midterm revision part 1 Flashcards
Explain how the 4 hallmarks of inflammation come about
1) Cytokines produced by macrophages cause vasodilation of blood vessles (Close to the site of infection) hense so heat and redness–> reduced velocity of blood flow
2) Activation of endothelial cells lining the blood vessel → expression of cell adhesion molecules → binding and extravasation of circulating leukocytes into tissues
3) Increased vascular permeability → plasma (+plasma proteins e.g. complement) invade the tissue at the point of infection (hence swelling (edema) and pain)
4) Clotting in microvessels in the site of infection prevents the spread of pathogen
* the 4 hallmarks: heat, redness, pain, swelling
which cell surface proteins are found on macropahges, neutrophils and DCs?
DCs: DENTRITIC CELLS
CD14
Which cell surface proteins are found on NK cells?
CD16,CD56
Which cell surface proteins are found on B cells?
BCR, CD19, CD20, CD21
Which cell surface protein is found on TH cells
TH : t-helper cells
TCR, CD3,CD4
Which cell surface proteins are found of TC cells
TC: cytotoxic T cells
TCR, CD3,CD8
Cells that act as APCs (antigen presenting cells)
Macrophages, DCs , B cells, monocytes
- positive for CD14 marker
What are the key elements of innate immunity?
1) Physical barrier –> epithelial layer of the skin and mucosal/glandular tissues , which prevent pathogen entery into the body’s interior
2) Chemical barrier –> acidic pH, anti-microbial proteins and peptides
immune cells that are part of Adaptive immunity
T (CD 4+ ,CD8+) and B cells ; antibodies
Immune cells that are part of Innate immunity
phagocytes, NKs, DCs, Mast cells, Complement proteins, macrophages, Antimicrobial molecules (AMPs)
MoA of AMPs in innate immunity
*AMPs: antimicrobial peptides
provide a first line defense against pathogens (bacteria, viruses,fungi etc) -> DNA, RNA, protein synthesis inhibition –> Apoptosis
- the cellular bridge btw innate and adaptive immunity
(Innate/Adaptive) immunity : immediate defence against by a pathogen (Response T: min/hr)
Innate
(Innate/Adaptive) immunity: response takes days/weeks to arise following exposure to Ag
Adaptive
Innate vs Adaptive Immunity
*
How does a phagocytic cell recognize microbes, triggering their phagocytosis?
- PRRs recognizing PAMPs
- Opsonin receptors recognizing opsonins (MBL, Ficolins, C1)
Not all PRRs trigger phagocytosis
* PAMPs : found on the cell components of pathogens
explain what causes Opsonization of bacteria
Fc receptors and complement receptors (CR1) on phagocytes connect opsonin-tagged pathogens (IgG/ C3b) to phagocytes –> Phagocytosis
*
what are the 2 primary opsonins used to defend against bacteria?
C3b (also C4b) and Immunoglobulin G (IgG)
In the complement system, what is the fxn of the plasma protein C3b?
Opsonization
(C4b too)
*
- NADPH oxidase deficiency resulting in reduced ROS production during phagocytosis, reduced ability to kill ingested microbes
- Most often X-linked recessive disorder
- Increased susceptibility to catalase positive microorganisms
- Treatment with IFNγ
- Diagnosis: negative nitroblue tetrazolium test and dihydrorhodamine assay
Type of innate immune deficiency?
Chronic granulomatous disease
sos
History : necrotic skin lesions, recurrent and prolonged infections forming pus (pyogenic bacteria)
complications: Lymphaedenopathy
LAB: marked neutrophilia, nomral no. of lymphocytes
pateints w/ defects in NADPH oxidase subunits resulting in No ——— production during
phagocytosis –> reduced ability to kill ingested microbes
ROS
* No reactive oxygen species –> increases susceptibility to catalase +ve microorganisms
Phagocytes employ an array of killing mechanisms to kill microbes. How?
By producing ROS , RNS and antimicrobial peptides –> which are highly toxic to phagocytosed microbes
———– : Components of the dead/dying cells & damaged tissues recognized by PRRs leading to cell clearance
DAMPs (Damage (Danger)- associated molecular patterns)
PRRs are expressed on?
Innate immune cells (macropahges, NKs, DCs, neutrophils)
PAMP recognition by PRRs induces the production of ————- that mediate the effector functions of the innate immune responses
Cytokines
Cytokines/ chemokines —> trigger inflammation
- Autosomal recessive disorder
- Caused by deficiency of CD18 which is the common β2 chain of a number of integrins including LFA-1
- First indication: delayed separation of umbilical cord stump and omphalitis (infection of the umbilicus)
- Recurrent bacterial and fungal infections
- Neutrophilia, no pus formation, necrotic lesions
- Diagnosis: evaluation of expression of CD18 by flow cytometry
Type of Deficiency ?
LAD - Leukocyte adhesion deficiency
- Autosomal recessive disorder caused by mutations in CHS1 which encodes for LYST (lysosomal trafficking regulator) protein: which regulates lysosome size, movement and function
- Partial oculocutaneous albinism(partial absence of pigment in skin, hair and eyes (metallic silver colour of hair, abnormal retinal pigment cells cause poor vision)
- Large intracellular granules in leukocytes are typical of CHS with H&E staining
Diagnosis : * neutropenia and detection of giant granules in neutrophils
* impairment in T cells, Nk cells and grnaulocytes
Type of Disorder?
