Chimeric antigen receptor T cells (CAR T cells) therapy simplified

Hey everyone! Upasana - our funny medical student made a simplified video on CAR T cell therapy. Check it out!

I copy-pasted a quick short post in text for reference :)

Burkitt’s Lymphoma types

There are three types of Burkitt’s Lymphoma: Endemic (African), Sporadic  (non-endemic) and immunodeficiency-associated.

Molecular mayhem - AML relapse after HSCT

For many hematological disorders including AML, CLL, ALL HSCT is the only viable therapeutic option when cytogenetics are not conducive for chemotherapeutic agents. However subsequent relapses are not uncommon which are due to subtle molecular alterations because of underlying and acquired mutations.

Pathophysiology: Multiple Sclerosis

Hey guys, let’s look at the fundamentals of multiple sclerosis.

Multiple sclerosis is an autoimmune disease of the CNS characterised by

- chronic inflammation

- demyelination

- reactive gliosis/ scarring

- neuronal loss

with a course that is relapsing-remitting or progressive

and lesions that are disseminated in time and space.

Here’s how it happens:

[Please click on the image to enhance it]

- Ashish Singh

Wiskott-Aldrich syndrome

1)Wiskott-Aldrich syndrome is an X-linked recessive disorder caused by mutations in the gene that encodes the Wiskott-Aldrich syndrome protein (WASp).

2)All hematopoietic cells produce WASp protein, and there is WIPF1 that encodes WASp-interacting protein (WIP), a protein that stabilizes WASp. Both of these proteins are required to reorganize cell's cytoskeleton.

3)Its absence impairs the:
 (a)Formation of the immunologic synapse, the site of interaction between T cells and antigen-presenting cells leading to immunodeficiency.
 (b)NK cell function is impaired as a result of defective immune synapse formation on the cell surface which leads to increase risk of malignancy.
 (c)Regulatory T cells are incapable of controlling autoimmunity, so there is increased risk of Autoimmune disease.
 (d)Myeloid lineage cells exhibit impaired phagocytosis and chemotaxis - susceptible to recurrent pyogenic infections.
 (e)Impaired cytoskeleton in megakaryocytes → Decrease in size and number of platelets →microthrombocytopenia.

4)Clinical manifestations :
(a)Bleeding-microthrombocytopenia.
(b)Recurrent pyogenic infections.
(c)Eczema
(d)Increase in risk of autoimmune diseases and malignancy.

5)Laboratory findings :
(a)low to normal IgG and IgM and high IgA and IgE.
(b)Peripheral smear-Thrombocytopenia with small platelets.


Mnemonic: Remember the movie Antman and thewasp :p. So WASP helps you remember,
(1)WASp mutation  (2)wasp is a small bee like insect🐝→small platelets and if wasp bites, you get eczema(↑IgE).


SOURCE-UpToDate.

-Srikar Sama.

Paroxysmal nocturnal hemoglobinuria

1)PNH originates from an acquired mutation ( frame-shift that creates a premature stop codon) in a myeloid stem cell, the acquired mutation in PNH occurs in the PIGA gene which is responsible for the first step in the synthesis of the GPI anchor that attaches CD55 and CD59 to the cell surface.

2)Complement detects self vs nonself cells by these complement inhibitors. Function of these complement inhibitors is to:

3)In the absence of these inhibitors, complement proteins bind cell membranes of our own cells and through the alternative complement pathway can lyse self-cells.

4)CD55/DAF decrease → More C3 convertase→Increase C3b→Increase opsonization→Extra Vascular Hemolysis.

   CD59/MIRL decrease→More MAC→Intra Vascular Hemolysis.


5)Why nocturnal hemoglobinuria- hemolysis occurs throughout day but its more at night because:   (a)Increased hemolysis in night due to respiratory acidosis(Shallow breathing).
 (b)Overnight concentration of urine is more and hemoglobinuria is clearly evident.

6)Diagnosis:(a)Flow cytometry- decrease CD55 and CD59 levels.
                     (b)HAM test-confirmatory.
                     (c)Direct coombs test-Negative (Helps to differentiate PNH and AIHA- its positive in AIHA)                                                                           

7)Treatment: 

(a)Ravulizumab- long acting C5 complement inhibitor

(b)Eculizumab- It is an Antibody to C5 and prevents its clevage to C5a and C5b, so no MAC. Ravulizumab has a half life that is three to four times longer than eculizumab.

-Srikar Sama

SOURCE: UpToDate, Uworld.

Ingenious Immune System

Hello friends, today let's take a moment to appreciate how amazing is our immune system.

In our immune system, just like any regular car, there are brakes in place to regulate its working. Removing brakes can certainly enhance its function which underlies the concept of immune checkpoint blockade.

Two such molecules on the surface of T-cells are CTLA-4(Cytotoxic T-lymphocyte associated protein 4) and PD-1(Programmed cell death protein 1).

When CTLA-4 binds to its ligands B7-1 and B7-2 which are often expressed in increased numbers on tumor cells it results in inhibition of T-cells and hence allowing tumor cells to evade apoptosis and survive.

Similarly when PD-1 binds to PD-L1on tumor cells inhibitory signals are relayed to T-cells.

In macrophages signal, regulatory protein alpha mediates inhibitory signals on interacting with CD47 on tumor cells.

