4 main components of the immune defence system
B-cells and antibodies (humoral, specific immunity)
T-cells (cellular, specific immunity)
Phagocytes (innate immunity)
Complement system (innate immunity)
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
Secondary Immunodeficiencies
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.
Antibody Deficiencies
Characterized by a deficiency of one of more (sub)classes of antibodies (e.g. IgG, IgA, IgM, IgG2) due to defective B-cell function. There is an absence of mature B cells
Cellular Immunodeficiencies
Characterised by impaired T-cell function or the absence of normal T-cells
Innate Immune Disorders
Defects in phagocyte function
Complement deficiencies
Absence or polymorphisms in Pathogen Recognition Receptors
Presentation of antibody deficiencies
Recurrent bacterial infection of the upper and lower respiratory tract
S.pneumoniae, H.influenza
Cellular Immunodeficiencies presentation
Unusual or opportunistic infections often combined with failure to thrive
Pneumocystic Jirovecii, CMV (pneumonia)
Defects in phagocyte function presentation
Pneumonia, osteomyelitis, skin infections, liver abscesses, suppurating lymph nodes.
Features of infection of primary immunodeficiencies
Severe Persistant Unusual Recurrent Runs in the family
10 warning signs of primary immune deficiency
- Four or more new ear infection within 1 year for children, two or more for adults
- Two or more serious sinus infections
- Two or more bouts of pneumonia
- Chronic diarrhoea with weight loss and failure to grow normally
- Recurrent viral infections
- Persistent thrush or fungal infectiion
- Recurrent deep skin or organ abscesses
- Need for IV antibiotics to clear infections
- Two or more deep seated infection
- A family history of primary immune deficiency
Neutrophil Defects
Absence of neutrophils - congenital neutropenia
Adhesion - leucocyte adhesion defect
Recognition and phagocytosis - deficiencies of RR
Intracellular killing - chronic granulomatous disease
Complement cascade disorders
Bacterial infections will be the consequence
Nisseria meningiditis infection are at increased risk
Severe meningococcal sepsis
Hereditary Angioedema
An autosomal dominant disorder characterised by recurrent attacks of painless, non-pitting, non-pruritic, non-erythematous swellings in subcutaneous tissues, intestinal walls, larynx and oropharynx. It results due to deficiency of one of the major control proteins preventing inappropriate activation of the classical complement pathway (C-1 inhibitor)
Management of Hereditary Angioedema
Acute emergency management of:
Pharyngeal/laryngeal obstruction
Acute abdominal pain
C1-inhibitor infusion OR fresh frozen plasma
(steroids, antihistamines ineffective)
Pneumocystis infections
Adaptive CD4 defeciency
Aspergillus Infection
Innate Neutrophil disorders
Candida Infection
Systemic - innate disorders
Mucosal - adaptive (IL-17 response)
Cryptococcus infection
Adaptive CD4 deficiency
Disorders of B-cell immunity
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 T cell immunity
Isolated T-cell subset deficiencies (CD3, CD4, CD8) Combined deficiencies (severe combined immunodeficiency) Syndromal immunodeficiencies
22q11 deletion syndrome
Hemizygous 22q11.2 deletion
1:4000
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
Immune system disorders 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
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
Management of PID
Immunoglobulin substitution
Gene therapy (ADA-SCID)
Stem cell transplant (CGD)
Thymus transplant (diGeorge)
Antibiotic prophylaxis
Antiviral prophylaxis
Antifungal prophylaxis
Chronic Granulomatous Disease
Inherited X-linked or autosomal recessive disorder in which gene defects lead to dysfunction or absence of cytochrome b558 enzyme which is involved in the generation of neutrophil and macrophage superoxide and oxygen radicals. Intracellular killing is usually severely impaired. Fatal unless treated aggressively.
Leucocyte Adhesion Deficiency
Autosomal recessive disorder in which neutrophils fail to express adhesion molecule (CD11.CD18) which is required for neutrophils to adhere to vascular endothelium and thereby exit the blood into tissues. They can still produce normal blood polymorph leucocytosis in response to an infective stimulus. Bone marrow transplantation is useful treatment.
Myeloperoxidase Deficiency
An autosomal recessive disorder which causes mild impairment of phagocyte oxidative burst. This is mild and frequently asymptomatic.
Bacterial infections found in phagocytic disorders
Staphylococci, E.coli, salmonella, pseudomonas, serratia, nocardia
Aspergillus fungi
Physiological functions of complement
1) chemotaxis of phagocytes to sites of inflammation (C3a, C5a) 2) opsonisation (C3b, C4b)
3) lysis of micro-organisms (C5b-9 complex)
4) maintenance of solubility of Ag / Ab (C3b, C4b, C2)
Clinical features of C1,4,2,3 deficiencies
Immune complex disease
Infection
Clinical features of c3 or alternate pathway component deficiencies
Recurrent staph infection
Recurrent strep/Haemophilus infection
Recurrent meningococcal infection
C5,6,7,8,9 deficiency presentation
Recurrent neisserial infection
Type 1 hereditary angioedema
Decreased level of C1-hibitors
Type 2 Hereditary Angioedema
Normal levels of C1-inhibitor but the molecule is functionally defective.
Working classification of primary defects of adaptive immunity
1) Severe Combined Immune Deficiency (SCID)
2) Predominantly antibody deficiencies
3) Predominantly T cell deficiencies
4) Other (usually combined T & B) deficiencies
Severe Combined Immune Deficiency
Severe dysfunction or defective development of T and B cells. Occur due to defects in pluripotent stem cells, lymphoid stem cells or T & B cells themselves
Clinical features of severe combined immune deficiency
1:60,000 live births (conservative estimate) clues - usually well for first 3 months of life persistent superficial candida diarrhoea and failure to thrive chronic bronchiolitis interstitial pneumonitis overwhelming bacterial sepsis
Treatment of severe combined immune deficiency
Intensive supportive therapy with nutritional support, prophylactic and therapeutic antibiotics, anti-fungal and anti-viral therapy as required and immunoglobulin replacement therapy.
Bone marrow transplant
IgA deficiency
1:700 of population
Recurrent sinus and respiratory tract infections, GI disease, allergic symptoms and autoimmune disease.
due to deletion or mutation of the IgA gene. Sometimes occurs secondary to use of particular drugs such as phenytoin, penicillamine, gold or sulphasalazine.
IgG deficiency
low levels of all four IgG subclasses have been described. The only important well defined, clinical entity however is an association between IgG2 deficiency and recurrent respiratory tract infections.
Specific antibody deficiency
a specific, isolated inability to make antibodies against pneumococcal surface polysaccharide. Generally associated with mild infections of middle ear, sinusus and respiratory tract. All other immune effector defences (including other antibodies) are normal.
X-linked agammaglobinaemia
male infants, symptoms start at age 3-6 months, patients fail to make immunoglobulins of any class because of defective B cell maturation with mature B cells and plasma cells being absent from blood, bone marrow and tissues. Due to mutation of a single gene (Btk) which is essential for B cell maturation. T cell immunity normal. Presents with bacterial infections but these patients are also susceptible to Echovirus infection
Common variable Immune deficiency
symptom onset at any age but especially 3rd/4th decades. Low IgG & IgA with normal IgM. Infectious complications dominate but non-infectious complications are also common. Numerous genetic defects predispose to development of CVID and as a result the clinical presentations tend to be fairly heterogeneous. 20-30% of cases also have variable T cell deficiencies (and are therefore combined rather than simple antibody deficiencies).
