Infection and Immunity Flashcards
Stem cells have the capacity to produce all the B cells in our repertoire. In order to do that, the immunoglobulin genes need to?
What types don’t get through and why?
What does this allow?
Commit to a particular cell, with only one antigen binding site specificity.
B cells with an affinity to self-antigens undergo clonal deletion as a protective mechanism before they even leave the bone marrow.
This allows a large repertoir of B cells, with nearly no self-antigens
What is thymus involution and what does it tell us?
- Develops under sternum, intially large and then involutes with age
- This tells us we produce most of our T cells early on in life (whereas B cells are more consistantly made)
Describe Thymus structure
- Outer cortical layer
- Inner medullary layer
- Bone marrow stem cells come into the thymus from the bone marrow and start from the top, going through a series of changes and alterations till they reach the inner, and are then exported around the body.
Describe T cell ontogeny
- Uncommited thymocyte
- stem cell come from bone marrow that is destined to be a T cell
- Rearranges T cell receptor genes ‘TCR” (both the alpha and beta)
- now we have thymocytes that are expressing genes comitted to one lineage
- TCRaB**
- TCRaB
- both CD4 (helper) or CD8 (cytotoxic) expressed!!!
- We need to make sure these cells can recognise HLA; and therefore these cells are tested to determine this, using their T cell receptor and CD4 or CD8
- Many of them will not be able to, and these will be negatively selected against ” positive selection”
- TCRaB CD8 or CD4 :These cells can recognise HLA:
- Class 1 with CD8
- Class 2 with CD4
- these down regulate the CD4/8 they don’t need
- secondary testing to make sure they’re not reactive to self peptides “negative selection”
- Left with cells that recognise HLA but to some foreign peptide!
- Both start expressing CD3
Important points from T cell oncology and T cell receptor genes
- Development occurs in the thymus
- Multiple V, D and J exons recombine to form a V-region
- Recombination is independnt of antigen
- T cells become comitted to one V<em>a</em> and one V<em>B</em>
- Positive selection for HLA class I or II recognition (required CD8 or CD4)
- Negative Selection against strong self reactivity
We develop a repertoire unique to us!! Change HLA, you change the positive selection process, and change everything!
Warning signs of immunological deficiency?
Blood count would show?
- You will only see signs post 6 months
- Recurrent infections since year old
- Sinus infections, pneumonia, strep, etc
- There will be a Failure to thrive
Blood: not massive difference but mismatch!
- WBC: lower then normal
- Neutrophils: lower
- Lymphocytes: normal
- Monocytes: higher
Serum immunoglobulin tests of an immunodeficient individual could look like who has “Hyper IgM syndrome”
- IgM: Really high
- IgG and IgA: really low!
Peripheral blood lymphocytes
- T cells (CD3) around 87%
- Activated T cells don’t bind soluble CD40 (shows co stimulator for this is low)
- Why is there High IgM but no antigen specific IgG?*
- Why no sIgG on B cells?*
What’s Hyper IgM syndrome?
Rare condition where there is an inability to switch from IgM class to the later classes, due to a CD40 ligand mutation that stops the co-stimulation.
There is no switch so the secondary response still only has IgM!
No IgG, IgA or IgE
Microbial Factors of immunity and Infection?
- Type of organism (eg; virus, bacterium, parasite)
- Dose (degree of exposure)
- Virulence
- ROute of entry
Host Factors of immunity and infection?
- Intergrity of innate barriers
- adaptive immune competence
- HLA, Ig and TCR genes
- Previous exposure
- Other infections
What types of pathogens/antigens will we see with viral, bacterial and protozoa infections?
Viruses:
- Lytic or integrated cycle
- Capsid antigens
- Internal structural components (HLA I associated with fragments of viral proteins, shows there’s something going on!)
- Metabolic Products
Bacteria and Fungi
- Extracellular (eg; S. aureus) or intracellular (eg; M. tuberculosis)
- Structural components
- metabolic products and toxins of pathogen
Parasites
- Large (multicellular) (slower)
- Life cycle changes
- Radical changes in antigenicity; to evade the IR
Immune factors to protect us from pathogens are?
- Direct neutralisation by antibodies
- Opsonisation and phagocytosis via Fc region
- Complement-mediated effects
- HLA-restricted T cell mediated Cytotoxicity
- NK cell-mediated cytotoxicity
- also have inflammatory and immunoregulatory cyctokines
- antiviral cytokines (eg interferons)
What antibodies are effective against what antigens?
- Viruses IgA, IgG and IgM
- Toxins IgG and IgM
- Extracellular bacteria IgA, IgM and IgG
- Parasites IgE and IgA
What are cytotoxic T cells effective against pathogens
Intracellular protein antigens
- Virus infections
- tumour cells: recognise changes
- transplanted organs: if not HLA identical then could be recognised
Babies failure to thrive, recurrent infections, pneumonia, otitis media, erysipelas.
Paired with Low IgG, IgA and IgM!!
Few B cells and therefore tiny/no tonsils
What is this?
Could be X-linked agammaglobulinaemia
An inability to make antibodies
THis correlates with an increase in only bacterial infections, but not really viral infections. B-cells are not vital in controlling viral infections
What are Pathogen Associated Molecular Patterns (PAMPs) and what does recognising them induce?
We have certain key signature molecules called PAMPs that our immune system (both innate and adaptive) we trigger inflammatory processes….
- Vascular permeability changes
- phagocytic recruitment
- Acute Phase Protein (APP) induction
- Local temperature change
This may involve complement activation and antibody production
What is our ‘mucosal immunity’?
Primarily IgA and IgE
IgA: first blocking process to stop bacterial adherence
IgE: Mast cells in the gut/resp tissues have a Fc receptor for the Fc epsolon component of IgE so are often coated with them, and pathogens associated with these then stick. This then degranulate and release vasoactive and chemotactic factors on blood vessels. Enhances non-specific mediator through mast cell degranulation.
ADCC killing is?
Antibody dependent Cellular Cytotoxicity
- Mediated by antibodies binding to materila (eg bacteria) where their Fc regions are pointing outwards
- We have a small portion of Lympphoid type cells in the blood that hace Fc receptors, called “NK or K cells’
- These interact with the Fc portion of the antibody, become activated and kill the targetted cell
these can also do NK cell killing
NK cell killing
- Can interact with cells in the body that have changed their expression of HLA due to infection or cancer down regulating HLA
- NK cells use the Killer activating and killer inhibiting receptors to kill these particular cells
- Ubiquitous molecule recognised by KA receptors
- HLA class I recognised by the K I receptor
- A normal cell will have both and so killing is prevented. When HLA is not detected non-specific short range killing will be activated.
What is the stages of defence against an acute viral infection
- Interferon: and most important. Antiviral cytokine that is produced to signal to other cells to induce a transient antiviral state to diminish infection
- NK cells
- Cytotoxic T cells: to be able to kill infected cells before they can release more virus, takes longer to activate
- Antibodies: produced much later, prevent spread cell-to-cell and re infection but ar not very useful against diminishing current infection
