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
