Respiratory Immunulogy 1 Flashcards
Major hallmarks of immune deficiency?
Recurrent infection
SPUR:
Serious infections - unresponsive to oral antibiotics
Persistent infections - early structural damage and chronic infections
Unusual infections - unusual organisms at unusual sites; perhaps, opportunistic (people with normal immune systems would not get these)
Recurrent infections - two major or one major & recurrent minor infections in 1 year
Other features suggestive of primary immune deficiencies?
Weight loss
Failure to thrive (children)
Severe skin rash (eczema)
Chronic diarrhoea
Mouth ulceration
Unusual autoimmune disease
Family history - many conditions are genetic and Sudden Infant Death Syndrome may have occurred in family
Compare occurrence of primary and secondary immunodeficiences?
Primary - rare as few survive after birth
Secondary - common, often subtle and often involve more than one complement of the immune system
Conditions associated with secondary immune deficiency and who they occur in?
At extremes of age: Birth (neo-natal). pre-maturity, old age
Conditions: HIV (knocks out CD4 cells)
Measles (become susceptible to other infections)
Cancer (can affect bone marrow so less wbcs)
End stage renal disease
Iron deficiency (leads to superficial bacterial infections but can be solved)
Cells and proteins of the innate immune system?
Cells:
Macrophages
Neutrophils
Mast cells
Natural Killer cells
Proteins:
Complement
Acute phase proteins
Cytokines
How do innate immune system cells recognise pathogens?
Recognise structures that are unique to infectious organisms, e.g: bacterial sugars Essentially, same response in everyone
Functions of innate system?
Rapid clearance of microorganisms
Stimulates the acquired immune response
Buys time while the acquired immune system is mobilised
Describe the acquired immune system
ACQUIRED as a response due to exposure to an antigen and there is HUGE VARIATION
Repertoire is not genetically encoded and is acquired as an adaptive response to exposure to an antigen
Responsive to an unlimited no. of molecules with specificity
Basis of immunological memory
Cells and proteins of the acquired immune system?
Cells:
B lymphocytes
T lymphocytes
Proteins:
Antibodies
Which of the leukocytes are phagocytes?
Neutrophils
Monocytes/macrophages
Phagocyte function?
Important in defense against BACTERIA & FUNGI (not a huge role against viruses, which mainly reside in host cells) - particularly important at exposed sites
INITIATION and AMPLIFICATION of inflammatory response
Scavenging of cellular & infectious debris
Ingest and kill microorganisms
Produce inflammatory molecules, which regulate other components of the immune system
Resolution and repair
Clinical features of phagocytes deficiencies?
RECURRENT INFECTIONS - may affect common (skin, GI tract) unusual sites (e.g: causing a muscle abscess, spinal disc infection without trauma)
Organisms:
Common bacteria, e.g: Staph. aureus
Unusual bacteria, e.g: Burkholderia cepacia
Mycobacteria - both TB and atypical mycobacteria Fungi, like candida and aspergillus
Clinical importance of Burkhodleria cepacia?
Opportunistic pathogen affecting ONLY 2 groups:
People with PHAGOCYTE DEFICIENCIES
People with CF
Explain the importance of phagocytes
Chances of severe infection rise with decreasing neutrophil count
Normal neutrophil count - 4000-10000 per mm3
Life cycle of a neutrophil?
Mobilisation of phagocytes and stem cell precursors from bone marrow/within tissues
Endothelial adhesion markers are up-regulated at infection site
Stimulates neutrophil adhesion and migration into tissues (affected tissue sens signals)
Phagocytosis and killing of organism, resulting in neutrophil death
Also, there is activation of other components of immune system
Problems with neutrophil life cycle?
Defect of phagocyte production, mobilisation and recruitment - do not enter blood vessel; two types:
RECTICULAR DYSGENESIS
KOSTMANN SYNDROME
Failure to express leukocyte adhesion markers - LEUKOCYTE ADHESION DEFICIENCY
Antibody/complement deficiency - failure of opsonisation
Failure of oxidative killing mechanisms - CHRONIC GRANULOMATOUS DISEASE
Failure of cytokine production- gIFN and IL12 deficiency
Describe defects of phagocyte production
Failure to produce neutrophils due to:
Stem cells failing to differentiate along myeloid lineage causing one of two defects:
Primary defect - recticular dysgenesis (die within first few weeks of life)
Secondary defect - after stem cell transplantation
OR
Specific failure of neutrophil maturation:
Kostmann syndrome - severe congenital neutropaenia or cyclic neutropaenia (episodic neutropaenia every 4-6 weeks)
Difference between recticular dysgenesis and Kostmann syndrom
Kostmann syndrome affects only neutrophils
Describe what Kostmann Syndrome is and clinical presentation
Rare autosomal recessive disorder causing severe chronic neutropaenia (low neutrophil count)
Clinical presentation: Infections often within 2 weeks after birth - recurrent bacterial infections and systemic/localised infection
Non-specific features - fever, irritability, oral ulceration and failure to thrive
Management of Kostmann syndrome?
Supportive treatment:
Prophyactic antibiotics
Prophylactic antifungals
Definitive treatment - mortality 70% in 1st year of life without definitive treatment:
Stem cell transplantation - defect is in neutrophil precursor, so replace all precursors with allogenic stem cells and start again
Granulocyte colony stimulating factor (G-CSF) - give specific growth factors to assist maturation of neutrophils until stem cell transplantation
What is leukocyte adhesion deficiency?
