Immune System in Health and Disease Flashcards
Key enablers of Immunology Knowledge
*Cell — and –
*Cell –
*Understanding of – and cell —
*Genetics and genomics
*Proteomics
*Monoclonal antibodies and other investigative tools
*Interaction with study of infection
structure n microscopy
biology
recpetors n signalling
SARS – CoV-2
* New pathogen in 2019
* Some immunological cross –reactivity with SARS
(2002/2003)
* Very limited — with seasonal corona viruses
Need immunity to be “just right”
* Too little or wrong type – fail to eliminate the virus
* Too much – hyperinflammatory state common cause of
death
Compartmentalisation of immune response:
* — vs – Immunity
cross reactivity
mucosal vs systemic
basic science discoveries and clinical practice :
1- Understanding Mechanism of — leading to new
therapeutics such as: heredity angioademia and the — deficiency , genetic variants causes reduction or absence of — , dysfunctional protein ad autosomal dominant condition
2- Rapid — Impacting Management
3- – Development & – Health
disease
c1 inhibitor ( which is a defence in plasma enzyme inhibitor )
protein
diagostics
vaccines
public
pathogenesis of HAE:
1990s & 2000s – considerable debate
* Strong support for a C2 kinin
* Based on non-peer-reviewed article
* Data could not be reproduced
Bradykinin difficult to measure
Simultaneous measurement of Bradykinin from HAE patients with hand attacks from affected and unaffected (control) arm
Rodent model (C1inhibitor knock out), cured by
Replacement of — , OR
Knock-out of the — receptor
Unique family where the C1inhibitor variant allowed C1inhibitor inhibit complement, but inhibited bradykinin-forming cascade
No angioedema attacks
c1 inhibitor
brandy kinin b2
brandykinin formation:
- Bradykinin binding to — receptor mediates
— in HAE
- Icatibant, a B2 receptor – licenced as a treatment for — attacks , — injection
Patients trained to – administer.
HAE: new therapeutics:
Standard treatment – Plasma derived C1inhibitor concentrate
Treat acute attacks
Periprocedural prophylaxis
Longterm prophylaxis
Licenced therapeutics (not all yet available in Ireland)
* Ecallantide – kallikrein inhibitor, injectable for —
* Berotralstat – oral kallikrein inhibitor – for —
* Lanadelumab – — kallikrein inhibitor – prophylaxis
* Ruconest – recombinant –
HAE - future therpatucs :
— Therapy – replace the faulty gene encoding
C1inhibitor
Gene-editing – knock-out kallikrein
Currently in clinical trials
Aim is “one and done” therapy
b2 receptor
angioedema
antagonist
acute
subcutaneous
self
acute attacks
longtime prophylaxis subcutaneous
c1 inhibitor
gene therapy
- C1-INH Deficiency Results in Unregulated Release and Buildup of – , Activating – Cells and Leading to –
- —- Regulates the Release and Buildup of Bradykinin
- CRISPR/Cas9-Mediated KO of KLKB1 Reduces the Undesired Bradykinin
Activity in People with HAE - Achieved Sustained Therapeutically Relevant Kallikrein Activity Reduction
After a Single Dose in NHPs
bradykinin
endothelial cells
angioedema
C1 Esterase Inhibitor (C1-INH)
SCID - severe combined immuodeficinecy
* Failure to develop – +/- other cells
* Some types lack – cells
* Most affected – die by 1 year without HSCT
* – in diagnosis / infection prior to transplant limits success
Key developments:
* — diagnosis & Neonatal HSCT (family history)
* – screening at population level
- rapid diagnosis impacting management:
Prenatal diagnosis of SCID
Families with a history/risk of SCID – known defect
Prenatal testing to see if foetus is affected
cell-free DNA techniques
Definitive testing – CVS/amniocentesis
Prenatal blood sample – HLA type the foetus
Allows for neonatal Haemopoietic stem cell
transplant
Cure in the first few weeks of life.
