immune Flashcards
non-living vaccines
– Whole dead organisms
– Many bacterial examples, known as KILLED
vaccines; some viral examples known as
INACTIVATED vaccines
– or TOXOIDS,
– or antigenic fragments: SUB-UNIT vaccines,
– or CONJUGATES - an antigen covalently carrier-linked
for increased immunogenicity
Is protection needed to kill the organism
itself, or against a toxin it secretes?
toxoid vaccines
is a toxin after modification to render it harmless but still immunogenic
Eg.
- Diphteria
- Tetanus
pathology of both due to secreted toxins
adjuvant vaccines
Immunogenicity of some vaccines is
improved with an ADJUVANT - a non
specific stimulator of immune
recognition
Probably important in engaging Toll-Like Receptors on APC
• Two types currently used:
– pertussis organisms
– Aluminium compounds eg Al(OH)3 gel
attenuated vaccine
means non-pathogenic, but still capable of limited multiplication and colonization
– Attenuation - these days, may be
genetically engineered by knocking out genes
– eg Aro mutants of Salmonella (typhoid, etc.)
– May occur after repeated growth in culture; historically an important approach
– eg BCG (for TB); Mycobacteria,
stands for bacille Calmette-Guerin
important examples of live vaccines
Important bacterial example:
– BCG for tuberculosis
• Important viral examples:
– OPV Oral Polio Vaccine
– MMR Measles, Mumps and Rubella
How vaccines are seen by the immune system:
NON-LIVING
A non-living vaccine will be processed by APCs
and antigen epitopes will be
presented in class II MHC molecules
how vaccines are seen by immune system
Live attenuated
A live attenuated virus vaccine or live attenuated
intracellular bacterial vaccine will ALSO result in
cass I MHC presentation - on the INFECTED
HOST CELLSURFACE of cells which are
colonised
risks from live attenuated vaccines
risk for:
- a patient with an impaired immune system
- includes treatment for malignancy as well as those on immunosuppressives or with known immunodeficiency disease
- – or a foetus
• may be dangerously pathogenic in them causing
virulent infection.
routinely used vaccines
- Dip and Tet are toxoids, with alum
- • aP: acellular Pertussis. Pert is currently whole dead cells, and also adjuvates Dip and Tet
- • IPV inactivated polio virus*
- • Hib and MenC are conjugates of coat carbohydrate on carriers
- • MMR - all attenuated virus
- • BCG - attenuated mycobacteria
CD4
A cell surface molecule:
• characteristic of one of the major subsets of T
cells, also known as Helper T cells (TH)
• also expressed on dendritic cells (DC) and
macrophages – DC probably usual portal of
entry for HIV infection
• CD4 stabilises a TH cell’s interaction withMHC
• specific for MHC Class II
• internally it recruits signalling molecules
in HIV, The numbers of CD4+ cells are depleted by:
- direct cytopathicity of virus
- killing by specific cytotoxic CD8+ cells
- Memory pool particularly depleted
common non-pathogen causes of acquired
(i.e. secondary) immunodeficiency
_Nutrition: malnutrition (w_orld wide this is a very
common cause of immunodeficiency) or
malabsorption / protein loss
• Physiological “gap”: Bottle fed babies x60 more
pneumonia in 1st quarter than breast fed
• Malignancies
– eg: chronic lymphocytic leukemia, myeloma.
such patients suffer 5-10 times number of infections in agematched controls
• Aging
– T cell production falls away
• Drugs - iatrogenic
– Deliberately immunosuppressive – eg for transplant, or treating autoimmune disease
– corticosteroids
– Others – eg anti-convulsants for epilepsy
• Stress
– eg bereavement, or excessive “training”, as in Infectious mononucleosis (“glandular fever” EBV infection) in athletes
• Splenectomy
– eg post RTA trauma - Pneumococcal disease !
