Immuno Flashcards
SUMMARY CARD:
What are the 4 main types of cells in the innate immune system?
- Granulocytes: neutrophils, eosinophils, basophils
- Monocytes (in blood) + macrophages (same as monocyte but found in tissue) –> APCs to T-cells
NOTE: macrophage named differently based on where it is found e.g. liver (Kupffer), kidney (mesangial), spleen (sinusoidal lining), bone (osteoclast), lung (alveolar macrophage), neural (microglia), connective (histiocyte), skin (langerhans) - Natural killer (NK) / cytotoxic cells: kill ‘altered’ self cells e.g. those that are malignant or
infected with a virus
- Dendritic cells: reside in peripheral tissues and modulate the innate and adaptive immune system
SUMMARY CARD:
How does the innate pathway normally function?
Phagocyte development; migration to infection; non vs oxidative methods
- Phagocytes produced in
bone marrow
–> released into blood - Types of phagocytes: neutrophils (die afterwards) + macrophages (signal to T-cells after) = phagocytosis; dendritic cells mediate the transition between innate and addaptive immune cells
- Endothelial cells in blood vessels release / express
adhesion molecules
e.g. ICAM-1 (make the blood vessel wall stickier) - Infection releases cytokines and chemokines, which attracts the phagocytes. Adhesion molecules allow the phagocytes to stick to the blood vessel wall + access the microorganisms
- Phagocytosis occurs (engulf the pathogen)
- Pathogen is killed via oxidative and non-oxidative methods
-
Oxidative
: Firstly, reduction: O2 –NADPH oxidase–> H2O2; then H2O2 + Cl2 –myeloperoxidase –> 2HClO (hydrocholorous acid) -
Non-oxidative
: lysozymes - As phagocytosis can be done by neutrophils OR macrophages:
- Neutrophils: Phagocytosis depletes glycogen reserve –> results in CELL DEATH and therefore residual enzymes liquify surrounding tissue (PUS!!)
- Macrophages: become activated + release cytokines to interact with T-cells
SUMMARY CARD:
What deficiencies in the phagocyte pathway can lead to which disorders?
Clue: production, maturation, migration, oxidative killing
Primary immune deficiences in PHAGOCYTES can lead to:
1. Failure to produce neutrophils:
-
Reticular dysgenesis
(auto reccessive = MOST SEVERE SCID) –> mutation in adenylate Kinase 2 (AK2) = NO lymphoid or myeloid cells(LOW B and T cells)
-
Kostmann Syndrome
(autosomal recessive = severe congenital neutropenia) –> mutation in HCLS1-associated protein X-1 (HAX-1) = LOW neutrophils (and as neutrophils are responsible for pus formation,NO PUS!
) -
Cyclical neutropenia
(autosomal dominant) –> mutation in Neutrophil Elastase (ELA-2) = fluctuating neutropenia every 4-6 weeks
2. Failure of phagocyte migration:
-
Leucocyte adhesion deficiency
(autosomal recessive) –> mutation in CD18 Beta-2 integrin subunit = LFA-1 on neutrophils cannot bind to adhesion molecule ICAM-1 so cannot migrate to infection site =very high neutrophil count
and NO PUS
3. Failure of oxidative killing:
-
Chronic granulomatous disease
(X-linked recessive / auto recessive) –> defective NADPH oxidase = lack of ROS = normal cell counts as deficiency is to do with the enzyme, not the granulocytes
4. Deficiency of cytokines:
-
Interferon-gamma/IL-12 deficiency
= deficiency in IFN-y, IL-12 and their receptors = ↑ susceptibility to mycobaterial infections (e.g. TB, salmonella) AND normal neutrophil count
SUMMARY:
What is the normal IL-12 and IFN-gamma pathways?
stimulates oxidative pathways!
- Infected macrophages produce IL-12
- IL-12 induces T-cells to secrete IFN-y
- IFN-y feeds back to macrophages & neutrophils
- Stimulates the production of TNF
- Activates NADPH oxidase = stimulation of the oxidative pathway(s)
DISEASE:
SEVERE sepsis few days after birth
Usually do not survive past 1 year in infancy
Sensorineural deafness
LOW T and B cells
- Diagnosis?
- Mutation?
- Inheritance pattern?
- Management?
Most severe phagocyte deficiency
reticular dysgenesis
- adenylate kinase 2 (AK-2)
- auto recessive
- fatal in early life unless corrected with bone marrow transplant
NOTE: AK2 is responsible for devloping certain structures in the ear –> which is why it presents with sensorineural deafness!
DISEASE:
ISOLATED low neutrophils
NO PUS formation
- Diagnosis?
- Mutation?
- Inheritance pattern?
- Management?
-
Kostamann Syndrome
(severe congenital neutropenia) - HCLS1-associated protein X-1 (HAX-1)
- auto recessive
- granulocyte-colony stimulating factor (G-CSF)
DISEASE:
Fluctuating neutropenia every 4-6 weeks
e.g. X pt is found to have low neutrophils. 6 weeks later, they are back to normal.
- Diagnosis?
- Mutation?
