Microbiology and immunogenetics Flashcards
What is bacterial meningites mode of transmission?
Respiratory droplets
What is the most important virulence factor for all bacterial meningitis causes?
Polysaccharide capsule
What bacteria and aetiology does meningococcus cause?
Aetiology: Meningococcaemia and meningitis
Bacteria: Neisseria meningitides
What tpe of bacteria is Neisseria meningitides?
Gram-negative capsulated diplococci with adjacent sides flattened
What is the most important virulence factor of Neisseria meningitides?
Its polysacharide capsule with antiphagocytic action.
What are the most common serogroups causing meningitis?
A, B, C, Y, W135
What does it mean when we say Neisseria meningitides is gram -ve?
Its cell walls have lipopolysaccharide (endotoxin)
What are the clinical features of Neissera meninitides?
Endotoxin mediated vasculitis
Skin rash
(DIC) Disseminated intravascular coagulopathy
What is Neisseria meningitides mode of infection?
It enters the blood stream (meningococcaemia) and than localizes in the meninges to cause meningitis and cerebral oedema
what is pneumococci?
Streptococcus pneumoniae a gram positive diplcocci
What is streptococcus pneumoniae’s most important virulence factor?
its polysaccharide capsule which ic antophagocytic
Who are the individuals at risk of getting infected with streptococcus pneumoniae?
Post-splenectomy
Immunosuppressed
Infants
Enderly
Where is s.pneumoniae ussually found?
In the pharynx of 1/3 of adults mostly endogenous infection
Where is haemophilus influenzae found?
In the normal flora of the upper respiratory tract
What is the haemophilus influenzae bacteria?
causatie agent of influenza, Gram -ve capsulated bacilli
What is the most common anitgenic type to cause bacterial meningitis?
Haemophlus influenza b (Hib)
What are the clinical presentation of meningitis in adults?
Vomiting
Fever
Headache
Stiff neck
light aversion
Drowsiness
Joint pain
Fits
What is the mode of infection of neonatal meningitis?
vaginal delivery
What is the most common of neonatal meningitis?
Group B streptococcus (streptococcus agalactia)
E. coli
Listeria monocytogenes
What are the meningitis symptoms in babies?
Fever (hands &feet may also feel cold)
Refusing feeds or vomiting, diarrhoea
High pitched moaning cry or whimpering
Dislike of being handled fretful
Neck retraction with arching neck
Diffcult to wake, lethargic
Pale blottchy complexion
Blank & staring expression, bulging fontanelle
What are the CSF examination tests?
Appearance
Chemical analysis: glucose, protein
Microscopic examination
Gram stain
Culture and sensitvity
Microbial antigen tests e.g. Latex agglutination
PCR
What are the characteristics of bacterial (septic) meningitis?
physically : CSF is cloudy and under tension
Cytologically: High leucocytic count (200-20000ml) with predominant neutrophils
chemically: Reduced glucose level and elevated protein level
What is the CSF profile bacterial meningitis?
increased neutrophils, decreased glucose and increased protein
What is the CSF profile in viral meningitis?
Increased lympohcytes, No glucose, no or increases protein
What is the CSF cryptococcal meningitis?
cells and biochemistry often normal
What are immediate empirical?
Third-generation cephalosprins eg; Ceftriaxone injection
What are the chemoprophylaxis recommended?
The antibiotic recommended is either rifampin for 2 days orally or 1 ceftriaxone injection
What are the available meningitis vaccine?
Conjugate Hib polysaccharide capsular vaccine
Conjugate pneumococcal polysaccharide vaccine
Meningococcal polysacchride vaccine (A,C,Y,W135)
When are children given the meningitis vaccine?
2, 4, 6
When are children given the meningitis vaccine?
2, 4, 6 months
What is an immune priviliged site?
Tissues evolved to be protected to a variable degree from immune respones
How is cns considered to be an immune privilged site?
Lacks classical lymphatic drainage
Scarcity of dendritic cells
DElivery of immune cells and inflammatory mediators into the brain is impaired by the BBB
Lymphoid cells are normally excluded from the brain, spinal cord and peripheral nerves
What proinflammatory cytokines do microglias secrete?
IL-6, IL-1 or TNF-a
How can immunecells enter the CNS?
Across the BBB into the brain
Across the spinal cord barrier into spinal cord parenchyma (BSpCB)
Across choroid plexus into the CSF-filled entricles (BCSFB)
What are the steps of priming of immune responses to CNS antigens in MS?
