Immunosenescence

Question 1

Define Immunosenescence.

Answer 1

It is both a Functional Decline of existing immune cells AND the abnormal ‘remodelling’ of the subsets of these cells.

Question 2

What sub-sets are we talking about ?

Bonus: why name it T?

Answer 2

Lymphocytes: CD4, CD 8, Bs… in the humorous…where is that ?
Bonus Point : T- lymphocytes ‘are named for the thymus where T-lymphocytes migrate from the bone marrow to mature.’
[ Side note: Today’s Herald Sun page 3- prostate cancer cells need uniquely CD36 surface antigen to absorb vital fatty acides/ block the coupling and you starve the cell !]

Question 3

What are some complications arising from being chronically immunocompromised ?

Answer 3

Serious infections and malignancies:
1) with growing aged PsMS showing a worse prognosis of infection-related mortality than normal
2) Unpredictable JCV status (antibodies levels erratic for this virus)
/modest confidence/ no…. redesign this… JCV not product.

Question 4

How do DMTs possibly interfere with immunosenescence ?

Answer 4

They weaken the immune system with age in two ways. Lowers significantly the lymphocytes. And it re-proportions the T cell subsets, leaving a lower level of CD8s… either additive or synergistically.
They therefore accelerate the subtle deleterious effects of Immsc.

Adequate numbers of CD8 T Cells are critically important for viral control and clearance. In PwMS, all three chronic immunosuppressants FGD/DMF/NZB remodel subsets by reversing them, from 1:2 to 2:1, meaning much fewer CD8 cells, at a much earlier age,some 10 to 20 years earlier.

Question 5

What do PML and CMV, EBV and West Nile virus cases tell us about the health of our immune system ?

Answer 5

1) Ageing - in ‘older age’ reactivation - higher frequency and magnitude.
2) Ageing - increasing prevalence (WNV) in over 50s ; 40x higher in over 70s

Question 6

So, do low ALCs lead to higher infection rates ? Depends on a drug’s mechanism - DMF affects

Answer 6

Generally, YES>
But at different grades of lymphopenia per drug. FGD Grade 3s vs Grade 4s from 55% of patients with infections to 75% (Longbrake)
For DMF moderately severe is actually at higher grades of Lymphopenia- Grade 2 and Grade 3.

Question 7

Why does there seem to be a focus on the thymus gland ?

Answer 7

1. Primary lymphoid organ-
   Production of T cell -‘naive T cells declines with age, from 20% at age 25 to 5% at 55.’ so thymic output of these immune cells falls due to ATROPHY - ‘thymic involution’
   The thymus production involves T Cell (progenitors ? migrated from bone marrow)’ for differentiation, maturation, and education.’ (?)
2. Sorting(‘selection’) - in positive (functional) and negative (deletion of autoreactive T cells) SELECTION of naive T cells and their output into the circulation.

Question 8

Some evidence of the thymus’s output changes over time ?

Answer 8

A. Thymic output of naive T cells declines with age, from 20% at age 25 to 5% at 55.
B. AdolescentHIV-infected patients on HAART have a ‘more robust naive T cell reconstitution’ than older adults.

Question 9

So, if the thymus is producing less naive T cells over time, does the body do anything here ?

Answer 9

Finite compensatory repertoire, that cumulatively produces less functional and diverse naive T cells :

With less thymic output, maintaing homeostasis in normal peripheral T cell requires other production centres. But also its pool is ‘limited in its diversity’… ‘which leads to a more restricted T cell receptor repertoire.’
After 65 yo, ‘repertoire drops precipitously.’
IN MS - ‘thymic involution occurs earlier.’

Question 10

What does an aged T cell loss of functionality mean ?

Answer 10

Loses function by losing sensitivity to foreign antigens as well as to destroy them :detection/lysis via different T cell production remodelling.
- 1. Decreased primary response to antigen stimulation to infections and vaccinations;
2. Reduced target cell lysis by reducing production of naive T cells.
So, shifts from Naive to Memory T Cells, almost a 2 -5 fold decrease of naives.

Question 11

But why are Naive T Cells vs memory cells so important ?

Answer 11

Naive cells combat the novel antigens that could be pathogenic. Reduced numbers of naive immune cells may lead to increased morbidity from infections.

Question 12

What about qualitative causes ?

Answer 12

Changes in the antibody production…

1. Reduced B cell numbers in periphery
2. Reduced (reversal) subset Naive to Memory cell numbers

Question 13

Tell me some vaccines….

Answer 13

Influenza, Tetanus, Salmonella, S.pneuminae….

Question 14

Level 3 Detail…

What is the normal process of B cell production ? Quantifiably what happens with age ?

Answer 14

In Bone marrow-
haematopoietic stem cells.
Numbers and repertoire. With age, the B cell progenitors decrease in production number (‘less B cell precursor levels’) from down-regulation of genes responsible for lymphoid specification….reduced lymphoid differentiation capability. SO»> lymphoid lineage unlike myeloid lineage is less prominent with age.

Question 15

Level 3

B Cell losing functionality ?

Answer 15

Less sensitivity to

Question 16

“Thymic involution” - describe.

Answer 16

The shrinking or return of the organ size to a former size. By PROTEOLYSIS of the basement membrane, resulting in 1)epithelial regression and 2)apoptosis, with accompanying 3)stromal fibrosis.
Result ? Reduced cell numbers + reorganised stromal tissue —>
reduced Organ Size and Mass !
‘…changes in the architecture of the thymus and a decrease in tissue mass.’
A ‘conserved (evolutionary) sequence’ throughout all Vertebrates ! Only the thymi of a few species of sharks ‘are known not to involute.’ Wiki

Question 17

Viral Reactivation rates with DMTs ?

Answer 17

FGD - VZV and EBV - increased higher rates of reactivation. Reduced antibodies specific for these viruses, and 20% patients showed sub-clinical reactivation of these viruses. Age itself is a independent reactivator of ZV, with almost doubling of this effect in a decade, from 60 to 70.