L19: Introduction to Immunological disorders Flashcards
List the different mechanisms of immunological tolerance
- central
- peripheral
explain what tolerance is
the education of the immune system to recognise self
Where does education / tolerance take place
lymphoid tissue - where lymphocytes are found
Where are the major sites of tolerance for central tolerance
thymus and bone marrow
what are the major sites of peripheral tolerance
spleen, lymph nodes, tonsils, adenoids
explain how central tolerance occurs
- immature lymphocytes specific for self antigens may encouter these in the lymphoid organs
- self-reactive immature cells are deleted, change their specificity (B cells), develop into regulatroy lymphocytes
too strong binding, no binding 203
explain how peripheral tolerance works
- Some self-reactive lymphocytes mature and enter peripheral tissues.
- There they may be inactivated or deleted by encounter with self antigens in these tissues, or are suppressed by the regulatory T cells
(peripheral tolerance).
anergy, apoptosis, suppression
what are the three mechanisms of central tolerance?
non-selective (death by neglect)
positive selection
negative selection
What is central tolerance based on?
mature T cells recognising both MHC and peptide - refers to the strength of binding
explain death by neglect
TCR that fail to bind self MHC - 80%
aka non selection
explain the term negative selection
TCR that bind too strongly to MHC - 20%
explain the term psositive selection
1-2% lymphocytes whose TCR recognise self MHC not too strong/weak - displays non-self peptides in the periphery
how do T-cells encounter self-antigen in the thymus?
- thymic epithelial cells (TECs) express extra-thymic antigens
- ETA are usually expressed in other tissues/organs
- lymphocytes negatively selected when their affinity with self antigen-MHC complexed presented to TEC is very high - apotptotic death
TEC
thymic epithelial cells
how are Tregs developed?
some self reactive thymocytes are not deleted by differentiate into Tregs
why are Tregs important
important for peripheral tolerance - otherwise you can get autoimmunity
Explain the process of central tolerance in B cells
- Immature B-cells recognise self antigens present at high concentration then B-cells edit sequence of BCR
- If editing fails B cells maybe deleted (mechanism not well understood)
- If self antigen recognition is weak the B cells become
unresponsive and exit bone marrow in an ‘unresponsive’ state (anergic)
What are the three mechanisms of peripheral tolerance
- clonal anergy
- suppression
- immunological tolerance
clonal anergy
Self-reactive lymphocytes still exist, but are
inactivated and are resistant to antigen stimulation.
Suppression
Tregs control the activation of self-reactive lymphocytes
Immunological tolerance
Self-reactive lymphocytes are present, but do not mount a pathological response
a) Antigens are sequestered in immunologically “privileged” sites (eg the anterior chamber of the eye or the testis)
b) B cells lacking adequate T cell help
c) Lack co-stimulation by other molecules
explain peripheral tolerance in B cells
B cells require help form T-cells to triger antibody secretion
- t cell tolerance therfore leads to B cell tolerance
define autoimmunity
failure of an organism to recognise its own molecules as “self” - loss of tolerance
List the requirements for AID
- Escape of autoreactive clones from thymus or bone marrow
- Autoreactive clones encounter self-antigens
- Peripheral tolerance failure
- Autoreactive tissue damage
explain the mechanism for AID
- genetic susceptibility
- infection or injury
- influx self reactive lymphocytes
- activation of self reactive lymphocytes
how does genetic susceptibility affect AID
disrupt self tolerance mechanisms
How does infection/injury affect AID
alter the way seld antigens are displayed
Explain how an influx of self reactive LC affect AID
infection or injury induces inflammation
What is molecular mimicry
component of pathogen has an epitope (small peptide piece) that resembles a self epitope. T and B cells think they look the same
How does molecular mimicry occur (genetically)
The antigens/proteins on pathogen and self
are NOT the same, but they have stretches of
sequence that ARE the same
give examples of AID
- ARF
- MS
- T1D
- Rheumatoid Arthitis
- Coeliac Disease
what is the relenvance of genetics in developing and AID
- suscetibility can increase
- polgenic - many genes invoved in suceptibility
- environmental factors involved too
Give some examples of genes involved in AID development
antigen presentation genes (MHC)
antigen receptr genes (TCR)
complement genes
regulatory genes (Cytokines)
What are the treatment types for T1 AID
palliative - treat resulting deficits
- replacement (lost secretions)
- infection treamtnet (AB)
- remove trigger (gluten)
What are the treatment types for T2 AID
- suppress immunity
- corticosteroids, NSAIDS, DMARDs