(A) Neural antigens are released into the lymph nodes, where they are presented to B and T cells (such as dendritic cells)
(B) T and B cells with high affinity receptors for these antigens are expanded and releases from the lymph nodes. The cells migrate through the body and accumulate at sites where they re-encounter their priming antigen
(C) On reactivation, these cells recruit effector functions
what are targeted myelin sheath antigens in MS?
MAG: Myelin-associated glycoprotein
MBP: Myelin basic protein
MOG: Myelin oligodendrocyte glycoprotein
PLP:Proteolipid protein
What is the immune response in MS?
- Antigens are released from the CNS or cross reactive antigens presented via dendritic cells (APCs) prime T and B cells in the peripheral lymphoid tissue
- After colonal expansion, t and b cells infiltrate the CNS. This is aided via focal changes in the BBB permeanility or focal increase in expression of cell adhesion molecules that are necessary for the disease activity
3.Clonally expanded B cells re-encounter their specific antgens, mature to plasma cells and release large amounts of igG antibodies.MS patients have elevated CSF levels of IgG
4.Clonally expanded CD8 positive T cels (cytotoxic T lymphocytes) invade the cNS where i encounters specific peptide ligand, presented by glial or neuronal cells in association with class I MHC molecules inducing direct cell damage
5.CD4 positive t cells (T helper cells) migrate to cNS, encounter antigens presented by microglial cells in association with class II MHC molecules leading to hightend production of inflammatory cytokines
6.Cytokines released by myelin reactive CD4 Th1 cells cause upregulation of mHC class II molevules and costimulatory molecules (B7-1) on astrocytes and microglia in cNS
(Activated macrophages contribute to inflammation and tissue damage through the release of injurious immune mediators and direct phagocytic attack on the meylin sheath)
What is the role of Th17 cells in MS?
EXpression of iL-17 and IL-22 receptors on BBB endothelial cell in MS disrupt BBB tight junctions, Th17 lymphocytes transmigrate efficiently across BBB-ECs, highly express granzyme B, kill human neurons and promote CNS inflammatio through CD4+ lymphocyte recruitment
what is the charcteristic findings of MS in CSF?
Mild pleocytosis
Elevated IgG synthesis levels
HIgh IgG synthesis levels
HIgh IgG index (0.7 or greater)
Oligoclonal banding on electrophoresis
Myelin basic protein is normally <1ng/ml but increases in 80% of acute MS relapses
What are some diagnostic tests than can be used for MS?
Evoked potential testing (Visual evoked potentials can establish evidence of optic nerve damage)
CSF
MRI
What is a common presenting symptom of MS?
Include visual/occulomotor problems
What are the types of MS and how are they classified?
Spinal MS variant, Cerebellar MS variant, Cognitive MS variant
they are classified according to the most affected neurologic subsystem
What are the classification of MS?
(RRMS) Relapsing remitting MS
most common and is charcterized by relapses and remissions of neurologic diasbility over years to decades
(SPMS) Secondary progressive MS
follows an initiial relapsing-remitting course. This subtype is charcterized by progressive worsening of neurologic function.
Primary progressive MS
Characterized by worsening neurologic function (accumulation of disability) from the onset of symptoms, without early relapses or remissions and prognosis is worse for this group of patients
What are infections linked to Guillain-Barre syndrome?
Camplyobacter jejuni
Cytomegalovirus
Epstein Barr virus
Varcilla-zoster virus
Mycoplasma pneumoniae
What events can trigger Guillain-Barre syndrome?
Upper respiratory tract infection or diarrhoea precedes onset in two thirds of cases
Immunisation
Pregnancy
Surgical procedure
Lymphoma
What are the first symptoms of guillai Barre syndrome?
Numbness, Parasthesia, weakness, pain in the limbs
Progressive bilateral and relatively symmetrical weakness of the limbs
Most patients have initially weakness, numbness and tingling in the distal parts of the lowerlimbs that ascends to the proximal legs
What cells in MS produce IL-10 and TGF-B?
FoxP3+ Tregs and type 1 tregs
How does IL-10 suppress the immune system?
Supress T-Cell response by inhibiting the production IL-2, IL-5 and TNFB and also through inhibitng the upregulation of MHC Class II as well as B7 co-stimulatory ligand on DCs and macrophages anatgonizing effective antige presentation and T cell co-stimulation
How does TGF-B suppress the immune system?
TGF-B blocks cytokine production by T cells, as well as cytoxicity and proliferation
What is meningitis?
