Immunodeficiency Flashcards
What are the features of innate immunity?
Structures shared by microbes, recognised as patterns - PAMPs
Germline encoded recognition receptors
Immediate speed of response
No memory
Complement components
Cellular components - dendritic cells, neutrophils, macrophages + NK, NKT , B1 , epithelial and mast cells
What are the features of adaptive immunity?
Wide range of very particular molecules or fragments of molecules
Somatic mutation results in wide range of specificities and affinities
Time for cell movement and interaction between cell types
Efficient memory
Antibodies
Lymphocytes
What are the barriers to infection in innate immunity?
Physical/ mechanical and biological
What are the antigen presenting cells of the immune system?
Macrophages and dendritic cells
What are the functions of the B cell?
Differentiates into plasma cells producing antibodies
Opsonization
Complement activation
Toxin neutralisation
What are the functions of the T cell?
Helper T cells provide B cells with signals necessary for antibody production
Cytotoxic T cells destroy virally infected cells and tumour cells
T regulatory cells suppress auto-reactive T cells
What are the functions of phagocytes?
Engulfs and destroys microbes
Antigen presentation
What are the functions of complements?
Opsonization
Terminal components create the membrane attack complex
What is the function of NK cells?
Destroys virally infected cells and tumour cells
How is immunodeficiency classified?
Primary (intrinsic defect) - innate or adaptive (congenital or late onset)
Secondary (underlying disease) - production or loss (always acquired)
What are the consequences of primary immunodeficiency?
Infections, autoimmunity, inflammation, atopy and malignancy
Often a delay in diagnosis
What are some consequences of primary immunodeficiency on T cells and phagocytes?
T cell - pneumocystis jerovecii pneumonia
Phagocyte - delayed separation of the umbilical cord (LAD) and disseminated NTM
When is primary immunodeficiency suspected?
FH, recurrent/ chronic infection, infections with unusual organisms, early-onset eczematous skin rashes, early-onset autoimmunity and failure to thrive
What is defined as recurrent infections?
4 or more ear infections a year
2 or more serious sinus infections, pneumonias or deep seated infections/ sepsis per year
What are the investigations in primary immunodeficiency in B cells?
FBC with differential
Immunoglobulin levels and subset
Flow cytometry for B cell subset
Functional antibody responses against vaccines
What are the investigations in primary immunodeficiency for T cell?
FBC with differential
Flow cytometry for T cell subset
T-cell proliferation to mitogens and antigens
What are the investigations for phagocytes in primary immunodeficiency?
FBC with differential
Neutrophil oxidative burst assay
Th1 cytokines and autoantibodies
What are the investigations in primary immunodeficiency for complements?
Individual complement components
CH50 and AP50
What are the investigations in primary immunodeficiency for NK cells?
Flow cytometry for NK cell numbers
NK cell functional assays
What is the management for primary immunodeficiency?
Antimicrobials - Prophylactic and aggressive treatment for clinical infection
Replacement - immunoglobulin replacement therapy
HSCT - haematopoietic stem cell transplant
Describe the epidemiology of primary antibody deficiency
Commonest form of primary immune deficiencies
Occurs in children and adults - may be congenital or late onset
More common to present in 4-15 yrs and 16-60 years
Most people who fail to produce protective antibodies present after 10 years of age
What are the clues from presentation in primary antibody deficiency?
Recurrent sinus/ chest infections, second system involvement, infections due to common bacteria, fungal + viral infections are uncommon and non-infectious features common (ITP)
What is the management for primary antibody deficiency?
Replace IgG - IV or SC
Antibiotics
Immunisation
Look after lungs - physio and exercise
Treat cause
Monitor and support
Describe immunoglobulin replacement
IV 2 to 3 weekly or SC weekly/ twice weekly
Aim to prevent infections - need 400-600mg per month
Derived from plasma pool
Describe transient hypogammaglobulinemia
Physiological IgG trough - infant has IgG equal to mother at birth then catabolism of maternal IgG outstrips IgG synthesised by the newborn
As maternal acquired antibodies fall, infant becomes susceptible to recurrent pyogenic infections
Describe Burton’s disease
XLA - X-linked so affects young boys
Failure to differentiate further from pre-B-lymphocyte so get recurrent pyogenic infections (no plasma cells or antibodies)
Mutation on BTK gene
What is the management of Burton’s disease?
Immunoglobulin replacement
Antibodies
Describe Hyper IgM syndromes - CD40 ligand deficiency and AID deficiency
Severe antibody deficiency but normal B cells and normal/ raised serum IgM levels
Failure of expression or functional activity of ligand results in failure of switching and poor organisation of germinal centres
Is Hyper IgM syndromes autosomal or X-linked?
X-linked due to CD40 ligand deficiency on T cells
Pure B cell form is deficiency of enzyme AID
Describe common variable immunodeficiency
Heterogenous group of disorders - variable nature of conditions
Most are not diagnosed until adulthood
Low serum levels of IgG and IgA with normal/ reduced IgM and B cells
Most live normal lives on immunoglobulin replacement
What is the presentation seen in common variable immunodeficiency?
