Immuno 1 - The immune response to infection/Primary immune deficiencies Part 1 Flashcards
Clinical features suggestive of immunodeficiency
• Infection o Two major or one major and recurrent minor infections in one year o Atypical organisms o Unusual site o Poor response to treatment
• Features to suggest primary immune deficiency
o FH
o Young age at presentation
o Failure to thrive
3 receptors that are expressed by cells of the innate immunity
• Express receptors for cytokines/chemokines to detect inflammation
• Express pattern recognition receptors to detect pathogens
o Pattern recognition receptors (Toll-like receptors or mannose receptors) – recognise generic motifs known as pathogen-associated molecular patterns (PAMPs) such as bacterial sugars, DNA, RNA
• Express Fc receptors for Ig to detect immune complexes
Which are the phagocytes
monocytes, macrophages, neutrophils, tissue dendritic cells, and mast cells
What do natural killer cells recognse
natural cytotoxicity receptors that recognise heparan sulfate proteoglycans
kill altered self as in malignant or virus infected cells - these cells downregulate their self-HLA molecules so that NK cells can be activated
Describe the functions of
Neutrophils
Macrophages
Natural killer cells
Dendritic cells
Neutrophils – polymorphonuclear cells capable of phagocytosing pathogens and killing by oxidative and non-oxidative mechanisms
Macrophages – derived from monocytes and resident in peripheral tissues
Natural killer cells – lymphocytes that express inhibitory receptors capable of recognizing HLA class I molecules and have cytotoxic capacity
Dendritic cells – immature cells are adapted for pathogen recognition and uptake whilst mature cells are adapted for antigen presentation to prime T cells
Microbial killing mechanisms – oxidative killing
- NADPH oxidase complex converts – Oxygen reactive oxygen species (superoxide, hydrogen peroxide)
- Myeloperoxidase catalyses – Hydrogen peroxide + Chloride hydrochlorous acid
Microbial killing mechanisms – non-oxidative killing
• Release of bactericidal enzymes e.g. lysozyme, lactoferrin into the phagolysosome
Lysozyme and antimicrobial peptides directly kill invading pathogens
Lactoferrin acts to starve invading bacteria of iron
Fates of neutrophils and macrophages after phagocytosis
- Process of phagocytosis depletes neutrophil glycogen reserves neutrophil cell death
- Macrophages survive and go on to communicate with T-cells
Describe
- Oxidative killing
- Non-oxidative killing
- Pathogen recognition
- Opsonisation
- Oxidative killing – describes killing mediated by reactive oxygen species generated by the action of the NADPH oxidase complex
- Non-oxidative killing – may be mediated by bactericidal enzymes such as lysozyme
- Pathogen recognition – is mediated by Toll like receptors which recognise pathogen associated molecular patterns
- Opsonisation – may be mediated by antibodies, complement components or acute phase proteins and facilitates phagocytosis
Reticular dysgenesis
Most severe form
AR SCID
• Failure of stem cells to differentiate along myeloid or lymphoid lineage
Mutation in mitochondrial energy metabolism enzyme adenylate kinase 2 (AK2)
Failure of production of – neutrophils, lymphocytes, monocytes/macrophages, platelets
Kostmann syndrome
• Specific failure of neutrophil maturation
mutation in HCLS1-associated protein X-1 (HAX1)
Congenital neutropenia
AR
Cyclic neutropenia
• Specific failure of neutrophil maturation
AD episodic neutropenia every 4-6 weeks
Mutation in neutrophil elastase (ELA-2)
Leukocyte adhesion deficiency
defect of phagocyte migration
o Deficiency of CD18
o CD11a/CD18 and CD11b/CD18 are usually expressed on neutrophils – bind to ligand ICAM-1 on endothelial cells – therefore regulate neutrophil adhesion/transmigration
o In leukocyte adhesion deficiency – neutrophils lack these adhesion molecules – neutrophils fail to exit the bloodstream
o Characteristics Very high neutrophil counts in blood Immunodeficiency – can’t get the neutrophils into the site of infection (neutrophils can get into the blood but can’t get out) Absence of pus/abscess formation Delayed umbilical cord separation
Chronic granulomatous disease
characteristics
ix
mx
• Chronic granulomatous disease
o Absent respiratory burst
Deficiency of one of the components of NADPH oxidase
Inability to generate oxygen free radials
o Excessive inflammation
Persistent neutrophil/macrophage accumulation
Failure to degrade antigens
o Granuloma formation
o Lymphadenopathy and hepatosplenomegaly
o Susceptibility to bacteria esp. catalase positive bacteria (PLACESS – Pseudomonas, Listeria, Aspergillus, Candida, E.coli, Staph Aureus, Serratia)
• Investigation of chronic granulomatous disease –
Normally activated neutrophils stimulate respiratory burst + produce H2O2
o Nitroblue tetrazolium (NBT) test
NBT is a dye that changes colour from yellow to blue following interaction with hydrogen peroxide (free radical)
o Dihydrorhodamine (DHR) flow cytometry test
DHR is oxidised to rhodamine which is strongly fluorescent following interaction with hydrogen peroxide
o In people with chronic granlomatus disease – no change in colours
• Treatment of chronic granulomatous disease
o Interferon gamma
Cytokine deficiency
o IL12, IL12R, IFNγ or IFNγR deficiency
o IL12-IFNγ network important in control of mycobacteria infection
o Susceptibility to infection with mycobacteria (TB and atypical), BCG, Salmonella
o Inability to form granulomas
o Infection with mycobacteria activates IL-12-IFNγ network
Infected macrophages stimulated to produce IL12 IL12 induces T cells to secrete IFNγ IFNγ feeds back to macrophages + neutrophils stimulates production of TNF activates NADPH oxidase stimulates oxidative pathways
Pus or no pus?