Infection & inflammation od meninges
What is encephalitis?
Inflammation and infection of the brain
What is meningoecephalitus?
Encephalitis with meninges
What is encephalomyelitis?
Encephalitis with involvements of the spinal cord
What are the 4 princinple routes by which infectious agents enter the CNS?
1.Hematogenous from blood
2.Direct inoculation by trauma or surgery
3.Spread from nearby infection
4.Retrograde through pripheral nerves
What part of the spinal cord does poliovirus infect?
The grey matter, anterior horn cell of the spinal cord
causes lower motor neuron lesion
What are the genotypes of poliovirus?
PV 1, 2, 3
What is the genus of poliovirus?
enterovirus
What type of virus is poliovirus?
family: Picornavirus with a very small RNA
+SS RNA non-enveloped
What is the most common form of poliovirus?
PV1
What can inactivate poliovirus?
Chlorination of water
What is the mode of infection of poliomyelitis?
Ingestion of contaminated foof and drinks by stool from infected human (feco0oral transmission)
What is the incubation period of poliomyelitis?
7 to 14 days
How can you diagnose poliomeylitis?
Through a nasopharyngeal swab and in the stool
What are the stages of polio infectiion?
1.Inapparant (asymptomatic)
The virus multiplies in the intestinal lymphoid tissues without invading the blood or CNS, excreted in faeces
2.Abortive infection (most common)
The virus invades the blooc (viraemia) but not CNS.
Mild symptoms: fever, malaise, headache, nausea and vomiting
3.Aseptic meningitis (non-paralytic poliomyelitis)
The virus reaches reaches the CNS
4.Paralytic poliomyelitis
Destroys lmns of the spinal cord causing flaccid paralysis
In what stage does protective immunity develop?
Innaparant stage
What is the clinical picture of aseptic meningitis?
headache, neck stiffness ad back pain ussually resolves spontaneously but may progress to paralysis
What are the polio endemic areas?
Nigeria, Afghanistan, Pakistan
Which areas are certified free of poliovirus?
Americas, western pacific, europe ans south east asia
What is the first inactivated polio vaccine ?
Salk vaccine
What is the live attenuated oral polio vaccine?
Sabin vaccine
What are the advantages of using oPV?
Inexpensive
Easy to administer (orally)
Produces excellent local immunity in the intestine (IgA)
Provides herd immunity (passes in stool)
Why have most developed countries switched to IPV?
It cannot revert
What is the immune basis of gullain Barre syndrome?
1.Through molecular similarity between myelin epitopes and glycolipids expressed on Caamplyobacter, Mycoplasma and other infectious agents (molecular mimicry) which precede attacks of gUllain-Barre syndrome
2.Antibodies directed against these infectious agents cross-react with specific antigens of myelin components
3.Binding of these antibodies to target antigens on the peripheral nerves may lead to conduction block before there is strucural nerve damage
What is the pathogenesis in Guillain-Barre syndrome?
1.Lipo-oligosaccharides on the c.jejuni outer membrane may elicit the production of antibodies that cross-react with gangliosides, such as GM1 on peripheral nerves
2.Antibodies binding leads to complement activation followed by membrane attack complex (MAC) formation
3.Macrophages then invade from the nodes into the periaxonal space, scavenging the injured axons
What are the antibodies of gangliosides?
GM1, GD1a, GT1a, and GQ1b
What are the immunological features of Guillain-Barre syndrome?
Mononuclear cell infiltration of affected peripheral nerves
Antibodies to meylin components
Peripheral T cell activaton
What is Guillan barre CSF diagnostic testing?
Elevated CSF protein levels in over 80% of ptients after 2 weeks
No or few mononuclear cells
ANti ganglioside antibodies, particularly anti-GM1 antibodies
Electrodiagnostic studies: demonstrate evidence of demyelination
What are the treatment opotions of Guillan barre?
Large doses of intravenous immunoglobulin (IVIG) (In severly affected patients as soon as a diagnosis is made)
Plasma exchange
What is CTLA-4?
The alternative receptor of b7 co-stimulatory ligands, is important for treg function. TRegs bearing surface CTLA-4 exert inhibitory effect on T-cells by a number of mechanisms
How do we rener naive T cells inactive?
Delivering negative signals to dendritic cells via CTLA-4 which down reglate B7 ligands on the latter renderig them incapable of activating naive t cells
How is the barrier of activation of autoreactive t cells is lowered for mS patients?
An increased frequency of IFN-Y secreting Tregs relative t healthy controls