Hypogammaglobulinemia causes recurrent infections - all patients
Polyclonal lymphoproliferation - lymphadenopathy
Autoimmune cytopenia - ITP and AIHA
Unexplained enteropathy
No disease related complications
Describe selective IgA deficiency
Commonly picked up on incidental findings
Undetectable or very low serum IgA levels with normal IgG + IgM and production of normal antibodies to pathogens
Most are healthy
What is the clinical relevance of selective IgA deficiency?
Coeliac disease diagnosis - anti-TTG IgA
Associated to development of coeliac disease
Anaphylaxis risk with blood products
What are the adaptive causes of primary immunodeficiency?
Antibody deficiency
Combined deficiency - depressed T cell function is usually accompanied by variable B-cell abnormalities
What are 2 examples of primary immunodeficiency?
Di-George syndrome
Wiskott-Aldrich syndrome
Describe Di-George syndrome
Thymus is abnormal - CD3 cells are low
If CD3 cells are absent - stem cell transplant is urgent
22q11del
CATCH22
Variable T cell quantities and normal B cell levels
What does CATCH 22 stand for in DI-George syndrome?
Cardiac defects
Abnormal faces
Thymic aplasia
Cleft palate
Hypoparathyroidism
Describe Wiskott-Aldrich syndrome
Mutation in WAS gene - leukocytes and platelet unable to recognise cytoskeleton
T-cell receptor function is affected
X-linked
Combined B and T cell disorder with impaired antigen presentation
What is the triad of Wiskott-Aldrich syndrome?
Immunodeficiency - recurrent pyogenic infections
Thrombocytopenia - bleeding
Eczema
Describe SCID - severe combined immunodeficiency
Immunological emergency
Diminished T cell function and abnormal B cell function
Absolute lymphocyte count is less than 2x10^9
What is the presentation of SCID?
Infections within first few months, failure to thrive and immune dysregulation
Chronic diarrhoea and chronic respiratory virus is common
Lymphopenia is present so rule out HIV
What is the normal lymphocyte count in children?
Fivefold higher than adults
Higher proportion of B cells
Fewer CD8 cells at birth
Absolute counts are essential
What are the types of SCID?
Reticular dysgenesis - autosomal recessive and no stem cells
Adenosine deaminase - autosomal recessive + toxic metabolites build up and kill precursor cells
Gamma chain - X-linked
RAG1/2 - autosomal recessive and lack of VDJ recombination
Multiple defects
Describe SCID newborn screening test
Heel prick test - DNA extraction - PCR amplification
If normal TREC:B actin then no further action
If low then urgent assessment by immunologist
What is the management of SCID?
Haematopoietic stem cell transplantation (HTC)
Gene therapy
Enzyme replacement
What are the professional phagocytic cells?
Monocyte/ macrophage, neutrophils, dendritic cells and mast cells
Involved in extravasation, recognition and phagocytosis
How is neutropenia classified?
Decreased production with marrow hypoplasia - can be primary or secondary
Increased destruction with marrow hyperplasia
What is G-CSF involved in?
Proliferation, differentiation, maturation, suppression of apoptosis and functional activation
What is the extravasation?
Chemoattraction of leukocyte - tethering _ rolling - migration causing inflammation and chemokines
Describe leucocyte adhesion deficiency (LAD)
Failure to adhere to endothelial cells and can’t transverse into tissues
Skin infections, gingivitis, deep abscesses, peritonitis, osteomyelitis and delayed separation of umbilical cord
What are the steps of recognition?
Ligand coated particle
Phagocyte surface receptors
Receptor cluster
Activation and entry then signal
Describe chronic granulomatous disease
Reduced oxidative metabolism - failure to kill pathogens
DHR screening test
X linked, recurrent infection, staph skin infections, lymphadenopathy and granuloma formation
What are the 3 pathways of complements?
Classic - antigen-antibody reaction
Lectin - mannose binding lectin
Alternative - microbes or injured tissue
What is the affect of immune-complex diseases?
Recurrent bacterial infection and Neisseria infections
What is an example of immune complex disease?
Hereditary angioedema - deficiency of C1 inhibitor and low C4 levels
What are pattern recognition receptors?
Are strategically located within cells
Each receptor recognises molecular patterns exclusive to pathogens or molecular patterns that are in an inappropriate compartment
Describe TLR3 deficiency - HSV encephalitis
dsRNA made as a biproduct of HSV replication
TLR3 sense dsRNA to initiate immunological and antiviral response
What is the aetiology of secondary immunodeficiency?
Production - malnutrition, drugs (chemo and immunosuppressants), malignancy (CLL and myeloma) and infections (HIV)
Loss - nephrotic syndrome, burns and protein-losing enteropathy
