Immune Flashcards
Why does SCID only present at 3 months of age?
- Why 3 months? Because prior to 3 months, there is active transport of maternal IgG across placental to help protect baby
Describe ADA def SCID. What will the T, B and NK cells be?
ADA deficiency
- 16.5% of all SCID
- Autosomal recessive
- Adenosine deaminase (ADA)
- Enzyme required for cell metabolism in lymphocytes
- Lack of this enzyme → accumulation of toxic productions e.g adenosine, 2deoxyaenosine, deoxyadenosine-triphosphate which kills lymphocyte
- Phenotype
- Low/absent T
- Low/absent B
- Low/absent NK
What is the most common form of SCID? Describe the molecular protein and clinical picture.
X-linked SCID
- Most common form of SCID
- 45% of SCID
- Mutation in gamma chain of IL2 receptor on chromosome Xq13.1
- This is shared between receptors for IL2, IL4, IL7, IL9, IL15 and IL21
- Inability to respond to cytokines, causing early arrest of T cell and NK cell development, production of immature B cells
- Phenotype
- Low/absent T
- Low/absent NK
- Normal or increased B but low Igs (because immature)
Clinical phenotype of SCID
- Infection of all types
- Candidate and diarrhoea common early features
- Bacterial, viral, fungal, protozoal
- Failure to thrive
- Unusual skin disease
- Colonisation of infant’s empty bone marrow by maternal lymphocytes
- Graft v host disease
- FH of early infant death
- Clinical features
- High forehead
- Low set, abnormally folded ears
- Cleft palate, small mouth and jaw
- Hypocalcaemia
- Oesophageal atresia
- Underdeveloped thymus
- Complex congenital heart disease
DiGeroge Syndrome
- Deletion of 22q11.2 → developmental defeat of pharyngeal pouch (blue box)
- Underdeveloped thymus → reduced T cells but normal B cells
- Immune function is usually only mildly impaired and improves with age
Common clinical picture of a T cell def (primary or secondary)
- Viral infections (CMV)
- Some bacterial infections (esp intracellular pathogens)
- Mycobacteria TB, Salmonella, Listeria
- Parasite infections
- Toxoplasma
- Fungal infection
- Pneumocystitis jiroveci (also associated with hyperIgM even though this is a B cell problem because of abnormal T cell function present in this condition)
- Early malignancy
- CD4 deficiency will impact development of T cell dependent antibody response
Common clinical picture of a B cell def (primary or secondary)
- Lack of antibodies!
- Bacterial infections
- Eep encapsulated bacteria (H.influexa, Strep pneu, Strep pyrogens, Pseudomonas)
- Some viral - enterovirus
- Toxins
- Tetanus, diphtheria
Skin barrier against infection (4)
- Tightly packed keratinised cells
- Limits colonisation by microbes
- Physiological factors
- Low pH
- Low oxygen tension
- Sebaceous glands
- Hydrophobic oils repel water and microbe
- Lysozyme destroys structural integrity of bacterial cell wall
- Ammonia and defensives have anti-bacterial properties
- Commensal bacteria
- Compete of pathogenic microbes for scarce resources
- Produce fatty acids and batericidins that inhibit growth of pathogen
Mucosal barriers against infection (2)
- Secretes mucus
- Physical barrier to trap invading pathogens
- Secretory IgA prevents bacteria and viruses attaching to and penetrating epithelial cells
- Lysozyme and antimicrobial peptides directly kill invading pathogen
- Lactoferrin acts to starve invading bacteria of iron
- Cilia
- Trap pathogens and contribute to removal of mucus
- Assisted by physical manoeuvres such as sneezing and coughing
Cells of the innate immune system (7 types and 4 classes)
- Polymorphs - neutrophils, eosinophils, basophils
- Monocytes and macrophages
- NK cells
- Dendritic cells
Soluble components of innate immune system (3-4 types)
- Complement
- Acute phase protein e.g. CRP
- Cytokines and chemokines
- Cytokines increase vascular permeability
- Chemokine’s attract neutrophils
Receptors expressed on polymorphs - neutrophils, eosinophils and basophils (4)
- Expresses cytokines and chemokine receptors - detect inflammation
- Expresses pattern recognition receptors - detect pathogens
- Express Fc receptors for Ig - detect immune complexes
Function of polymorphs (innate immunity)
- Capable of phagocytosis/oxidative and non-oxidative killing - particularly neutrophils
- Release enzymes, histamine, lipid mediators of inflammation from granules
- Secrete cytokine and chemokine to regulate inflammation
Describe oxidative killing in macrophages and neutrophils
- NAPDH oxidase complex convert oxygen to ROS - superoxide and H2O2
- Myeloperoxidase catalyses production of hydrochlorous acid from H2O2 and chloride
- Hydrochlorous acid is a very effective oxidant and anti-microbial
Describe non-oxidative killing by phagocytes e..g neutrophils and macrophages
- Release of bactericidal enzymes e.g lysozyme and lactoferrin (depletes pathogen of iron) into phagolysosome
- Enzymes are present in granules
- Each has unique antimicrobial spectrum
- Results in broad coverage against bacteria and fungi
How does phagocytes recognise a pathogen?
- Recognition of pathogen by pattern recognition receptors
- Toll-like receptors and mannose receptors
- Generic pathogen-associated molecular patterns (PAMPS) such as bacterial sugar, DNA, RNA
- Fc receptors for Fc portion of Ig to allow recognition of immune complexes
NK cell function (2)
- When inhibitory signals are lost (altered) e.g when cells are infected or becomes malignant. NK cells become activated and kills those altered cells
- Secrete cytokines to regulate inflammation - promote dendritic cell function
Background:
- Present within the blood and can migrate to inflamed tissue
- Innate immunity but a lymphocyte
- Inhibitory receptors for self-HLA and prevent inappropriate activation by normal self
- Activator receptors including natural cytotoxicity receptors that recognise heparin sulphate proteoglycans
- But generally inhibitory signal > activator signals
Functions of T helper (CD4) cells (2)
- Immunoregulatory functions via cell-cell interactions and expression of cytokines
- Development of full B lymphocytes and some CD8+ lymphocyte response
Functions of CD8 T cells
- Specialised cytotoxic cells which kill cells directly (perforin, granzyme, Fas/FasL pathway)
- Secrete cytokines e.g. IFN-y, TNF-a
- Particularly impt. in the defence against viruses and tumours
What is immunological memory
Response to successive exposures is qualitatively and quantitatively different
- pool of memory T/B cells that are more easily activated (T and B)
- Secretes more antibodies (B) that are of higher specificity IgG instead of IgM
- B memory cells do not require CD4+ help
Express receptors that recognise peptides usually derived from intracellular proteins and expressed on HLA Class 1
CD8 T cells
Subset of lymphocytes that express Foxp3 and CD25
T reg
Subbed of cells that express CD4 and secret IFNa and IL2
Th1
Play an important role in promoting germinal centre reactions and differentiation of B cells in to IgG and IgA secreting plasma cells
T follicular helper cells