- Inheritance pattern?
- Management?
cyclic neutropenia
- neutrophil elastase = enzyme (ELA-2 = gene)
- auto dom
- granulocyte-colony stimulating factor (G-CSF)
DISEASE:
Delayed umbilical cord separation
Absence of pus formation
VERY HIGH neutrophil counts in blood
- Diagnosis?
- Mutation?
- Inheritance pattern?
- Management?
leukocyte adhesion deficiency
- CD18 B2 integrin subunit
- auto recessive
- neutrophils are deficienct in adhesion receptors therefore are useless –> Mx with haematopoietic stem cell transplant
DISEASE:
Increases susceptibilibity to bacterial infections: PLACESS (pseudomonas, listeria, aspergillus, candida, E coli, staph, serratia)
CHRONIC INFLAMMATION
Non-caseating granuloma formation
Lymphadenopathy, hepatosplenomegaly, recurrent skin / fungal infections
NORMAL neutrophil / WBC count
- Diagnosis?
- Mutation?
- Inheritance pattern?
- Investigations?
- Management?
(failure of oxidative killing)
chronic granulomatous disease
- mutation in ENZYME NADPH oxidase (so normal WCC)
- X-linked recessive or autosomal recessive
- abnormal
dihydrorhodamine
= no flourescence (normal: flourescence); abnormal nitroblue tetrozolium (NBT
) test = remains yellow (normal: colour change yellow –> blue) - interferon-gamma therapy
DISEASE:
Increased susceptibility to atypical mycobacterial
infections e.g. TB, salmonella
Inability to form granulomas
NORMAL neutrophil count
- Diagnosis?
- Mutation?
Interferon-gamma/IL-12 deficiency
- IFN-y, IL-12 and their receptors
SUMMARY CARD:
What is the purpose of natural killer (cytotoxic) T-cells?
How do they kill cells?
- Present within the blood + migrate to inflamed tissue
- Typically, they express inhibitory receptors for self-HLA molecules to avoid accidental inappropriate action against self cells
- HOWEVER, they express a range of activating receptors that allow it to kill ‘altered’ self cells e.g. those that are malignant or
infected with a virus
(as these lack the inhibitory signals of normal self antigens) –> so deficiency in this = ↑risk of viral infection
2 main mechanisms of killing ‘altered’ self cells:
1. Perforin (pokes holes in membranes) + granzymes
2. Fas ligand expression –> triggers apoptosis
DISEASE:
↑risk of viral infection e.g. HERPES
Typical SBA: child with severe chickenpox or disseminated CMV
Which 2 NK deficiencies could this be and how is it managed?
-
Classical NK deficiency =
ABSENCE
of NK cells in peripheral blood -
Functional NK deficiency = NORMAL levels of NK cells in blood BUT
non-functional
Mx for both = prophylactic antivirals; IFN-alpha to stimulate NK cells and if severe –> HSCT
SUMMARY CARD:
What is the complement cascade and how does it normally function?
How is the complement cascade activated?
Complement cascade = sequence of reactions that complement/enhance the rest of the immune system
They are inactive proteins produced by the liver + exist in the circulation
Triggers e.g. infection = series of enzymes cleave the proteins and initiate a cascade of reactions
This leads to the END POINT: membrane attack complex (MAC
) –> attacks pathogen cell membrane (pokes holes)
ALSO: fragments released during cascade leads to:
- ↑ vascular permeability –> immune cells can reach the infected tissue more easily
- Activated phagocytes = ↑ phagocytosis
- Opsonise (make pathogen more susceptible to phagocytosis e.g. by marking it for destruction) pathogens + immune complexes
- Promote mast cell + basophil degranulation
Activation of complement cascade:
Classical pathway: C1, C2, C4
- Requires a functioning immune system as they are activated via an antigen-antibody (Ag-Ab) complex
- Conformational change in Ag-Ab complex exposes binding site for C1 activation –> the binding initiates cascade
Alternative pathway: C3
- Activated by pathogens of apoptotic tissue
Mannose-binding lectin: C4, C2
- Activated by serum lectin binding sugars (which may be found on bacterial cell walls or yeast cells)
The combination of C4b+C2a forms C3 convertase, which converts C3 to C3a (inflammation) and C3b (opsonisation)
Afterwards, this all feeds into a final common pathway composed of C5 convertase and C5-C9 –> this eventually forms the end product: MEMBRANE ATTACK COMPLEX (MAC)
NOTE: a cleaved complement divides into a (smaller) and b (bigger) fragments e.g. C3a + C3b
SUMMARY CARD:
What deficiencies in the complement cascade can lead to which disorders?