M. tuberculosis – the “life cycle”
• Bacilli are expectorated by patients with active TB
– Inhaled by susceptible persons
– Bacillary replication in lung macrophages
• Induction of a pathogen‐specific immune response
– Contains bacillary replication (dormancy)
• Results in latent infection
• Fails to eradicate the bacilli
• Reactivation of latent infection
– Bacillary replication
– Cavitory lung disease
– Expectoration of bacilli
TB primary infection
– Phagocytosis of M. tuberculosis
• Failure of innate immunity to control MTB replication
– Generation of cell mediated immunity
• Control of MTB replication within granulomas (95%)
TB clinical latency
– Control of MTB within granulomas
• Immunological evidence of MTB infection (skin test)
reactivation
– Loss of control of the infection
• MTB replication, tissue destruction, cavitation
– Expectoration of bacilli
Primary TB stages
HOST
- Phagocytosis of bacilli by lung macrophages
- Transformation of phagocytes into antigen‐presenting cells
- Migration of antigen‐presenting cells to the regional lymph nodes
- Generation of MTB‐specific T‐lymphocytes
- Recruitment of MTB‐specific T‐cells to the site of infection
- Activation of MTB‐infected phagocytes by these T‐cells
- Formation of granulomas
TB innate immune response
Phagocytosis by macrophages
• Recognition by Toll‐like receptors (TLR‐2, TLR‐4)
TB adaptive immune response
Generation of MTB‐specific T lymphocytes
Dendritic Cells (DC)
– Transformation from immature DC (phagocytes) to mature DC (antigen‐presenting cells)
– Production of Immune Regulatory Cytokines
• Immune stimulatory (TH1): Tumor necrosis factor‐alpha (TNF‐α), Interleukin‐12 (IL‐12)
• Immune inhibitory: IL‐10
Generation of MTB‐specific T‐Lymphocytes
Immunological synaps:
• A_ntigen‐presenting cell (DC):_
– Antigen presenting molecules (MHC,CD1)
– Co‐stimulatory molecules (CD40, CD80, CD86, ICAM‐1)
– TH1 Cytokines (IL‐12, TNF‐α)
• Naïve T‐Lymphocytes:
– Receptors for:
• Antigen recognition (T‐cell receptor)
• Co‐stimulatory molecules (CD40L, CD28,
CTLA‐4, LFA‐1)
• Cytokines (IL‐12 receptor)
M. Tuberculosis specific T‐cells
_**Different lymphocyte subsets**:_ • **CD4+ T**‐cells (**MHC class II‐restricted**) – _Most important mediators of host resistance to MTB_
*• **CD8+ T‐cells** (MHC class I / CD1‐restricted)* • **CD4‐CD8‐ T‐cells** (“double negative” T‐cells) **• gamma delta T‐cel**l receptor‐expressing lymphocytes
Actions:
• Macrophage activation (MTB inhibition)
– Production of TNF-alpha and IFN‐gamma
• Destruction of MTB infected macrophages
– Apoptosis (FAS mediated)
– Necrosis (perforin, granzymes, granulysin)
Activation of macrophages in TB
Activation of macrophages by IFN‐gamma and TNF-alpha
– Induction of inducible nitric oxide synthase (iNOS)
• Generation of reactive nitrogen intermediates (RNI) such as nitric oxide
(NO), NO2 ‐, and HNO2
latent TB
• Persistent cytokine activation of infected macrophages and T‐cell mediated immunity are important in the control of latent/chronic MTB infection
– In mice
• Treatment directed against TNF‐alpha, IFN‐gamma, NOS2 or CD4 T‐cells results in worsening of chronic stable TB
– In man
• MTB‐specific CD4+/CD8+/CD4‐CD8‐ T‐cells are present in peripheral blood of PPD‐positive persons and household contacts of TB patients
• Immune suppression with glucocorticosteroids or TNF‐alpha neutralizing mAbs, solid organ transplantation and HIV‐induced CD4+T‐cell depletion are associated with increased rates of reactivation of latent MTB infection
reactivation (post-primary) TB
Host Susceptibility to TB
• Genetic polymorphisms (may be population specific)
– Defects in the IL‐12/IFN‐γ pathway confer susceptibility to atypical mycobacterial (and salmonella) infections
– NRAMP1 (SLC11A1; encoding a phago‐lysosome membrane protein), Vitamin D receptor, HLA class II, IFN‐γ, IL‐12RB1, IL‐8 associated with susceptibility to TB
• Non‐genetic (“environmental”) factors
– Nutritional status, age‐related immune impairment, immune suppressants, diabetes mellitus
Virulence of the M. tuberculosis strain
generally, CD8 cells
cytotoxic lymphocytes
Kill target cells with proteins in lytic granules (perforin, granzymes, granulysin)
important in viral, intra-cellular pathogens, tumour respons
produce IL-2 =>it stimulates CD8 Tcell proliferation, differentiation
CD4 Th1 cells help CTLs, by IL-2, INFgamma
what is necessary to activate naive T cells?
interaction of MHC with TCR is insufficient ot activate naive cells
signal 2 (co-stimualtory melecules) are required to activate T cells +> stimulate T cell rpoliferation
slignal 3 (different cytokynes) regulate T cell differentiation
generally CD4 Th1
- help other immune factors
- activate, regualte macrophages, CTL
- produce INFgamma, IL-2, CCL2
- target INTRACELLULAR pathogens mainly
- induces macrophage differentiation in bone marrow
- activates endothelium to bind macrophages
generally CD Th2
stimulate B cells to produce antibody
DO NOT activate macrophages
produce IL-2, IL-4 (important for B cells), IL-5, IL-13
Target: extracellular pathogens, toxins
IgG
main antibody
good at osponisation for NK cells
4 subclasses
IgA
mucosal, breast milK
forms dimers in gut to protect from enzyme degradation
monomeric in plasma
2 subtypes
IgE
parasitic infections
binds mast cell via Fc region (without antigen) =>causes degranualtion => release of histamine
Increased in allergies
IgM
pentamer
10 binding sites
high AVIDITY
default Ig that B cells start with in developmenet
pentamers too large to diffuse through placenta or into tissues
present during active response first
v. efficient at activating somplement through CLASSICAL pathway
killing mechanism in neutrophils
reactive oxygen intermediates
Respiratory burst after phagocytosis => Increased O2 uptake
O2 reduced by NADPHoxidase to form HYDROXYL radicals, hypochlorite
Causes DNA damage, alterations in bacterial membrane
killing mechanisms in macrophages
L-arginine + O2 => L-citrulline + NO radicals (catalysed by inducible NO synthase <= induced by cytokines, bacterial componenets)
Causes DNA damage, membrane damage
major components of the cell walls of Gram-positive bacteria and are recognized by
peptidoglycans
TLR2
major constituent of the outer cell membrane of Gram-negative bacteria and recognised by
lipopolysaccharide LPS
TLR4 < molecules on monocytes,
macrophages, dendritic cells, mast cells, and intestinal epithelial cells bear toll-like receptor 4