In NK-cells KIR2DL1(killer cell immunoglobulin-like receptor 2DL1) mediates inhibitory signals.

So blocking these inhibitory signals by monoclonal antibodies can remove "brakes" on the immune system ultimately enhancing their ability to kill tumor cells.

Approved antibodies include:

Anti CTLA-4-Ipilimumab

Anti PD-1-Nivolumab, Pembrolizumab

Anti PD-L1-Avelumab,Durvalumab

Kirtan Patolia

True or False #9

1.Atopic dermatitis presents on flexor surfaces in infants. T or F

ANSWER

F

Extensor surfaces

Flexor in older children and adults

How to remember this?

Infants slEEEEEEEp a lot right.

Hence EEEEEEEExtensor surface involved in infants in atopic dermatitis

That will help you remember the opposite ( flexor surfaces) involved in older children and adults

That's all.

True or False #4

1. Imaging is contraindicated in pregnancy for diagnosing latent TB. T or F

2. Check for latent TB before prescribing Infliximab. T or F

ANSWERS

1. False

Diagnostic evaluation after positive test — Patients with a positive TST or IGRA must undergo clinical evaluation to rule out active tuberculosis. This includes evaluation for symptoms (eg, fever, cough, weight loss) and radiographic examination of the chest (with appropriate shielding), regardless of gestational age.

Patients with a positive TST or IGRA with no evidence of active TB may be presumed to have latent TB.

2. True

Toxicity of Infliximab includes :

Respiratory infection (possible reactivation of latent TB)

Fever

Hypotension

Last man standing wins. Keep grinding.

Anti-Ro/SSA antibodies and neonatal lupus

Hello everyone!

Did you know? Anti-Ro/SSA antibodies are associated with neonatal lupus (congenital heart block (CHB), neonatal transient skin rash, hematological and hepatic abnormalities).

How do I remember this? 

Step 2 CK: Confusing vesicular skin manifestations

Skin manifestations that sometimes confuse us:

1) Dermatitis herpetiformis: It is a skin manifestation of celiac disease (adult and pediatric) - clusters of vesicles, pustules on extensor surfaces of elbow, knees etc.
Treatment:  Gluten free diet and anti-inflammatory drugs (Dapsone, Sulfapyridine)

2) Eczema herpeticum: Infection of eczematous skin by HSV (fluid filled , honey crusted vesicles on red, indurated skin of eczema).
Treatment: Acyclovir, Valaciclovir.

IkaN addition: I know honey crust makes us think of impetigo right away but put the presentation and distribution whenever inferring the diagnosis. I've got a number of questions wrong on the USMLE practice tests because of the honey crust bias.

This mini note was submitted by Disha Sharma :)

Opportunistic infections in AIDS

AIDS is a retroviral disease caused by HIV. It is characterized by the triad of immunosuppression associated with:
1) Opportunistic infections.
2) ‎Secondary neoplasms.
3) ‎Neurological manifestation.

Opportunistic infections seen are:

1) Bacterial infections:

MANS.

M-M.tuberculosis
A-Atypical mycobacterial infections
N-Nocardiosis
S-Salmonella

M.tuberculosis is the most common infection with HIV in India.

2) Viral infection:

H.C. verma of John Cunningham.

H-Herpes simplex virus
C-Cytomegalovirus
V-Varicella zoster virus
John Cunningham -JC virus causing     progressive multifocal leukoencephalopahty.

3) Fungal infections:

H P computers creates crossword

H-Histoplasmosis
P-Pneumocystis jiroveci
computers-Cryptococcosis
creates-Coccidiomycosis
crosswords-Candidiasis

Candidiasis is the most common fungal infection of AIDS in India

Pneumocystis jiroveci is the most common fungal infection of AIDS in world.

4) Protozoal infection:
CITy

C-Cryptosporidium
I-Isosporidium
T-Toxoplasmosis

-Demotional bloke.

Interesting physical exam finding in Henoch-Schonlein purpura

Hello everyone!

Here's a cool fact that someone I absolutely adore shared with me: The Pediatricians call Henoch-Schonlein purpura as, “Butt-itis” because the rash frequently coalesces on the pressure points and is gravity dependent, in other words, on the buttock!

Immunology question

Hola awesomites!!

So, this is answer of our previous question. Lets have a look into it.

Q1)Which of the following features is not shared between T cells and B cells
a)Antigen specific Receptors
b)Class 1 MHC expression
c)Positive selection during development
d)All of the above

Answer is
C) Positive selection during development

Explanation:

Positive selection:
Site is thymic cortex.
-T cells having affinity for MHC molecules are selected since T cells having affinity for MHC molecules can interect with APC  and one who don't have recognisation is killed

Negative selection:
Site:Thymic medulla
Selected T cells are sent to medulla,where there affinity for self antigens are tested.If the have affinity they are programmed to death.

Incase of B cells,if they recognize self antigens they do not undergo death instead there receptors are changed by the process called as "Receptor editing" .If receptor editing dose not take place,then apoptosis takes place.This is negative selection of immature B cells. B cells negative selection occurs in the bone marrow

Both T-cell and B-cell have TCRs and BCRs respectively.
Class I MHC is expressed on both T cells and B cells..

Stay awesome:)

~Ojas

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