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Summary BMS88 - Advanced Immunology
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MED-BMS88 - Advanced ImmunologySSA 1 - Memory
Vaccines
● Vaccines train the adaptive immune system (Th-, B-, NK-cell, DC)
● immunity → created by memory T and B cells
● types of vaccines:
○ live attenuated vaccines; work by introducing a weakened version of the
pathogen
■ not so safe for people with weakened immune systems
○ subunit vaccine; contain part of the pathogen (i.e.HPV), need adjuvants to
activate the immune system
■ safe for everyone
■ not long lasting effect; does not trigger as many memory cells as live
attenuated vaccines do
T cell memory
● recognize antigens via TLRs in the form of peptide fragments associated with MHC
molecules
● Viral infections are controlled by the Tfh (= T follicular helper cell) that induce B
cells to produce high affinity antibodies capable of neutralizing the pathogen and
CD8+ T cells that kill pathogen-infected cells.
○ In a productive immune response the specific T cell proliferates to create a
big elimination response. Followed by a loss of effector cells but preservation
of an elevated number of durable memory T cells of various types.
● Generation of robust and durable T and B cell memory is a goal of vaccines
● Hallmarks memory T cells
○ increased pool of memory T cells reactive to the pathogen through specific
recognition of pathogen-derived antigens by the TLR
, ○ more rapid and powerful response to infection
○ preprogramming to generate a tailored set of effector cell types optimized to
fight the pathogen, which includes recall Tfh responses to help boost humoral
immunity
○ presence of memory T cells in barrier tissues as a means of rapid detection
and control of infection (dominated by resident memory T cells (Trm)).
● Assuming a high-quality pool of naive T cells is available (decrease with age), these
cells must also receive the proper signals during activation to mount a successful
effector response to control the infection while also producing memory progenitor
cells to deal with potential future reinfections
○ signals include; soluble factors such as cytokines and cell-cell interactions
○ if any of the requirements are not met → primary response may be ineffective
or overblown resulting in pathology
● SARS-CoV2/ covid-19:
○ CD4+ and CD8+ T cells produce IFN-y
○ CD4+ Tfh cells promoting potent virus-neutralizing antibody generation by B
cells
○ CD8+ T cell kills infected cells
○ two scenarios reinforce the relevance of effective T cell memory:
■ 1. inadequate generation or persistence of neutralizing antibodies
could limit the efficacy and longevity of serological immunity against
SARS-CoV-2 infection or vaccination
● long-term studies of SARS (2002-2004) indicated anti-SARS T
cells were long lived and remained nearly two decades later,
while anti-SARS circulating memory B cells and antibodies
were below the limit of detection in most individuals.
■ 2. Regardless of the potency of the initial SARS-CoV2 response,
mutations in the virus or emergence of distinct but related
SARS-CoV2 strains could limit the efficacy of neutralizing antibodies.
B cell memory
● During an immune response some pathogen-specific B cells are induced to
differentiate and secrete their antigen receptors (antibodies) into the blood.
○ selecting the B cells with the highest affinity to the pathogen antigen to get the
most efficient response and less collateral damage.
● Once the pathogen has been eliminated, the response is effectively over, most
pathogen-specific B and T cells die, but a small number of B, T and Ab-secreting
plasma cells remain as long-lived immune memory cells
● immune memory should have both specificity and the capacity to adapt to potential
diversification of its targets.
● over the course of infection the affinity for antigen improves and the class/isotype
changes (IgM, IgG, IgA, IgE), enabling Abs to better bind to and neutralize
pathogens.
● Improvements in B cell affinity occur in specialized, transient, micro-anatomical
structures called germinal centers, which develop in the secondary lymphoid organs
such as lymph nodes and spleen following an immune response and are central to
the production of immunological memory.
,Not just antibodies
- still unclear how long immunity to covid-19 lasts after recovery from infection
- decrease in antibodies is expected
- half-life of IgG = 21 days
- memory B cells and T cells may be maintained even if there are not measurable
levels of serum antibodies
- upon viral clearance, there will no longer be stimulation and proliferation of new B
cells
- potent neutralizing antibody response have been found in hospitalized patients with
covid-19, and human monoclonal antibodies generated from these patients target
multiple epitopes of the spike protein and could be a promising therapy.
- The induction of SARS-CoV2 specific memory T and B cells is important for
long-term protection. In particular TfH cells indicate maturation of the humoral
immune response and the establishment of a pool of specific memory B cells ready
to rapidly respond to possible reinfection
Immune memory in individuals with COVID-19 (article)
- vaccine techniques
- mRNA
- adenovirus platforms
- recombinant proteins
- inactivated viruses
, - While memory responses in B and T lymphocytes are expected after viral infection, it
appears that long-term adaptive changes happen in monocytes as well.
- This de facto non specific immunological memory of myeloid cells is mediated
by transcriptional and epigenetic rewiring, termed ‘trained immunity’.
- trained immunity by covid involved both CD14+ and CD16+
monocytes, increased chromatin accessibility in monocytes for IL1B
and chemokine genes.
- increased chromatin accessibility was associated with higher
production of these cytokines
- identification of trained monocytes after recovery of covid is important at
several levels
- 1. more comprehensive understanding of changes in immune
responses after infection with covid-19 → long-term adaptation not
only in lymphocytes but also myeloid cells
- 2. discovery of these processes helpful in understanding the potential
consequences of the disease → needed for future vaccines
- B cells promote differentiation of T cells into T follicular helper cells (Tfh)
that thereafter direct the behavior of the B cells in the immune response
- within germinal centers B cells rapidly proliferate and deliberately mutate the DNA
encoding the epitope-binding component of their antigen-binding receptor, potentially
changing its affinity. This occurs as repeated cycles of proliferation, mutations and
selective survival of those B cells with improved binding affinity to the antigen
- B cell mutation and selection in the GC provides a capacity to counteract escape
attempts that pathogens may make by mutating their targets of the Ab response
- GCs give rise to 2 forms of long-lived Ab memory:
- circulating MBCs (=memory B cells)
- PC-secreting high affinity AB
- (some Tfh cells differentiate into long-lived memory Tfh (mTfh))
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