1. Classical
pathway deficiencies:
- Deficiency in
C2
(auto recessive) = most common –>↑ SLE in childhood + severe skin disease
NOTE: normally classical pathway is activated by Ag-Ab complexes and it triggers phagocyte mediated clearance of these immune complexes, therefore lack of this = immune complex deposited in organs/joints (SLE)
2. MBL
pathway deficiencies:
MBL deficiency (auto recessive) on its own is not an issue (no immunodeficiency), HOWEVER, paired with another immune impairment e.g. HIV, prematurity, chemotherapy, antibody deficiency etc. –> can cause immunodeficiency + ↑infection risk
3. C3
deficiency:
Severe susceptibility to ENCAPSULATED bacterial
infections
4. Secondary
C3
deficiency:
-
C3 deficiency w/ nephritic factors
= nephritic factors stabilise C3 convertase which results in ↑activation + consumption of C3 –> associated with membranoproliferative glomerulonephritis + partial lipodystrophy (abnormal fat distribution) –> LOW C3, NORMAL C4 -
SLE
= production of immune complexes results in consumption of C3 + C4 –> LOW C3 and LOW C4
5. Alternative pathway deficiency:
- Properdin deficiency = RARE: properdin is a protein in the alternative pathway that typically stabilises C3 convertase –> absence = recurrent
encapsulated
bacterial infection esp. Neisseria - Other alternative pathway deficiencies = factor B or factor D
6. Terminal pathway deficiency (C5-C9):
Any defect results in inability to form membrane attack complex (MAC) –> recurrent encapsulated
bacterial infection esp. recurrent meningococcal disease + FAMILY HISTORY
NOTE: C9 deficiency often asymptomatic
NOTE: NHS for encapsulated bacteria = Neisseria meningitis; Haemophilus influenzae; Streptococcus pneumoniae
DISEASE:
How do you differentiate between complement deficiency causing SLE and SLE causing complement deficiency?
Most common complement deficiency to cause SLE = C2 deficiency –> therefore, NORMAL levels of C3 + C4
HOWEVER, if pt has SLE, lupus causes the production and deposition of immune complexes which consumes and consequently depletes C3/C4 levels –> so LOW levels of C3 + C4
SUMMARY CARD:
How can you remember the encapsulated bacteria?
NHSN
-eisseria meningitisH
-aemophillus influenzaeS
-treptococcus pneumoniae
DISEASE:
What are the investigations to test for complement pathway deficiencies?
classical vs alternative?
Measure C3 + C4 levels:
- LOW C3 + LOW C4 = active SLE
- LOW C3, NORMAL C4 = C3 deficiency with nephritic factors (membranoproliferative glomerulonephritis)
- NORMAL C3 + NORMAL C4 but SLE = C2 deficiency
C
H50:
- Marker of
c
lassical pathway (+ve = normal; -ve/absent = abnormal)
A
P50:
- Marker of
a
lternative pathway (+ve = normal; -ve/absent = abnormal)
NOTE: both CH50 + AP50 are markers of C3 to C5-C9
DISEASE:
Recurrent neisseria / Hib / strep pneumoniae infections
- Diagnosis?
- Management?
- Presenting with recurrent NHS (
encapsulated
bacterial infections) –>complement deficiency
- Mx = vaccinations against NHS, prophylactic abx, treating infections aggressively,
screen family members
(esp w/ C5-C9 deficiency)
DISEASE:
SLE in childhood
vasculitic rash / severe skin disease
glomerulonephritis
arthritis
What is the diagnosis?
What is absent on Ix?
Classical pathway deficiency –> C2
deficiency = most common
Absent CH50
DISEASE:
Aymptomatic on its own
Immunodeficient when paired with prematurity / HIV/ chemo therapy –> Pt has recurrent Neisseria infection
What is the diagnosis?
MBL (mannose-binding lectin) complement pathway deficiency
DISEASE:
Membranoproliferative glomerulonephritis + partial lipodystrophy (abnormal fat distribution)
What is the diagnosis?
C3 deficiency with nephritic factors
–> nephritic factors cause consumption of C3
Therefore LOW C3, normal C4
Recurrent Nesseria infection
What is the diagnosis?
What is absent on Ix?
Alternative complement pathway deficiency
- Properdin deficiency = RARE: properdin is a protein in the alternative pathway that typically stabilises C3 convertase –> absence = recurrent
encapsulated
bacterial infection esp. Neisseria - Other alternative pathway deficiencies = factor B or factor D
Absent AP50
DISEASE:
Recurrent meningococcal disease (e.g. NHS) + FAMILY HISTORY
What is the diagnosis?
Terminal complement pathway deficiency (C5-C9 deficiency
)
NOTE: C9 deficiency often asymptomatic
SUMMARY CARD:
Development of the T-cell adaptive immune response and how does it normally function?
- T-cells are produced in the bone marrow + undergo
maturation in the thymus
-
Central tolerance:
HLA matching
in the thymus –> those with a too low OR too high affinity for HLA are not selected for maturation (die as immature T-cells) as they would have inadequate reactivity - Only the INTERMEDIATE affinity for HLA are selected for during maturation (~10% of the immature of T cells) –> they can have an affinity to class I or II
- Those with an affinity for
class I
develop into CD8+ T-cells (NK) –> important for virus infected cells + tumours:
- Kill cells via perforin (holes in membrane) + granzyme
- Can also kill cells via fas ligand expression
- Those with an affinity for
class II
develop into CD4+ T-cells:
- Help with the B-cell response
- Help promote CD8+ (NK) cell action