- population screening TRECs:
* TRECs are found in recent–
* Used to measure supply of—
* Reduced in all forms of –
* Also reduced with prematurity –
repeat until child reaches – age
if TRECs are low:
* Definitive — typing & enumeration of –
* – diagnosis
* Urgent –
t cells
nk
children
delay
pre natal
nerowborn
thyme emigrant
T cells
scid
gestational
lymphocyte
subset
genetic
HSCT
vaccine development:
*Require knowledge of – immunity
*Most successful when natural immunity is —
*Need to know the type of immunity you need to elicit
*Build on advances in other areas of science
*Protection against infectious diseases changes lives
*Elimination of smallpox
*Good start against SARS-CoV-2
mRNA vaccines for SARS-COV2:
* Were not produced —
* Built on developments in — & – particles
* Initial development focussed on —
vaccines
* Modified RNA avoids activation of TLRs
* Strongly — elicits
humoral and T cell responses
protective
sterilising
rapidly
mRNA and lipid
cancer
immunogenic
vaccines no just infectious disease:
Elicit protective immunity:
* – diseases
* —
Immunomodulation:
* – – — immunotherapy
* — – potential future
therapeutics
- learning from understanding genetic immune defects advancing therapeutics include :
Immunodeficiency
Allergy
Autoimmunity
Malignancy
infectious
oncology
allergy - allergy
autoimmunity
Bruton’s Agammaglobulinaemia
(x-linked agammaglobulinaemia)
Defect in —
No –
No–
No – , limited –
Management by –
- Ibrutinib is a —
Effectively blocks — development
Used to treat malignancy of—:
* — leukaemia
*— lymphoma
*Waldenstrom’s Macroglobulinaemia
BTK –
Bruton’s tyrosine kinase
immunoglobin
b cell
tonsils
nodes
immunolgobin replacement
BTK inhibitor
b cell development
late b cell
chronić lymphocytic
mantle cell
allergy and genetics :
Genetic variants can be
*Pathogenetic: — gene disorders
*Risk – – confer significant risk, but require
other factors for disease to occur
*Contribute to risk in complex – disorders
filaggrin - genetic risk factor for atopic eczema:
Filaggrin has essential role in maintaining –
Retaining –
Inhibiting –
Avoiding entrance of –
Enhanced risk of other — diseases
10% Europeans carry LOF variant
Of these 42% develop atopic eczema
Many will outgrow eczema despite continued filaggrin deficiency
so basically:
*Refocussed on – function
*Filaggrin expression modified by — may be involved even when
no genetic variant present
*Eczema therapy focusses on restoring —
*Potential approaches to increase—
single
risk
mutligene
skin barrier
hydration
staph aureus
allergen
allergic reaction
barrier function
inflammation
restoring barrier
filaggrin
genetic defects in autoimmunity:
1- Impaired – selection of T cells in the – :
- APECED – Autoimmune Polyglandular Endocrinopathy Candidiasis & Ectodermal dysplasia.
-Defect in AIRE
- AIRE ensures ectopic – of proteins in thymus, allowing – selection
-In the absence of AIRE many autoreactive T cells are not –
2- Impaired handling of immune complexes
- Defects in early – cascade
-Prevent immune complex disposal by – carriage / removal by reticulo-endothelial system
negative
thymus
transpcriton
negative
deleted
complement
RBC
CTLA 4 haploinsufficiency:
*Immune dysregulation: — and –
* – and –
* –
Treatment:
* –
* –
* – (binds CD80/CD86)
*Other immunomodulators
healthy individuals:
* T cell activation requires –
specific signalling and
costimulation via –
* Once T cell activated, CTLA4 is – .
* CTLA4 binds to CD80/CD86 at – affinity than CD28
* Strips CD80/CD86 off the APC
* Important role in —
of the immune response
When CTLA4 is deficient:
* Can use – to
downregulate cells
autoimmunity n lymphoproliferation
infection n immunodeficineyc
malignancy
steroids
immunoglobin
abatacept
antigen
CD28
unregulated
higher
downregualtion
abatacept
understanding CTLA4 - immunomodulation:
Block – to inhibit – activity
*Abatacept for –
*Also used in – transplantation
Block CTLA-4 to enhance – activity
*Cancer Immunotherapy
*Ipilimumab
summary:
*Immune system plays a key role in keeping us healthy
*Also plays a key role in multiple disease types
*Advances in understanding basic immunology inform
clinical practice in many different specialties
*Exploiting scientific advances has allowed us improve
patient care and contribute to improved public health
*Understanding the genetic basis and pathogenesis of
immune disorders has led to the development of
therapeutic agents, used to treat immunological and
non-immunological disorders.
co situation
T cell
RA
renal
T cell
