Thread by @DrGrimaldesJ

#immunosuppression

IMMUNE CONTROL POINTS AND COVID-19

✅IMMUNOLOGIC CONTROL POINT MOLECULES ARE #INHIBITOR RECEPTORS EXPRESSED IN IMMUNE CELLS THAT TRIGGER IMMUNOSUPPRESSOR SIGNALING PATHWAYS.

These molecules are crucial to maintaining self-tolerance. 👉SIGNALING THROUGH THESE MOLECULES MAY TAKE IMMUNE EFFECT CELLS (ESPECIALLY T CELLS) TO A STATE KNOWN AS "DEPLETION". T cell depletion is defined by reduced effector function, poor memory responses

👉 due to sustained expression of immune checkpoint molecules (such as PD1, # CTLA4, # LAG3 ...). There are numerous types of activating and inhibitory interactions that occur between antigen presenting cells (APC) and T cells and thus regulate the nature of immunity.

Now👉 IT IS CLEAR THAT MANY PATHOGENS AND CANCERS PROMOTE INHIBITORY INTERACTIONS BETWEEN IMMUNE CELLS THROUGH IMMUNE CONTROL POINT PROTEINS TO ESCAPE IMMUNE CONTROL🎯. bxcell.com/immune-checkpo… nature.com/articles/nri.2…

Receptor-ligand interactions that suppress effector T cell responses (red square arrows) to maintain self-tolerance and limit the duration of immune responses to minimize bystander damage to host tissue. These include LAG3 - TIM3 - PD1 - PDL1...

IMMUNE CONTROL POINTS AND COVID-19

👉The role of T cells in the resolution or exacerbation of COVID-19, as well as their potential to provide long-term protection against reinfection with SARS-CoV-2, remains under debate.

✅ Lymphopenia in COVID-19

A prominent feature of SARS-CoV-2 infection is lymphopenia, which is associated with severe disease, but reverses when patients recover.
The data suggest that infection has a preferential impact on CD8 + and CD4 + T cells.

Transient lymphopenia is a common feature of many respiratory viral infections, such as influenza A H3N2 virus, human rhinovirus, or RSV, but lymphopenia in these other infections typically occurs for only 2 to 4 days and recovers quickly.

On the contrary 👉 LYMPHOPENIA ASSOCIATED WITH COVID-19 MAY BE MORE
SEVERE OR PERSISTENT THAN IN OTHER INFECTIONS AND APPEARS TO BE MORE SELECTIVE FOR 👉 T-CELL LINEAGES.

It is possible that the peripheral lymphopenia observed in patients with COVID reflects lymphocyte recruitment to the respiratory tract or adhesion to the inflamed respiratory vascular endothelium or in severe cases it may be associated with elevated levels of IL-6, IL-10 or TNF.

🎯🔥 THERE IS EVIDENCE OF TERMINALLY DIFFERENTIATED T-CELLS OR POSSIBLY EXHAUSTED T-CELLS IN SERIOUS COVID-19 ILLNESS, DUE TO INCREASED EXPRESSION LEVELS OF INHIBITOR RECEPTORS 👉 PDKGLA4, CD39A, CTLA4, LAG3.
nature.com/articles41577-…

A proposed model of CD8 + T cell responses (a) and CD4 + T cell responses (b) during COVID-19 progression in mild versus severe disease.

#immunosuppression
Covid-19, immune escape and its similarity to other chronic infections.
Malaria also causes acute clinical disease and is characterized by hyperinflammation due to strong production of pro-inflammatory cytokines and massive activation of T cells.

⬆️In #malaria, T cells express a variety of co-inhibitory receptors that can be a consequence of their activation, but can also limit their overwhelming function. Therefore, T cells are involved in both protection and pathology

👉 The outcome of malaria is believed to be a consequence of the balance between co-activation and co-inhibition of T cells 👉 Following the hypothesis that cells T in COVID-19 could have a similar dual function.

✅CoVID-19 patients with a more severe course of the disease showed higher levels of LAG-3 and TIM-3 than patients with a mild course.
From other viral infections, 👉 we know that cytotoxic T cells play an important role in the destruction of virus-infected cells and thus

contribute to the clearance of the infection.
✅Inhibitory receptors and their role in T-cell depletion have been extensively studied in #cancer and chronic infections such as #VHC and #VIH.

In COVID-19 patients we saw similar upregulation of LAG-3 and TIM-3 in T cells of even

higher frequencies in CD8 + T cells. A significant increase in LAG-3 and TIM-3 on CD8 + and CD4 + T cells could be detected in all subpopulations in COVID-19 patients.

Overall, we saw a strong increase in the expression of LAG-3 and TIM-3 on T cells in COVID-19 and malaria.

PD1 only slightly increased in T cells in COVID-19 patients.

frontiersin.org/articles/10.33…

#immunosuppression
IMMUNE CONTROL POINTS COVID-19 👉 MALARIA, HEPATITIS B VIRUS (HBV) AND HUMAN IMMUNODEFICIENCY VIRUS (HIV).

✅Malaria and depletion of T cells. Field studies in Mali and Kenya found that individuals recently

👉infected with P. falciparum expressed PD1 on CD4 + T cells, implicating this molecule in immune evasion. Similarly, a higher proportion of TCD4 + cells from individuals with acute phase infections by P. vivax, P. falciparum, or both had higher CTLA4 expression, suggesting a

role for regulatory T (T reg cells) in the suppression of immunity to malaria. Finally, the expression of the immunoglobulin T-cell mucin receptor 3 (TIM3) immune checkpoint molecule was significantly increased in key lymphocyte populations in P. falciparum-infected patients.

✅Depletion of T cells and immune checkpoint proteins in HIV infection.

T-cell depletion is a hallmark of many chronic viral infections, including HIV. In untreated HIV infection, there is 👉 positive expression of multiple immune checkpoint proteins, including PD1, CTLA4, TIM3,

and LAG3, in both TCD4 + and CD8 + cells

ncbi.nlm.nih.gov/labs/pmc/artic…

researchgate.net/publication/33…

✅Depletion of T cells and immune checkpoint proteins in HBV infection.

In chronic untreated HBV infection, HBV-specific and total CD8 + T cells express elevated levels of PD1, CTLA4, and TIM3.
journals.lww.com/md-journal/ful…

Rómulo Daniel Grimaldes J., MD
Internal Medicine
14/11/2021

Increase co-inhibitory levels LAG3 CTLA4, PDL, TIM3 👉 promotes cancer cell proliferation and infections 👉 by depletion of TCD4 + and TCD8 + cells ???
nature.com/articles/s4142…

IMMUNODEFICIENCY...

nature.com/articles/d4158…