Kostmann syndrome
Leukocyte adhesion deficiency
Chronic granulomatous disease
Kostmann syndrome + Leukocyte adhesion deficiency No pus
Chronic granulomattus disease Pus
NK cell deficiencies
when to suspect
abnormalities in
classical NK deficiency
Functional NK deficiency
treatment
• NK cell deficiencies
o Recurrent episodes of infection
o Virus infection – Herpes virus (HIS + HSII), VZV, EBC, CMV, papillomavirus)
o Malignancy – papillomavirus associated cancers
classical NK deficiency
o Abnormalities described in GATA2 or MCM4 genes in subtypes 1 and 2
Functional NK deficiency
o Abnormality described in FCGR3A gene in subtype 1
• Treatment
o Prophylactic antiviral drugs e.g. acyclovir, ganciclovir
o Cytokines to stimulate NK cytotoxic function e.g. IFNα
o HSCT in severe phenotypes
Complement definition
• >20 tightly regulated linked proteins
o Produced by the liver
o Present in circulation as inactive molecules
• When triggered enzymatically, activate other proteins in a biological cascade results in rapid, highly amplified response
How does the complement get activated?
classical pathway
B cell has developed into an IgG producing plasma cell after the germinal centre reaction produces IgG which binds to the extracellular pathogen immune complex activates complement
• Activated by antibody-antigen immune complexes
o Results in change in antibody shape – exposes binding site for C1
o Binding of C1 to the binding site on antibody activation of the cascade
• Depends on activation of the adaptive immune system/ acquired immune response (antibody)
o This requires you to already have activated the adaptive immune response
How does the complement get activated?
mannose binding lectin pathway
- Activated by the direct binding of MBL to microbial cell surface carbohydrates
- Directly stimulates the classical pathway, involving C2 and C4 (not C1)
- Not dependent on adaptive immune system/acquired immune response
How does the complement get activated?
alternative pathway
• Directly triggered by binding of C3 to bacterial cell wall components
o E.g. lipopolysaccharide of gram -ve bacteria
o Teichoic acid of gram +ve bacteria
• Not dependent on adaptive immune system/acquired immune response
Deficiency of complement/alternative pathway/C3/terminal common pathway consequences
increased susceptibility to encapsulated bacterial infections
(remember using acronym NHS)
Neisseria meningitides – esp. properidin and C5-C9 deficiency
Haemophilus influenzae
Streptococcus pneumoniae
Which factors does the alternative pathway invovle
• Involves factors B, I, Properidin
• Factor H – control protein
o Normally properdin stabilizes C3 convertase triggers MAC complex
Deficiency of classical pathway consequences
• Classical pathway deficiency (C1q, C2)
Classical pathway necessary against infection and phagocyte mediated clearance of apoptotic cells and immune complexes
Susceptibility to SLE
C2 deficiency is the most common in SLE
o Does not affect c3 or c4 – these will be normal
o However, active SLE leads to consumption of C3 +C4 secondary deficiency
Active lupus causes persistent production of immune complexes + consequent consumption of complement functional complement deficiency low C3 + low C4
o Clinical phenotype
Almost all patients with C2 deficiency have SLE
Severe skin disease
Increased number of infections
(((( no phagocytosis of dead cells increased nuclear debris that isn’t being cleared up increased load of self-antigens (particularly nuclear components) danger of stimulating antibodies against nuclear components development of SLE and immune complexes
Failure to clear immune complexes immune complex disposition in blood vessels inflammation in skin, joints and kidneys vasculitis SLE )))
MBL deficiency
o MBL2 mutations are common but not usually associated with immunodeficiency
o Tends to be relatively benign
o Associated with increased infection in patients who have another cause of impairment
Premature infants
Chemotherapy
HIV infection
Antibody deficiency
What is secondary C3 deficiency
o C3 nephritic factors lead to consumption of C3
o Nephritic factors are auto-antibodies directed against components of the complement pathway
o Nephritic factors stabilise C3 convertases this results in C3 activation + consumption
o Often associated with glomerulonephritis – classically membranoproliferative
o May be associated with partial lipodystrophy (abnormal fat distribution)
How can autoimmune disease lead to complement deficiency
o SLE in someone with normal complement system will lead to CONSUMPTION of the complement low C3 + low C4
o AUTOANTIBODIES directed against components of the complement pathway may lead to consumption of the complement (usually C3)
Importance of
C3
C1
C9
MBL
C3 – cleavage of this protein may be triggered via the classical, MBL or alternative pathways
C1 – binding of immune complexes to this protein triggers the classical pathway of complement activation
C9 – part of the final common pathway resulting in the generation of the membrane attack complex
MBL – binds to microbial surface carbohydrates to activate the complement cascade in an immune complex independent manner