Failure to recognise activation markers expressed on endothelial cells; so, neutrophils are mobilised but CANNOT EXIT BLOODSTREAM
Characteristics of leukocyte adhesion deficiency?
Recurrent bacterial and fungal infections and very high neutrophil counts (leukocytosis)
Localised bacterial infections that are difficult to detect
Site of infection - deep tissues although NO PUS (dead and dying neutrophils) formation and NO REDNESS
Describe how leukocyte adhesion deficiency arises
Caused by genetic defect in leukocyte integrins (CD18)
Results in failure of neutrophil adhesion and migration
Describe methods of direct recognition of pathogens by phagocytes
Considerable overlap in recognition profiles
PATHOGEN RECOGNITION RECEPTORS (PRRs):
Toll like receptors
Scavenger receptors
Lectin receptors
Recognise MICROBIAL-SPECIFIC STRUCTURES:
Bacterial sugars
Lipopolysaccharide (LPS)
What does genetic polymorphism in terms of direct recognition mean?
Exhibit genetic polymorphism - some associated with increased susceptibility to bacterial infection but most do not cause significant disease
Describe methods of indirect recognition of pathogens by phagocytes
Via OPSONINS - act as binding enhancers for phagocytosis, inc. complement C3b, IgG antibody and C-Reactive Protein
OR
Can bind to receptors on phagocyte surface (express Fc RECEPTORS that allow bind of an antibody that is also bound to antigen); also express COMPLEMENT RECEPTOR 1 (CR1) which binds to complement fragments which are also bound to antigens
Defects in opsonin receptors?
May cause defective phagocytosis, however, significant redundancy means that it generally does not cause harm
Defects in complement or antibody productions?
Results in decreased efficiency of opsonisation causing a functional defect in phagocytosis, i.e: defect not in phagocytes but in other components of the immune response
What causes Chronic Granulomatous Disease?
Failure of oxidative killing mechanisms:
ABSENT RESPIRATORY BURST - deficiency of intra-cellular killing mechanism of phagocytes
Inability to generate oxygen free radicals and so killing substances are not created; impaired killing of intracellular microorganisms
Most common cause of chronic granulomatous disease?
Deficiency of p47phox component of NADPH oxidase (X-LINKED SO ONLY MALES EXPRESS IT)
What are the consequences of chronic granulomatous disease?
Inability to clear organisms so EXCESSIVE INFLAMMATION - failure to degrade chemoattractants and antigens and there is persistent accumulation of neutrophils, activated macrophages and lymphocytes
Causes GRANULOMA FORMATION
Features of chronic granulomatous disease?
RECURRENT DEEP BACTERIAL INFECTION, esp. Staphylococcus, Aspergillus, Pseudomonas cepacia; also, mycobacteria and atypical mycobacteria
RECURRENT FUNGAL INFECTION
FAILURE TO THRIVE
LYMPHADENOPATHY (enlarged lymph nodes) and HEPATOSPLENOMEGALY (liver and spleen enlargement) due to inflammation
GRANULOMA FORMARION
How to test from chronic granulomatous disease?
NBT TEST (nitroblue tetrazolium): in petri dish, can the neutrophils kill, e.g: E.coli (dye that is sensitive to H2O2; so, if neutrophils produce hydrogen peroxide is produced by the neutrophils, dye changes colour
Treatment of chronic granulomatous disease?
Supportive treatment:
Prophylactic antibiotics
Prophylactic antifungals
Definitive treatment:
Stem cell transplantation
Gene therapy
What are intracellular organisms and give examples?
Hide from immune system by locating within cells, like Salmonella, Chlamydia, Rickettsia
Some hide within immune cells, particularly in macrophages, including mycobacteria species like TB (difficult to clear)
Describe what occurs in infection with mycobacteria TB
Activated IL12 - gIFN network:
Infected macrophages are stimulated to produce IL12
IL12 induces T cells to secrete gamma interferon (gIFN)
Stimulates production of TNF
Activates NADPH oxidase
Stimulates oxidative pathways
Any defects of this pathway can cause susceptibility to mycobacterial infections
Iatrogenic factor that increases TB risk?
Giving anti TNF drug can have a side effect of reactivating latent TB
Defects that are associated with susceptibility to intracellular bacteria?
Single gene defects:
gIFN receptor deficiency
IL12 deficiency
IL12 receptor deficiency
Mycobacterial infection:
TB
Atypical mycobacteria
Salmonella
Summarise congenital neutropaenia?
Neutrophil count - 0
Pus formation - None
Leukocyte adhesion markers- normal
NBT test - abnormal as no neutrophils
Summarise leukocyte adhesion defect?
Neutrophil count -
Pus formaiton -
Leukocyte adhesion markers -
NBT test -
Summarise chronic granulomatous disease?
Neutrophil count - normal
Pus formation - normal
Leukocyte adhesion markers - normal
NBT test - abnormal
Summary of phagocyte deficiency treatment?
Aggressive management of infection:
Infection prophylaxis with Septrin and Itraconazole (antifungal)
Oral/intravenous antibiotics
Surgical draining of abscesses
Definitive therapy:
Bone marrow transplantation
Specific treatment for chronic granulomatous disease - gIFN therapy and gene therapy