Chediak-Higashi syndrome (CHS)
The 3 pathways of the complement system
1) Lectin pathway
2) classical pathway
3) Alternative pathway
What are the functions of the complement system?
1) Lysis of pathogens through the MAC(membrane attack complex)
2) Opsonization, which promotes phagocytosis (C3b mainly but also C4b)
3) Clearnace which of immune complexes from the circulation, deposits them to the spleen and liver
4) Release of Anaphylatoxins (C3a, C5a, C4a) , that induce inflammation
* Complement system
Cleavage of ——– is the critical step in complement activation and leads directly or indirectly to all the effector activities of the complement system
C3
In the complement system, the activation of what two plasma proteins can cause anaphylaxis?
C3a, C4a, C5a
(induce inflammation)
- C5a has the highest biological activity then C3a –> C4a
(C5a> C3a> C4a)
What triggers the activation of Complement via the Lectin pathway?
Microbial surfaces
Notes:
soluble protein MBL (lectines) binds to microbial surfaces –> MASPs attach to lectine –> cleaves C4 and C2 to form —> C3 converatse (C4b2a)–> deposition of C3b on the surface of the pathogen
What triggers the activation of Complement via the Classical pathway?
Antigen-antibody complexes
Notes:
C1 complex recognizes IgG &IgM antibodies bound to antigens –> Cleavage of C4 ,then C2–> C3 convertase (C4b2a)
What triggers the activation of Complement via the Alternative pathway?
Microbial surfaces (esp. Properdin aka factor P and factor D)
Exaplain how the Alternative pathway works
-
1st way of activation –> acts as an amplification step for the classical and lectin pathways
[Once C3b has been formed by whichever pathway, the alternative pathway can act as an amplification to increase C3b production rapidly] -
2nd way of activation -> spontaneous hydrolysis ‘tickiver’ of C3 to form C3(H2O)
[Properdin binds to C3(H2O) or C3b which stabilizes the C3 converatse (C3bBb) in the alternative pathway]
MoA of Properdin
*factor P
1) Can act as a PRRs
2) facilitates pahgocytosis on cells undergoing apoptosis ( through the alternative pathyway)
The 3 pathways of complement activation (Classical, lectin & Alternative), involve diffrent initiators but all converge in the generation of the same enzyme ————— , which cleaves C3 into ——- &———
C3 convertase
C3a & C3b
which two types of immunoglobulins activate complement via the classic pathway?
IgG & IgM
(recongnized by C1 antibodies)
C1 complex consists of?
C1q , C1r & C1s
*initiators of the classical pathway
After the generation of C3 converatse, all three pathways cluminate in the fromation of ———– ?
C5 convertase –> C5 (by the addition of C3b to C3 converatse) -> C5a and C5b
what is the fxn of C5a vs C5b
C5a –> Anaphylatoxin so inflammation
C5b –> provides a binding site on the surface of the target cell for the generation of MAC
The membrane attack complex (MAC) is composed of which complement proteins?
C5b, C6, C7, C8, and C9
The membrane attack complex of complement is esp important in the defence against what type of bacteria?
Gram -ve bacteria
what is the fxn of MAC in the complement system?
Lysis of target antigen
In the complement system, the deficinecy of which plasma proteins can predispose someone to * recurrent meningococcal and gonococcal infections w/ Neisseria spp*?
C5-C9
[MAC components]
SLE is related to a deficinecy is what type of complement protein?
C4 deficiency
–> leads to a reduction of C3b deposited on immune complexes
which complement protein is responsible for neutrophil chemotaxis ?
C5a
the deficeincy of what plasma protein leads to overactive complement and hereditary angioedmea?
C1 esterase inhibitor (C1INH)
What are the clinical sequelae of hereditary complement C3 deficiency?
Recurrent pyogenic sinus, Neisseria spp.
sometimes immune-complex disease
In the complement system, the deficinecy of which plasma proteins can predispose someone to bacterial infections, mainly in childhood?
*bacterial infections: pyogenic infections/ recurrent respiratory tract infections
MBL
(MBL pathway- lectine)
In the complement system, the deficinecy of which plasma proteins can predispose someone to immune complex disease (e.g., SLE, Glomerulonephritis, vasculitis?
C1, C2, C4
(Classical pathway)
In the complement system, the deficinecy of which plasma proteins can predispose someone to pyogenic bacterai and Neisseria spp. but no immune complex disease?
Factor D , Factor P [Properdin]
(Alternative pathway)
- Dominant autosomal inheritance
- Defective or absent C1INH (C1 esterase inhibitor) which results in increased levels of edema-factors C2-kinin and bradykinin
- Recurrent attacks of skin, laryngeal or intestinal oedema
- Diagnosis when disease is active: reduced C4 and C2 levels, normal C3
- Treatment Danazol
Syndrome?
Hereditary angioedema (HAE)
- Mutations in PIG-A gene result in lack of GPI-anchor
- Presents with lack of complement regulatory proteins DAF (CD55) and CD59 –> affect RBCs, platelets and granulocytes
- symptoms:
Abdominal pain, drak-coloured urine in the morning, Jaundice, Hemoglobinuria (25% of patients), Thromboembolic events, Fatigue, SOB - Treatment: Eculizumab
Syndrome?
Paroxysmal nocturnal hemoglobinuria (PNH)
Deficiency in what molecule would lead to resistance to septic shock?
TNF-α
Deficiency in any of the components of MAC causes?
Fatal meningitis caused by bacterial species (Neisseria Meningitudis)
